Sample records for antipsychotic drug aripiprazole
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Aripiprazole: the evidence of its therapeutic impact in schizophrenia
Winlow, William; Profit, Louise; Chrisp, Paul
2006-01-01
Introduction: An ideal antipsychotic would rapidly stabilize acute psychotic symptoms and maintain the patient, without relapse, for prolonged periods in the absence of extrapyramidal, endocrine, diabetic, or cardiovascular side effects, and without weight gain. The dopamine partial agonist aripiprazole is compared with this ideal and with conventional antipsychotics, such as haloperidol, and with atypical antipsychotics. Aims: To review the evidence for the clinical impact of aripiprazole in the treatment of patients with schizophrenia. Evidence review: There is clear evidence that aripiprazole is as effective as haloperidol in reducing the positive and negative symptoms of schizophrenia and schizoaffective disorder. In patients with schizophrenia, aripiprazole has been shown to stabilize acute psychotic symptoms, prevent relapse in stabilized patients, and maintain patients with schizophrenia following acute relapse. Furthermore, in common with other atypical antipsychotics, aripiprazole appears to be associated with a lower incidence of side effects than typical antipsychotics and may reduce discontinuation of drug therapy. Evidence also suggests that aripiprazole may be associated with a lower incidence of extrapyramidal symptoms than conventional antipsychotics, but further long-term studies concerning tardive dyskinesia are required. Studies on the cost effectiveness of aripiprazole, as well as the quality of life and general functioning of patients taking the drug are still required, although there is some evidence of improved quality of life. Further evidence comparing aripiprazole with other atypical antipsychotics would be welcome. Clinical value: In conclusion, aripiprazole is an atypical antipsychotic suitable for first-line use in patients with schizophrenia. Its clinical value in relation to other atypical antipsychotics remains to be elucidated. PMID:22496680
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Classics in Chemical Neuroscience: Aripiprazole.
Casey, Austen B; Canal, Clinton E
2017-06-21
Aripiprazole was the first antipsychotic developed to possess agonist properties at dopamine D 2 autoreceptors, a groundbreaking strategy that presented a new vista for schizophrenia drug discovery. The dopamine D 2 receptor is the crucial target of all extant antipsychotics, and all developed prior to aripiprazole were D 2 receptor antagonists. Extensive blockade of these receptors, however, typically produces extrapyramidal (movement) side effects, which plagued first-generation antipsychotics, such as haloperidol. Second-generation antipsychotics, such as clozapine, with unique polypharmacology and D 2 receptor binding kinetics, have significantly lower risk of movement side effects but can cause myriad additional ones, such as severe weight gain and metabolic dysfunction. Aripiprazole's polypharmacology, characterized by its unique agonist activity at dopamine D 2 and D 3 and serotonin 5-HT 1A receptors, as well as antagonist activity at serotonin 5-HT 2A receptors, translates to successful reduction of positive, negative, and cognitive symptoms of schizophrenia, while also mitigating risk of weight gain and movement side effects. New observations, however, link aripiprazole to compulsive behaviors in a small group of patients, an unusual side effect for antipsychotics. In this review, we discuss the chemical synthesis, pharmacology, pharmacogenomics, drug metabolism, and adverse events of aripiprazole, and we present a current understanding of aripiprazole's neurotherapeutic mechanisms, as well as the history and importance of aripiprazole to neuroscience.
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Suzuki, Shuhei; Okada, Masashi; Kuramoto, Kenta; Takeda, Hiroyuki; Sakaki, Hirotsugu; Watarai, Hikaru; Sanomachi, Tomomi; Seino, Shizuka; Yoshioka, Takashi; Kitanaka, Chifumi
2016-10-01
There is a growing interest in repurposing antipsychotic dopamine antagonists for cancer treatment; however, antipsychotics are often associated with an increased risk of fatal events. The anticancer activities of aripiprazole, an antipsychotic drug with partial dopamine agonist activity and an excellent safety profile, remain unknown. The effects of aripiprazole alone or in combination with chemotherapeutic agents on the growth, sphere-forming ability and stem cell/differentiation/chemoresistance marker expression of cancer stem cells, serum-cultured cancer cells from which they were derived, and normal cells were examined. At concentrations non-toxic to normal cells, aripiprazole inhibited the growth of serum-cultured cancer cells and cancer stem cells. Furthermore, aripiprazole induced differentiation and inhibited sphere formation, as well as stem cell marker expression of cancer stem cells while inhibiting their survivin expression and sensitizing them to chemotherapeutic agents. Repurposing aripiprazole as an anticancer stem cell drug may merit further consideration. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.
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Possible Oxcarbazepine Inductive Effects on Aripiprazole Metabolism: A Case Report.
McGrane, Ian R; Loveland, Joshua G; de Leon, Jose
2017-01-01
Oxcarbazepine is a cytochrome P450 (CYP) 3A4 inducer, which is structurally similar to carbamazepine. Although lacking Food and Drug Administration approval, oxcarbazepine is sometimes prescribed to treat aggressive behavior in youth with autism spectrum disorder (ASD). These youths may also be taking second-generation antipsychotics, some of which are substrates of the CYP3A4 metabolic pathway. The combination of these medications may result in decreased serum antipsychotic concentrations, potentially reducing effectiveness. A limited number of reports are available which discuss reduced atypical antipsychotic concentrations secondary to oxcarbazepine CYP3A4 induction. We report a young boy taking oxcarbazepine (1200 mg/d) who presented with an unexpectedly low serum aripiprazole concentration. Utilizing therapeutic drug monitoring, pharmacogenetic testing, and a tool to evaluate drug-drug interactions, we estimate that oxcarbazepine possibly reduced his serum aripiprazole concentration by 68%. Our report is important, as it is the first to describe a drug-drug interaction between oxcarbazepine and aripiprazole. This report should encourage the completion of in vitro and clinical studies and the publication of case reports describing the possible inductive effects of oxcarbazepine on atypical antipsychotics (including cariprazine, lurasidone, quetiapine, aripiprazole, brexpiprazole, iloperidone, and risperidone) mediated by induction of the CYP3A4 metabolic pathway.
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Movement Disorders Induced by the "Atypical" Antipsychotic Aripiprazole.
Selfani, Karim; Soland, Valérie L; Chouinard, Sylvain; Huot, Philippe
2017-01-01
Aripiprazole is an antipsychotic that acts as a partial agonist at dopamine D2 receptors. Because of its partial agonist activity, it was believed that aripiprazole would be less susceptible than typical antipsychotics to induce extrapyramidal side effects. However, a few case-reports and case-series detailing aripiprazole-induced movement disorders have been published, suggesting that aripiprazole-induced movement disorders may arise. Here, we seek to report further cases of aripiprazole-induced movement disorders to raise the awareness of clinicians on this adverse effect. Patients referred to the André-Barbeau Movement Disorder clinic treated with aripiprazole were enrolled in this study. Their charts were retrospectively reviewed and data regarding past psychiatric history, past antipsychotic medication, duration of aripiprazole treatment, daily dose of aripiprazole administered, and resulting movement disorders were collected. We report 14 cases of parkinsonism, tardive dyskinesia and akathisia induced by aripiprazole. Some of these, mostly the parkinsonian phenotype, abated spontaneously following drug discontinuation, whereas others, mostly related to tardive phenomena, persisted after aripiprazole was discontinued, and required treatment. This case-series adds to the existing literature that suggests that movement disorders may arise following treatment with aripiprazole. Clinicians should be aware of this potential side effect when prescribing aripiprazole to patients.
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Aripiprazole, A Drug that Displays Partial Agonism and Functional Selectivity.
Tuplin, Erin W; Holahan, Matthew R
2017-11-14
The treatment of schizophrenia is challenging due to the wide range of symptoms (positive, negative, cognitive) associated with the disease. Typical antipsychotics that antagonize D2 receptors are effective in treating positive symptoms, but extrapyramidal side-effects (EPS) are a common occurrence. Atypical antipsychotics targeting 5-HT2A and D2 receptors are more effective at treating cognitive and negative symptoms compared to typical antipsychotics, but these drugs also result in side-effects such as metabolic syndromes. To identify evidence in the literature that elucidates the pharmacological profile of aripiprazole.s. We searched PubMed for peer reviewed articles on aripiprazole and its clinical efficacy, side-effects, pharmacology, and effects in animal models of schizophrenia symptoms. Aripiprazole is a newer atypical antipsychotic that displays a unique pharmacological profile, including partial D2 agonism and functionally selective properties. Aripiprazole is effective at treating the positive symptoms of schizophrenia and has the potential to treat negative and cognitive symptoms at least as well as other atypical antipsychotics. The drug has a favorable side-effect profile and has a low propensity to result in EPS or metabolic syndromes. Animal models of schizophrenia have been used to determine the efficacy of aripiprazole in symptom management. In these instances, aripiprazole resulted in the reversal of deficits in extinction, pre-pulse inhibition, and social withdrawal. Because aripiprazole requires a greater than 90% occupancy rate at D2 receptors to be clinically active and does not produce EPS, this suggests a functionally selective effect on intracellular signaling pathways. A combination of factors such as dopamine system stabilization via partial agonism, functional selectivity at D2 receptors, and serotonin-dopamine system interaction may contribute to the ability of aripiprazole to successfully manage schizophrenia symptoms. This review examines these mechanisms of action to further clarify the pharmacological actions of aripiprazole. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
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Use of aripiprazole for delirium in the elderly: a short review.
Kirino, Eiji
2015-03-01
The effects and tolerability of antipsychotics in delirium treatment remain controversial. Compared to other antipsychotics, aripiprazole differs in pharmacological activity because it exerts its effect as a dopamine D2 partial agonist. The guidelines of the American Psychiatric Association rank aripiprazole highly among antipsychotics with regard to safety, and this drug is likely to be useful for delirium treatment. Here, we reviewed the efficacy and safety of aripiprazole for delirium. The results of our literature review on the efficacy and safety of delirium treatments suggest that aripiprazole is an effective treatment option for delirium in the elderly. Aripiprazole is as effective as other antipsychotics in improving delirium symptoms, and it is safer because it is less likely to cause extrapyramidal symptoms, excessive sedation, and weight gain. However, these findings are based on only a few clinical studies of elderly patients with delirium. Therefore, further investigations are necessary. © 2014 The Author. Psychogeriatrics © 2014 Japanese Psychogeriatric Society.
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Suzuki, Hidenobu; Hibino, Hiroyuki; Inoue, Yuichi; Matsumoto, Hideo; Mikami, Katsunaka
2017-01-01
Schizophrenia is a chronic disease that requires long-term management with antipsychotics; however, an important barrier to the success of long-term treatment is drug noncompliance, which increases the risk of recurrence and hospitalization. Second-generation long-acting injectable antipsychotics have improved drug adherence, and the pharmacological effects of the drugs, and therefore, have become useful treatment options. We report on three schizophrenia patients who switched from oral low-dose aripiprazole to aripiprazole once-monthly 300 mg. We examined the efficacy and safety of aripiprazole once-monthly 300 mg, as well as its influence on quality of life, from baseline to 20 weeks after aripiprazole once-monthly 300 mg treatment. Aripiprazole once-monthly 300 mg did not exacerbate the depressive and negative symptoms, and extrapyramidal symptoms were improved, which may have helped improve the quality of life. The results suggest the efficacy of aripiprazole once-monthly 300 mg in maintenance treatment for schizophrenia when mental symptoms are stable.
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Effects of aripiprazole on caffeine-induced hyperlocomotion and neural activation in the striatum.
Batista, Luara A; Viana, Thércia G; Silveira, Vívian T; Aguiar, Daniele C; Moreira, Fabrício A
2016-01-01
Aripiprazole is an antipsychotic that acts as a partial agonist at dopamine D2 receptors. In addition to its antipsychotic activity, this compound blocks the effects of some psychostimulant drugs. It has not been verified, however, if aripiprazole interferes with the effects of caffeine. Hence, this study tested the hypothesis that aripiprazole prevents caffeine-induced hyperlocomotion and investigated the effects of these drugs on neural activity in the striatum. Male Swiss mice received injections of vehicle or antipsychotic drugs followed by vehicle or caffeine. Locomotion was analyzed in a circular arena and c-Fos protein expression was quantified in the dorsolateral, dorsomedial, and ventrolateral striatum, and in the core and shell regions of nucleus accumbens. Aripiprazole (0.1, 1, and 10 mg/kg) prevented caffeine (10 mg/kg)-induced hyperlocomotion at doses that do not change basal locomotion. Haloperidol (0.01, 0.03, and 0.1 mg/kg) also decreased caffeine-induced hyperlocomotion at all doses, although at the two higher doses, this compound reduced basal locomotion. Immunohistochemistry analysis showed that aripiprazole increases c-Fos protein expression in all regions studied, whereas caffeine did not alter c-Fos protein expression. Combined treatment of aripiprazole and caffeine resulted in a decrease in the number of c-Fos positive cells as compared to the group receiving aripiprazole alone. In conclusion, aripiprazole prevents caffeine-induced hyperlocomotion and increases neural activation in the striatum. This latter effect is reduced by subsequent administration of caffeine. These results advance our understanding on the pharmacological profile of aripiprazole.
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Brust, Tarsis F.; Hayes, Michael P.; Roman, David L.; Watts, Val J.
2014-01-01
The dopamine D2 receptor (DRD2) is a G protein-coupled receptor (GPCR) that is generally considered to be a primary target in the treatment of schizophrenia. First generation antipsychotic drugs (e.g. haloperidol) are antagonists of the DRD2, while second generation antipsychotic drugs (e.g. olanzapine) antagonize DRD2 and 5HT2A receptors. Notably, both these classes of drugs may cause side effects associated with D2 receptor antagonism (e.g. hyperprolactemia and extrapyramidal symptoms). The novel, “third generation” antipsychotic drug, aripiprazole is also used to treat schizophrenia, with the remarkable advantage that its tendency to cause extrapyramidal symptoms is minimal. Aripiprazole is considered a partial agonist of the DRD2, but it also has partial agonist/antagonist activity for other GPCRs. Further, aripiprazole has been reported to have a unique activity profile in functional assays with the DRD2. In the present study the molecular pharmacology of aripiprazole was further examined in HEK cell models stably expressing the DRD2 and specific isoforms of adenylyl cyclase to assess functional responses of Gα and Gβγ subunits. Additional studies examined the activity of aripiprazole in DRD2-mediated heterologous sensitization of adenylyl cyclase and cell-based dynamic mass redistribution (DMR). Aripiprazole displayed a unique functional profile for modulation of G proteins, being a partial agonist for Gαi/o and a robust antagonist for Gβγ signaling. Additionally, aripiprazole was a weak partial agonist for both heterologous sensitization and dynamic mass redistribution. PMID:25449598
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Gao, Jun; Qin, Rongyin; Li, Ming
2015-04-01
The present study investigated how repeated administration of aripiprazole (a novel antipsychotic drug) alters its behavioral effects in two behavioral tests of antipsychotic activity and whether this alteration is correlated with an increase in dopamine D2 receptor function. Male adult Sprague-Dawley rats were first repeatedly tested with aripiprazole (3, 10 and 30 mg/kg, subcutaneously (sc)) or vehicle in a conditioned avoidance response (CAR) test or a phencyclidine (PCP) (3.20 mg/kg, sc)-induced hyperlocomotion test daily for five consecutive days. After 2-3 days of drug-free retraining or resting, all rats were then challenged with aripiprazole (1.5 or 3.0 mg/kg, sc). Repeated administration of aripiprazole progressively increased its inhibition of avoidance responding and PCP-induced hyperlocomotion. More importantly, rats previously treated with aripiprazole showed significantly lower avoidance response and lower PCP-induced hyperlocomotion than those previously treated with vehicle in the challenge tests. An increased sensitivity to quinpirole (a selective D2/3 agonist) in prior aripiprazole-treated rats was also found in the quinpirole-induced hyperlocomotion test, suggesting an enhanced D2/3-mediated function. These findings suggest that aripiprazole, despite its distinct receptor mechanisms of action, induces a sensitization effect similar to those induced by other antipsychotic drugs and this effect may be partially mediated by brain plasticity involving D2/3 receptor systems. © The Author(s) 2014.
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Gao, Jun; Qin, Rongyin; Li, Ming
2016-01-01
The present study investigated how repeated administration of aripiprazole (a novel antipsychotic drug) alters its behavioral effects in two behavioral tests of antipsychotic activity and whether this alteration is correlated with an increase in dopamine D2 receptor function. Male adult Sprague-Dawley rats were first repeatedly tested with aripiprazole (3, 10 and 30 mg/kg, subcutaneously (sc)) or vehicle in a conditioned avoidance response (CAR) test or a phencyclidine (PCP) (3.20 mg/kg, sc)-induced hyperlocomotion test daily for five consecutive days. After 2–3 days of drug-free retraining or resting, all rats were then challenged with aripiprazole (1.5 or 3.0 mg/kg, sc). Repeated administration of aripiprazole progressively increased its inhibition of avoidance responding and PCP-induced hyperlocomotion. More importantly, rats previously treated with aripiprazole showed significantly lower avoidance response and lower PCP-induced hyperlocomotion than those previously treated with vehicle in the challenge tests. An increased sensitivity to quinpirole (a selective D2/3 agonist) in prior aripiprazole-treated rats was also found in the quinpirole-induced hyperlocomotion test, suggesting an enhanced D2/3-mediated function. These findings suggest that aripiprazole, despite its distinct receptor mechanisms of action, induces a sensitization effect similar to those induced by other antipsychotic drugs and this effect may be partially mediated by brain plasticity involving D2/3 receptor systems. PMID:25586399
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Intraoperative floppy-iris syndrome associated with use of antipsychotic drugs.
Matsuo, Masato; Sano, Ichiya; Ikeda, Yoshifumi; Fujihara, Etsuko; Tanito, Masaki
2016-08-01
We report 3 cases of intraoperative floppy-iris syndrome (IFIS) during cataract surgery in patients without a history of selective α1-blocker use but with a long-term history of antipsychotic drug use. We reviewed previously reported cases of antipsychotic drug-associated IFIS cases. Observational case series. In case 1, bilateral IFIS developed in a 39-year-old man with chronic angle-closure glaucoma. He had used several classes of antipsychotic drugs to treat schizophrenia, including the first-generation antipsychotic drugs haloperidol and chlorpromazine, the dopamine system stabilizer aripiprazole, the dopamine serotonin antagonists olanzapine and quetiapine, and the serotonin dopamine antagonists risperidone and blonanserin for 7 years. In case 2, a 63-year-old woman with schizophrenia had used aripiprazole, quetiapine, and risperidone for more than 10 years. In case 3, a 65-year-old woman with an organic mental disorder had used haloperidol for more than 10 years. At least 5 cases of antipsychotic drug-induced IFIS have been reported in the literature. Any class of antipsychotic drugs can cause IFIS. Although antipsychotic drug-induced IFIS can be mild, surgeons should be alert to the possibility of IFIS when they treat patients with current and past use of antipsychotic drugs. Copyright © 2016 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.
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Mizumura, Naoto; Uematsu, Masato; Ito, Aya; Okumura, Satoshi; Maehira, Hiromitsu; Ogawa, Masao; Kawasaki, Masayasu
2017-11-15
Neuroleptic malignant syndrome (NMS) with characteristic symptoms is a potentially lethal reaction to antipsychotic drugs. Atypical NMS usually lacks major symptoms and frequently occurs after treatment using atypical antipsychotics, such as aripiprazole. A 64-year-old man developed aripiprazole-induced NMS after surgery, and our early recognition of the NMS was based on high creatine kinase levels and low serum iron levels. His characteristic symptoms (a fever, rigidity, and altered mental status) were only present for a few hours and were resolved by aripiprazole discontinuation and supportive care. Aripiprazole-induced NMS can present with brief but major symptoms, and clinicians may overlook this "brief" appearance of NMS.
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Bolstad, Ingeborg; Andreassen, Ole A; Groote, Inge; Server, Andres; Sjaastad, Ivar; Kapur, Shitij; Jensen, Jimmy
2015-12-01
The atypical antipsychotic drug aripiprazole is a partial dopamine (DA) D2 receptor agonist, which differentiates it from most other antipsychotics. This study compares the brain activation characteristic produced by aripiprazole with that of haloperidol, a typical D2 receptor antagonist. Healthy participants received an acute oral dose of haloperidol, aripiprazole or placebo, and then performed an active aversive conditioning task with aversive and neutral events presented as sounds, while blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) was carried out. The fMRI task, targeting the mesolimbic motivational system that is thought to be disturbed in psychosis, was based on the conditioned avoidance response (CAR) animal model - a widely used test of therapeutic potential of antipsychotic drugs. In line with the CAR animal model, the present results show that subjects given haloperidol were not able to avoid more aversive than neutral task trials, even though the response times were shorter during aversive events. In the aripiprazole and placebo groups more aversive than neutral events were avoided. Accordingly, the task-related BOLD-fMRI response in the mesolimbic motivational system was diminished in the haloperidol group compared to the placebo group, particularly in the ventral striatum, whereas the aripiprazole group showed task-related activations intermediate of the placebo and haloperidol groups. The current results show differential effects on brain function by aripiprazole and haloperidol, probably related to altered DA transmission. This supports the use of pharmacological fMRI to study antipsychotic properties in humans. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.
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Prommer, Eric
2017-03-01
Delirium is a palliative care emergency where patients experience changes in perception, awareness, and behavior. Common features include changes in the sleep-wake cycle, emotional lability, delusional thinking, and language and thought disorders. Delirium results from neurotransmitter imbalances involving several neurotransmitters such as dopamine, glutamate, norepinephrine, acetylcholine, gamma-aminobutyric acid, and serotonin. Untreated delirium causes significant morbidity and mortality. Nonpharmacologic and pharmacologic approaches treat delirium. Current pharmacologic management of delirium involves using agents such as haloperidol or second-generation antipsychotics. Third-generation atypical antipsychotic drugs have emerged as a potential choice for delirium management. Aripiprazole is a third-generation antipsychotic with a dopamine receptor-binding profile distinct from other second-generation antipsychotics. Aripiprazole acts as partial agonist at dopamine D 2 and 5-hydroxytryptamine (5-HT) 1A receptors, stabilizing the dopamine receptor leading to improvement in symptoms. The article reviews the pharmacology, pharmacodynamics, metabolism, and evidence of clinical efficacy for this new antipsychotic agent. This article explores possible roles in palliative care.
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Stachnik, Joan; Gabay, Michael
2010-01-01
Autistic disorder is a largely misunderstood and difficult to treat neurodevelopmental disorder. Three core domains of functioning are affected by autistic disorder, ie, socialization, communication, and behavior. Signs of autistic disorder may be present early, but are frequently overlooked, resulting in a delay in its diagnosis and a subsequent delay in treatment. No one definitive therapy is available, and treatment consists of early educational and behavioral interventions, as well as drug therapy. Atypical antipsychotics have often been used in the treatment of autistic disorder to target irritability, aggression, and self-injurious behavior, all of which can interfere with other aspects of treatment. One atypical antipsychotic, aripiprazole, has recently been approved for treatment of irritability associated with autistic disorder. Based on the results from two randomized, controlled trials, with efficacy data from nearly 300 patients, treatment with aripiprazole was associated with reductions in irritability, global improvements in behavior, and improvements in quality of life from both the patient and caregiver perspectives. Dosage of aripiprazole ranged from 5 mg to 15 mg per day. Aripiprazole was well tolerated during clinical trials, with most adverse events considered mild or moderate. Clinically relevant weight gain occurred in about 30% of patients given aripiprazole, although when compared with other atypical antipsychotics, aripiprazole appears to have fewer metabolic effects and a lower risk of weight gain. However, pediatric patients taking any atypical antipsychotic should be carefully monitored for potential adverse events, because the long-term effects of antipsychotic therapy in this population are not well known. When used appropriately, aripiprazole has the potential to be an effective treatment for children with autistic disorder to improve irritability and aggressive behavior and improve quality of life.
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Stachnik, Joan; Gabay, Michael
2010-01-01
Autistic disorder is a largely misunderstood and difficult to treat neurodevelopmental disorder. Three core domains of functioning are affected by autistic disorder, ie, socialization, communication, and behavior. Signs of autistic disorder may be present early, but are frequently overlooked, resulting in a delay in its diagnosis and a subsequent delay in treatment. No one definitive therapy is available, and treatment consists of early educational and behavioral interventions, as well as drug therapy. Atypical antipsychotics have often been used in the treatment of autistic disorder to target irritability, aggression, and self-injurious behavior, all of which can interfere with other aspects of treatment. One atypical antipsychotic, aripiprazole, has recently been approved for treatment of irritability associated with autistic disorder. Based on the results from two randomized, controlled trials, with efficacy data from nearly 300 patients, treatment with aripiprazole was associated with reductions in irritability, global improvements in behavior, and improvements in quality of life from both the patient and caregiver perspectives. Dosage of aripiprazole ranged from 5 mg to 15 mg per day. Aripiprazole was well tolerated during clinical trials, with most adverse events considered mild or moderate. Clinically relevant weight gain occurred in about 30% of patients given aripiprazole, although when compared with other atypical antipsychotics, aripiprazole appears to have fewer metabolic effects and a lower risk of weight gain. However, pediatric patients taking any atypical antipsychotic should be carefully monitored for potential adverse events, because the long-term effects of antipsychotic therapy in this population are not well known. When used appropriately, aripiprazole has the potential to be an effective treatment for children with autistic disorder to improve irritability and aggressive behavior and improve quality of life. PMID:24600266
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Ishima, T; Iyo, M; Hashimoto, K
2012-01-01
Aripiprazole is an atypical antipsychotic drug approved for the treatment of psychiatric disorders such as schizophrenia, bipolar disorder, major depressive disorder and autism. The drug shows partial agonistic activity at dopamine D2 receptors and 5-hydroxytryptamine (5-HT) 5-HT1A receptors, and antagonistic activity at 5-HT2A receptors. However, the precise mechanistic pathways remain unclear. In this study, we examined the effects of aripiprazole on neurite outgrowth. Aripiprazole significantly potentiated nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells, in a concentration-dependent manner. The 5-HT1A receptor antagonist WAY-100635, but not the dopamine D2 receptor antagonist sulpiride, blocked the effects of aripiprazole, although, only partially. Specific inhibitors of inositol 1,4,5-triphosphate (IP3) receptors and BAPTA-AM, a chelator of intracellular Ca2+, blocked the effects of aripiprazole. Moreover, specific inhibitors of several common signaling pathways phospholipase C-γ (PLC-γ), phosphatidylinositol-3 kinase (PI3K), mammalian target of rapamycin, p38 MAPK, c-Jun N-terminal kinase, Akt, Ras, Raf, ERK, MAPK) also blocked the effects of aripiprazole. Using proteomic analysis, we found that aripiprazole significantly increased levels of the heat shock protein Hsp90α in cultured cells. The effects of aripiprazole on NGF-induced neurite outgrowth were significantly attenuated by treatment with Hsp90α RNA interference, but not by the negative control of Hsp90α. These findings suggest that both 5-HT1A receptor activation and Ca2+ signaling via IP3 receptors, as well as their downstream cellular signaling pathways play a role in the promotion of aripiprazole-induced neurite outgrowth. Furthermore, aripiprazole-induced increases in Hsp90α protein expression may form part of the therapeutic mechanism for this drug. PMID:23047241
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Horska, Katerina; Ruda-Kucerova, Jana; Drazanova, Eva; Karpisek, Michal; Demlova, Regina; Kasparek, Tomas; Kotolova, Hana
2017-09-01
Schizophrenia appears to be linked to higher incidence of metabolic syndrome even in the absence of antipsychotic treatment. Atypical antipsychotics substantially differ in their propensity to induce metabolic alterations. Aripiprazole is considered to represent an antipsychotic drug with low risk of metabolic syndrome development. The aim of this study was to evaluate metabolic phenotype of neurodevelopmental polyI:C rat model and assess metabolic effects of chronic aripiprazole treatment with regard to complex neuroendocrine regulations of energy homeostasis. Polyinosinic:polycytidylic acid (polyI:C) was administered subcutaneously at a dose of 8 mg/kg in 10 ml on gestational day 15 to female Wistar rats. For this study 20 polyI:C and 20 control adult male offspring were used, randomly divided into 2 groups per 10 animals for chronic aripiprazole treatment and vehicle. Aripiprazole (5 mg/kg, dissolved tablets, ABILIFY ® ) was administered once daily via oral gavage for a month. Altered lipid profile in polyI:C model was observed and a trend towards different dynamics of weight gain in polyI:C rats was noted in the absence of significant antipsychotic treatment effect. PolyI:C model was not associated with changes in other parameters i.e. adipokines, gastrointestinal hormones and cytokines levels. Aripiprazole did not influence body weight but it induced alterations in neurohumoral regulations. Leptin and GLP-1 serum levels were significantly reduced, while ghrelin level was elevated. Furthermore aripiprazole decreased serum levels of pro-inflammatory cytokines. Our data indicate dysregulation of adipokines and gastrointestinal hormones present after chronic treatment with aripiprazole which is considered metabolically neutral in the polyI:C model of schizophrenia. Copyright © 2017 Elsevier Ltd. All rights reserved.
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Vázquez-Bourgon, Javier; Pérez-Iglesias, Rocío; Ortiz-García de la Foz, Víctor; Suárez Pinilla, Paula; Díaz Martínez, Álvaro; Crespo-Facorro, Benedicto
2018-01-01
The use of second-generation antipsychotics (SGA) has been associated with metabolic changes. However, there are differences in the metabolic profile between SGAs. We have previously observed that ziprasidone had a more benign early metabolic profile compared to aripiprazole and quetiapine. However, a long-term follow-up is preferred to detect clinically relevant impairment in metabolic parameters. We aimed to compare the effect of aripiprazole, ziprasidone, and quetiapine on metabolic measures in first-episode non-affective psychosis patients after 1 year of treatment. One hundred and sixty-five drug-naïve patients, suffering from a first episode of non-affective psychosis, were randomly assigned to receive quetiapine, ziprasidone, or aripiprazole. Weight and glycemic/lipid parameters were recorded at baseline and after 1 year of treatment. After 1 year of antipsychotic treatment, we found significant increments in weight, BMI, total cholesterol, LDL-cholesterol, triglycerides, and the triglyceride/HDL index in the sample as a whole. These changes produced a significant rise in the percentage of patients with obesity, hypercholesterolemia, and hypertriglyceridemia. However, when comparing the differential effect of each antipsychotic medication, we found no significant differences in any of the metabolic parameters between antipsychotics groups after 1 year of treatment. We concluded that the antipsychotics studied present similar metabolic profiles. However, the primary exposure to SGAs during the first year of psychosis was associated with significant increases in weight and metabolic parameters, leading to increments in obesity, hypertriglyceridemia, and hypercholesterolemia.
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Hara, Yuta; Ago, Yukio; Taruta, Atsuki; Hasebe, Shigeru; Kawase, Haruki; Tanabe, Wataru; Tsukada, Shinji; Nakazawa, Takanobu; Hashimoto, Hitoshi; Matsuda, Toshio; Takuma, Kazuhiro
2017-11-01
Rodents exposed prenatally to valproic acid (VPA) exhibit autism spectrum disorder (ASD)-like behavioral abnormalities. We recently found that prenatal VPA exposure causes hypofunction of the prefrontal dopaminergic system in mice. This suggests that the dopaminergic system may be a potential pharmacological target for treatment of behavioral abnormalities in ASD patients. In the present study, we examined the effects of antipsychotic drugs, which affect the dopaminergic system, on the social interaction deficits, recognition memory impairment, and reduction in dendritic spine density in the VPA mouse model of ASD. Both acute and chronic administrations of the atypical antipsychotic drugs risperidone and aripiprazole increased prefrontal dopamine (DA) release, while the typical antipsychotic drug haloperidol did not. Chronic risperidone and aripiprazole, but not haloperidol, increased the expression of c-Fos in the prefrontal cortex, although they all increased c-Fos expression in the striatum. Chronic, but not acute, administrations of risperidone and aripiprazole improved the VPA-induced social interaction deficits and recognition memory impairment, as well as the reduction in dendritic spine density in the prefrontal cortex and hippocampus. In contrast, chronic administration of haloperidol did not ameliorate VPA-induced abnormalities in behaviors and dendritic spine density. These findings indicate that chronic risperidone and aripiprazole treatments improve VPA-induced abnormalities in behaviors and prefrontal dendritic spine density, which may be mediated by repeated elevation of extracellular DA in the prefrontal cortex. Our results also imply that loss of prefrontal dendritic spines may be involved in the abnormal behaviors in the VPA mouse model of ASD.
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ERIC Educational Resources Information Center
de Leon, Jose; Greenlee, Brian; Barber, Jack; Sabaawi, Mohamed; Singh, Nirbhay N.
2009-01-01
New generation antipsychotic (NGA) drugs introduced to the US market after clozapine (aripiprazole, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone) are frequently used in individuals with intellectual disabilities (ID). However, there is very limited research to fully establish evidence-based or personalized medicine approaches…
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Citrome, Leslie
2017-10-01
Long-acting injectable (LAI) antipsychotics are a useful but underutilized option in the management of schizophrenia. Areas covered: This is a narrative review of newer LAI antipsychotics approved by the US Food and Drug Administration and is an update to a previously published review from 2013. Emphasized are new indications and new dosing intervals. Expert commentary: Ensuring that persons receiving oral antipsychotics are aware that LAI antipsychotics are available is important. The use of LAI antipsychotics can decrease the risk of relapse in both first-episode and chronic schizophrenia. Available treatments differ in terms of specific indications, approved injection sites, needle gauge, injection volume, injection interval, requirements for oral supplementation, availability of pre-filled syringes, storage needs, and post-injection observation period, as well as potential drug-drug interactions and commonly encountered adverse reactions. Approved indications have expanded beyond schizophrenia to also include bipolar maintenance (risperidone microspheres and aripiprazole monohydrate) and schizoaffective disorder (paliperidone palmitate monthly). Intervals between injections can be longer than one month (six-week or two-month aripiprazole lauroxil, and three-month paliperidone palmitate). After a review of the evidence-base, guidance is offered on the appropriate selection among the LAI formulations of both first and second-generation antipsychotics.
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Aripiprazole-Induced Hyperlipidemia: An Update.
Tarraf, Caroline; Naja, Wadih J
2016-08-25
To review the literature on the metabolic side effects of aripiprazole. Three cases of aripiprazole-induced hypertriglyceridemia are also presented. A search was conducted of English-language articles and abstracts (meta-analyses, randomized controlled trials, clinical trials, naturalistic open-label trials, reviews, and case reports) published up to August 31, 2014, in electronic databases (PubMed, MEDLINE). Free-text and MeSH search keywords included aripiprazole, cholesterol, triglyceride, lipid profile, hyperlipidemia, and hypercholesterolemia and their differing terminations and combinations. The search was supplemented by a manual review of reference lists from the identified publications. Pediatric studies were excluded. Twenty-two articles were found and 3 aspects of the metabolic side effects of aripiprazole were reviewed: (1) the prevalence of the metabolic syndrome in mentally ill patients prior to any antipsychotic use to highlight the initial predisposition of this group of patients to develop the metabolic syndrome, (2) the prevalence of metabolic changes depending on the choice of antipsychotic (aripiprazole compared to other antipsychotics), and (3) metabolic changes reported after switching from an antipsychotic to aripiprazole. Patients with mental disorders are at high risk for developing dyslipidemia, diabetes, and the full criteria of the metabolic syndrome. Antipsychotic use exacerbates this risk, thus increasing the mortality in this population. Nevertheless, it seems that the risk for these side effects varies with each antipsychotic. Although by and large the literature supports the supposition that aripiprazole causes less metabolic effects than other antipsychotics, we report 3 cases of serious aripiprazole-related dyslipidemia in young subjects. On the basis of these 3 cases, aripiprazole can cause hypertriglyceridemia. Triglyceride levels should be carefully monitored in patients with mental disorders taking aripiprazole. © Copyright 2016 Physicians Postgraduate Press, Inc.
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Masoumi, Hamid Reza Fard; Basri, Mahiran; Samiun, Wan Sarah; Izadiyan, Zahra; Lim, Chaw Jiang
2015-01-01
Aripiprazole is considered as a third-generation antipsychotic drug with excellent therapeutic efficacy in controlling schizophrenia symptoms and was the first atypical anti-psychotic agent to be approved by the US Food and Drug Administration. Formulation of nanoemulsion-containing aripiprazole was carried out using high shear and high pressure homogenizers. Mixture experimental design was selected to optimize the composition of nanoemulsion. A very small droplet size of emulsion can provide an effective encapsulation for delivery system in the body. The effects of palm kernel oil ester (3-6 wt%), lecithin (2-3 wt%), Tween 80 (0.5-1 wt%), glycerol (1.5-3 wt%), and water (87-93 wt%) on the droplet size of aripiprazole nanoemulsions were investigated. The mathematical model showed that the optimum formulation for preparation of aripiprazole nanoemulsion having the desirable criteria was 3.00% of palm kernel oil ester, 2.00% of lecithin, 1.00% of Tween 80, 2.25% of glycerol, and 91.75% of water. Under optimum formulation, the corresponding predicted response value for droplet size was 64.24 nm, which showed an excellent agreement with the actual value (62.23 nm) with residual standard error <3.2%.
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Yoon, Hui Woo; Lee, Jung Suk; Park, Sang Jin; Lee, Seon-Koo; Choi, Won-Jung; Kim, Tae Yong; Hong, Chang Hyung; Seok, Jeong-Ho; Park, Il-Ho; Son, Sang Joon; Roh, Daeyoung; Kim, Bo-Ra; Lee, Byung Ook
Hyperprolactinemia is an important but often overlooked adverse effect of antipsychotics. Several studies have shown that switching to or adding aripiprazole normalizes antipsychotic-induced hyperprolactinemia. However, no study has directly compared the effectiveness and safety of the 2 strategies. A total of 52 patients with antipsychotic-induced hyperprolactinemia were recruited. Aripiprazole was administered to patients with mild hyperprolactinemia (serum prolactin level < 50 ng/mL). Patients with severe hyperprolactinemia (serum prolactin level > 50 ng/mL) were randomized to an aripiprazole-addition group (adding aripiprazole to previous antipsychotics) or a switching group (switching previous antipsychotics to aripiprazole). Serum prolactin level, menstrual disturbances, sexual dysfunction, psychopathologies, and quality of life were measured at weeks 0, 1, 2, 4, 6, and 8. Both the addition and switching groups showed significantly reduced serum prolactin level and menstrual disturbances and improved sexual dysfunction. In patients with severe hyperprolactinemia, the numbers of patients with hyperprolactinemia and menstrual disturbance in the switching group were significantly lower than those in the addition group at week 8. Both the addition and switching strategies were effective in resolving antipsychotic-induced hyperprolactinemia and hyperprolactinemia-related adverse events, including menstrual disturbances and sexual dysfunction. In addition, these findings suggest that switching to aripiprazole may be more effective than addition of aripiprazole for normalizing hyperprolactinemia and improving hyperprolactinemia-related adverse events in patients with schizophrenia.
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Azekawa, Takaharu; Ohashi, Shizuko; Itami, Akira
2011-01-01
Background Effectiveness of a drug is a key concept dependent on efficacy, safety, and tolerability. Time to discontinuation of treatment is also representative of effectiveness. We investigated differences in treatment discontinuation among newly started second-generation antipsychotics in the clinical setting. Methods Using a retrospective cohort study design, we screened all outpatients (n = 7936) who visited the Shioiri Mental Clinic between July 1, 2008 and June 30, 2010. We identified a cohort of patients (n = 703) diagnosed with schizophrenia or schizoaffective disorder and calculated the time to discontinuation of each second-generation antipsychotic. Results Of the 703 patients, 149 were newly treated with aripiprazole, 67 with blonanserin, 95 with olanzapine, 36 with quetiapine, 74 with perospirone, and 120 with risperidone. The time to discontinuation for all causes was significantly longer for aripiprazole than for blonanserin, olanzapine, and risperidone. In addition, aripiprazole tended to be continued for longer than quetiapine and perospirone, but these differences were not significant. Conclusion Aripiprazole may be considered the best available option for long-term treatment of patients with schizophrenia or schizoaffective disorder. PMID:22128254
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Azekawa, Takaharu; Ohashi, Shizuko; Itami, Akira
2011-01-01
Effectiveness of a drug is a key concept dependent on efficacy, safety, and tolerability. Time to discontinuation of treatment is also representative of effectiveness. We investigated differences in treatment discontinuation among newly started second-generation antipsychotics in the clinical setting. Using a retrospective cohort study design, we screened all outpatients (n = 7936) who visited the Shioiri Mental Clinic between July 1, 2008 and June 30, 2010. We identified a cohort of patients (n = 703) diagnosed with schizophrenia or schizoaffective disorder and calculated the time to discontinuation of each second-generation antipsychotic. Of the 703 patients, 149 were newly treated with aripiprazole, 67 with blonanserin, 95 with olanzapine, 36 with quetiapine, 74 with perospirone, and 120 with risperidone. The time to discontinuation for all causes was significantly longer for aripiprazole than for blonanserin, olanzapine, and risperidone. In addition, aripiprazole tended to be continued for longer than quetiapine and perospirone, but these differences were not significant. Aripiprazole may be considered the best available option for long-term treatment of patients with schizophrenia or schizoaffective disorder.
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Takaesu, Yoshikazu; Kishimoto, Taishiro; Murakoshi, Akiko; Takahashi, Nobutada; Inoue, Yuichi
2016-02-28
The purpose of the study was to identify factors associated with discontinuation of aripiprazole after switching from other antipsychotics in patients with schizophrenia in real world clinical settings. From January 2011 to December 2012, a prospective, 48-week open-label study was undertaken. Thirty-eight subjects on antipsychotic monotherapy were switched to aripiprazole. Patients who discontinued aripiprazole were compared to those who continued with regards to demographic characteristics as well as treatment factors. Multiple regression analysis was conducted to identify predictors for aripiprazole discontinuation. Thirteen out of 38 patients (34.2%) discontinued aripiprazole during the follow up period. Nine patients (23.7%) discontinued aripiprazole due to worsening of psychotic symptoms. Multiple logistic regression analysis revealed that only the duration of previous antipsychotic treatment was associated with aripiprazole discontinuation after switching to aripiprazole. The receiver operating curve (ROC) analysis identified that the cut-off length for duration of illness to predict aripiprazole discontinuation was 10.5 years. Longer duration of illness was associated with aripiprazole discontinuation. Greater caution may be required when treating such patients with aripiprazole. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
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Kirino, Eiji
2014-01-01
Children with autism have a high rate of irritability and aggressive symptoms. Irritability or self-injurious behavior can result in significant harm to those affected, as well as to marked distress for their families. This paper provides a literature review regarding the efficacy and tolerability of pharmacotherapy for the treatment of irritability in autistic children. Although antipsychotics have not yet been approved for the treatment of autistic children by many countries, they are often used to reduce symptoms of behavioral problems, including irritability, aggression, hyperactivity, and panic. However, among antipsychotics, the Food and Drug Administration has approved only risperidone and aripiprazole to treat irritability in autism. Among atypical antipsychotics, olanzapine and quetiapine are limited in their use for autism spectrum disorders in children because of high incidences of weight gain and sedation. In comparison, aripiprazole and ziprasidone cause less weight gain and sedation. However, potential QTc interval prolongation with ziprasidone has been reported. Contrary to ziprasidone, no changes were evident in the QT interval in any of the trials for aripiprazole. However, head-to-head comparison studies are needed to support that aripiprazole may be a promising drug that can be used to treat irritability in autistic children. On the other hand, risperidone has the greatest amount of evidence supporting it, including randomized controlled trials; thus, its efficacy and tolerability has been established in comparison with other agents. Further studies with risperidone as a control drug are needed. PMID:24932108
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Predicting Pharmacokinetic Stability by Multiple Oral Administration of Atypical Antipsychotics
Aoki, Kazuo; Sakiyama, Yojiro; Ohnishi, Takashi; Sugita, Makoto
2013-01-01
Lower fluctuation, i.e., lower peak-to-trough plasma-concentration variation at steady-state pharmacokinetics, has several advantages for the treatment of schizophrenia with antipsychotics. The reduction of peak concentration can decrease the risk of dose-dependent side effects, such as extrapyramidal symptom and somnolence, and by contrast the increase in trough concentration can decrease the incidence of lack of efficacy due to subtherapeutic drug concentration. Using a one-compartment simulation technique with pharmacokinetic parameters of each atypical antipsychotic collected from package inserts, the fluctuation index was calculated. Among the antipsychotics, the indices varied from 0.018 to 1.9, depending on dosing regimens, formulations and several pharmacokinetic properties. The order of simulated fluctuation index is active-moiety aripiprazole (b.i.d.)
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Shajahan, Polash; Keith, Sonia; Majjiga, Chetan; Murphy, Jennifer; MacRae, Alison; Bashir, Muhammad; Taylor, Mark
2009-05-01
Naturalistic studies offer advantages over randomized clinical trials by including patients seen in routine practice. Aripiprazole and quetiapine are the most recent second-generation antipsychotics available in the United Kingdom. We aimed to study all patients who were prescribed these medications in a defined geographic area in order to identify and compare those who had a good clinical response. We conducted an electronic chart review of a sample of all people attending secondary mental health care in the county of Lanarkshire, Scotland, who were treated with aripiprazole or quetiapine for schizophrenia and related psychoses (ICD-10 criteria) between 2002 and 2007. To measure effectiveness, we retrospectively assigned Clinical Global Impressions (CGI) scores and examined medication discontinuation rates. Eighty-nine patients were started on treatment with aripiprazole and 132 patients with quetiapine over the 5-year period. Those treated with quetiapine had a higher initial illness severity (CGI-Severity of Illness scale) (p = .0003), were more likely to be starting rather than switching antipsychotics (p = .0003), were more likely to have a mood disorder (p = .03), were less likely to be treatment resistant (p = .005), and had lower rates of prescription of additional antipsychotics (p = .009). After adjusting for these variables, the proportions who improved according to CGI were 74% with aripiprazole and 67% with quetiapine. Overall medication discontinuation rates were also similar, 42% for aripiprazole and 45% for quetiapine, with early discontinuation of aripiprazole being noticeable, often due to agitation (13% of all patients treated with the drug). Despite their different pharmacologic properties, aripiprazole and quetiapine were similarly effective in the majority of patients. Early discontinuation of aripiprazole due to agitation was an important finding. Copyright 2009 Physicians Postgraduate Press, Inc.
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[Aripiprazole in pregnancy: a review of literature].
Bellantuono, Cesario; Di Massimo, Giorgia; Mauro, Antonella; Martellini, Mariasole; Nardi, Bernardo
2015-01-01
Data on tolerability and safety of aripiprazolo during pregnancy and in childbirth are so far limited. Aim of the present study is to provide a review of the literature on the safety profile of aripiprazole during pregnancy and on maternal and neonatal outcomes, including two cases coming from our database (www.degradatabase.it). Medline database was searched for English language articles by using the following keywords: "aripiprazole", "atypical antipsychotic", "major malformations", "perinatal complications", "pregnancy". We reported 2 cases of women treated with aripiprazole during their pregnancy at the Clinic of Affective Disorders in Pregnancy and Postpartum of the United Hospital of Ancona (DEGRA Center - www.depressionegravidanza.it). The data available in the literature did not provide clear evidence about the safety and potential risks related to this drug during pregnancy. Data coming from our database did not detected any malformations and perinatal complications after exposure to aripiprazole in 2 newborns beyond the first trimester of pregnancy. From the evidence available, aripiprazole seems to be an antipsychotic effective and well tolerated in the treatment of women with psychotic disorders in pregnancy. However, further studies are needed to better establish the safety of aripiprazole during pregnancy, particularly as the risk of major malformtions and perinatal complications is concerned.
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Mental disorder diagnoses among children and adolescents who use antipsychotic drugs.
Nesvåg, Ragnar; Hartz, Ingeborg; Bramness, Jørgen G; Hjellvik, Vidar; Handal, Marte; Skurtveit, Svetlana
2016-09-01
Antipsychotic drugs are used increasingly by children and adolescents and there is concern about off-label use. We aimed to study which substances, and for which mental disorder diagnoses, antipsychotic drugs were prescribed to 0-18-year-old boys and girls in Norway. Linked data from the national health registry for prescription drugs in 2010 and mental disorder diagnoses in 2008-2012 were used to study the prevalence of antipsychotic drug use, the type of antipsychotic drug substances used, mental disorder diagnoses in users and distribution of drugs per diagnostic category across gender. In total, 0.18% of Norwegian children and adolescents were prescribed antipsychotic drugs during 2010, of which there were more boys (0.23%) than girls (0.13%). Risperidone was the most frequently used substance among boys (57.4%) and girls (32.3%), followed by aripiprazole (19.4%) in boys and quetiapine (27.4%) in girls. The most common mental disorder diagnoses among male users were hyperkinetic (49.9%) and autism spectrum disorder (27.1%), while anxiety disorders (41.5%) and depressive illness (33.6%) were most common among female users. A schizophrenia-like psychosis diagnosis was given to 11.1% of the male and 18.2% of the female users. A hyperkinetic disorder was diagnosed among 56.9% and 52.4% of the male risperidone and aripiprazole users, respectively. Among female quetiapine users, 57.1% were diagnosed with anxiety disorders and 52.4% with depressive illness. These results demonstrate that children and adolescents who use antipsychotic drugs are predominantly diagnosed with non-psychotic mental disorders such as hyperkinetic disorder among boys and anxiety disorder or depressive illness among girls. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.
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Fard Masoumi, Hamid Reza; Basri, Mahiran; Sarah Samiun, Wan; Izadiyan, Zahra; Lim, Chaw Jiang
2015-01-01
Aripiprazole is considered as a third-generation antipsychotic drug with excellent therapeutic efficacy in controlling schizophrenia symptoms and was the first atypical anti-psychotic agent to be approved by the US Food and Drug Administration. Formulation of nanoemulsion-containing aripiprazole was carried out using high shear and high pressure homogenizers. Mixture experimental design was selected to optimize the composition of nanoemulsion. A very small droplet size of emulsion can provide an effective encapsulation for delivery system in the body. The effects of palm kernel oil ester (3–6 wt%), lecithin (2–3 wt%), Tween 80 (0.5–1 wt%), glycerol (1.5–3 wt%), and water (87–93 wt%) on the droplet size of aripiprazole nanoemulsions were investigated. The mathematical model showed that the optimum formulation for preparation of aripiprazole nanoemulsion having the desirable criteria was 3.00% of palm kernel oil ester, 2.00% of lecithin, 1.00% of Tween 80, 2.25% of glycerol, and 91.75% of water. Under optimum formulation, the corresponding predicted response value for droplet size was 64.24 nm, which showed an excellent agreement with the actual value (62.23 nm) with residual standard error <3.2%. PMID:26508853
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Can a digital medicine system improve adherence to antipsychotic treatment?
Papola, D; Gastaldon, C; Ostuzzi, G
2018-06-01
A substantial proportion of people with mental health conditions do not adhere to prescribed pharmacological treatments. Poor adherence is probably one of the most critical elements contributing to relapse in people with schizophrenia and other severe mental disorders. In order to tackle this global issue, in November 2017 the Food and Drug Administration approved a tablet formulation of the atypical antipsychotic aripiprazole embedded with a novel digital adherence-assessment device. In this commentary, we critically appraised the potential beneficial and harmful consequences of this new digital formulation of aripiprazole, and we highlighted expected implications for clinical practice.
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McKeage, Kate
2014-02-01
Aripiprazole (Abilify(®)) is an atypical antipsychotic that is widely used in the treatment of psychiatric conditions. Unlike other currently available atypical antipsychotics that primarily have varying degrees of dopamine D2 receptor antagonism, aripiprazole is a partial agonist at D2 and serotonin 5-HT1A receptors, which may explain differences in tolerability profiles. Recently in the EU, oral aripiprazole 10 mg once daily for 12 weeks was approved for the treatment of moderate to severe manic episodes in adolescents (aged ≥13 years) with bipolar I disorder. Approval was based on a phase 3, 30-week US trial in children and adolescents with bipolar I disorder experiencing manic or mixed episodes. Using trial data together with ancillary analyses, the European Medicines Agency concluded that aripiprazole 10 mg once daily for 12 weeks was effective in reducing symptoms of mania, but because of the high drop-out rate, efficacy over 30 weeks of treatment was not proven. Aripiprazole was generally well tolerated in the phase 3 trial. Ancillary analyses indicated that tolerability was less favourable in younger (10-12 years) than in older (≥13 years) subjects, and less favourable with the higher (30 mg/day) than the lower dosage (10 mg/day). The drug is associated with sedation, weight gain and extrapyramidal symptoms (EPS), although the incidence of EPS over 12 weeks was not significantly different between aripiprazole 10 mg/day and placebo. Data comparing the use of atypical antipsychotics in the treatment of mania in adolescents with bipolar I disorder are limited, but evidence shows that aripiprazole provides a valuable additional therapeutic option for use in this population.
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Aggarwal, Arpit; Gopalakrishna, Ganesh; Lauriello, John
2016-01-01
Antipsychotics have long been the mainstay for the treatment of schizophrenia and other psychotic disorders. Long-acting injectables (LAI) of antipsychotics-provided once every two weeks to once every three months-promise to reduce the incidence of nonadherence. ARISTADA(™) (aripiprazole lauroxil; ALLAI) extended-release injectable suspension was approved by the U.S. Food and Drug Administration in October 2015 for the treatment of schizophrenia, and is the newest entrant in the LAI market. ALLAI is available as a single-use, pre-filled syringe, can be started in three different dosages, and also has the option of every six-week dosing. Treatment with oral aripiprazole is recommended for the first twenty-one days after the first ALLAI injection, which is a potential disadvantage. Adverse effects include sensitivity to extrapyramidal symptoms, especially akathisia, which is well documented in other aripiprazole preparations. There is no available data comparing ALLAI to other antipsychotics, and more head-to-head trials comparing different LAI formulations are needed. Based on the available data, ALLAI is an effective and safe option for treatment of schizophrenia. Further studies and post-marketing data will provide better understanding of this formulation.
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Effects of atypical antipsychotic drugs on QT interval in patients with mental disorders
Aronow, Wilbert S.
2018-01-01
Background Drug-induced QT prolongation is associated with higher risk of cardiac arrhythmias and cardiovascular mortality. We investigated the effects of atypical antipsychotic drugs on QT interval in children and adults with mental disorders. Methods We conducted random-effects direct frequentist meta-analyses of aggregate data from randomized controlled trials (RCT) and appraised the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Our search in PubMed, EMBASE, the Cochrane Library, clinicaltrials.gov, and PharmaPendium up to October 2017 identified studies that examined aripiprazole, quetiapine, risperidone, olanzapine, ziprasidone and brexpiprazole. Results Low quality evidence suggests that aripiprazole (four meta-analyses and twelve RCTs), brexpiprazole (one systematic review and four RCTs) or olanzapine (five meta-analyses and twenty RCTs) do not increase QT interval. Low quality evidence suggests that ziprasidone (five meta-analyses and 11 RCTs) increases QT interval and the rates of QT prolongation while risperidone (four meta-analyses, 70 RCTs) and quetiapine (two meta-analyses and seven RCTs) are associated with QT prolongation and greater odds of torsades de pointes ventricular tachycardia especially in cases of drug overdose. Conclusions The main conclusion of our study is that in people with mental disorders and under treatment with atypical antipsychotic drugs, in order to avoid QT prolongation and reduce the risk of ventricular tachycardia clinicians may recommend aripiprazole, brexpiprazole or olanzapine in licensed doses. Long-term comparative safety needs to be established. PMID:29862236
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Goozee, Rhianna; Reinders, Antje A T S; Handley, Rowena; Marques, Tiago; Taylor, Heather; O'Daly, Owen; McQueen, Grant; Hubbard, Kathryn; Mondelli, Valeria; Pariante, Carmine; Dazzan, Paola
2016-06-01
Antipsychotic drugs target neurotransmitter systems that play key roles in working memory. Therefore, they may be expected to modulate this cognitive function via their actions at receptors for these neurotransmitters. However, the precise effects of antipsychotic drugs on working memory function remain unclear. Most studies have been carried out in clinical populations, making it difficult to disentangle pharmacological effects from pathology-related brain activation. In this study, we aim to investigate the effects of two antipsychotic compounds on brain activation during working memory in healthy individuals. This would allow elucidation of the effects of current antipsychotic treatments on brain function, independently of either previous antipsychotic use or disease-related pathology. We carried out a fully counterbalanced, randomised within-subject, double-blinded and placebo-controlled, cross-over study of the effects of two antipsychotic drugs on working memory function in 17 healthy individuals, using the n-back task. Participants completed the functional MRI task on three separate occasions (in randomised order): following placebo, haloperidol, and aripiprazole. For each condition, working memory ability was investigated, and maps of neural activation were entered into a random effects general linear regression model to investigate main working memory function and linear load. Voxel-wise and region of interest analyses were conducted to attain regions of altered brain activation for each intervention. Aripiprazole did not lead to any changes in neural activation compared with placebo. However, reaction time to a correct response was significantly increased following aripiprazole compared to both placebo (p=0.046) and haloperidol (p=0.02). In contrast, compared to placebo, haloperidol dampened activation in parietal (BA 7/40; left: FWE-corr. p=0.005; FWE-corr. right: p=0.007) and frontal (including prefrontal; BA 9/44/46; left: FWE-corr. p=0.009; right: FWE-corr. p=0.014) cortices and the left putamen (FWE-corr. p=0.004). Compared with aripiprazole, haloperidol dampened activation in parietal cortex (BA7/40; left: FWE-corr. p=0.034; right: FWE-corr. p=0.045) and the left putamen (FWE-corr.p=0.015). Haloperidol had no effect on working memory performance compared with placebo. Cognitive functions are known to be impaired in schizophrenia and as such are an important target of treatments. Elucidating the mechanisms by which antipsychotic medications alter brain activation underlying cognition is essential to advance pharmacological treatment of this disorder. Studies in healthy individuals can help elucidate some of these mechanisms, whilst limiting the confounding effect of the underlying disease-related pathology. Our study provides evidence for immediate and differential effects of single-dose haloperidol and aripiprazole on brain activation during working memory in healthy individuals. We propose that these differences likely reflect their different receptor affinity profiles, although the precise mechanisms underlying these differences remain unclear. Copyright © 2015 Elsevier B.V. All rights reserved.
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Aripiprazole in schizophrenia and schizoaffective disorder: A review.
Stip, Emmanuel; Tourjman, Valérie
2010-01-01
During the past decade, there has been some progress in the pharmacotherapy of schizophrenia and schizoaffective disorder. Current evidence supports the use of various second-generation, or atypical, antipsychotic medications, although few of these agents have been associated with long-term efficacy and tolerability. Aripiprazole is an atypical antipsychotic that has been found to improve positive and negative symptoms of schizophrenia with a favorable adverse-effect profile. This article reviews the efficacy and tolerability of aripiprazole in the context of recommended management strategies for schizophrenia and schizoaffective disorder, and in comparison with first-generation and other second-generation antipsychotics. A search of MEDLINE (1999-May 2009) was conducted for reports of short- and long-term clinical studies of atypical antipsychotics (including aripiprazole) and meta-analyses of randomized controlled trials comparing first- and second-generation antipsychotics (including aripiprazole) in the treatment of schizophrenia or schizoaffective disorder. The search terms were schizophrenia; schizoaffective disorder; pharmacogenetics; adverse effects; tardive dyskinesia AND atypical antipsychotics; aripiprazole; aripiprazole, schizophrenia, AND double-blind studies; and atypical antipsychotics AND adverse effects. The reference lists of identified articles were reviewed for additional relevant publications. Only full study publications were included. Based on the clinical evidence, including data from short-term (4-8 weeks) and long-term (26-52 weeks) randomized, double-blind clinical trials, aripiprazole has been associated with improvements in positive, negative, cognitive, and affective symptoms of schizophrenia and schizoaffective disorder. It has been associated with long-term (up to 52 weeks) symptom control in schizophrenia, as well as with efficacy in treatment-resistant schizophrenia. Common adverse effects associated with aripiprazole were nausea, insomnia, and agitation. These effects were usually transient. The evidence suggests that aripiprazole is unlikely to be associated with clinically significant weight gain or dyslipidemia, increased prolactin levels, or prolongation of the QTc interval. Compared with placebo, aripiprazole has been reported to have a relatively low potential for inducing metabolic syndrome. Based on the evidence reviewed, aripiprazole monotherapy appears to be effective and well tolerated in treating the positive, negative, and cognitive symptoms of schizophrenia and schizoaffective disorder. It was associated with a low risk for the common adverse effects of antipsychotic therapy, including metabolic and endocrine alterations. 2010 Excerpta Medica Inc. All rights reserved.
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Aripiprazole blocks reinstatement of cocaine seeking in an animal model of relapse.
Feltenstein, Matthew W; Altar, C Anthony; See, Ronald E
2007-03-01
Aripiprazole (Abilify) is an atypical antipsychotic drug primarily characterized by partial agonist activity at dopamine (DA) D2 receptors and low side effects. Based on pharmacologic properties that include a stabilization of mesocorticolimbic DA activity, a pathway implicated in addiction, aripiprazole was tested for its ability to prevent relapse to cocaine seeking in rats. We assessed the dose-dependent effects of aripiprazole on conditioned cue-induced and cocaine-primed reinstatement of drug-seeking behavior following chronic intravenous cocaine self-administration in an animal model of relapse. Aripiprazole potently and dose-dependently attenuated responding on the previously cocaine-paired lever during both reinstatement conditions, with slightly greater efficacy at reducing conditioned-cued reinstatement. Aripiprazole was effective at doses that failed to alter cocaine self-administration, food self-administration, reinstatement of food-seeking behavior, or basal locomotor activity, suggesting selective effects of aripiprazole on motivated drug-seeking behavior. These results in a relapse model show that aripiprazole can block cocaine seeking without affecting other behaviors. The D2 partial agonist properties of aripiprazole likely account for the blockade of reinstatement of cocaine-seeking behavior. Given its established efficacy and tolerability as a treatment for psychosis, aripiprazole may be an excellent therapeutic choice for reducing craving and preventing relapse in people with cocaine dependency.
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Weiden, Peter J; Du, Yangchun; Liu, Chih-Chin; Stanford, Arielle D
2018-06-26
Switching antipsychotic medications is common in patients with schizophrenia who are experiencing persistent symptoms or tolerability issues associated with their current drug regimen. This analysis assessed the safety of switching from an oral antipsychotic to the long-acting injectable antipsychotic aripiprazole lauroxil (AL). This was a post hoc analysis of outpatients with schizophrenia who were prescribed an oral antipsychotic and who enrolled in an international, open-label, long-term (52-week) safety study of AL. The analysis focused on the first 3 injections of AL 882 mg over 12 weeks, divided into the immediate 4-week crossover period between the first and second AL injections (initiation phase) and the subsequent 8 weeks (stabilization phase). Patients were grouped by preswitch oral antipsychotic medication, and safety and clinical symptoms were assessed. In total, 190 patients had switched from one of the following oral antipsychotic medications: aripiprazole, conventional antipsychotics, risperidone/paliperidone, olanzapine, or quetiapine. The 12-week completion rate was high (92.1%) and similar across the different preswitch oral antipsychotic groups. Overall, adverse event (AE) rates experienced over 12 weeks were modest; no AEs were considered serious. The most common AEs in the initiation phase were injection site pain (5.8%), insomnia (5.8%), and akathisia (3.2%). No apparent relationship was observed between preswitch medication and early-onset AEs. Mean Positive and Negative Syndrome Scale total scores remained stable during this period across preswitch antipsychotic groups. Switching from an oral antipsychotic to AL was feasible in an outpatient setting for patients with schizophrenia, and the 12-week retention rate was favorable.
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Miura, Itaru; Shiga, Tetsuya; Katsumi, Akihiko; Kanno-Nozaki, Keiko; Mashiko, Hirobumi; Niwa, Shin-Ichi; Yabe, Hirooki
2014-03-01
Blonanserin is a novel atypical antipsychotic drug that has efficacy equal to risperidone. We investigated the effects of aripiprazole and blonanserin on clinical symptoms and plasma levels of homovanillic acid (pHVA) and 3-methoxy-4hydroxyphenylglycol in the switching strategy of schizophrenia. Twenty two Japanese patients with schizophrenia were enrolled into this open study. The antipsychotics of all patients were switched to aripiprazole or blonanserin for the improvement of clinical symptoms or side effects. Plasma monoamine metabolites levels were analyzed with high-performance liquid chromatography. There were no significant effects for time (p = 0.346) or time × group interaction (p = 0.27) on the changes of positive and negative syndrome scale (PANSS) total score, although blonanserin decreased PANSS scores. We observed negative correlation between pHVA at baseline and the change in PANSS total score (rs = -0.450, p = 0.046). We also found positive correlation between the changes in pHVA and the changes in PANSS total (rs = 0.536, p = 0.015) and positive (rs = 0.572, p = 0.008) scores. There were no differences between blonanserin and aripiprazole in the improvement of clinical symptoms. Our results suggest that pHVA may be useful indicator for the switching strategy to aripiprazole or blonanserin in schizophrenia. Copyright © 2014 John Wiley & Sons, Ltd.
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Bardin, Laurent; Kleven, Mark S; Barret-Grévoz, Catherine; Depoortère, Ronan; Newman-Tancredi, Adrian
2006-09-01
A new generation of proven or potential antipsychotics, including aripiprazole, bifeprunox, SSR181507 and SLV313, exhibit agonist actions at serotonin 5-HT1A receptors, but little comparative data are available on their pharmacological profiles. Here, we compared in mice the in vivo antipsychotic-like vs cataleptogenic activities of these compounds with those of drugs that exhibit little interaction at 5-HT1A receptors, such as haloperidol, olanzapine and risperidone. All the drugs dose-dependently reduced apomorphine-induced climbing or sniffing and, with the exception of ziprasidone, produced complete suppression of these responses. In the bar catalepsy test, when administered alone, haloperidol, olanzapine and risperidone produced marked catalepsy, whereas, at doses up to 40 mg/kg, aripiprazole, SLV313, SSR181507, and sarizotan produced little or no catalepsy. The latter compounds, therefore, displayed a large separation between doses with 'antipsychotic-like' and those with cataleptogenic actions. When 5-HT1A receptors were blocked by pretreatment with WAY100635 (2.5 mg/kg, s.c.), cataleptogenic properties of SSR181507 and sarizotan were unmasked, and the catalepsy induced by bifeprunox was enhanced. In the case of aripiprazole and SLV313, although WAY100635 produced upward shifts in their dose-response, the magnitude of catalepsy appeared to reach an asymptotic plateau, suggesting that other mechanisms may be involved in their low cataleptogenic liability. The present data confirm that 5-HT1A receptor activation reduces or even completely prevents the cataleptogenic potential of novel antipsychotic agents. Further, they indicate that the balance of affinity and/or efficacy between D2 and 5-HT1A receptors profoundly influences their pharmacological activities, and will likely impact their therapeutic profiles.
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Do Atypical Antipsychotics Have Antisuicidal Effects? A Hypothesis-Generating Overview
Pompili, Maurizio; Baldessarini, Ross J.; Forte, Alberto; Erbuto, Denise; Serafini, Gianluca; Fiorillo, Andrea; Amore, Mario; Girardi, Paolo
2016-01-01
Modern antipsychotic drugs are employed increasingly in the treatment of mood disorders as well as psychoses, stimulating interest in their possible contributions to altering suicidal risk. Clozapine remains the only treatment with an FDA-recognized indication for reducing suicidal risk (in schizophrenia). We carried out a systematic, computerized search for reports of studies involving antipsychotic drug treatment and suicidal behaviors. A total of 19 reports provide data with preliminary support for potential suicide risk-reducing effects of olanzapine, quetiapine, ziprasidone, aripiprazole, and asenapine in addition to clozapine, and provide some support for antipsychotic drug treatment in general. These preliminary findings encourage further testing of antipsychotics for effects on suicidal behavior, making use of explicit, pre-planned assessments of suicidal behavior. PMID:27727180
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Risk of Extrapyramidal Adverse Events With Aripiprazole.
Etminan, Mahyar; Procyshyn, Ric M; Samii, Ali; Carleton, Bruce C
2016-10-01
Aripiprazole is a unique atypical antipsychotic with partial agonist activity on the dopamine-2 (D2) receptor. This unique pharmacological profile of aripiprazole was thought to lead to a lower incidence of extrapyramidal symptoms (EPSs). However, recent case reports have alluded to an increase in the risk of EPS in aripiprazole users compared with nonusers of the drug. No epidemiologic studies to date have quantified this risk. We conducted a pharmacoepidemiologic study composed of a nested case-control study using a large health claims database (IMS Health) in the United States. In the nested case-control analysis, there were 5242 cases of EPS with 50,532 corresponding controls in the entire cohort. The odds ratio (OR) for EPS among those with any prescription of aripiprazole was 5.38 (95% confidence interval [CI], 3.03-9.57). The OR was lower among those taking 2 to 3 prescriptions (OR, 2.9; 95% CI, 1.07-7.85) but increased in those receiving greater than 4 prescriptions (OR, 8.64; 95% CI, 2.63-28.38). All risk periods were compared with those of subjects who had not used aripiprazole or other antipsychotics. For the secondary outcome of dyskinesia, the risk for aripiprazole was 8.50 (95% CI, 8.53-2.27-31.97) compared with that of nonusers. In conclusion, we found an increase in the risk of EPS and dyskinesias among users of aripiprazole.
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Tron, Camille; Kloosterboer, Sanne M; van der Nagel, Bart C H; Wijma, Rixt A; Dierckx, Bram; Dieleman, Gwen C; van Gelder, Teun; Koch, Birgit C P
2017-08-01
Risperidone, aripiprazole, and pipamperone are antipsychotic drugs frequently prescribed for the treatment of comorbid behavioral problems in children with autism spectrum disorders. Therapeutic drug monitoring (TDM) could be useful to decrease side effects and to improve patient outcome. Dried blood spot (DBS) sample collection seems to be an attractive technique to develop TDM of these drugs in a pediatric population. The aim of this work was to develop and validate a DBS assay suitable for TDM and home sampling. Risperidone, 9-OH risperidone, aripiprazole, dehydroaripiprazole, and pipamperone were extracted from DBS and analyzed by ultra-high-performance liquid chromatography-tandem mass spectrometry using a C18 reversed-phase column with a mobile phase consisting of ammonium acetate/formic acid in water or methanol. The suitability of DBS for TDM was assessed by studying the influence of specific parameters: extraction solution, EDTA carryover, hematocrit, punching location, spot volume, and hemolysis. The assay was validated with respect to conventional guidelines for bioanalytical methods. The method was linear, specific without any critical matrix effect, and with a mean recovery around 90%. Accuracy and imprecision were within the acceptance criteria in samples with hematocrit values from 30% to 45%. EDTA or hemolysis did not skew the results, and no punching carryover was observed. No significant influence of the spot volume or the punch location was observed. The antipsychotics were all stable in DBS stored 10 days at room temperature and 1 month at 4 or -80°C. The method was successfully applied to quantify the 3 antipsychotics and their metabolites in patient samples. A UHPLC-MS/MS method has been successfully validated for the simultaneous quantification of risperidone, 9-OH risperidone, aripiprazole, dehydroaripiprazole, and pipamperone in DBS. The assay provided good analytical performances for TDM and clinical research applications.
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Differences in Antipsychotic-Related Adverse Events in Adult, Pediatric, and Geriatric Populations.
Sagreiya, Hersh; Chen, Yi-Ren; Kumarasamy, Narmadan A; Ponnusamy, Karthik; Chen, Doris; Das, Amar K
2017-02-26
In recent years, antipsychotic medications have increasingly been used in pediatric and geriatric populations, despite the fact that many of these drugs were approved based on clinical trials in adult patients only. Preliminary studies have shown that the "off-label" use of these drugs in pediatric and geriatric populations may result in adverse events not found in adults. In this study, we utilized the large-scale U.S. Food and Drug Administration (FDA) Adverse Events Reporting System (AERS) database to look at differences in adverse events from antipsychotics among adult, pediatric, and geriatric populations. We performed a systematic analysis of the FDA AERS database using MySQL by standardizing the database using structured terminologies and ontologies. We compared adverse event profiles of atypical versus typical antipsychotic medications among adult (18-65), pediatric (age < 18), and geriatric (> 65) populations. We found statistically significant differences between the number of adverse events in the pediatric versus adult populations with aripiprazole, clozapine, fluphenazine, haloperidol, olanzapine, quetiapine, risperidone, and thiothixene, and between the geriatric versus adult populations with aripiprazole, chlorpromazine, clozapine, fluphenazine, haloperidol, paliperidone, promazine, risperidone, thiothixene, and ziprasidone (p < 0.05, with adjustment for multiple comparisons). Furthermore, the particular types of adverse events reported also varied significantly between each population for aripiprazole, clozapine, haloperidol, olanzapine, quetiapine, risperidone, and ziprasidone (Chi-square, p < 10 -6 ). Diabetes was the most commonly reported side effect in the adult population, compared to behavioral problems in the pediatric population and neurologic symptoms in the geriatric population. We also found discrepancies between the frequencies of reports in AERS and in the literature. Our analysis of the FDA AERS database shows that there are significant differences in both the numbers and types of adverse events among these age groups and between atypical and typical antipsychotics. It is important for clinicians to be mindful of these differences when prescribing antipsychotics, especially when prescribing medications off-label.
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Costa, Maria do Carmo; Ashraf, Naila S.; Fischer, Svetlana; Yang, Yemen; Schapka, Emily; Joshi, Gnanada; McQuade, Thomas J.; Dharia, Rahil M.; Dulchavsky, Mark; Ouyang, Michelle; Cook, David; Sun, Duxin; Larsen, Martha J.; Gestwicki, Jason E.; Todi, Sokol V.; Ivanova, Magdalena I.; Paulson, Henry L.
2016-01-01
No disease-modifying treatment exists for the fatal neurodegenerative polyglutamine disease known both as Machado-Joseph disease and spinocerebellar ataxia type 3. As a potential route to therapy, we identified small molecules that reduce levels of the mutant disease protein, ATXN3. Screens of a small molecule collection, including 1250 Food and Drug Administration-approved drugs, in a novel cell-based assay, followed by secondary screens in brain slice cultures from transgenic mice expressing the human disease gene, identified the atypical antipsychotic aripiprazole as one of the hits. Aripiprazole increased longevity in a Drosophila model of Machado-Joseph disease and effectively reduced aggregated ATXN3 species in flies and in brains of transgenic mice treated for 10 days. The aripiprazole-mediated decrease in ATXN3 abundance may reflect a complex response culminating in the modulation of specific components of cellular protein homeostasis. Aripiprazole represents a potentially promising therapeutic drug for Machado-Joseph disease and possibly other neurological proteinopathies. PMID:27645800
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Spielmans, Glen I.; Berman, Margit I.; Linardatos, Eftihia; Rosenlicht, Nicholas Z.; Perry, Angela; Tsai, Alexander C.
2013-01-01
Background Atypical antipsychotic medications are widely prescribed for the adjunctive treatment of depression, yet their total risk–benefit profile is not well understood. We thus conducted a systematic review of the efficacy and safety profiles of atypical antipsychotic medications used for the adjunctive treatment of depression. Methods and Findings We included randomized trials comparing adjunctive antipsychotic medication to placebo for treatment-resistant depression in adults. Our literature search (conducted in December 2011 and updated on December 14, 2012) identified 14 short-term trials of aripiprazole, olanzapine/fluoxetine combination (OFC), quetiapine, and risperidone. When possible, we supplemented published literature with data from manufacturers' clinical trial registries and US Food and Drug Administration New Drug Applications. Study duration ranged from 4 to 12 wk. All four drugs had statistically significant effects on remission, as follows: aripiprazole (odds ratio [OR], 2.01; 95% CI, 1.48–2.73), OFC (OR, 1.42; 95% CI, 1.01–2.0), quetiapine (OR, 1.79; 95% CI, 1.33–2.42), and risperidone (OR, 2.37; 95% CI, 1.31–4.30). The number needed to treat (NNT) was 19 for OFC and nine for each other drug. All drugs with the exception of OFC also had statistically significant effects on response rates, as follows: aripiprazole (OR, 2.07; 95% CI, 1.58–2.72; NNT, 7), OFC (OR, 1.30, 95% CI, 0.87–1.93), quetiapine (OR, 1.53, 95% CI, 1.17–2.0; NNT, 10), and risperidone (OR, 1.83, 95% CI, 1.16–2.88; NNT, 8). All four drugs showed statistically significant effects on clinician-rated depression severity measures (Hedges' g ranged from 0.26 to 0.48; mean difference of 2.69 points on the Montgomery–Asberg Depression Rating Scale across drugs). On measures of functioning and quality of life, these medications produced either no benefit or a very small benefit, except for risperidone, which had a small-to-moderate effect on quality of life (g = 0.49). Treatment was linked to several adverse events, including akathisia (aripiprazole), sedation (quetiapine, OFC, and aripiprazole), abnormal metabolic laboratory results (quetiapine and OFC), and weight gain (all four drugs, especially OFC). Shortcomings in study design and data reporting, as well as use of post hoc analyses, may have inflated the apparent benefits of treatment and reduced the apparent incidence of adverse events. Conclusions Atypical antipsychotic medications for the adjunctive treatment of depression are efficacious in reducing observer-rated depressive symptoms, but clinicians should interpret these findings cautiously in light of (1) the small-to-moderate-sized benefits, (2) the lack of benefit with regards to quality of life or functional impairment, and (3) the abundant evidence of potential treatment-related harm. Please see later in the article for the Editors' Summary PMID:23554581
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Kim, Sun H; Ivanova, Oxana; Abbasi, Fahim A; Lamendola, Cindy A; Reaven, Gerald M; Glick, Ira D
2007-08-01
Switching antipsychotic regimen to agents with low weight gain potential has been suggested in patients who gain excessive weight on their antipsychotic therapy. In an open-label pilot study, we evaluated the metabolic and psychiatric efficacy of switching to aripiprazole in 15 (9 men, 6 women) outpatients with schizophrenia who had gained at least 10 kg on their previous antipsychotic regimen. Individuals had evaluation of glucose tolerance, insulin resistance (insulin suppression test), lipid concentrations, and psychiatric status before and after switching to aripiprazole for 4 months. A third of the individuals could not psychiatrically tolerate switching to aripiprazole. In the remaining individuals, psychiatric symptoms significantly improved with decline in Clinical Global Impression Scale (by 26%, P = 0.015) and Positive and Negative Syndrome Scale (by 22%, P = 0.023). Switching to aripiprazole did not alter weight or metabolic outcomes (fasting glucose, insulin resistance, and lipid concentrations) in the patients of whom 73% were insulin resistant and 47% had impaired or diabetic glucose tolerance at baseline. In conclusion, switching to aripiprazole alone does not ameliorate the highly prevalent metabolic abnormalities in the schizophrenia population who have gained weight on other second generation antipsychotic medications.
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Citrome, Leslie; Kalsekar, Iftekhar; Guo, Zhenchao; Laubmeier, Kimberly; Hebden, Tony
2013-12-01
Atypical antipsychotics are indicated for specific psychiatric conditions; however, they are frequently used for US Food and Drug Administration-nonapproved indications. This study assessed the types of medical diagnoses associated with atypical antipsychotic prescriptions in commercial health care plans. This retrospective cohort study used the OptumInsight commercial data set from January 2008 to June 2011. The index date was defined as the earliest date of prescription for the atypical antipsychotics aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone, from January 1, 2009, through June 30, 2010. Medical claims during a 2-year period (12 months before and 12 months after the index date) were used to identify relevant diagnostic codes from the International Classification of Diseases, Ninth Edition, Clinical Modification associated with the antipsychotic prescription. A logistic regression analysis was conducted to examine the predictors of use of atypical antipsychotics without a relevant diagnosis, that is, schizophrenia, bipolar, or major depressive disorder (MDD). Of 18,352 patients included in the analysis, 3593 (19.5%) who filled a prescription for atypical antipsychotics did not have an approved diagnosis. Off-label utilization varied, with approximately a quarter of patients with prescriptions for quetiapine (24.1%), risperidone (23.1%), or olanzapine (21.8%) being without a relevant diagnostic code, whereas proportions were lower for patients prescribed aripiprazole (14.0%) or ziprasidone (13.1%). Of those with a psychiatric disorder other than schizophrenia, bipolar disorder, or MDD, approximately a third of prescriptions were for anxiety disorders, with similar proportions across all atypical antipsychotics. Patients were often prescribed quetiapine for substance abuse (22.7%), whereas patients with "other psychiatric conditions" were prescribed risperidone (26.3%) or ziprasidone (25.0%). The logistic regression analysis indicated that patients prescribed olanzapine, quetiapine, or risperidone were significantly more likely to have no diagnostic code for schizophrenia, bipolar disorder, or MDD compared with patients prescribed aripiprazole. Nearly a fifth of commercially insured patients were prescribed atypical antipsychotics, in particular, olanzapine, quetiapine, or risperidone, for diagnoses that were not aligned with US Food and Drug Administration-approved indications. 2013 The Authors. Published by Elsevier HS Journals, Inc. All rights reserved.
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Repeated aripiprazole administration attenuates cocaine seeking in a rat model of relapse.
Feltenstein, Matthew W; Do, Phong H; See, Ronald E
2009-12-01
Aripiprazole (Abilify) is an atypical antipsychotic drug characterized by partial agonist activity at dopamine (DA) D(2)/D(3) receptors and a low side-effect profile. While we previously demonstrated that acute aripiprazole blocked the reinstatement of cocaine seeking in an animal model of relapse, clinical treatment of relapse prevention necessitates testing the effects of aripiprazole following prolonged abstinence, as well as after repeated administration during withdrawal from cocaine. We assessed the effects of repeated aripiprazole treatment on cocaine seeking after abstinence and during conditioned cue-induced and cocaine-primed reinstatement in rats. Rats self-administered intravenous cocaine paired with a light + tone stimulus for 10-14 days, followed by 2 weeks of abstinence. Following post-abstinence relapse testing, lever responding was allowed to extinguish, with subsequent reinstatement testing occurring either in the presence of the conditioned stimulus, or after a cocaine-priming injection (10 mg/kg, intraperitoneal (IP)). Following 3 or 7 days of pretreatment, rats received an injection of aripiprazole (0.25, 0.5, and 1.0 mg/kg, IP) or vehicle prior to post-abstinence relapse and reinstatement testing. Vehicle-pretreated animals showed robust cocaine seeking during relapse and reinstatement testing, an effect that was significantly attenuated by aripiprazole pretreatment, although no lasting effects were found in the absence of acute injection. These findings support the possibility that repeated aripiprazole may be an effective therapeutic agent for the prevention of relapse in abstinent cocaine users. Based on its antipsychotic profile, aripiprazole may be particularly useful for individuals diagnosed with comorbid psychoses, such as schizophrenia or bipolar disorder.
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Chan, Chia-Hsiang; Chan, Hung-Yu; Chen, Yen-Ching
2018-05-01
Aripiprazole is a second-generation antipsychotics, acting as a partial dopamine D2 receptor agonist. Previous studies on aripiprazole for tardive dyskinesia (TD) treatment were limited and inconclusive. This study was aimed to examine the effectiveness of aripiprazole in psychotic patients with a pre-existing TD. This was an open-label 24-week prospective cohort study conducted in a public mental hospital in Northern Taiwan from January 2009 to February 2010. Psychotic patients were cross-titrated of prior antipsychotics with aripiprazole, and the severity of TD was assessed at baseline and at weeks 2, 4, 8, 12, 16, 20, and 24. The primary study outcome was the change of TD severity, assessed by Abnormal Involuntary Movement Scale (AIMS) total score. Responder was defined as the reduction of AIMS total scores of no less than 50% from baseline to the study endpoint (24 weeks). Thirty psychotic patients with neuroleptic-induced TD were recruited. The AIMS total scores significantly decreased from baseline to the study endpoint (-7.17±5.55). The significant decrease of AIMS total scores started at week 2 (P<0.0001), and the change remained significant throughout the entire study period (P<0.0001). A greater severity of TD (adjusted odds ratio: 1.35, 95% confidence interval: 1.04-1.76, P=0.03) or a lower severity of parkinsonism (adjusted odds ratio: 0.78, 95% confidence interval: 0.61-0.99, P=0.04) at baseline was significantly associated with treatment responders. Our findings implicated that aripiprazole can be a promising treatment for clinicians considering drug switch in psychotic patients with TD. Further large randomized, controlled trials are warranted to confirm our findings.
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Li, Xianbin; Tang, Yilang; Wang, Chuanyue
2013-01-01
Objective To compare the safety and efficacy of adjunctive aripiprazole versus placebo for antipsychotic-induced hyperprolactinemia. Methods Population: adult patients presenting with antipsychotic-induced hyperprolactinemia diagnosed by prolactin level with or without prolactin-related symptoms. Interventions: adjunctive aripiprazole vs. adjunctive placebo. Outcome measures: adverse events and efficacy of treatment. Studies: randomized controlled trials. Results Five randomized controlled trials with a total of 639 patients (326 adjunctive aripiprazole, 313 adjunctive placebo) met the inclusion criteria. Adjunctive aripiprazole was associated with a 79.11% (125/158) prolactin level normalization rate. Meta-analysis of insomnia, headache, sedation, psychiatric disorder, extrapyramidal symptom, dry mouth, and fatigue showed no significant differences in the adjunctive aripiprazole treatment group compared with the placebo group (risk difference (Mantel-Haenszel, random or fixed) −0.05 to 0.04 (95% confidence interval −0.13 to 0.16); I2 = 0% to 68%, P = 0.20 to 0.70). However, sedation, insomnia, and headache were more frequent when the adjunctive aripiprazole dose was higher than 15 mg/day. Meta-analysis of the prolactin level normalization indicated adjunctive aripiprazole was superior to placebo (risk difference (Mantel-Haenszel, random) 0.76 (95% confidence interval 0.67 to 0.85); I2 = 43%, P<0.00001). The subgroup analysis confirmed that the subjects who received adjunctive aripiprazole 5 mg/day showed a degree of prolactin normalization similar to that of all participants. No significant differences between groups in discontinuation and improvements of psychiatric symptoms. Conclusion Adjunctive aripiprazole is both safe and effective as a reasonable choice treatment for patients with antipsychotic-induced hyperprolactinemia. The appropriate dose of adjunctive aripiprazole may be 5 mg/day. PMID:23936389
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Eum, Seenae; Schneiderhan, Mark E; Brown, Jacob T; Lee, Adam M; Bishop, Jeffrey R
2017-07-03
Given the complex nature of symptom presentation and medication regimens, psychiatric clinics may benefit from additional tools to personalize treatments. Utilizing pharmacogenetic information may be helpful in assessing unique responses to therapy. We report herein a case of wearing-off phenomena during treatment with aripiprazole long-acting injectable (LAI) and a proof of concept strategy of how pharmacogenetic information may be used to assess possible genetic factors and also hypothesize potential mechanisms for further study. A 51-year-old African American male with schizoaffective disorder was referred to a psychiatric clinic for medication management. After unsuccessful trials of multiple antipsychotics, oral aripiprazole was initiated (up to 30 mg/day) and transitioned to aripiprazole LAI with symptom improvement. At a high dose of aripiprazole LAI (400 mg Q3wks), the patient experienced breakthrough symptoms approximately 3 days prior to his next injection. Various considerations were examined to explain his atypical dose requirements, including but not limited to pharmacogenetic influences. Pharmacogenetic testing ruled out genetic influences on drug metabolism but noted a -141C Del variant in the dopamine-D2 receptor (DRD2) gene associated in prior studies of poor-response to antipsychotics. At this time, a new formulation, aripiprazole lauroxil, was explored due to its availability in higher dose options. Transition to the new formulation (882 mg Q4wks) greatly improved and stabilized the patient's symptoms with no breakthrough psychosis. Comparable daily dose equivalents were achieved with two different formulations due to the Q3wks vs Q4wks dosing strategies, although the two agents have some differences in pharmacokinetic profiles. We report a case of a patient experiencing wearing-off symptoms with aripiprazole LAI who benefited from switching to aripiprazole lauroxil. Pharmacogenetic testing revealed normal activity for relevant metabolism pathways but a DRD2 -141C variant that may influence brain D2 expression and antipsychotic responsiveness. The clinical utility of DRD2 information and what to do with genotyping results has not been previously addressed, despite availability on clinical test panels. Our case report suggests further investigations of altered dosing strategies and receptor genotype sensitivities to pharmacokinetic factors may be helpful in understanding symptom re-emergence observed in some patients taking LAI antipsychotics.
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Aripiprazole-Induced Hypoprolactinemia in an Adult Male with First-Episode Psychosis.
Propst, Alanna J; Jarvis, G Eric; Margolese, Howard C
2016-01-01
Aripiprazole is an atypical antipsychotic that acts as a partial agonist at dopamine D2 receptors. Compared to other atypical antipsychotics, aripiprazole has less metabolic side effects and is less likely to increase prolactin. Moreover, it has been shown to have a unique prolactin lowering effect. While aripiprazole has been associated with subnormal prolactin levels in children, no documented cases of hypoprolactinemia in adults exist thus far. Here we report a case of aripiprazole-induced hypoprolactinemia in an adult male with first-episode psychosis, and the possible effects of abnormally low prolactin are discussed.
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Sárvári, Anitta K; Veréb, Zoltán; Uray, Iván P; Fésüs, László; Balajthy, Zoltán
2014-08-08
Schizophrenia requires lifelong treatment, potentially causing systemic changes in metabolic homeostasis. In the clinical setting, antipsychotic treatment may differentially lead to weight gain among individual patients, although the molecular determinants of such adverse effects are currently unknown. In this study, we investigated changes in the expression levels of critical regulatory genes of adipogenesis, lipid metabolism and proinflammatory genes during the differentiation of primary human adipose-derived stem cells (ADSCs). These cells were isolated from patients with body mass indices <25 and treated with the second-generation antipsychotics olanzapine, ziprasidone, clozapine, quetiapine, aripiprazole and risperidone and the first-generation antipsychotic haloperidol. We found that antipsychotics exhibited a marked effect on key genes involved in the regulation of cell cycle, signal transduction, transcription factors, nuclear receptors, differentiation markers and metabolic enzymes. In particular, we observed an induction of the transcription factor NF-KB1 and NF-KB1 target genes in adipocytes in response to these drugs, including the proinflammatory cytokines TNF-α, IL-1β, IL-8 and MCP-1. In addition, enhanced secretion of both IL8 and MCP-1 was observed in the supernatant of these cell cultures. In addition to their remarkable stimulatory effects on proinflammatory gene transcription, three of the most frequently prescribed antipsychotic drugs, clozapine, quetiapine and aripiprazole, also induced the expression of essential adipocyte differentiation genes and the adipocyte hormones leptin and adiponectin, suggesting that both glucose and fat metabolism may be affected by these drugs. These data further suggest that antipsychotic treatments in patients alter the gene expression patterns in adipocytes in a coordinated fashion and priming them for a low-level inflammatory state. Copyright © 2014 Elsevier Inc. All rights reserved.
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Blonanserin Augmentation for Treatment-Resistant Somatic Symptom Disorder: A Case Series.
Nagoshi, Yasuhide; Tominaga, Toshiyuki; Fukui, Kenji
2016-01-01
The augmentation of selective serotonin reuptake inhibitors with antipsychotics that have a high dopamine-receptor-D2 affinity may be effective in treatment-resistant obsessive-compulsive disorder and somatic symptom disorder, which is similar to illness anxiety disorder. Blonanserin, a novel antipsychotic developed in Japan, has a high affinity for the D2 receptor and weak or very little affinity for other receptors. This article presents two case studies that demonstrate the efficacy of blonanserin augmentation for treatment-resistant somatic symptom disorder. Two patients with treatment-resistant somatic symptom disorder were prescribed concomitant use of blonanserin. Augmentation with blonanserin resulted in the remarkable amelioration of all symptoms. Sedative adverse drug reactions produced by aripiprazole were improved after replacing it with blonanserin. Blonanserin is effective in treatment-resistant somatic symptom disorder. Furthermore, compared with aripiprazole, blonanserin is more likely to result in medication adherence in patients with somatic symptom disorder because it reduced adverse drug reactions.
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Newman-Tancredi, Adrian; Assié, Marie-Bernadette; Leduc, Nathalie; Ormière, Anne-Marie; Danty, Nathalie; Cosi, Cristina
2005-09-01
Serotonin 5-HT1A receptors are promising targets in the management of schizophrenia but little information exists about affinity and efficacy of novel antipsychotics at these sites. We addressed this issue by comparing binding affinity at 5-HT1A receptors with dopamine rD2 receptors, which are important targets for antipsychotic drug action. Agonist efficacy at 5-HT1A receptors was determined for G-protein activation and adenylyl cyclase activity. Whereas haloperidol, thioridazine, risperidone and olanzapine did not interact with 5-HT1A receptors, other antipsychotic agents exhibited agonist properties at these sites. E(max) values (% effect induced by 10 microM of 5-HT) for G-protein activation at rat brain 5-HT1A receptors: sarizotan (66.5), bifeprunox (35.9), SSR181507 (25.8), nemonapride (25.7), ziprasidone (20.6), SLV313 (19), aripiprazole (15), tiospirone (8.9). These data were highly correlated with results obtained at recombinant human 5-HT1A receptors in determinations of G-protein activation and inhibition of forskolin-stimulated adenylyl cyclase. In binding-affinity determinations, the antipsychotics exhibited diverse properties at r5-HT1A receptors: sarizotan (pK(i)=8.65), SLV313 (8.64), SSR181507 (8.53), nemonapride (8.35), ziprasidone (8.30), tiospirone (8.22), aripiprazole (7.42), bifeprunox (7.19) and clozapine (6.31). The affinity ratios of the ligands at 5-HT1A vs. D2 receptors also varied widely: ziprasidone, SSR181507 and SLV313 had similar affinities whereas aripiprazole, nemonapride and bifeprunox were more potent at D2 than 5-HT1A receptors. Taken together, these data indicate that aripiprazole has low efficacy and modest affinity at 5-HT1A receptors, whereas bifeprunox has low affinity but high efficacy. In contrast, SSR181507 has intermediate efficacy but high affinity, and is likely to have more prominent 5-HT1A receptor agonist properties. Thus, the contribution of 5-HT1A receptor activation to the pharmacological profile of action of the antipsychotics will depend on the relative 5-HT1A/D2 affinities and on 5-HT1A agonist efficacy of the drugs.
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San, L; Estrada, G; Oudovenko, N; Vieta, E
2017-04-04
The management of acute agitation manifesting in patients with schizophrenia or bipolar disorder requires swift pharmacological intervention to provide rapid symptomatic relief and prevent escalation to aggression and violence. Antipsychotic medications are widely used in this setting and the availability of an inhaled formulation with deep lung absorption of the antipsychotic loxapine has the potential to deliver a faster onset of therapeutic effect than the available intramuscular formulations of antipsychotics. The efficacy of inhaled loxapine and the alternative antipsychotic aripiprazole delivered via intramuscular (IM) injection will be compared in the Phase IIIb PLACID study. Adults (18-65 years) with a confirmed diagnosis of schizophrenia or bipolar I disorder presenting with acute agitation will be randomly assigned to open-label treatment in a 1:1 ratio. Clinical evaluation will be conducted by raters blinded to treatment assignment. The primary efficacy endpoint is time to response (defined as a Clinical Global Impression of Improvement [CGI-I] score of 1 [very much improved] or 2 [much improved]). Secondary endpoints will include the percentage of responders at different time points after dosing; the proportion of patients who receive 1 or 2 doses of study drug; time to second dose; time to rescue medication; satisfaction with study drug (evaluated using Item 14 of the Treatment Satisfaction Questionnaire for Medication); and safety and tolerability. Approximately 360 patients will be recruited with an interim analysis conducted once 180 patients have completed the study to decide whether to stop for futility or continue with or without an increase in the sample size up to additional 288 patients. The PLACID trial will assess the efficacy and safety of inhaled loxapine with deep lung absorption compared with the IM antipsychotic, aripiprazole, in acutely agitated patients with schizophrenia or bipolar disorder. In the event that the median time to response of inhaled loxapine is significantly shorter than that of the intramuscular aripiprazole, the PLACID study has the potential to support the inhaled antipsychotic therapy as the standard of care in this setting. The study protocol was registered with the European Clinical Trials Database on the 31 October 2014 (EudraCT number 2014-000456-29 ).
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M. Badr-Eldin, Shaimaa; A. Ahmed, Tarek; R Ismail, Hatem
2013-01-01
Objective(s): The aim of this work was to investigate the effect of the natural and the chemically modified form of cyclodextrins namely; β-cyclodextrin (β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD) respectively on the solubility and dissolution rate of aripiprazole; an antipsychotic medication showing poor aqueous solubility. Materials and Methods: Phase solubility of aripiprazole with the studied CDs and the complexation efficiency values (CE) which reflect the solubilizing power of the CDs towards the drug was performed. Solid binary systems of aripiprazole with CDs were prepared by kneading, microwave irradiation and freeze-drying techniques at 1:1 and 1:2 (drug to CD) molar ratios. Drug-CD physical mixtures were also prepared in the same molar ratios for comparison. The dissolution of aripiprazole-binary systems was carried out to select the most appropriate CD type, molar ratio and preparation technique. Results: Phase solubility study indicated formation of higher order complexes and the complexation efficiency values was higher for HP-β-CD compared to β-CD. Drug dissolution study revealed that aripiprazole dissolution was increased upon increasing the CD molar ratio and, the freeze-drying technique was superior to the other studied methods especially when combined with the HP-β-CD. The cyclodextrin type, preparation technique and molar ratio exhibited statistically significant effect on the drug dissolution at P≤ 0.05. Conclusion: The freeze-dried system prepared at molar ratio 1:2 (drug: CD) can be considered as efficient tool for enhancing aripiprazole dissolution with the possibility of improving its bioavailability. PMID:24570827
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Sárvári, Anitta K., E-mail: anittasarvari@med.unideb.hu; Veréb, Zoltán, E-mail: jzvereb@gmail.com; Uray, Iván P., E-mail: ipuray@mdanderson.org
Highlights: • Antipsychotics modulate the expression of adipogenic genes in human adipocytes. • Secretion of proinflammatory cytokine IL8 and MCP-1 is induced by antipsychotics. • Adipocyte-dependent inflammatory abnormality could develop during chronic treatment. • Infiltrated macrophages would further enhance proinflammatory cytokine production. - Abstract: Schizophrenia requires lifelong treatment, potentially causing systemic changes in metabolic homeostasis. In the clinical setting, antipsychotic treatment may differentially lead to weight gain among individual patients, although the molecular determinants of such adverse effects are currently unknown. In this study, we investigated changes in the expression levels of critical regulatory genes of adipogenesis, lipid metabolism andmore » proinflammatory genes during the differentiation of primary human adipose-derived stem cells (ADSCs). These cells were isolated from patients with body mass indices <25 and treated with the second-generation antipsychotics olanzapine, ziprasidone, clozapine, quetiapine, aripiprazole and risperidone and the first-generation antipsychotic haloperidol. We found that antipsychotics exhibited a marked effect on key genes involved in the regulation of cell cycle, signal transduction, transcription factors, nuclear receptors, differentiation markers and metabolic enzymes. In particular, we observed an induction of the transcription factor NF-KB1 and NF-KB1 target genes in adipocytes in response to these drugs, including the proinflammatory cytokines TNF-α, IL-1β, IL-8 and MCP-1. In addition, enhanced secretion of both IL8 and MCP-1 was observed in the supernatant of these cell cultures. In addition to their remarkable stimulatory effects on proinflammatory gene transcription, three of the most frequently prescribed antipsychotic drugs, clozapine, quetiapine and aripiprazole, also induced the expression of essential adipocyte differentiation genes and the adipocyte hormones leptin and adiponectin, suggesting that both glucose and fat metabolism may be affected by these drugs. These data further suggest that antipsychotic treatments in patients alter the gene expression patterns in adipocytes in a coordinated fashion and priming them for a low-level inflammatory state.« less
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Parabiaghi, A; Tettamanti, M; D'Avanzo, B; Barbato, A
2016-01-01
To determine whether the prescription of aripiprazole, compared with olanzapine and haloperidol, was associated with a lower frequency of metabolic syndrome (MS) and treatment discontinuation at 1 year. Patients were randomly assigned to be treated open-label and according to usual clinical practice with either aripiprazole, olanzapine, or haloperidol and followed up for 1 year. Three hundred out-patients with persistent schizophrenia were recruited in 35 mental health services. The intention-to-treat (ITT) analysis found no significant differences in the rate of MS between aripiprazole (37%), olanzapine (47%), and haloperidol (42%). Treatment discontinuation for any cause was higher for aripiprazole (52%) than for olanzapine (33%; OR, 0.41; P = 0.004), or haloperidol (37%; OR, 0.51; P = 0.030). No significant difference was found between olanzapine and haloperidol. Time to discontinuation for any cause was longer for olanzapine than for aripiprazole (HR, 0.55; P < 0.001). No significant differences were found between haloperidol and aripiprazole, or between olanzapine and haloperidol. The prescription of aripiprazole did not significantly reduce the rates of MS, but its treatment retention was worse. Aripiprazole cannot be considered the safest and most effective drug for maintenance treatment of schizophrenia in routine care, although it may have a place in antipsychotic therapy. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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Aripiprazole-Related Diurnal Enuresis in Children: 2 Cases (Aripiprazole-Related Enuresis).
Gunes, Serkan
Aripiprazole is an atypical antipsychotic with dopaminergic and serotonergic effects. Enuresis as an adverse effect has been reported with aripiprazole use in children with autism spectrum disorders. Here, we report 2 cases without autism spectrum disorders who developed diurnal enuresis after starting aripiprazole and ceased after discontinuation of the medication.
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Macaluso, Matthew; Flynn, Alexandra; Preskorn, Sheldon
2016-05-01
This series of columns has 3 main goals: (1) to explain class warnings as used by the United States Food and Drug Administration, (2) to increase awareness of movement disorders that may occur in patients treated with antipsychotic medications, and (3) to understand why clinicians should refrain from immediately assuming a diagnosis of tardive dyskinesia/dystonia (TD) in patients who develop abnormal movements during treatment with antipsychotics. The first column in the series presented a patient who developed abnormal movements while being treated with aripiprazole as an augmentation strategy for major depressive disorder and reviewed data concerning the historical background, incidence, prevalence, and risk factors for tardive and spontaneous dyskinesias, the clinical presentations of which closely resemble each other. The second column in the series reviewed the unique mechanism of action of aripiprazole and reviewed preclinical studies and an early-phase human translational study that suggest a low, if not absent, risk of TD with aripiprazole. The third column in this series reviewed the registration trial data for aripiprazole across all of its indications and found a raw incidence of TD ranging from 0.004 (4 out of 987) in long-term studies of the drug as an augmentation strategy for major depressive disorder to 0.0016 (19 out of 11,897) based on all short-term (ie, weeks to <6 mo) and long-term (6 mo to 1 y) studies combined. This fourth column in the series reviews the "real-world" data on aripiprazole and assesses whether these data also support the conclusion that aripiprazole has a low to absent risk of causing TD. The "real-world" data consist of case reports from the medical literature and the United States Food and Drug Administration Adverse Event Reporting System (FAERS). We found 37 cases in the medical literature reporting what was termed TD in association with aripiprazole treatment as well as 27 case reports suggesting improvement in preexisting TD with aripiprazole treatment. On the basis of the case reports from the medical literature, the potential or raw incidence of TD during "real-world" treatment with aripiprazole was 0.0000062 (37 out of the 6 million individuals who had been treated with aripiprazole in the United States as of 2013 according to a report from Otsuka). A query of the FAERS yielded 312 cases of TD in which aripiprazole was the primary suspect. On the basis of the FAERS data and again assuming 6 million individuals exposed to aripiprazole, this yields a raw incidence of 0.000052 (312 out of 6 million) for TD in patients treated with aripiprazole. However, these estimates have limitations because they are based on anecdotal reports and pharmacovigilance data and, thus, the events themselves were not confirmed or verified in a systematic way. Further, the figure of 6 million people exposed to aripiprazole was based on data reported to the authors by the drug's manufacturer and only applies to exposure in the United States. The final column in this 5-part series will discuss the types of prohibitively expensive and logistically difficult studies that would be needed to determine whether a definitive causal relationship between aripiprazole and TD exists.
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Malla, Ashok; Mustafa, Sally; Rho, Aldanie; Abadi, Sherezad; Lepage, Martin; Joober, Ridha
2016-07-01
Aripiprazole has been associated with a low prevalence of metabolic side effects as compared to other second generation antipsychotic (SGA) medications mostly in patients with long standing illness. The purpose of the present study was to assess specifically the effectiveness and safety of aripiprazole as a first choice for antipsychotic therapy for young patients presenting with a previously untreated first episode of a psychotic disorder (FEP). Seventy-three patients presenting with a FEP and with minimal prior exposure to antipsychotic medications were recruited to be part of an open label naturalistic outcome study using aripiprazole as the first choice of antipsychotic medication. Data on positive, negative and total symptom severity including general psychopathological symptoms, level of functioning and metabolic indices were collected prospectively over a one-year period. As compared to baseline, patients treated with aripiprazole (mean dose 9.6mg) improved significantly on measures of positive (p<0.001), negative (p<0.001) and total severity-general psychopathology symptoms (p<0.001) and level of functioning (p<0.001). Seventy two percent of the participants achieved positive symptom remission and 50% achieved total remission (positive and negative) at one year of follow up. Unlike reports on patients with longer standing illness, significant weight gain (p<0.001) was observed, with 44% of participants experiencing >7% increase in body weight. FEP patients starting treatment with aripiprazole improved on symptoms and social and occupational functioning. Aripiprazole was well tolerated except for a significant weight gain. Copyright © 2016 Elsevier B.V. All rights reserved.
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Ganguli, Rohan; Brar, Jaspreet S; Garbut, Ronald; Chang, Chung-Chou H; Basu, Ranita
2011-07-01
For patients who gain a troublesome amount of weight on antipsychotics, switching to a less obesogenic agent is an option. Aripiprazole appears to cause less weight gain than many other antipsychotics. We report on changes in weight, and other risk factors for heart disease, in thirty-three schizophrenia patients who agreed to switch from other antipsychotics to aripiprazole in an open, flexible-dose, eight-week trial. All patients were successfully switched. There were no significant changes in PANSS symptom scores or in CGI. Weight (Wt), waist circumference (WC), and low-density lipoprotein (LDL) decreased significantly in the group as a whole. In patients switched from olanzapine to aripiprazole, Wt, WC, LDL, fasting glucose, and triglycerides were significantly decreased as compared to baseline. Substantial decreases in several risk factors were also seen in patients switched from quetiapine, but these changes did not reach statistical significance.
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2012-01-01
Background Use of atypical antipsychotics (AA) in combination with an antidepressant is recommended as an augmentation strategy for patients with depression. However, there is a paucity of data comparing aripiprazole and other AAs in terms of patient reported outcomes. Therefore, the objective of this study was to examine the levels of HRQoL and health utility scores in patients with depression using aripiprazole compared with patients using olanzapine, quetiapine, risperidone and ziprasidone. Methods Data were obtained from the 2009, 2010, and 2011 National Health and Wellness Survey (NHWS), a cross-sectional, internet-based survey that is representative of the adult US population. Only those patients who reported being diagnosed with depression and taking an antidepressant and an atypical antipsychotic for depression were included. Patients taking an atypical antipsychotic for less than 2 months or who reported being diagnosed with bipolar disorder or schizophrenia were excluded. Patients taking aripiprazole were compared with patients taking other atypical antipsychotics. Health-related quality of life (HRQoL) and health utilities were assessed using the Short Form 12-item (SF-12) health survey. Differences between groups were analyzed using General Linear Models (GLM) controlling for demographic and health characteristics. Results Overall sample size was 426 with 59.9% taking aripiprazole (n = 255) and 40.1% (n = 171) taking another atypical antipsychotic (olanzapine (n = 19), quetiapine (n = 127), risperidone (n = 14) or ziprasidone (n = 11)). Of the SF-12 domains, mean mental component summary (MCS) score (p = .018), bodily pain (p = .047), general health (p = .009) and emotional role limitations (p = .009) were found to be significantly higher in aripiprazole users indicating better HRQoL compared to other atypical antipsychotics. After controlling for demographic and health characteristics, patients taking aripiprazole reported significantly higher mean mental SF-12 component summary (34.10 vs. 31.43, p = .018), bodily pain (55.19 vs. 49.05, p = .047), general health (50.05 vs. 43.07, p = .009), emotional role limitations (49.44 vs. 41.83, p = .009), and SF-6D utility scores (0.59 vs. 0.56, p = .042). Conclusions Comparison of patients taking aripiprazole with a cohort of patients using another AA for depression demonstrated that aripiprazole was independently associated with better (both statistically and clinically) HRQoL and health utilities. PMID:22805425
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Goto, Naoki; Yoshimura, Reiji; Kakeda, Shingo; Moriya, Junji; Hori, Hikaru; Hayashi, Kenji; Ikenouchi-Sugita, Atsuko; Nakano-Umene, Wakako; Katsuki, Asuka; Nishimura, Joji; Korogi, Yukunori; Nakamura, Jun
2010-12-01
We investigated the effects of atypical antipsychotic drugs on GABA concentrations in early-stage, first-episode schizophrenia patients. Sixteen (8 males, 8 females; age, 30±11 years old) patients were followed up for six months. We also included 18 sex- and age-matched healthy control subjects. All patients were treated with atypical antipsychotic drugs (5 patients with risperidone, 5 patients with olanzapine, 4 patients with aripiprazole, and 2 patients with quetiapine). In all three regions measured (frontal lobe, left basal ganglia, and parieto-occipital lobe), no differences in GABA concentrations were observed in a comparison of pre-treatment levels and those six months after treatment. These results suggest that relatively short-term treatment with atypical antipsychotic drugs may not affect GABAergic neurotransmission; however, it is also possible that such treatment prevents further reductions in brain GABA levels in people with early-stage, first-episode schizophrenia. Copyright © 2010 Elsevier Inc. All rights reserved.
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Partial agonist therapy in schizophrenia: relevance to diminished criminal responsibility.
Gavaudan, Gilles; Magalon, David; Cohen, Julien; Lançon, Christophe; Léonetti, Georges; Pélissier-Alicot, Anne-Laure
2010-11-01
Pathological gambling (PG), classified in the DSM-IV among impulse control disorders, is defined as inappropriate, persistent gaming for money with serious personal, family, and social consequences. Offenses are frequently committed to obtain money for gambling. Pathological gambling, a planned and structured behavioral disorder, has often been described as a complication of dopamine agonist treatment in patients with Parkinson's disease. It has never been described in patients with schizophrenia receiving dopamine agonists. We present two patients with schizophrenia, previously treated with antipsychotic drugs without any suggestion of PG, who a short time after starting aripiprazole, a dopamine partial agonist, developed PG and criminal behavior, which totally resolved when aripiprazole was discontinued. Based on recent advances in research on PG and adverse drug reactions to dopamine agonists in Parkinson's disease, we postulate a link between aripiprazole and PG in both our patients with schizophrenia and raise the question of criminal responsibility. © 2010 American Academy of Forensic Sciences.
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Nasrallah, Henry A; Newcomer, John W; Risinger, Robert; Du, Yangchun; Zummo, Jacqueline; Bose, Anjana; Stankovic, Srdjan; Silverman, Bernard L; Ehrich, Elliot W
2016-11-01
Aripiprazole lauroxil, a long-acting injectable antipsychotic, demonstrated safety and efficacy in treating symptoms of schizophrenia in a double-blind, placebo-controlled trial. Because the metabolic profile of antipsychotics is an important safety feature, the effects of aripiprazole lauroxil on body weight, endocrine and metabolic profiles, and safety were examined in a secondary analysis. Patients with schizophrenia (DSM-IV-TR criteria) were randomly assigned to aripiprazole lauroxil 441 mg, aripiprazole lauroxil 882 mg, or placebo intramuscularly once monthly between December 2011 and March 2014. Changes in body weight, body mass index, fasting blood glucose and serum lipids, glycosylated hemoglobin (HbA1c), and prolactin over 12 weeks were assessed. The incidence of treatment-emergent adverse events (AEs) was evaluated. Among 622 randomized patients, no clinically relevant changes from baseline to week 12 were observed for any serum lipid, lipoprotein, plasma glucose, or HbA1c value with placebo or either dose of aripiprazole lauroxil. Both doses of aripiprazole lauroxil were associated with reductions in mean prolactin levels, whereas placebo treatment was not. The mean (standard deviation) change from baseline for body weight was 0.74 (3.9) kg, 0.86 (3.7) kg, and 0.01 (3.6) kg for aripiprazole lauroxil 441 mg, aripiprazole lauroxil 882 mg, and placebo groups, respectively. AEs related to metabolic parameters were reported in 2.4%, 1.4%, and 2.4% of patients in the aripiprazole lauroxil 441 mg, aripiprazole lauroxil 882 mg, and placebo groups, respectively. Aripiprazole lauroxil was well tolerated, with a low-risk metabolic profile relative to published data for other antipsychotics. Changes similar to those observed with placebo were observed in the aripiprazole lauroxil groups for metabolic parameters, with modest weight gain in the active treatment groups over the 12-week course. ClinicalTrials.gov identifier: NCT01469039. © Copyright 2016 Physicians Postgraduate Press, Inc.
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Pan, Bo; Huang, Xu-Feng; Deng, Chao
2016-03-28
Aripiprazole, a dopamine D₂ receptor (D₂R) partial agonist, possesses a unique clinical profile. Glycogen synthase kinase 3β (GSK3β)-dependent signalling pathways have been implicated in the pathophysiology of schizophrenia and antipsychotic drug actions. The present study examined whether aripiprazole differentially affects the GSK3β-dependent signalling pathways in the prefrontal cortex (PFC), nucleus accumbens (NAc), and caudate putamen (CPu), in comparison with haloperidol (a D₂R antagonist) and bifeprunox (a D₂R partial agonist). Rats were orally administrated aripiprazole (0.75 mg/kg), bifeprunox (0.8 mg/kg), haloperidol (0.1 mg/kg) or vehicle three times per day for one week. The levels of protein kinase B (Akt), p-Akt, GSK3β, p-GSK3β, dishevelled (Dvl)-3, and β-catenin were measured by Western Blots. Aripiprazole increased GSK3β phosphorylation in the PFC and NAc, respectively, while haloperidol elevated it in the NAc only. However, Akt activity was not changed by any of these drugs. Additionally, both aripiprazole and haloperidol, but not bifeprunox, increased the expression of Dvl-3 and β-catenin in the NAc. The present study suggests that activation of GSK3β phosphorylation in the PFC and NAc may be involved in the clinical profile of aripiprazole; additionally, aripiprazole can increase GSK3β phosphorylation via the Dvl-GSK3β-β-catenin signalling pathway in the NAc, probably due to its relatively low intrinsic activity at D₂Rs.
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Stapel, Britta; Kotsiari, Alexandra; Scherr, Michaela; Hilfiker-Kleiner, Denise; Bleich, Stefan; Frieling, Helge; Kahl, Kai G
2017-05-01
The use of antipsychotics carries the risk of metabolic side effects, such as weight gain and new onset type-2 diabetes mellitus. The mechanisms of the observed metabolic alterations are not fully understood. We compared the effects of two atypical antipsychotics, one known to favor weight gain (olanzapine), the other not (aripiprazole), on glucose metabolism. Primary human peripheral blood mononuclear cells (PBMC) were isolated and stimulated with olanzapine or aripiprazole for 72 h. Cellular glucose uptake was analyzed in vitro by 18F-FDG uptake. Further measurements comprised mRNA expression of glucose transporter (GLUT) 1 and 3, GLUT1 protein expression, DNA methylation of GLUT1 promoter region, and proteins involved in downstream glucometabolic processes. We observed a 2-fold increase in glucose uptake after stimulation with aripiprazole. In contrast, olanzapine stimulation decreased glucose uptake by 40%, accompanied by downregulation of the cellular energy sensor AMP activated protein kinase (AMPK). GLUT1 protein expression increased, GLUT1 mRNA expression decreased, and GLUT1 promoter was hypermethylated with both antipsychotics. Pyruvat-dehydrogenase (PDH) complex activity decreased with olanzapine only. Our findings suggest that the atypical antipsychotics olanzapine and aripiprazole differentially affect energy metabolism in PBMC. The observed decrease in glucose uptake in olanzapine stimulated PBMC, accompanied by decreased PDH point to a worsening in cellular energy metabolism not compensated by AMKP upregulation. In contrast, aripiprazole stimulation lead to increased glucose uptake, while not affecting PDH complex expression. The observed differences may be involved in the different metabolic profiles observed in aripiprazole and olanzapine treated patients. Copyright © 2016 Elsevier Ltd. All rights reserved.
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Deiana, Serena; Watanabe, Akihito; Yamasaki, Yuki; Amada, Naoki; Kikuchi, Tetsuro; Stott, Colin; Riedel, Gernot
2015-12-01
Deficiencies in social activities are hallmarks of numerous brain disorders. With respect to schizophrenia, social withdrawal belongs to the category of negative symptoms and is associated with deficits in the cognitive domain. Here, we used the N-methyl-D-aspartate receptor antagonist dizocilpine (MK-801) for induction of social withdrawal in rats and assessed the efficacy of several atypical antipsychotics with different pharmacological profiles as putative treatment. In addition, we reasoned that the marijuana constituent cannabidiol (CBD) may provide benefit or could be proposed as an adjunct treatment in combination with antipsychotics. Hooded Lister rats were tested in the three-chamber version for social interaction, with an initial novelty phase, followed after 3 min by a short-term recognition memory phase. No drug treatment affected sociability. However, distinct effects on social recognition were revealed. MK-801 reduced social recognition memory at all doses (>0.03 mg/kg). Predosing with aripiprazole dose-dependently (2 or 10 mg/kg) prevented the memory decline, but doses of 0.1 mg/kg risperidone or 1 mg/kg olanzapine did not. Intriguingly, CBD impaired social recognition memory (12 and 30 mg/kg) but did not rescue the MK-801-induced deficits. When CBD was combined with protective doses of aripiprazole (CBD-aripiprazole at 12 : or 5 : 2 mg/kg) the benefit of the antipsychotic was lost. At the same time, activity-related changes in behaviour were excluded as underlying reasons for these pharmacological effects. Collectively, the combined activity of aripiprazole on dopamine D2 and serotonin 5HT1A receptors appears to provide a significant advantage over risperidone and olanzapine with respect to the rescue of cognitive deficits reminiscent of schizophrenia. The differential pharmacological properties of CBD, which are seemingly beneficial in human patients, did not back-translate and rescue the MK-801-induced social memory deficit.
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Hwang, Tzung-Jeng; Lo, Wei-Ming; Chan, Hung-Yu; Lin, Ching-Feng; Hsieh, Ming H; Liu, Chen-Chun; Liu, Chih-Min; Hwu, Hai-Gwo; Kuo, Ching-Hua; Chen, Wei J
2015-12-01
This study aimed to compare strategies differing in the speed of switching schizophrenic patients to aripiprazole from other antipsychotic agents, with dual administration for 2 weeks and then tapering off the current antipsychotic in fast (within 1 week) versus slow (within 4 weeks) strategies. This 8-week, open-label, randomized, parallel study assigned patients with a primary Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of schizophrenia or schizoaffective disorder to either the fast-switching (n = 38) or slow-switching (n = 41) group. Efficacy assessments at 5 time points included Positive and Negative Syndrome Scale and Clinical Global Impression scale. Safety assessments included extrapyramidal symptoms, metabolic profile, serum prolactin level, QTc interval, and adverse events. Drug concentrations and cytochrome P450 CYP2D6 and CYP3A4 genotypes were also measured. The fast- and slow-switching groups were comparable in demographical and clinical features at baseline and dropout rate. In the intention-to-treat analysis using mixed-effects models, there were significant within-group decreases over time in the Positive and Negative Syndrome Scale total scores (P = 0.03) and its subscores except for positive subscores, whereas no between-group differences were found. A reduction in body weight (P = 0.01) and lower levels of total cholesterol (P = 0.03), triglycerides (P = 0.03), and prolactin (P = 0.01) were noted in both groups but no increase in extrapyramidal symptoms or prolongation of QTc. The blood concentrations of aripiprazole in all patients were in a therapeutic range at day 56, with CYP2D6*10 polymorphisms being associated with aripiprazole concentrations. In conclusion, there is no significant difference between the fast- and slow-switching strategy in terms of improvements in clinical symptoms and metabolic profile in this 8-week study.
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Heusler, Peter; Newman-Tancredi, Adrian; Loock, Timothé; Cussac, Didier
2008-02-26
Antipsychotic drugs act preferentially via dopamine D(2) receptor blockade, but interaction with serotonin 5-HT(1A) receptors has attracted interest as additional target for antipsychotic treatment. As receptor internalisation is considered crucial for drug action, we tested the propensity of antipsychotics to internalise human (h)D(2S) receptors and h5-HT(1A) receptors. Agonist-induced internalisation of hemaglutinin (HA)-tagged hD(2S) and HA-h5-HT(1A) receptors expressed in HEK293 cells was increased by coexpression of G-protein coupled receptor kinase 2 and beta-arrestin2. At the HA-hD(2S) receptor, dopamine, quinpirole and bromocriptine behaved as full agonists, while S(-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine [(-)-3PPP] and sarizotan were partial agonists. The typical antipsychotic, haloperidol, and the atypical compounds, olanzapine, nemonapride, ziprasidone and clozapine did not internalise HA-hD(2S) receptors, whereas aripiprazole potently internalised these receptors (>50% relative efficacy). Among antipsychotics with combined D(2)/5-HT(1A) properties, bifeprunox and (3-exo)-8-benzoyl-N-[[(2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl]methyl]-8-azabicyclo-[3.2.1]octane-3-methanamine (SSR181507) partially internalised HA-hD(2S) receptors, piperazine, 1-(2,3-dihydro-1,4-benzodioxin-5-yl)-4-[[5-(4-fluorophenyl)-3-pyridinyl]methyl (SLV313) and N-[(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)ethyl]-3-(cyclopent-1-enyl)-benzylamine (F15063) were inactive. At the HA-h5-HT(1A) receptor, serotonin, (+)-8-hydroxy-2-(di-n-propylamino)tetralin [(+)-8-OH-DPAT] and sarizotan were full agonists, buspirone acted as partial agonist. (-)-Pindolol showed little activity and no internalising properties were manifested for the 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide (WAY100635). Most antipsychotics induced HA-h5-HT(1A) receptor internalisation, with an efficacy rank order: nemonapride>F15063>SSR181507>bifeprunox approximately SLV313 approximately ziprasidone>aripiprazole and potencies: SLV313>SSR181507 approximately F15063>bifeprunox approximately nemonapride approximately aripiprazole>ziprasidone. Interestingly, the internalisation induced by clozapine was only minimal, whereas aripirazole and bifeprunox were more potent for internalisation than for G-protein activation. These different profiles of antipsychotics for receptor internalisation may help to evaluate their potential therapeutic impact in the treatment of schizophrenia.
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Trends in Scientific Literature on Atypical Antipsychotics in South Korea: A Bibliometric Study
Shen, Winston W.; Pae, Chi-Un; Moreno, Raquel; Rubio, Gabriel; Molina, Juan D.; Noriega, Concha; Pérez-Nieto, Miguel A.; Huelves, Lorena; Álamo, Cecilio
2013-01-01
Objective We have carried out a bibliometric study on the scientific publications in relation to atypical or second-generation antipsychotic drugs (SGAs) in South Korea. Methods With the EMBASE and MEDLINE databases, we selected those publications made in South Korea whose title included the descriptors atypic* (atypical*) antipsychotic*, second-generation antipsychotic*, clozapine, risperidone, olanzapine, ziprasidone, quetiapine, sertindole, aripiprazole, paliperidone, amisulpride, zotepine, asenapine, iloperidone, lurasidone, perospirone and blonanserin. We applied some bibliometric indicators of paper production and dispersion with Price's law and Bradford's law, respectively. We also calculated the participation index (PI) of the different countries, and correlated the bibliometric data with some social and health data from Korea (such as total per capita expenditure on health and gross domestic expenditure on research and development). Results We collected 326 original papers published between 1993 and 2011. Our results state fulfilment of fulfilled Price's law, with scientific production on SGAs showing exponential growth (correlation coefficient r=0.8978, as against an r=0.8149 after linear adjustment). The most widely studied drugs were risperidone (91 papers), aripiprazole (77), olanzapine (53), and clozapine (43). Division into Bradford zones yielded a nucleus occupied by the Progress in Neuro-Psychopharmacology and Biological Psychiatry (36 articles). A total of 86 different journals were published, with 4 of the first 10 used journals having an impact factor being greater than 4. Conclusion The publications on SGAs in South Korea have undergone exponential growth over the studied period, without evidence of reaching a saturation point. PMID:23482954
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Roffeei, Siti Norsyuhada; Reynolds, Gavin P; Zainal, Nor Zuraida; Said, Mas Ayu; Hatim, Ahmad; Aida, Syarinaz Ahmad; Mohamed, Zahurin
2014-01-01
Various genetic polymorphisms have been reported to be associated with antipsychotic-induced weight gain. In this study, we aimed to determine whether risk polymorphisms in 12 candidate genes are associated with reduction in body mass index (BMI) of patients following switching of antipsychotics to aripiprazole or ziprasidone. We recruited 115 schizophrenia patients with metabolic abnormalities and who have been on at least 1 year treatment with other antipsychotics; they were then switched to either aripiprazole or ziprasidone. They were genotyped, and their BMI monitored for 6 months. Significant associations with reduction in BMI at 6 months following switching were found in two of these genes: with rs1800544 of the ADRA2A gene (CC + CG [-0.32 ± 1.41 kg/m²] vs GG [-1.04 ± 1.63 kg/m²], p = 0.013) and with rs1801131 of the MTHFR gene (AA [-0.36 ± 1.53] vs AC + CC [-1.07 ± 1.53], p = 0.015). The study data indicated that carriage of the ADRA2A rs1800544 GG genotype and the MTHFR rs1801131 C allele are associated with BMI reduction in this population following switching of antipsychotics to aripiprazole and ziprasidone. Copyright © 2013 John Wiley & Sons, Ltd.
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Macaluso, Matthew; Flynn, Alexandra; Preskorn, Sheldon
2016-01-01
This series of columns has 3 main goals: (1) to explain class warnings as used by the United States Food and Drug Administration, (2) to increase awareness of movement disorders that may occur in patients treated with antipsychotic medications, and (3) to understand why clinicians should refrain from immediately assuming a diagnosis of tardive dyskinesia/dystonia (TD) in patients treated with antipsychotics. The first column in this series began with the case of a 76-year-old man with major depressive disorder who developed orofacial dyskinesias while being treated with aripiprazole as an antidepressant augmentation strategy. It was alleged that a higher than intended dose of aripiprazole (ie, 20 mg/d for 2 wk followed by 10 mg/d for 4 wk instead of the intended dose of 2 mg/d) was the cause of the dyskinetic movements in this man, and the authors were asked to review the case and give their opinion. The principal basis for this theory of causation was the class warning about TD in the package insert for aripiprazole. The rationale for concluding aripiprazole caused TD in the 76-year-old man led to this series of columns about aripiprazole, its potential--if any--to cause TD, and the presence of a class warning about TD in its package insert. The central point is to illustrate why class warnings exist and their implications for practice. The first column in this series focused on the historical background, incidence, prevalence, risk factors, and clinical presentations of tardive and spontaneous dyskinesias and concluded with a discussion of diagnostic considerations explaining why clinicians should avoid making a diagnosis of TD until a thorough differential diagnosis has been considered. This second column in the series reviews the pharmacology of aripiprazole and the preclinical and phase I translational human studies that suggest aripiprazole should have a low to nonexistent risk of causing TD compared with other antipsychotics. The third column in the series will review the systematic clinical trial data and "real-world" data on TD and the use of aripiprazole as adjunctive treatment with antidepressants for major depressive disorder to see whether these data support the conclusion of a low to nonexistent relationship between aripiprazole treatment and the development of TD. The fourth and final column in the series will consider the type of study that would need to be performed to avoid a specific class warning, focusing on the TD class warning as an example and discussing why such studies are rarely done.
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Pan, Bo; Huang, Xu-Feng; Deng, Chao
2016-01-01
Aripiprazole, a dopamine D2 receptor (D2R) partial agonist, possesses a unique clinical profile. Glycogen synthase kinase 3β (GSK3β)-dependent signalling pathways have been implicated in the pathophysiology of schizophrenia and antipsychotic drug actions. The present study examined whether aripiprazole differentially affects the GSK3β-dependent signalling pathways in the prefrontal cortex (PFC), nucleus accumbens (NAc), and caudate putamen (CPu), in comparison with haloperidol (a D2R antagonist) and bifeprunox (a D2R partial agonist). Rats were orally administrated aripiprazole (0.75 mg/kg), bifeprunox (0.8 mg/kg), haloperidol (0.1 mg/kg) or vehicle three times per day for one week. The levels of protein kinase B (Akt), p-Akt, GSK3β, p-GSK3β, dishevelled (Dvl)-3, and β-catenin were measured by Western Blots. Aripiprazole increased GSK3β phosphorylation in the PFC and NAc, respectively, while haloperidol elevated it in the NAc only. However, Akt activity was not changed by any of these drugs. Additionally, both aripiprazole and haloperidol, but not bifeprunox, increased the expression of Dvl-3 and β-catenin in the NAc. The present study suggests that activation of GSK3β phosphorylation in the PFC and NAc may be involved in the clinical profile of aripiprazole; additionally, aripiprazole can increase GSK3β phosphorylation via the Dvl-GSK3β-β-catenin signalling pathway in the NAc, probably due to its relatively low intrinsic activity at D2Rs. PMID:27043526
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Miura, Itaru; Kunii, Yasuto; Hino, Mizuki; Hoshino, Hiroshi; Matsumoto, Junya; Kanno-Nozaki, Keiko; Horikoshi, Sho; Kaneko, Haruka; Bundo, Miki; Iwamoto, Kazuya; Yabe, Hirooki
2018-05-01
Epigenetic modification including DNA methylation may affect pathophysiology and the response to antipsychotic drugs in patients with schizophrenia. The objective of the present study was to investigate the effect of the DNA methylation of ANKK1 (ankyrin repeat and kinase domain containing 1) on the response to aripiprazole and plasma levels of monoamine metabolites in antipsychotic-free acute schizophrenia patients. The subjects were 34 Japanese patients with schizophrenia who had been treated with aripiprazole for 6 weeks. Comprehensive DNA methylation of ANKK1 was determined using a next-generation sequencer. DNA methylation levels at CpG site 387 of ANKK1 were higher in responders to treatment with aripiprazole and correlated with the changes in Positive and Negative Syndrome Scale scores, although the associations did not remain significant after Bonferroni correction. In responders, methylation at all CpG sites was significantly correlated with plasma levels of homovanillic acid (r = 0.587, p = 0.035) and 3-methoxy-4hydroxyphenylglycol (r = 0.684, p = 0.010) at baseline. Despite our non-significant results after multiple correction, our preliminary findings suggest that methylation levels at CpG site 387 of ANKK1 may be associated with treatment response to aripiprazole. Furthermore, methylation of ANKK1 may affect dopaminergic neural transmission in the treatment of schizophrenia, and may influence treatment response. Caution is needed in interpreting these findings because of the small sample size, and further studies are needed to confirm and expand our preliminary results. Copyright © 2018. Published by Elsevier Ltd.
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[Aripiprazole, gambling disorder and compulsive sexuality].
Mété, D; Dafreville, C; Paitel, V; Wind, P
2016-06-01
Aripiprazole, an atypical or second-generation antipsychotic, is usually well tolerated. It is an approved treatment for schizophrenia and mania in bipolar disorder type 1. Unlike the other antipsychotics, it has high affinity agonist properties for dopamine D2 and D3 receptors. It has also 5-HT1A partial agonist and 5-HT2A antagonist properties. Aripiprazole is a first or second line treatment frequently used because it has reduced side effects such as weight gain, sleepiness, dyslipidemia, insulin resistance, hyperprolactinemia and extrapyramidal symptoms. We report the case of a 28-year-old male patient diagnosed with schizoid personality disorder. He was a moderate smoker with occasional social gambling habits. After several psychotic episodes, he was first treated with risperidone, but he experienced excessive sedation, decreased libido, erectile dysfunction and was switched to 15 mg aripiprazole. He developed an addiction habit for gambling at casino slot machines. Due to large gambling debts, he requested placement on a voluntary self-exclusion list. Thereafter, he turned his attention towards scratch card gambling. The patient described his experience of gambling as a "hypnotic state". He got several personal loans to obtain money to continue gambling. He was then referred to an addiction unit. Before being treated with aripiprazole, he was an exclusive heterosexual with a poor sexual activity. Under treatment, he switched to a homosexual behavior with hypersexuality, unprotected sex and sadomasochistic practices. The craving for gambling and compulsive sexual behavior ceased two weeks after aripiprazole was discontinued and he was switched to amisulpride. Thereafter, he reported a return to a heterosexual orientation. Compulsive behaviors such as gambling, hypersexuality and new sexual orientation are common in patients with Parkinson's disease treated with dopaminergic agonists. These behaviors involve the reward system, with an enhanced dopaminergic activity in the mesolimbic pathways and occur more frequently in young subjects, males with previous gambling habits and tobacco use. A few cases of aripiprazole-induced pathological gambling as well as aripiprazole-induced hypersexuality have been reported. To our knowledge, we are the first to report a case of gambling disorder associated with hypersexuality and change of sexuality orientation. Aripiprazole is the only antipsychotic with agonist properties for the D2 dopamine receptor. It may also act as an enhancer in the mesolimbic dopaminergic pathways. Aripiprazole also has 5-HT1A partial agonist and 5-HT2A antagonist properties that may promote sexual activity. Aripiprazole is an antipsychotic associated with reduced side effects compared to other antipsychotics. We report the case of a patient who experienced gambling disorder, hypersexuality and a new sexual orientation under treatment. These side effects are little known. They are usually difficult for patients to mention due to feelings of guilt. The consequences on social life, family and health may be serious. Clinicians and patients should be aware about the possible issue of these behavior disorders with aripiprazole. Copyright © 2016 L'Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.
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Antipsychotic-Induced Dopamine Supersensitivity Psychosis: Pharmacology, Criteria, and Therapy.
Chouinard, Guy; Samaha, Anne-Noël; Chouinard, Virginie-Anne; Peretti, Charles-Siegfried; Kanahara, Nobuhisa; Takase, Masayuki; Iyo, Masaomi
2017-01-01
The first-line treatment for psychotic disorders remains antipsychotic drugs with receptor antagonist properties at D2-like dopamine receptors. However, long-term administration of antipsychotics can upregulate D2 receptors and produce receptor supersensitivity manifested by behavioral supersensitivity to dopamine stimulation in animals, and movement disorders and supersensitivity psychosis (SP) in patients. Antipsychotic-induced SP was first described as the emergence of psychotic symptoms with tardive dyskinesia (TD) and a fall in prolactin levels following drug discontinuation. In the era of first-generation antipsychotics, 4 clinical features characterized drug-induced SP: rapid relapse after drug discontinuation/dose reduction/switch of antipsychotics, tolerance to previously observed therapeutic effects, co-occurring TD, and psychotic exacerbation by life stressors. We review 3 recent studies on the prevalence rates of SP, and the link to treatment resistance and psychotic relapse in the era of second-generation antipsychotics (risperidone, paliperidone, perospirone, and long-acting injectable risperidone, olanzapine, quetiapine, and aripiprazole). These studies show that the prevalence rates of SP remain high in schizophrenia (30%) and higher (70%) in treatment-resistant schizophrenia. We then present neurobehavioral findings on antipsychotic-induced supersensitivity to dopamine from animal studies. Next, we propose criteria for SP, which describe psychotic symptoms and co-occurring movement disorders more precisely. Detection of mild/borderline drug-induced movement disorders permits early recognition of overblockade of D2 receptors, responsible for SP and TD. Finally, we describe 3 antipsychotic withdrawal syndromes, similar to those seen with other CNS drugs, and we propose approaches to treat, potentially prevent, or temporarily manage SP. © 2017 S. Karger AG, Basel.
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Pan, Bo; Huang, Xu-Feng; Deng, Chao
2016-07-20
Aripiprazole is a D2-like receptor (D2R) partial agonist with a favourable clinical profile. Previous investigations indicated that acute and short-term administration of aripiprazole had effects on PKA activity, GSK3β-dependent pathways, GABAA receptors, NMDA receptor and CREB1 in the brain. Since antipsychotics are used chronically in clinics, the present study investigated the long-term effects of chronic oral aripiprazole treatment on these cellular signalling pathways, in comparison with haloperidol (a D2R antagonist) and bifeprunox (a potent D2R partial agonist). We found that the Akt-GSK3β pathway was activated by aripiprazole and bifeprunox in the prefrontal cortex; NMDA NR2A levels were reduced by aripiprazole and haloperidol. In the nucleus accumbens, all three drugs increased Akt-GSK3β signalling; in addition, both aripiprazole and haloperidol, but not bifeprunox, increased the expression of Dvl-3, β-catenin and GABAA receptors, NMDA receptor subunits, as well as CREB1 phosphorylation levels. The results suggest that chronic oral administration of aripiprazole affects schizophrenia-related cellular signalling pathways and markers (including Akt-GSK3β signalling, Dvl-GSK3β-β-catenin signalling, GABAA receptor, NMDA receptor and CREB1) in a brain-region-dependent manner; the selective effects of aripiprazole on these signalling pathways might be associated with its unique clinical effects.
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Summary of the comparative effectiveness review on off-label use of atypical antipsychotics.
Maher, Alicia R; Theodore, George
2012-06-01
Conventional and atypical antipsychotic medications are approved by the FDA for treatment of schizophrenia and bipolar disorder. Over many decades, the widespread use of conventional antipsychotics produced various side effects requiring additional medications, such as the atypical antipsychotics. Beginning in 2006, 9 atypical antipsychotic drugs have been approved by the FDA for indications that were previously off-label uses: aripiprazole (as augmentation for major depressive disorder [MDD] and for autism spectrum disorders), asenapine, clozapine, iloperidone, olanzapine (in combination with fluoxetine for MDD and bipolar depression), paliperidone, quetiapine (quetiapine and quetiapine XR [extended release] as monotherapy in bipolar depression and quetiapine XR as augmentation for MDD), risperidone (for autism spectrum disorders), and ziprasidone. In 2006, the Agency for Healthcare Research and Quality (AHRQ) published a systematic review on the comparative effectiveness of off-label uses of atypical antipsychotics. Since that time, numerous studies have been published evaluating these therapies in various new off-label uses; new or increased adverse effects have been observed with off-label uses; new atypical antipsychotics have been approved; and previously off-label uses have been approved for some atypical antipsychotics. Hence, AHRQ published an updated review in September 2011 that summarized the benefits and harms of atypical antipsychotics in the treatment of attention-deficit hyperactivity disorder/attention deficit disorder (ADHD), anxiety, behavioral disturbances of dementia and severe geriatric agitation, depression, eating disorders, insomnia, obsessive-compulsive disorder (OCD), personality disorder, post-traumatic stress disorder (PTSD), substance use and dependence disorders, and Tourette's syndrome. The new report also investigated topics for which data in the previous report were found to be insufficient to make conclusions, including subpopulations (i.e., race/ethnicity, gender) that would benefit most from atypical antipsychotics, appropriate dose, and time needed to see clinical improvement. The 2011 review included the following atypical antipsychotics: aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone; no clinical trials were found for off-label use of the 3 most recently FDA-approved atypical antipsychotics (asenapine, iloperidone, and paliperidone). To (a) familiarize health care professionals with the methods and findings from AHRQ's 2011 Comparative Effectiveness Review (CER) of off-label use of atypical antipsychotics, (b) encourage consideration of the clinical and managed care applications of the review findings, and (c) identify limitations and gaps in the existing research with respect to the benefits and risks of off-label use of atypical antipsychotics. Antipsychotic medications are FDA approved for the treatment of schizophrenia and bipolar disorder. Conventional antipsychotics have been widely used for decades and spurred the development of the atypical antipsychotics. Atypical antipsychotics were produced and are now being used for patients who may have experienced various side effects while using conventional antipsychotics.In 2006, an AHRQ study reviewed off-label uses of atypical antipsychotics (excluding clozapine because of its association with potentially fatal bone marrow suppression and the requirement for frequent blood tests for safety monitoring). Findings indicated that the most common off-label uses of these drugs included depression, OCD, PTSD, personality disorders, Tourette's syndrome, autism, and agitation in dementia. The reviewers concluded in 2006 that overall there was not sufficiently high strength of evidence of efficacy for any off-label use of atypical antipsychotics. There was, however, strong evidence for an increased risk of adverse events with off-label use, including significant weight gain and sedation and increased mortality among the elderly.Since the 2006 review, significant developments occurred in the use of atypical antipsychotics, including FDA approval of the atypical antipsychotics asenapine, iloperidone, and paliperidone and FDA approval of previous off-label uses: (a) quetiapine and quetiapine XR as monotherapy in bipolar depression; (b) quetiapine XR as augmentation therapy for MDD; (c) aripiprazole as augmentation therapy for MDD; (d) olanzapine/fluoxetine combination for MDD; (e) olanzapine/fluoxetine combination for bipolar depression; and (f) risperidone and aripiprazole for autism spectrum disorders. Additional studies have been published for new off-label uses, and there have been reports of new or increased adverse effects for off-label uses.Further review of previously insufficient information was warranted on subpopulations where treatment modification such as dosing may increase efficacy. The 2006 review did not have sufficient information to make conclusions regarding subpopulations (i.e., race/ethnicity, gender) that would benefit most from atypical antipsychotics, appropriate dosing, and the duration of treatment needed to see clinical improvement. The updated AHRQ report in 2011 reviewed off-label uses of atypical antipsychotic medications in anxiety, ADHD, behavioral disturbances of dementia and severe geriatric agitation, MDD, eating disorders, insomnia, OCD, PTSD, personality disorders, substance abuse, and Tourette's syndrome; autism was included in the 2006 review but is now reviewed in a separate report of the comparative effectiveness of antipsychotics for on-label uses. The significant findings in the updated review include (a) small but statistically significant benefits for olanzapine, aripiprazole, and risperidone for elderly patients with dementia; (b) quetiapine appears superior to placebo for general anxiety disorder (GAD); (c) risperidone was associated with benefits in the treatment of OCD; and (d) adverse events are common. Atypical antipsychotics were not effective in the treatment of eating disorders or personality disorder. The evidence did not support the use of atypical antipsychotics in the treatment of substance abuse, and data were inconclusive for the use of these medications for insomnia. The number needed to harm (NNH) was calculated for adverse events in elderly patients, including risk of death (NNH = 87), stroke (NNH = 53 for risperidone), extrapyramidal symptoms (NNH = 10 for olanzapine and NNH = 20 for risperidone), and urinary symptoms (NNH = 16 to 36). Adverse events in nonelderly adults included weight gain (particularly with olanzapine), fatigue, sedation, akathisia (with aripiprazole), and extrapyramidal symptoms.
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Goozee, Rhianna; O'Daly, Owen; Handley, Rowena; Reis Marques, Tiago; Taylor, Heather; McQueen, Grant; Hubbard, Kathryn; Pariante, Carmine; Mondelli, Valeria; Reinders, Antje A T S; Dazzan, Paola
2017-04-01
The dopaminergic system plays a key role in motor function and motor abnormalities have been shown to be a specific feature of psychosis. Due to their dopaminergic action, antipsychotic drugs may be expected to modulate motor function, but the precise effects of these drugs on motor function remain unclear. We carried out a within-subject, double-blind, randomized study of the effects of aripiprazole, haloperidol and placebo on motor function in 20 healthy men. For each condition, motor performance on an auditory-paced task was investigated. We entered maps of neural activation into a random effects general linear regression model to investigate motor function main effects. Whole-brain imaging revealed a significant treatment effect in a distributed network encompassing posterior orbitofrontal/anterior insula cortices, and the inferior temporal and postcentral gyri. Post-hoc comparison of treatments showed neural activation after aripiprazole did not differ significantly from placebo in either voxel-wise or region of interest analyses, with the results above driven primarily by haloperidol. We also observed a simple main effect of haloperidol compared with placebo, with increased task-related recruitment of posterior cingulate and precentral gyri. Furthermore, region of interest analyses revealed greater activation following haloperidol compared with placebo in the precentral and post-central gyri, and the putamen. These diverse modifications in cortical motor activation may relate to the different pharmacological profiles of haloperidol and aripiprazole, although the specific mechanisms underlying these differences remain unclear. Evaluating healthy individuals can allow investigation of the effects of different antipsychotics on cortical activation, independently of either disease-related pathology or previous treatment. Hum Brain Mapp 38:1833-1845, 2017. © 2017 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.
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Chan, Hung-Yu; Pan, Yi-Ju; Chen, Jiahn-Jyh; Chen, Chiung-Hsu
2017-02-01
A retrospective study was conducted to evaluate the time to discontinuation (TTD) of the first- (FGAs) and second-generation antipsychotics (SGAs). In total, 918 treatment episodes of patients with schizophrenia, initiated on one of the investigated drugs on an outpatient basis during 2004-2006, were entered into the study. The primary outcome was the duration of the investigated treatment episode. Discontinuation was defined when either patients were admitted or the investigated drug had been stopped for more than 28 days. We used the Cox proportional hazard model to compare hazards of discontinuations among 8 SGAs versus 2 FGAs (haloperidol and sulpiride). The follow-up period was up to 18 months. During the follow-up period, clozapine had the highest rate of continuous treatment in the primary analysis: clozapine, 40.6%; olanzapine, 23.4%; aripiprazole, 22.9%; amisulpride, 21.9%; zotepine, 21.3%; sulpiride, 17.0%; risperidone, 12.8%; quetiapine, 12.5%; haloperidol, 10.6%; and ziprasidone, 10.4%. Compared with haloperidol, 5 SGAs had significantly longer TTD (adjusted hazard ratios and 95% confidence intervals): clozapine (0.403, 0.267-0.607), olanzapine (0.611, 0.439-0.849), aripiprazole (0.570, 0.407-0.795), amisulpride (0.680, 0.487-0.947), and zotepine (0.687, 0.497-0.948), but only clozapine had significantly longer TTD compared with sulpiride (0.519, 0.342-0.786). The sensitivity analysis showed similar results. The current findings suggested that SGAs or FGAs are not homogeneous groups. Clozapine has the highest rate of continuous treatment among SGAs, and haloperidol is not the representative drug for all FGAs. Furthermore, antipsychotics dropout rate is high in naturalistic situation. A good service model needs to be constructed to enhance antipsychotic treatment adherence of people with schizophrenia.
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Case Reports of Aripiprazole Causing False-Positive Urine Amphetamine Drug Screens in Children.
Kaplan, Justin; Shah, Pooja; Faley, Brian; Siegel, Mark E
2015-12-01
Urine drug screens (UDSs) are used to identify the presence of certain medications. One limitation of UDSs is the potential for false-positive results caused by cross-reactivity with other substances. Amphetamines have an extensive list of cross-reacting medications. The literature contains reports of false-positive amphetamine UDSs with multiple antidepressants and antipsychotics. We present 2 cases of presumed false-positive UDSs for amphetamines after ingestion of aripiprazole. Case 1 was a 16-month-old girl who accidently ingested 15 to 45 mg of aripiprazole. She was lethargic and ataxic at home with 1 episode of vomiting containing no identifiable tablets. She remained sluggish with periods of irritability and was admitted for observation. UDS on 2 consecutive days came back positive for amphetamines. Case 2 was of a 20-month-old girl who was brought into the hospital after accidental ingestion of an unknown quantity of her father's medications which included aripiprazole. UDS on the first day of admission came back positive only for amphetamines. Confirmatory testing with gas chromatography-mass spectrometry (GC-MS) on the blood and urine samples were also performed for both patients on presentation to detect amphetamines and were subsequently negative. Both patients returned to baseline and were discharged from the hospital. To our knowledge, these cases represent the first reports of false-positive amphetamine urine drug tests with aripiprazole. In both cases, aripiprazole was the drug with the highest likelihood of causing the positive amphetamine screen. The implications of these false-positives include the possibility of unnecessary treatment and monitoring of patients. Copyright © 2015 by the American Academy of Pediatrics.
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Hard, Marjie L; Mills, Richard J; Sadler, Brian M; Turncliff, Ryan Z; Citrome, Leslie
2017-06-01
Aripiprazole lauroxil is an extended-release prodrug of aripiprazole for intramuscular injection, approved for schizophrenia treatment. We developed a population pharmacokinetic (PopPK) model to characterize aripiprazole lauroxil PK and evaluate dosing scenarios likely to be encountered in clinical practice. Data from 616 patients with schizophrenia, collected from 5 clinical studies, were used to construct the PopPK model. The model was subsequently used to evaluate various dose levels and frequency and the impact of dosing delay on aripiprazole concentrations. The results of the model indicate that aripiprazole is released into the systemic circulation after 5 to 6 days, and release continues for an additional 36 days. The slow increase in aripiprazole concentration after injection necessitates the coadministration of oral aripiprazole for 21 days with the first injection. Based on the PopPK model simulations, a dosing interval of 882 mg every 6 weeks results in aripiprazole concentrations that fall within the concentration range associated with the efficacious aripiprazole lauroxil dose range (441-882 mg dosed monthly). A 662-mg monthly dose also resulted in aripiprazole concentrations within the efficacious dose range. Aripiprazole lauroxil administration results in prolonged exposure, such that dose delays of 2 to 4 weeks, depending on the dose regimen, do not require oral aripiprazole supplementation upon resumption of dosing. This PopPK model and model-based simulations were effective means for evaluating aripiprazole lauroxil dosing regimens and management of missed doses. Such analyses play an important role in determining the use of this long-acting antipsychotic in clinical practice.
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Caloro, Matteo; Pucci, Daniela; Calabrò, Giuseppa; de Pisa, Eleonora; Mancinelli, Iginia; Rosini, Enrico; Montebovi, Franco; De Filippis, Sergio; Telesforo, Carla Ludovica; Cuomo, Ilaria; Kotzalidis, Georgios D; Girardi, Paolo
2016-01-01
The aim of this study was to identify hiccup cases among patients hospitalized in a psychiatric ward and focus on their treatment, so to establish intervention risk. We reviewed records of 354 consecutively admitted patients during the year 2013 to identify hiccup cases. Hiccup occurred in 7 patients on both aripiprazole and benzodiazepines and in one on delorazepam. No patient on aripiprazole alone developed hiccup. No patient on drugs other than aripiprazole or benzodiazepines developed hiccup. The symptom subsided in 3 cases upon discontinuing aripiprazole and in 5 cases after discontinuing the benzodiazepine (including the case on delorazepam alone); in 2 cases of persistent hiccup, the symptom resolved after adding the calcium channel blocker, pregabalin. All patients developing hiccup were male. There was a 70-fold increase in the risk for developing hiccup in the aripiprazole/benzodiazepine intake condition versus all other conditions, and it further increased if limiting to the male sex. The retrospective nature of the study was its limitation. Hospitalized psychiatric patients on both aripiprazole and benzodiazepines may be at significant risk of hiccup. This clinical awareness could lead to antipsychotic and/or benzodiazepine discontinuation or switch or to the addition of calcium channel blocker inhibitors.
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Pozzi, Marco; Pisano, Simone; Bertella, Silvana; Capuano, Annalisa; Rizzo, Renata; Antoniazzi, Stefania; Auricchio, Fabiana; Carnovale, Carla; Cattaneo, Dario; Ferrajolo, Carmen; Gentili, Marta; Guastella, Giuseppe; Mani, Elisa; Rafaniello, Concetta; Riccio, Maria Pia; Scuderi, Maria Grazia; Sperandeo, Serena; Sportiello, Liberata; Villa, Laura; Radice, Sonia; Clementi, Emilio; Rossi, Francesco; Pascotto, Antonio; Bernardini, Renato; Molteni, Massimo; Bravaccio, Carmela
2016-12-01
The practical effectiveness of second-generation antipsychotics in children and adolescents is an understudied issue. It is a crucial area of study, though, because such patients are often treated for long-lasting disorders. We carried out a 24-month (March 2012-March 2014) observational study on an unselected population of pediatric outpatients treated with risperidone, aripiprazole, olanzapine, or quetiapine aiming to (1) describe drug use, (2) compare post hoc the discontinuation rates due to specific causes and dose adjustments by Kaplan-Meier analyses between drugs, and (3) analyze predictors influencing these outcomes by Cox multivariate models. Among 184 pediatric patients, 77% patients were prescribed risperidone, and 18% were prescribed aripiprazole. Olanzapine or quetiapine were scantly used; therefore, they were excluded from analyses. Risperidone was prevalent in younger, male patients with disruptive behavioral disorders; aripiprazole, in patients with tic disorders. Overall, discontinuations occurred mostly in the first 6 months, and, at 24 months, the discontinuation numbers were similar between users of risperidone and aripiprazole (41.5% vs 39.4%). In univariate analyses, dose reduction was higher for aripiprazole (P = .033). Multivariate analyses yielded the following predictors: for all-cause discontinuation, baseline severity (hazard ratio [HR] = 1.48, P = .001) and dose increase (HR = 3.55, P = .001); for patient-decided discontinuation, dose change (increase: HR = 6.43, P = .004; reduction: HR = 7.89, P = .049) and the presence of concomitant drugs (HR = 4.03, P = .034), while autistic patients discontinued less (HR = 0.23, P = .050); for clinician-decided discontinuation due to adverse drug reactions, baseline severity (HR = 1.96, P = .005) and dose increase (HR = 5.09, P = .016); for clinician-decided discontinuation due to inefficacy, baseline severity (HR = 2.88, P = .014) and the use of aripiprazole (HR = 5.55, P = .013); for dose increase, none; for dose reduction, the occurrence of adverse drug reactions (HR = 4.74, P = .046), while dose reduction was less probable in autistic patients (HR = 0.22, P = .042). The findings of this study show a similarity between the overall effectiveness of risperidone and aripiprazole in a real-life pediatric outpatient setting. © Copyright 2016 Physicians Postgraduate Press, Inc.
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Shafaroodi, Hamed; Oveisi, Simin; Hosseini, Mahsa; Niknahad, Hossein; Moezi, Leila
2015-07-01
Aripiprazole is an antipsychotic drug which acts through dopamine and serotonin receptors. Aripiprazole was noted to have antiseizure effects in a study on mice, while it induced seizures in a few human case reports. Dopaminergic and serotonergic systems relate to nitric oxide, and aripiprazole also has effects on dopamine and serotonin receptors. This study investigated the effects of aripiprazole on seizures and the potential role of nitric oxide in the process. The following three models were examined to explore the role of aripiprazole on seizures in mice: 1 - pentylenetetrazole administered intravenously, 2 - pentylenetetrazole administered intraperitoneally, and 3 - electroshock. Aripiprazole administration delayed clonic seizure in intravenous and intraperitoneal pentylenetetrazole models. In the electroshock-induced seizure model, tonic seizure and mortality protection percent were increased after aripiprazole administration. In intraperitoneal administration of pentylenetetrazole, aripiprazole effects on clonic seizure latency were significantly decreased when l-NAME - a nonselective nitric oxide synthase (NOS) inhibitor, 7-nitroindazole - a selective neuronal NOS (nNOS) inhibitor, or aminoguanidine - a selective inducible NOS (iNOS) inhibitor was injected before aripiprazole administration. In the intravenous pentylenetetrazole method, administration of l-NAME or aminoguanidine inhibited aripiprazole effects on clonic seizure threshold. Aminoguanidine or l-NAME administration decreased aripiprazole-induced protection against tonic seizures and death in the electroshock model. In both intravenous and intraperitoneal seizure models, aripiprazole and l-arginine coadministration delayed the onset of clonic seizures. Moreover, it increased protection against tonic seizures and death in intraperitoneal pentylenetetrazole and electroshock models. In conclusion, the release of nitric oxide via iNOS or nNOS may be involved in anticonvulsant properties of aripiprazole. Copyright © 2015 Elsevier Inc. All rights reserved.
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Kirino, Eiji
2010-10-01
We present the case of a fifteen-year-old adolescent male with schizophrenia who had long-term catatonic stupor and was successfully treated with aripiprazole. The onset of his stupor manifested rapidly after experiencing prodromal symptoms for two months. He was left untreated without adequate food ingestion for three weeks because of his parents' religious faith, and was severely dehydrated and malnourished upon admission to our hospital. After his physical recovery, treatment with risperidone (0.5-2.0 mg, 5 weeks) was started. However, hypersedation occurred, and the risperidone was switched to aripiprazole, with dose increases up to 18 mg/day (5 months). As a result, he recovered from his totally noncommunicative state. Aripiprazole, which has a unique pharmacological mechanism of action distinct from other atypical antipsychotics and an excellent safety profile, may be effective in the treatment of some schizophrenic patients with stupor, which sometimes carries a risk of physical debilitation and requires special attention due to the risk of adverse drug reactions.
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A review of aripiprazole long-acting injection.
Chue, Pierre; Chue, James
2016-01-01
To review the published literature on aripiprazole once monthly, a second generation antipsychotic (SGA) recently developed as a long-acting injection (LAI), in the form of a suspension of lyophilized aripiprazole reconstituted with an aqueous diluent, for intramuscular administration. An electronic database search was conducted using the key words; relevant articles were then hand searched and websites (FDA, EMA, Otsuka, Lundbeck, NIH) reviewed. Efficacy has been demonstrated in preventing relapse in a 52 week study versus placebo, and non-inferiority to oral aripiprazole in a 38 week study, as well as in the treatment of hospitalized adult patients with acutely relapsed schizophrenia. Aripiprazole LAI appears cost-effective versus other SGA-LAIs, with improved health-related quality of life and functioning in a head-to-head study with paliperidone LAI. A 6 month (pre and post), mirror-image switch study demonstrated a reduction in hospitalization and associated costs compared with previous antipsychotic treatment. Safety and tolerability are comparable to oral aripiprazole with no new safety signals. Experience with oral aripiprazole and the current availability of the long-acting formulation suggest a potential benefit in a variety of clinical scenarios and therefore consideration as a treatment option in the treatment of schizophrenia.
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Uzun, Suzana; Kozumplik, Oliver; Sedić, Biserka
2010-06-01
Metabolic syndrome can contribute to significant morbidity and premature mortality and should be accounted for in the treatment of mental disorders. Patients with schizophrenia are at risk of undetected somatic comorbidity. Patients with schizophrenia have metabolically unfavorable body composition, comprising abdominal obesity, high fat percentage and low muscle mass, leading to increased risk of metabolic and cardiovascular diseases. Smoking, poor diet, reduced physical activity and alcohol or drug abuse are prevalent in people with schizophrenia and contribute to the overall cardiovascular disease risk. Side effects of antipsychotics may cause diagnostic problems in deciding regarding the origin of particular symptoms (somatic illness vs. side effects) during treatment of psychotic disorders. Bearing in mind frequent comorbidity between of psychotic and somatic disorders, early recognition of such comorbidity is important, as well as the selection of antipsychotics. The aim of this article is to report a case of changes in values of cholesterol and tryglicerides after weight loss, during treatment with aripiprazole in a patient with schizophrenia. This case report emphasizes the importance of regular monitoring of values of cholesterol and tryglicerides during treatment with antipsychotics.
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Kose, Eiji; Uno, Kana; Hayashi, Hiroyuki
2017-01-01
Typical antipsychotics are easily expressed as adverse events such as extrapyramidal symptom (EPS). On the other hand, incidence of adverse events due to atypical antipsychotics is low. Therefore, currently, atypical antipsychotics are widely used to treat schizophrenia. However, it has been reported that there is no difference in the frequency of EPS in atypical and typical antipsychotics. This study aimed to evaluate the expression profile of EPS in atypical and typical antipsychotics treatment using the Japanese Adverse Drug Event Report (JADER) database. We analyzed reports of EPS in the JADER database and calculated the reporting odds ratio (ROR) of antipsychotics potentially associated with EPS. We applied the Weibull shape parameter to time-to-event data in the JADER database. Consequently, there was little information to distinguish between the ROR of atypical and typical antipsychotics. A significant difference related to the time of onset of EPS in both antipsychotics was not recognized. However, when comparing each drug, Paliperidone, Perospirone, Blonanserin, and Aripiprazole were relatively developed as EPS in the early stage. On the other hand, Risperidone, Clozapine, Olanzapine, and Quetiapine were developed as EPS not only at an early stage but also after long-term use. In addition, this finding was suggested from the result of the cumulative incidence of EPS in each drug and of the time-to-onset analysis using Weibull distribution. These findings may contribute to future clinical practice because we revealed the expression profile of EPS in treatment with atypical and typical antipsychotics.
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Peripheral Antinociception Induced by Aripiprazole Is Mediated by the Opioid System.
Ferreira, Renata Cristina Mendes; Almeida-Santos, Ana Flávia; Duarte, Igor Dimitri Gama; Aguiar, Daniele C; Moreira, Fabricio A; Romero, Thiago Roberto Lima
2017-01-01
Aripiprazole is an antipsychotic drug used to treat schizophrenia and related disorders. Our previous study showed that this compound also induces antinociceptive effects. The present study aimed to assess the participation of the opioid system in this effect. Male Swiss mice were submitted to paw pressure test and hyperalgesia was induced by intraplantar injection of prostaglandin E 2 (PGE 2 , 2 μ g). Aripiprazole was injected 10 min before the measurement. Naloxone, clocinnamox, naltrindole, nor-binaltorphimine, and bestatin were given 30 min before aripiprazole. Nociceptive thresholds were measured in the 3rd hour after PGE 2 injection. Aripiprazole (100 μ g/paw) injected locally into the right hind paw induced an antinociceptive effect that was blocked by naloxone (50 μ g/paw), a nonselective opioid receptor antagonist. The role of μ -, δ -, and κ -opioid receptors was investigated using the selective antagonists, clocinnamox (40 μ g/paw), naltrindole (15, 30, and 60 μ g/paw), and nor-binaltorphimine (200 μ g/paw), respectively. The data indicated that only the δ -opioid receptor antagonist inhibited the peripheral antinociception induced by aripiprazole. Bestatin (400 μ g), an aminopeptidase-N inhibitor, significantly enhanced low-dose (25 μ g/paw) aripiprazole-induced peripheral antinociception. The results suggest the participation of the opioid system via δ -opioid receptor in the peripheral antinociceptive effect induced by aripiprazole.
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A case series: evaluation of the metabolic safety of aripiprazole.
De Hert, Marc; Hanssens, Linda; van Winkel, Ruud; Wampers, Martien; Van Eyck, Dominique; Scheen, Andre; Peuskens, Joseph
2007-05-01
Metabolic abnormalities occur frequently in patients treated with antipsychotics and are of growing concern to clinicians. This study sought to determine whether antipsychotic-associated metabolic abnormalities identified through intensive monitoring can be reversed by switching to aripiprazole. Recent evidence suggests that aripiprazole may exhibit a favorable metabolic safety profile. The study population is a subset of a large (n > 500) ongoing prospective cohort. Thirty-one consecutive patients with schizophrenia who were started on aripiprazole were included in the study. All patients underwent an extensive metabolic evaluation, including an oral glucose tolerance test, at baseline, at 6 weeks, and at 3 months post switch. Metabolic abnormalities were defined as any of the following: new onset diabetes, impaired fasting glucose, impaired glucose tolerance, metabolic syndrome (MetS) according to various definitions, and dyslipidemia. After 3 months of treatment with aripiprazole (mean daily dose 16.3 mg), there was a significant decrease in body weight, body mass index, and waist circumference. There was a significant reduction in fasting glucose, fasting insulin, insulin resistance index, and serum lipids levels (cholesterol, triglycerides, low-density lipoprotein (LDL), LDL/HDL, Chol/HDL, and non-HDL cholesterol). There was also a significant reduction in prolactin levels. All 7 cases of recent onset diabetes were reversed at 3 months follow-up. The MetS was reversed in 50% of patients at 3 months follow-up. Our results support the reversibility of recent onset diabetes on antipsychotic medication when detected early and followed by a switch to aripiprazole.
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Mizuno, Yuya; Suzuki, Takefumi; Nakagawa, Atsuo; Yoshida, Kazunari; Mimura, Masaru; Fleischhacker, Walter Wolfgang; Uchida, Hiroyuki
2014-01-01
Background: Antipsychotic-induced metabolic adversities are often difficult to manage. Using concomitant medications to counteract these adversities may be a rational option. Objective: To systematically determine the effectiveness of medications to counteract antipsychotic-induced metabolic adversities in patients with schizophrenia. Data Sources: Published articles until November 2013 were searched using 5 electronic databases. Clinical trial registries were searched for unpublished trials. Study Selection: Double-blind randomized placebo-controlled trials focusing on patients with schizophrenia were included if they evaluated the effects of concomitant medications on antipsychotic-induced metabolic adversities as a primary outcome. Data Extraction: Variables relating to participants, interventions, comparisons, outcomes, and study design were extracted. The primary outcome was change in body weight. Secondary outcomes included clinically relevant weight change, fasting glucose, hemoglobin A1c, fasting insulin, insulin resistance, cholesterol, and triglycerides. Data Synthesis: Forty trials representing 19 unique interventions were included in this meta-analysis. Metformin was the most extensively studied drug in regard to body weight, the mean difference amounting to −3.17 kg (95% CI: −4.44 to −1.90 kg) compared to placebo. Pooled effects for topiramate, sibutramine, aripiprazole, and reboxetine were also different from placebo. Furthermore, metformin and rosiglitazone improved insulin resistance, while aripiprazole, metformin, and sibutramine decreased blood lipids. Conclusion: When nonpharmacological strategies alone are insufficient, and switching antipsychotics to relatively weight-neutral agents is not feasible, the literature supports the use of concomitant metformin as first choice among pharmacological interventions to counteract antipsychotic-induced weight gain and other metabolic adversities in schizophrenia. PMID:24636967
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Naono-Nagatomo, Keiko; Naono, Hisao; Abe, Hiroshi; Takeda, Ryuichiro; Funahashi, Hideki; Uchimura, Daisuke; Ishida, Yasushi
2017-02-01
Aripiprazole (ARP) is a popular antipsychotic drug that has demonstrated ameliorative effects on hyperprolactinemia. However, no study to date has studied the utility of ARP in patients with a long history of schizophrenia and antipsychotic treatment. We therefore examined the effect of partial antipsychotic regimen replacement with ARP on hyperprolactinemia induced by chronic antipsychotic use in patients with schizophrenia. Sixteen patients with a schizophrenia diagnosis (F2) based on the International Classification of Diseases (version 10) were recruited. At months 0, 1, 3, and 6 of the study, serum prolactin, body weight, and blood glucose were measured, and QOL and psychotic symptoms were assessed using Global Assessment of Functioning scores and Clinical Global Impressions of Improvement (CGI-I) scores. Nine patients with an average age of 46.7±9.6 years and mean disease duration of 15.9±10.4 years were included in the final analysis. Serum prolactin levels significantly decreased and GAF and CGI-I scores improved significantly over the 6-month period after partial replacement with ARP. Additionally, no changes were observed in body weight or blood glucose over the 6-month period. Partial antipsychotic regimen replacement with ARP improves hyperprolactinemia, and may improve the QOL of patients with a long history of schizophrenia. Japan Medical Association, Center for clinical trials D: JMA-IIA00245. Copyright © 2016 Elsevier B.V. All rights reserved.
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Pan, Bo; Huang, Xu-Feng; Deng, Chao
2016-01-01
Aripiprazole is a D2-like receptor (D2R) partial agonist with a favourable clinical profile. Previous investigations indicated that acute and short-term administration of aripiprazole had effects on PKA activity, GSK3β-dependent pathways, GABAA receptors, NMDA receptor and CREB1 in the brain. Since antipsychotics are used chronically in clinics, the present study investigated the long-term effects of chronic oral aripiprazole treatment on these cellular signalling pathways, in comparison with haloperidol (a D2R antagonist) and bifeprunox (a potent D2R partial agonist). We found that the Akt-GSK3β pathway was activated by aripiprazole and bifeprunox in the prefrontal cortex; NMDA NR2A levels were reduced by aripiprazole and haloperidol. In the nucleus accumbens, all three drugs increased Akt-GSK3β signalling; in addition, both aripiprazole and haloperidol, but not bifeprunox, increased the expression of Dvl-3, β-catenin and GABAA receptors, NMDA receptor subunits, as well as CREB1 phosphorylation levels. The results suggest that chronic oral administration of aripiprazole affects schizophrenia-related cellular signalling pathways and markers (including Akt-GSK3β signalling, Dvl-GSK3β-β-catenin signalling, GABAA receptor, NMDA receptor and CREB1) in a brain-region-dependent manner; the selective effects of aripiprazole on these signalling pathways might be associated with its unique clinical effects. PMID:27435909
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Miura, Itaru; Takeuchi, Satoshi; Katsumi, Akihiko; Kanno, Keiko; Watanabe, Kenya; Mashiko, Hirobumi; Niwa, Shin-Ichi
2012-09-01
In the treatment of acute schizophrenia, risperidone and aripiprazole are both placed the first line antipsychotics. These two antipsychotics have different pharmacological effects. We investigated the effects of risperidone on plasma levels of homovanillic acid (HVA) and 3-methoxy-4hydroxyphenylglycol after unsuccessful aripiprazole treatment in acute schizophrenia. Ten Japanese patients with acute schizophrenia were enrolled to this study. Plasma levels of monoamine metabolites were analyzed with high-performance liquid chromatography with electrochemical detection. Risperidone improved the symptoms and 4 of 10 patients were responders. Risperidone showed a tendency to decrease plasma HVA (pHVA) levels in responders (p = 0.068), but not in non-responders (p = 1.0). At baseline, pHVA levels of responders were significantly higher than that of non-responders (p = 0.033). A trend for negative correlation was found between pHVA at baseline and the changes in Positive and Negative Syndrome Scale-Total (p = 0.061, r = -0.61). Our results suggest that high pHVA level before switching may predict good response to the second line antipsychotics after unsuccessful first antipsychotic treatment. If aripiprazole is not effective in acute schizophrenia, switching to risperidone may be effective and reasonable strategy for improving symptoms. Copyright © 2012 John Wiley & Sons, Ltd.
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Aripiprazole in pediatric psychosis and bipolar disorder: a clinical review.
Doey, Tamison
2012-01-01
Aripiprazole is an atypical antipsychotic with unique pharmacological properties, used for a variety of indications, including psychotic and mood disorders in youth. Existing literature was reviewed to summarize experience with this agent in that population. A review of relevant literature using the key words aripiprazole, children, pediatric, all child, schizophrenia, bipolar disorder, and atypical antipsychotics was conducted. A total of 140 articles and book chapters were identified, of which 7 reported double-blind controlled trials with aripiprazole, 5 were meta-analyses of pooled data, 11 were open label trials, 10 were chart reviews, and 17 were case reports or case series. Although every effort was made to locate all available data, some information from posters or researchers was not available. Publication bias tends to report positive outcomes with a treatment, while negative studies are less likely to be reported. Most trials are of short duration. Treatment with aripiprazole is associated with significant reduction of the Positive and Negative Symptom Scale (PANSS) scores in youth with schizophrenia, and reductions in items in the negative symptom scores at higher doses (30 mg/day). Significant reductions in the Young Mania Rating Scale (YMRS) have been demonstrated in youth with bipolar disorder. In mixed populations, reductions in the Clinical Global Impressions Scale (CGI-S) have also been demonstrated when compared with treatment with placebo. Head-to-head comparisons are fewer in number, and overall aripiprazole compares favorably with other atypical antipsychotics (ATAs) in the populations studied. Treatment with aripiprazole is reported to have a lower incidence of weight gain, and less elevation of prolactin. At higher doses, it appears more likely to result in extrapyramidal symptoms (EPS) and tremor. Copyright © 2012. Published by Elsevier B.V.
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Schizophrenia: multi-attribute utility theory approach to selection of atypical antipsychotics.
Bettinger, Tawny L; Shuler, Garyn; Jones, Donnamaria R; Wilson, James P
2007-02-01
Current guidelines/algorithms recommend atypical antipsychotics as first-line agents for the treatment of schizophrenia. Because there are extensive healthcare costs associated with the treatment of schizophrenia, many institutions and health systems are faced with making restrictive formulary decisions regarding the use of atypical antipsychotics. Often, medication acquisition costs are the driving force behind formulary decisions, while other treatment factors are not considered. To apply a multi-attribute utility theory (MAUT) analysis to aid in the selection of a preferred agent among the atypical antipsychotics for the treatment of schizophrenia. Five atypical antipsychotics (risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole) were selected as the alternative agents to be included in the MAUT analysis. The attributes identified for inclusion in the analysis were efficacy, adverse effects, cost, and adherence, with relative weights of 35%, 35%, 20%, and 10%, respectively. For each agent, attribute scores were calculated, weighted, and then summed to generate a total utility score. The agent with the highest total utility score was considered the preferred agent. Aripiprazole, with a total utility score of 75.8, was the alternative agent with the highest total utility score in this model. This was followed by ziprasidone, risperidone, and quetiapine, with total utility scores of 71.8, 69.0, and 65.9, respectively. Olanzapine received the lowest total utility score. A sensitivity analysis was performed and failed to displace aripiprazole as the agent with the highest total utility score. This model suggests that aripiprazole should be considered a preferred agent for the treatment of schizophrenia unless found to be otherwise inappropriate.
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Kleven, Mark S; Barret-Grévoz, Catherine; Bruins Slot, Liesbeth; Newman-Tancredi, Adrian
2005-08-01
Compounds possessing 5-HT(1A) agonist properties attenuate catalepsy induced by D(2) receptor blockade. Here we examined the role of 5-HT(1A) receptor agonism in the reduced cataleptogenic potential of several novel antipsychotic agents in the crossed leg position (CLP) and the bar catalepsy tests in rats. When administered alone, ziprasidone produced marked catalepsy, whereas aripiprazole, bifeprunox, SLV313, SSR181507 and sarizotan did not. However, when 5-HT(1A) receptors were blocked with the selective antagonist, WAY100635 (0.63 mg/kg, SC), robust cataleptogenic properties of SLV313, bifeprunox and sarizotan were unmasked and the catalepsy induced by ziprasidone was accentuated. In contrast, only modest catalepsy was induced by aripiprazole and SSR181507, even following a higher dose of WAY100635 (2.5 mg/kg). This suggests that these compounds possess other anti-cataleptic properties, such as partial agonism at dopamine D(2) receptors. The capacity to reverse neuroleptic-induced catalepsy was investigated in interaction studies with haloperidol (2.5 mg/kg, SC). Whereas ziprasidone and aripiprazole did not markedly reduce the effects of haloperidol, SLV313 and sarizotan attenuated CLP catalepsy. In contrast, SSR181507 and bifeprunox potently inhibited both CLP and bar catalepsy. Taken together, these data show that 5-HT(1A) receptor activation reduces the cataleptogenic potential of novel antipsychotic agents but indicate marked diversity in the contribution of 5-HT(1A) and/or other mechanisms to the profiles of the drugs.
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Preskorn, Sheldon H; Macaluso, Matthew
2016-03-01
This series of columns has 3 main goals: (1) to explain class warnings as used by the United States Food and Drug Administration, (2) to increase awareness of movement disorders that may occur in patients treated with antipsychotic medications, and (3) to understand why clinicians should refrain from immediately assuming a diagnosis of tardive dyskinesia/dystonia (TD) in patients who develop abnormal movements during treatment with antipsychotics. The first column in the series presented a patient who developed abnormal movements while being treated with aripiprazole as an augmentation strategy for major depressive disorder (MDD) and reviewed data concerning the historical background, incidence, prevalence, and risk factors for tardive and spontaneous dyskinesias, the clinical presentations of which closely resemble each other. The second column in the series reviewed the unique mechanism of action of aripiprazole and preclinical studies and an early-phase human translational study that suggest a low, if not absent, risk of TD with aripiprazole. This column reviews clinical trial data to assess whether those data support the conclusion that aripiprazole has a low to absent risk of causing TD when used as an augmentation strategy to treat MDD. To date, no randomized, placebo-controlled trials have established a definitive link between exposure to aripiprazole and TD in patients with MDD. One long-term, open-label, safety trial examined aripiprazole as an augmentation strategy in individuals with MDD and found a rare occurrence (4/987, 0.4%, the confidence interval of which overlaps with zero) of an adverse event termed TD. In all 4 cases, the observed movements resolved within weeks of aripiprazole discontinuation, suggesting that they were either amenable to treatment or represented an acute syndrome rather than TD. No cases of TD were reported in the registration trials for the MDD indication for aripiprazole. These data were presented in a pooled analysis of three, 14-week studies involving 1088 subjects, 409 of whom were elderly like the 76-year-old individual presented in the case in the first column of this series. Finally, 3 short-term studies evaluated the use of aripiprazole in patients with psychosis associated with Alzheimer disease, a population who would be considered a relatively higher risk group for developing TD when exposed to antipsychotics and that also closely matches the patient in the case presented at the beginning of this series in terms of age. No incidence of TD was reported in this sample and mean scores on the Abnormal Involuntary Movement Scale decreased in individuals exposed to aripiprazole compared with those on placebo. On the basis of results of this review and data from registration trials of aripiprazole for all indications, the potential (or raw) incidence of what was termed TD occurred at rates ranging from 0.004 (4/987) based on long-term safety data from the program investigating aripiprazole augmentation treatment in MDD, to 0.0016 (19/11,897) based on the total safety database from aripiprazole registration trials for all indications, to 0 in trials in elderly individuals with Alzheimer disease. The confidence intervals for all of these potential incidence rates overlap with zero. The next column in this 5-part series reviews 37 case reports that reported TD in association with aripiprazole treatment and 27 case reports that suggested an improvement in preexisting TD with aripiprazole treatment. The fifth and final column in this series will discuss the types of prohibitively expensive and logistically difficult studies that would be needed to determine whether a definitive causal relationship between aripiprazole and TD exists.
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Aripiprazole-induced sleep-related eating disorder: a case report.
Kobayashi, Nobuyuki; Takano, Masahiro
2018-04-05
Sleep-related eating disorder is characterized by parasomnia with recurrent episodes of nocturnal eating or drinking during the main sleep period. Several drugs, including atypical antipsychotics, induce sleep-related eating disorder. However, aripiprazole has not previously been associated with sleep-related eating disorder. A 41-year-old Japanese man visited our clinic complaining of depression. The patient was treated with sertraline, which was titrated up to 100 mg for 4 weeks. A sleep inducer and an anxiolytic were coadministered. His depressive mood slightly improved, but it continued for an additional 4 months. Subsequently, aripiprazole (3 mg) was added as an adjunctive therapy. After 3 weeks, the patient's mother found that the patient woke up and ate food at night. The next morning, the patient was amnesic for this event, felt full, and wondered why the bags of food were empty. This episode lasted for 2 days. The patient gained 5 kg during these 3 weeks. After the aripiprazole dose was reduced to 1.5 mg, the patient's nocturnal eating episodes rapidly and completely disappeared. To the best of our knowledge, this is first report of sleep-related eating disorder induced by aripiprazole, and it indicates that this disorder should be considered a possible side effect of aripiprazole. Although aripiprazole is used mainly in patients with schizophrenia, its recently documented use as an adjunctive therapy in patients with depression might induce hitherto unknown side effects.
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Lum, Jeremy S; Pan, Bo; Deng, Chao; Huang, Xu-Feng; Ooi, Lezanne; Newell, Kelly A
2017-11-21
The D2 receptor partial agonist, aripiprazole, has shown increased therapeutic efficacy for schizophrenia, autism and Tourette's syndrome compared to traditional antipsychotics such as the D2 receptor antagonist, haloperidol. Recent evidence suggests this superior profile may be associated with downstream effects on glutamatergic synapses. Group 1 metabotropic glutamate receptors (mGluRs) and their endogenous modulators, Norbin and Homer1, are regulated by D2 receptor activity, particularly within the nucleus accumbens (NAc), a target region of aripiprazole and haloperidol. This study sought to evaluate the effects of aripiprazole on Group 1 mGluRs, Norbin and Homer1 in the NAc, in comparison to haloperidol. Sprague-Dawley rats were orally administered daily doses of aripiprazole (2.25mg/kg), haloperidol (0.3mg/kg) or vehicle for 1 or 10-weeks. Immunoblot analyses revealed Group 1 mGluR protein levels were not altered following 1-week and 10-week aripiprazole or haloperidol treatment, compared to vehicle treated rodents. However, 1-week aripiprazole and haloperidol treatment significantly elevated Homer1a and Norbin protein expression, respectively. After 10 weeks of treatment, aripiprazole, but not haloperidol, significantly increased Norbin expression. These findings indicate the antipsychotics, aripiprazole and haloperidol, exert differential temporal effects on Norbin and Homer1 expression that may have consequences on synaptic glutamatergic transmission underlying their therapeutic profile. Copyright © 2017 Elsevier B.V. All rights reserved.
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Peripheral Antinociception Induced by Aripiprazole Is Mediated by the Opioid System
Ferreira, Renata Cristina Mendes; Almeida-Santos, Ana Flávia; Aguiar, Daniele C.; Moreira, Fabricio A.
2017-01-01
Background Aripiprazole is an antipsychotic drug used to treat schizophrenia and related disorders. Our previous study showed that this compound also induces antinociceptive effects. The present study aimed to assess the participation of the opioid system in this effect. Methods Male Swiss mice were submitted to paw pressure test and hyperalgesia was induced by intraplantar injection of prostaglandin E2 (PGE2, 2 μg). Aripiprazole was injected 10 min before the measurement. Naloxone, clocinnamox, naltrindole, nor-binaltorphimine, and bestatin were given 30 min before aripiprazole. Nociceptive thresholds were measured in the 3rd hour after PGE2 injection. Results Aripiprazole (100 μg/paw) injected locally into the right hind paw induced an antinociceptive effect that was blocked by naloxone (50 μg/paw), a nonselective opioid receptor antagonist. The role of μ-, δ-, and κ-opioid receptors was investigated using the selective antagonists, clocinnamox (40 μg/paw), naltrindole (15, 30, and 60 μg/paw), and nor-binaltorphimine (200 μg/paw), respectively. The data indicated that only the δ-opioid receptor antagonist inhibited the peripheral antinociception induced by aripiprazole. Bestatin (400 μg), an aminopeptidase-N inhibitor, significantly enhanced low-dose (25 μg/paw) aripiprazole-induced peripheral antinociception. Conclusion The results suggest the participation of the opioid system via δ-opioid receptor in the peripheral antinociceptive effect induced by aripiprazole. PMID:28758123
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Atypical Antipsychotics and the Risk of Hyperlipidemia: A Sequence Symmetry Analysis.
Takeuchi, Yoshinori; Kajiyama, Kazuhiro; Ishiguro, Chieko; Uyama, Yoshiaki
2015-07-01
Although hyperlipidemia is a well known adverse event of atypical antipsychotic (AAP) medication, there are few studies that have quantitatively compared the risks of various AAPs. Our aim was to comparatively evaluate the risk of hyperlipidemia associated with the use of AAPs approved in Japan through a consecutive epidemiological study. We conducted a sequence symmetry analysis (SSA) using health insurance claims data to analyze the following nine AAPs approved for use in Japan: risperidone, paliperidone, perospirone hydrochloride hydrate, blonanserin, clozapine, olanzapine, quetiapine fumarate, aripiprazole, and zotepine. Exposed cases were identified from drug dispensing records as those who had been administered both AAPs and antihyperlipidemic drugs. The adjusted sequence ratio (ASR) and 95 % confidence interval (CI) for each individual AAP and for all AAPs were calculated while controlling for time trends in dispensing patterns. Olanzapine was significantly associated with increased hyperlipidemia occurrence (ASR 1.56; 95 % CI 1.25-1.95). The ASRs obtained for risperidone (1.01; 95 % CI 0.80-1.27), perospirone hydrochloride hydrate (0.93; 95 % CI 0.63-1.39), blonanserin (0.83; 95 % CI 0.52-1.33), quetiapine fumarate (0.93; 95 % CI 0.73-1.18), and aripiprazole (1.02; 95 % CI 0.82-1.26) were approximately 1.0. Unstable estimates (wide CIs) were obtained for paliperidone and zotepine due to the small sample sizes. Among the AAPs used in Japan, only olanzapine was found to have an elevated risk of hyperlipidemia. In contrast, risperidone, perospirone hydrochloride hydrate, blonanserin, quetiapine fumarate, and aripiprazole had relatively low risks.
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Csomor, Philipp A; Preller, Katrin H; Geyer, Mark A; Studerus, Erich; Huber, Theodor; Vollenweider, Franz X
2014-01-01
Despite advances in the treatment of schizophrenia spectrum disorders with atypical antipsychotics (AAPs), there is still need for compounds with improved efficacy/side-effect ratios. Evidence from challenge studies suggests that the assessment of gating functions in humans and rodents with naturally low-gating levels might be a useful model to screen for novel compounds with antipsychotic properties. To further evaluate and extend this translational approach, three AAPs were examined. Compounds without antipsychotic properties served as negative control treatments. In a placebo-controlled, within-subject design, healthy males received either single doses of aripiprazole and risperidone (n=28), amisulpride and lorazepam (n=30), or modafinil and valproate (n=30), and placebo. Prepulse inhibiton (PPI) and P50 suppression were assessed. Clinically associated symptoms were evaluated using the SCL-90-R. Aripiprazole, risperidone, and amisulpride increased P50 suppression in low P50 gaters. Lorazepam, modafinil, and valproate did not influence P50 suppression in low gaters. Furthermore, low P50 gaters scored significantly higher on the SCL-90-R than high P50 gaters. Aripiprazole increased PPI in low PPI gaters, whereas modafinil and lorazepam attenuated PPI in both groups. Risperidone, amisulpride, and valproate did not influence PPI. P50 suppression in low gaters appears to be an antipsychotic-sensitive neurophysiologic marker. This conclusion is supported by the association of low P50 suppression and higher clinically associated scores. Furthermore, PPI might be sensitive for atypical mechanisms of antipsychotic medication. The translational model investigating differential effects of AAPs on gating in healthy subjects with naturally low gating can be beneficial for phase II/III development plans by providing additional information for critical decision making. PMID:24801767
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2014-01-01
Background The evidence for choices between antipsychotics for children and adolescents with schizophrenia and other psychotic disorders is limited. The main objective of the Tolerability and Efficacy of Antipsychotics (TEA) trial is to compare the benefits and harms of quetiapine versus aripiprazole in children and adolescents with psychosis in order to inform rational, effective and safe treatment selections. Methods/Design The TEA trial is a Danish investigator-initiated, independently funded, multi-centre, randomised, blinded clinical trial. Based on sample size estimation, 112 patients aged 12-17 years with psychosis, antipsychotic-naïve or treated for a limited period are, 1:1 randomised to a 12- week, double-blind intervention with quetiapine versus aripiprazole. Effects on psychopathology, cognition, health-related quality of life, and adverse events are assessed 2, 4, and 12 weeks after randomisation. The primary outcome is change in the positive symptom score of the Positive and Negative Syndrome Scale. The recruitment period is 2010-2014. Discussion Antipsychotics are currently the only available pharmacologic treatments for psychotic disorders. However, information about head-to-head differences in efficacy and tolerability of antipsychotics are scarce in children and adolescents. The TEA trial aims at expanding the evidence base for the use of antipsychotics in early onset psychosis in order to inform more rational treatment decisions in this vulnerable population. Here, we account for the trial design, address methodological challenges, and discuss the estimation of sample size. Trial registration ClinicalTrials.gov: NCT01119014 PMID:25015535
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Carbon, Maren; Kapoor, Sandeep; Sheridan, Eva; Al-Jadiri, Aseel; Azzo, Sally; Sarkaria, Tania; Kane, John M; Saito, Ema; Correll, Christoph U
2015-09-01
Second-generation antipsychotic (SGA) effects in youth were monitored to quantify extrapyramidal side effects (EPS) and to identify risk profiles for treatment-emergent EPS. Data were analyzed for the nonrandomized, prospective Second-generation Antipsychotic Treatment Indications, Effectiveness and Tolerability in Youth (SATIETY) inception cohort study. EPS were assessed at baseline and 4, 8, and 12 weeks after naturalistic SGA initiation for schizophrenia, mood, disruptive behavior, and autism spectrum disorders using the Simpson-Angus Scale (SAS), Barnes Akathisia Scale, Abnormal Involuntary Movement Scale (AIMS), and Treatment Emergent Side Effect Scale. Drug-induced parkinsonism was defined by incident mean SAS score >0.33, anticholinergic initiation, or increasing total SAS score ≥2 in patients with baseline EPS. In 342 youth aged 13.6 ± 3.5 years (male = 58.2%, antipsychotic-naive = 65.8%), 15.2% developed drug-induced parkinsonism. Raw SGA-grouped drug-induced parkinsonism rates were as follows: quetiapine = 1.5%, olanzapine = 13.8%, risperidone = 16.1%, ziprasidone = 20.0%, and aripiprazole = 27.3%. SGA type, dose, higher age, and lower baseline functioning were jointly associated with drug-induced parkinsonism (R(2) = 0.18; p < .0001). Controlling for these factors, drug-induced parkinsonism rates were significantly lower only for quetiapine and olanzapine. Subjectively reported EPS (5%), EPS-related treatment discontinuation (3.3%), and anticholinergic initiation (3%) were infrequent. Anticholinergic initiation was most frequent with risperidone (10.2%; p = .0004). Treatment-emergent dyskinesia ranged from 4.5% (aripiprazole) to 15.5% (olanzapine). SGA type, younger age, white race/ethnicity, and baseline AIMS were jointly associated with treatment-emergent dyskinesia (R(2) = 0.31; p < .0001). Controlling for these factors, treatment-emergent dyskinesia rates differed among SGA subgroups, with higher rates with olanzapine and ziprasidone. At baseline, psychostimulant use was associated with dyskinesia, and number of psychotropic comedications was associated with subjective EPS. In youth, SGA-related EPS rates did not generally exceed those reported in adults, with particularly low rates with quetiapine and olanzapine. Copyright © 2015 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.
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Tardive Dyskinesia and Covert Dyskinesia with Aripiprazole: A Case Series.
Patra, Suravi
2016-01-01
Aripiprazole, a dopamine stabilizing atypical antipsychotic is used in treatment of tardive dyskinesia caused by other neuroleptics. Tardive dyskinesia is rarely caused by Aripiprazole and has only been documented in high risk patients i.e., female gender, advanced age, affective illness, coexisting neurological disorders. Here the author describes two atypical cases of tardive dyskinesia associated with Aripiprazole. First case of tardive dyskinesia was observed in a neuroleptic naïve young adult male with paranoid illness after six months of treatment with Aripiprazole upon addition of Fluoxetine and the second case was a middle aged female with affective illness where dyskinetic movements appeared after stopping Aripiprazole. The role of Fluoxetine in causing tardive dyskinesia with Aripiprazole and covert dyskinesia due to Aripiprazole with appropriate management is discussed.
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Mankoski, Raymond; Stockton, Gwen; Manos, George; Marler, Sabrina; McQuade, Robert; Forbes, Robert A; Marcus, Ronald
2013-10-01
The purpose of this study was to evaluate the impact of prior antipsychotic exposure (PAE) on safety and tolerability outcomes in pediatric subjects receiving aripiprazole treatment. This study was a post-hoc analysis of pooled data from two 8-week, double-blind, randomized, placebo-controlled studies evaluating aripiprazole for the treatment of irritability in pediatric subjects with autistic disorder, aged 6-17 years. Subjects were stratified by PAE; adverse events (AEs), and changes in weight, and metabolic measures were evaluated. For subjects receiving aripiprazole, regardless of PAE, baseline weight, age, gender, and symptom severity were evaluated in a regression model predicting body weight change. Of 316 randomized subjects, 259 (82.0%) were antipsychotic naïve (AN) and 57 (18.0%) had a PAE. Aripiprazole-treated AN subjects were more likely than PAE subjects to report somnolence (11.9% vs. 2.8%), sedation (22.7% vs. 11.1%), or fatigue (17.0% vs. 13.9%). Rates of extrapyramidal disorder and drooling, but not akathisia or tremor, were marginally higher in AN subjects. Overall, 10.8% of aripiprazole-treated AN subjects had at least one AE leading to discontinuation compared with 8.3% of aripiprazole-treated PAE subjects. AN subjects receiving aripiprazole had a larger change in weight from baseline to endpoint compared with those receiving placebo (1.9 vs. 0.7 kg; treatment difference 1.2 kg, 95% CI: 0.5, 1.9) than PAE subjects receiving aripiprazole compared with subjects receiving placebo (0.4 vs. -0.4 kg; treatment difference 0.9 kg, 95% CI: -0.6, 2.4). Regression analysis identified that younger subjects with higher baseline weight z-score were at highest risk for weight gain. There were no significant changes in metabolic measures compared with placebo in either group. Weight gain was more pronounced in AN subjects and more likely to occur in younger subjects with a higher baseline weight z-score. AN subjects were more likely to experience AEs related to somnolence. However, based on discontinuations rates from AEs, overall tolerability was good for both AN and PAE groups. Study of aripiprazole in the treatment of children and adolescents with autistic disorder. Registry: www.clinicaltrials.gov . Identifiers: NCT00332241 and NCT00337571.
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Zheng, Wei; Zheng, Ying-Jun; Li, Xian-Bin; Tang, Yi-Lang; Wang, Chuan-Yue; Xiang, Ying-Qiang; de Leon, Jose
2016-12-01
This meta-analysis of randomized controlled trials (RCTs) evaluated the efficacy and safety of adding aripiprazole to other antipsychotics in schizophrenia. A systematic computer search identified 55 RCTs including 4457 patients who were randomized to aripiprazole (14.0 ± 7.0 mg/d) versus placebo (18 RCTs) or open antipsychotic treatment (37 RCTs). Aripiprazole significantly outperformed the comparison interventions based on psychiatric scales: (1) total score in 43 RCTs (N = 3351) with a standardized mean difference (SMD) of -0.48 (95% confidence interval [CI], -0.68 to -0.28; P < 0.00001; I = 88%), (2) negative symptom score in 30 RCTs (N = 2294) with an SMD of -0.61(95% CI, -0.91 to -0.31; P < 0.00001; I = 91%), and (3) general psychopathology score in 13 RCTs (N = 1138) with a weighted mean difference (WMD) of -4.02 (95% CI, -7.23 to -0.81; P = 0.01; I = 99%), but not in positive symptoms in 29 RCTs (N = 2223) with a SMD of -0.01 (95% CI, 0.26 to 0.25; P = 0.95; I = 88%). Differences in total score based on psychiatric scales may be explained by the use of an antipsychotic for comparison rather than placebo in 31 RCTs with a nonblind design. Aripiprazole outperformed the comparison interventions for body weight in 9 RCTs (N = 505) with a WMD of -5.08 kg (95% CI, -7.14 to -3.02; P < 0.00001; I = 35%) and for body mass index (BMI) in 14 RCTs (N = 809) with a WMD of -1.78 (CI: -2.25 to -1.31; P < 0.00001; I = 54%). The BMI meta-regression analysis indicated aripiprazole's association with lower BMI was stronger in females. Adjunctive aripiprazole appears safe but better RCTs are needed to demonstrate efficacy. Chinese journals and scientific societies should encourage the publication of high-quality RCTs and require registration in a centralized Chinese database.
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The Potential Risks of Commonly Prescribed Antipsychotics
Aneja, Alka; Rahman, Atiq; Megna, James; Freemont, Wanda; Shiplo, Mohammed; Nihilani, Nikil; Lee, Kathy
2005-01-01
Chlorpromazine, haloperidol, fluphenazine, clozapine, risperidone, quetiapine, olanzapine, ziprasidone, and aripiprazole are antipsychotics commonly used in psychiatric medicine. Approximately one third of pregnant women with psychotic symptoms use antipsychotics at least once. This review will discuss the effects of antipsychotic use during pregnancy and lactation on the fetus and infant. Although adequate and well-controlled studies have not been done in any one of these antipsychotic drugs, animal studies have revealed evidence of teratogenic or embryo/fetotoxic effects in all of them. Toxicities include skeletal malformations, central nervous system (CNS) defects, cleft palate, cardiac abnormalities, decreased fetal growth, and fetal death. For example, in pregnant women, congenital malformations and perinatal death have been reported with chlorpromazine use. Both chlorpromazine and fluphenazine in monotherapy have been shown to cause extrapyramidal symptoms and respiratory distress in infants born to mothers treated with these medications. Haloperidol use during pregnancy has been linked to severe limb reduction defects. Effects of antipsychotic use in lactating mothers are mostly unknown. However, the use of chlorpromazine has been reported to result in drowsiness and lethargy in breastfed infants. Additionally, clozapine has been reported to cause sedation, decreased suckling, restlessness, irritability, seizures, and cardiovascular instability of infants were also reported with clozapine use in lactating mother. Use of antipsychotic drugs by pregnant and lactating mother may only be justified if the potential benefit outweighs the potential risk to the fetus. PMID:21152171
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Nicol, Ginger E; Yingling, Michael D; Flavin, Karen S; Schweiger, Julia A; Patterson, Bruce W; Schechtman, Kenneth B; Newcomer, John W
2018-06-13
Antipsychotic medications are commonly used to treat nonpsychotic disruptive behavioral disorders in youths. To characterize the metabolic effects of first exposure to antipsychotics in youths using criterion standard assessments of body composition and insulin sensitivity. This randomized clinical trial recruited antipsychotic-naive youths aged 6 to 18 years in the St Louis, Missouri, metropolitan area who were diagnosed with 1 or more psychiatric disorders and clinically significant aggression and in whom antipsychotic treatment was considered. Participants were enrolled from June 12, 2006, through November 10, 2010. Enrolled participants were randomized (1:1:1) to 1 of 3 antipsychotics commonly used in children with disruptive behavioral disorders and evaluated for 12 weeks. Data were analyzed from January 17, 2011, through August 9, 2017. Twelve weeks of treatment with oral aripiprazole (n = 49), olanzapine (n = 46), or risperidone (n = 49). Primary outcomes included percentage total body fat measured by dual-energy x-ray absorptiometry (DXA) and insulin sensitivity in muscle measured via hyperinsulinemic clamps with stable isotopically labeled tracers. Secondary outcomes included abdominal adiposity measured by magnetic resonance imaging (MRI) and adipose and hepatic tissue insulin sensitivity measured via clamps with tracers. The intention-to-treat sample included 144 participants (98 males [68.1%]; mean [SD] age, 11.3 [2.8] years); 74 (51.4%) were African American, and 43 (29.9%) were overweight or obese at baseline. For the primary outcomes, from baseline to week 12, DXA percentage total body fat increased by 1.18% for risperidone, 4.12% for olanzapine, and 1.66% for aripiprazole and was significantly greater for olanzapine than risperidone or aripiprazole (time by treatment interaction P < .001). From baseline to week 12, insulin-stimulated change in glucose rate of disappearance increased by 2.30% for risperidone and decreased by 29.34% for olanzapine and 30.26% for aripiprazole, with no significant difference across medications (time by treatment interaction, P < .07). This primary measure of insulin sensitivity decreased significantly during 12 weeks in the pooled study sample (effect of time, F = 17.38; P < .001). For the secondary outcomes from baseline to week 12, MRI measured abdominal fat increased, with subcutaneous fat increase significantly greater for olanzapine than risperdone or aripiprazole (time by treatment, P = .003). Behavioral improvements occurred with all treatments. Adverse changes in adiposity and insulin sensitivity were observed during 12 weeks of antipsychotic treatment in youths, with the greatest fat increases on olanzapine. Such changes, likely attributable to treatment, may be associated with risk for premature cardiometabolic morbidity and mortality. The results inform risk-benefit considerations for antipsychotic use in youths. ClinicalTrials.gov identifier: NCT00205699.
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Selle, V; Schalkwijk, S; Vázquez, G H; Baldessarini, R J
2014-03-01
Optimal treatments for bipolar depression, and the relative value of specific drugs for that purpose, remain uncertain, including agents other than antidepressants. We searched for reports of placebo-controlled, monotherapy trials of mood-stabilizing anticonvulsants, second-generation antipsychotics, or lithium for acute major depressive episodes in patients diagnosed with type I or II bipolar disorder and applied random-effects meta-analysis to evaluate their efficacy, comparing outcomes based on standardized mean drug-placebo differences (SMD) in improvement, relative response rates (RR), and number-needed-to-treat (NNT). We identified 24 trials of 10 treatments (lasting 7.5 weeks, with ≥ 50 collaborating sites/trial) that met eligibility criteria: lamotrigine (5 trials), quetiapine (5), valproate (4), 2 each for aripiprazole, olanzapine, ziprasidone, and 1 each for carbamazepine, lithium, lurasidone, and olanzapine-fluoxetine. Overall, pooled drug-over-placebo responder-rate superiority (RR) was moderate (29% [CI: 19-40%]), and NNT was 8.2 (CI: 6.4-11). By SMD, apparent efficacy ranked: olanzapine + fluoxetine ≥ valproate > quetiapine > lurasidone > olanzapine, aripiprazole, and carbamazepine; ziprasidone was ineffective, and lithium remains inadequately studied. Notably, drugs were superior to placebo in only 11/24 trials (5/5 with quetiapine, 2/4 with valproate), and only lamotrigine, quetiapine and valproate had > 2 trials. Treatment-associated mania-like reactions were uncommon (drugs: 3.7%; placebo: 4.7%). Controlled trials of non-antidepressant treatments for bipolar depression remain scarce, but findings with olanzapine-fluoxetine, lurasidone, quetiapine, and perhaps carbamazepine and valproate were encouraging; lithium requires adequate testing. © Georg Thieme Verlag KG Stuttgart · New York.
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Aripiprazole once-monthly long-acting injectable for the treatment of schizophrenia.
Potkin, Steven G; Preda, Adrian
2016-01-01
Patient non-adherence increases the risk for relapse and the long-term care of schizophrenia. Long-acting injectable (LAI) antipsychotics can decrease this risk by ensuring adherence. An extended formulation, aripiprazole 400 mg once-monthly (AOM 400) LAI (AOM LAI), received regulatory approval in the year 2013 for the treatment of schizophrenia. AOM LAI is the first dopamine D2 partial agonist available in a long-acting formulation for the treatment of schizophrenia. This review covers data on the efficacy and tolerability/safety of AOM LAI. AOM LAI is a lyophilized powder of aripiprazole, with an elimination half-life of 29.9 - 46.5 days, allowing for a 4-week injection interval. Antipsychotic efficacy was documented in a 12-week double-blind trial (n = 340) and in two maintenance-of-effect trials: a 38-week trial (n = 662) and a 52-week trial (n = 403). The side effect profile is similar to that of oral aripiprazole. Adverse events (≥5% and at least twice that for placebo) were typically mild or moderate and did not lead to discontinuation: increased weight, akathisia, injection site pain and sedation. The 400 mg dose is tolerated by >90% of patients. Injection does not require additional training of health personnel or post-injection observation. AOM LAI is an efficacious and well-tolerated antipsychotic treatment for schizophrenia.
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Cost-effectiveness of antipsychotics for outpatients with chronic schizophrenia.
Obradovic, M; Mrhar, A; Kos, M
2007-12-01
The aim of the present analysis was to evaluate the cost-effectiveness of alternative treatments for outpatients with chronic schizophrenia from the healthcare payer's perspective. Decision analysis was used to evaluate the cost-effectiveness of the following antipsychotic drugs: amisulpride, aripiprazole, haloperidol (oral formulation), haloperidol (depot formulation), olanzapine, quetiapine, risperidone (oral formulation), risperidone (depot formulation) and ziprazidone. Clinical and economic outcomes were modelled over 1-year time horizon. Effectiveness was measured as a percentage of patients in remission. Clinical parameters used in the model included compliance rates, rehospitalisation rates for compliant and non-compliant patients, duration and frequency of hospitalisation, and adverse event rates. One-way sensitivity analysis was performed to test the robustness of the model. The most effective treatment was treatment with olanzapine where 64.1% of patients remained in remission. The least effective treatment was treatment with quetiapine where 32.7% of patients remained in remission. Overall costs ranged from 3,726.78 Euro for haloperidol to 8,157.03 Euro for risperidone in depot formulation. Inpatient costs represented the major part of costs for most of antipsychotic drugs. Typical antipsychotic drugs had substantially smaller outpatient costs (6.5%) compared with atypical antipsychotics (37.9%). In the base case scenario the non-dominated treatment strategies were haloperidol, haloperidol decanoate and olanzapine. Additionally, risperidone can also be considered to be part of the efficient frontier based on the sensitivity analysis results. Among second-generation antipsychotics, which have a better safety profile than first-generation antipsychotics, olanzapine and risperidone showed to be the most cost-effective treatment strategies for outpatient treatment of chronic schizophrenia.
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Assié, Marie-Bernadette; Ravailhe, Véronique; Faucillon, Valérie; Newman-Tancredi, Adrian
2005-10-01
Several novel antipsychotics, such as aripiprazole, bifeprunox, SSR181507 [(3-exo)-8-benzoyl-N-(((2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl)methyl)-8-azabicyclo(3.2.1)octane-3-methanamine], and SLV313 [1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-4-[5-(4-fluorophenyl)-pyridin-3-ylmethyl]-piperazine], activate serotonin 5-hydroxytryptamine (5-HT)1A receptors. Such activity is associated with enhanced treatment of negative symptoms and cognitive deficits, which may be mediated by modulation of cerebral dopamine and serotonin levels. We employed microdialysis coupled to high pressure liquid chromatography with electrochemical detection to examine 5-HT1A receptor activation in the modulation of extracellular dopamine in medial prefrontal cortex and serotonin in hippocampus of freely moving rats. The above compounds were compared with drugs that have less interaction with 5-HT1A receptors (clozapine, nemonapride, ziprasidone, olanzapine, risperidone, and haloperidol). Hippocampal 5-HT was decreased by bifeprunox, SSR181507, SLV313, sarizotan, and nemonapride, effects similar to those seen with the 5-HT1A agonist, (+)-8-hydroxy-2-(di-n-propylamino)tetralin [(+)8-OH-DPAT], consistent with activation of 5-HT1A autoreceptors. These decreases were reversed by the selective 5-HT1A antagonist, WAY100635 [N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide]. In contrast, haloperidol, risperidone, clozapine, olanzapine, ziprasidone, and aripiprazole did not significantly modify hippocampal serotonin levels. In medial prefrontal cortex, dopamine levels were increased by SSR181507, SLV313, sarizotan, and (+)8-OH-DPAT. These effects were reversed by WAY100635, indicating mediation by 5-HT1A receptors. In contrast, the increases in dopamine levels induced by clozapine, risperidone, olanzapine, and ziprasidone were not blocked by WAY100635, consistent with predominant influence of other mechanisms in the actions of these drugs. Haloperidol, nemonapride, and the D2 partial agonists, aripiprazole and bifeprunox, did not significantly alter dopamine release. Taken together, these data demonstrate the diverse contribution of 5-HT1A receptor activation to the profile of antipsychotics and suggest that novel drugs selectively targeting D2 and 5-HT1A receptors may present distinctive therapeutic properties.
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In Vitro and In Vivo Characterization of the Alkaloid Nuciferine.
Farrell, Martilias S; McCorvy, John D; Huang, Xi-Ping; Urban, Daniel J; White, Kate L; Giguere, Patrick M; Doak, Allison K; Bernstein, Alison I; Stout, Kristen A; Park, Su Mi; Rodriguiz, Ramona M; Gray, Bradley W; Hyatt, William S; Norwood, Andrew P; Webster, Kevin A; Gannon, Brenda M; Miller, Gary W; Porter, Joseph H; Shoichet, Brian K; Fantegrossi, William E; Wetsel, William C; Roth, Bryan L
2016-01-01
The sacred lotus (Nelumbo nucifera) contains many phytochemicals and has a history of human use. To determine which compounds may be responsible for reported psychotropic effects, we used in silico predictions of the identified phytochemicals. Nuciferine, an alkaloid component of Nelumbo nucifera and Nymphaea caerulea, had a predicted molecular profile similar to antipsychotic compounds. Our study characterizes nuciferine using in vitro and in vivo pharmacological assays. Nuciferine was first characterized in silico using the similarity ensemble approach, and was followed by further characterization and validation using the Psychoactive Drug Screening Program of the National Institute of Mental Health. Nuciferine was then tested in vivo in the head-twitch response, pre-pulse inhibition, hyperlocomotor activity, and drug discrimination paradigms. Nuciferine shares a receptor profile similar to aripiprazole-like antipsychotic drugs. Nuciferine was an antagonist at 5-HT2A, 5-HT2C, and 5-HT2B, an inverse agonist at 5-HT7, a partial agonist at D2, D5 and 5-HT6, an agonist at 5-HT1A and D4 receptors, and inhibited the dopamine transporter. In rodent models relevant to antipsychotic drug action, nuciferine blocked head-twitch responses and discriminative stimulus effects of a 5-HT2A agonist, substituted for clozapine discriminative stimulus, enhanced amphetamine induced locomotor activity, inhibited phencyclidine (PCP)-induced locomotor activity, and rescued PCP-induced disruption of prepulse inhibition without induction of catalepsy. The molecular profile of nuciferine was similar but not identical to that shared with several approved antipsychotic drugs suggesting that nuciferine has atypical antipsychotic-like actions.
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Fagiolini, Andrea; Alfonsi, Emilia; Amodeo, Giovanni; Cenci, Mario; Di Lella, Michele; Farinella, Francesco; Ferraiuolo, Fabrizio; Fraguas, David; Loparco, Natale; Gutierrez-Rojas, Luis; Mignone, Maria Laura; Pataracchia, Giuseppe; Pillai, Gianluca; Russo, Felicia; Sanchez-Gistau, Vanessa; Spinogatti, Franco; Toscano, Marco; Villari, Vincenzo; De Filippis, Sergio
2016-01-01
Aripiprazole long acting once-monthly (AOM) is a long acting atypical antipsychotic with proven efficacy in schizophrenia and with a pharmacological and a side effect profile that is different from other antipsychotics. These and other characteristics make AOM a possible alternative in patients requiring a change in long acting antipsychotic treatment due to issues such as lack of efficacy or persistent side effects. Both clinical and pharmacological factors should be considered when switching antipsychotics, and specific guidelines for long acting antipsychotic switching that address all these factors are needed. A panel of Italian and Spanish experts in psychiatry met to discuss the strategies for the switch to AOM in patients with schizophrenia. Real life clinical experiences were shared and the clinical strategies to improve the likelihood of success were discussed. Due to its specific pharmacological and tolerability profile, AOM represents a suitable alternative for patients with schizophrenia requiring a switch to a new LAI treatment because of lack of efficacy or persistent side effects from another LAI. Possible strategies for the switch to AOM are presented in this expert consensus paper in an attempt to provide guidance throughout the entire switching process.
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Stroup, T. Scott; McEvoy, Joseph P.; Ring, Kimberly D.; Hamer, Robert H.; LaVange, Lisa M.; Swartz, Marvin S.; Rosenheck, Robert A.; Perkins, Diana O.; Nussbaum, Abraham M.; Lieberman, Jeffrey A.
2013-01-01
Objective We conducted a multi-site, randomized controlled trial examining the strategy of switching from olanzapine, quetiapine, or risperidone to aripiprazole to ameliorate metabolic risk factors for cardiovascular disease. Method Patients with schizophrenia or schizoaffective disorder with BMI ≥ 27 and non-HDL cholesterol (non-HDL-C) ≥ 130 mg/dl on a stable dosage of olanzapine, quetiapine, or risperidone were randomly assigned to stay on the current medication (n=106) or switch to aripiprazole (n=109) for 24 weeks. All participants were enrolled in a behaviorally oriented diet and exercise program. Raters were blinded to treatment assignment. The primary and key secondary outcomes were non-HDL-C change and efficacy failure, respectively. Results The pre-specified primary analysis included 89 switchers and 98 stayers who had at least one post-baseline non-HDL-C measurement. The least squares mean estimates of non-HDL-C decreased more for the switch than the stay groups (−20.2 vs. −10.8 mg/dl). Switching was associated with larger reductions in weight (2.9 kg) and a net reduction of serum triglycerides of 32.7 mg/dl. Twenty-two (20.6%) switchers and 18 (17.0%) stayers experienced protocol-defined efficacy failure. Forty-seven (43.9%) switchers and 26 (24.5%) stayers discontinued the assigned antipsychotic before 24 weeks. Conclusion Switching to aripiprazole led to improvement of non-HDL-C and other metabolic parameters. Rates of efficacy failure were similar between groups, but switching to aripiprazole was associated with a higher rate of treatment discontinuation. In the context of close clinical monitoring, switching from an antipsychotic with high metabolic risk to one with lower risk to improve metabolic parameters is an effective strategy. PMID:21768610
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Woo, Young Sup; Bahk, Won-Myong; Park, Young-Min; Chung, Sangkeun; Yoon, Bo-Hyun; Won, Seunghee; Lee, Jeong Goo; Lee, Hwang-Bin; Kim, Won; Jeong, Jong-Hyun; Lee, Kwanghun; Kim, Moon-Doo
2016-09-01
We evaluated the effectiveness of aripiprazole among bipolar patients who had switched to this medication as a result of difficulty maintaining on their prestudy atypical antipsychotics (AAPs) because of subsyndromal mood symptoms or intolerance. This study included 77 bipolar patients who were in syndromal remission with an AAP as monotherapy or with an AAP combined with a mood stabilizer(s) who needed to switch from their present AAP because of subsyndromal symptoms or intolerance. At 24 weeks after switching to aripiprazole, the remission rates on the Montgomery-Åsberg Depression Rating Scale (MADRS) and on both the MADRS and the Young Mania Rating Scale were increased significantly in the full sample and in the inefficacy subgroup. In the inefficacy subgroup, the MADRS score change was significant during the 24 weeks of study. Total cholesterol and prolactin decreased significantly after switching to aripiprazole. The proportion of patients who had abnormal values for central obesity and hypercholesterolemia decreased significantly from baseline to week 24. These findings suggest that a change from the current AAP to aripiprazole was associated with improvement in subsyndromal mood symptoms and several lipid/metabolic or safety profile parameters in patients with bipolar disorder with tolerability concerns or subsyndromal mood symptoms.
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Peters-Strickland, Timothy; Zhao, Cathy; Perry, Pamela P; Eramo, Anna; Salzman, Phyllis M; McQuade, Robert D; Johnson, Brian R; Sanchez, Raymond
2016-12-01
To assess the effects of aripiprazole once-monthly 400 mg (AOM 400) on clinical symptoms and global improvement in schizophrenia after switching from an oral antipsychotic. In a multicenter, open-label, mirror-image, naturalistic study in patients with schizophrenia (>1 year, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision [DSM-IV-TR] criteria), changes in efficacy measures were assessed during prospective treatment (6 months) with AOM 400 after switching from standard-of-care oral antipsychotics. During prospective treatment, patients were cross-titrated to oral aripiprazole monotherapy (1-4) weeks followed by open-label AOM 400 (24 weeks). Mean change from baseline of the open-label AOM 400 phase in Positive and Negative Syndrome Scale (PANSS) scores (total, positive and negative subscales) and Clinical Global Impression-Severity (CGI-S) scores; mean CGI-Improvement (CGI-I) score; and proportion of responders (≥30% decrease from baseline in PANSS total score or CGI-I score of 1 [very much improved] or 2 [much improved]) were assessed. PANSS and CGI-S scores improved from baseline (P<0.0001) and CGI-I demonstrated improvement at all time points. By the end of the study, 49.0% of patients were PANSS or CGI-I responders. In a community setting, patients with schizophrenia who were stabilized at baseline and switched to AOM 400 from oral antipsychotics showed clear improvements in clinical symptoms.
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Pan, Bo; Chen, Jiezhong; Lian, Jiamei; Huang, Xu-Feng; Deng, Chao
2015-01-01
Aripiprazole is a wide-used antipsychotic drug with therapeutic effects on both positive and negative symptoms of schizophrenia, and reduced side-effects. Although aripiprazole was developed as a dopamine D2 receptor (D2R) partial agonist, all other D2R partial agonists that aimed to mimic aripiprazole failed to exert therapeutic effects in clinic. The present in vivo study aimed to investigate the effects of aripiprazole on the D2R downstream cAMP-PKA and Akt-GSK3β signalling pathways in comparison with a D2R antagonist – haloperidol and a D2R partial agonist – bifeprunox. Rats were injected once with aripiprazole (0.75mg/kg, i.p.), bifeprunox (0.8mg/kg, i.p.), haloperidol (0.1mg/kg, i.p.) or vehicle. Five brain regions – the prefrontal cortex (PFC), nucleus accumbens (NAc), caudate putamen (CPu), ventral tegmental area (VTA) and substantia nigra (SN) were collected. The protein levels of PKA, Akt and GSK3β were measured by Western Blotting; the cAMP levels were examined by ELISA tests. The results showed that aripiprazole presented similar acute effects on PKA expression to haloperidol, but not bifeprunox, in the CPU and VTA. Additionally, aripiprazole was able to increase the phosphorylation of GSK3β in the PFC, NAc, CPu and SN, respectively, which cannot be achieved by bifeprunox and haloperidol. These results suggested that acute treatment of aripiprazole had differential effects on the cAMP-PKA and Akt-GSK3β signalling pathways from haloperidol and bifeprunox in these brain areas. This study further indicated that, by comparison with bifeprunox, the unique pharmacological profile of aripiprazole may be attributed to the relatively lower intrinsic activity at D2R. PMID:26162083
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Cost-effectiveness analysis of antipsychotics in reducing schizophrenia relapses
2012-01-01
Background Schizophrenia is a severe form of mental illness which is associated with significant and long-lasting health, social and financial burdens. The aim of this project is to assess the efficiency of the antipsychotics used in Spain in reducing schizophrenia relapses under the Spanish Health System perspective. Material and methods A decision-analytic model was developed to explore the relative cost-effectiveness of five antipsychotic medications, amisulpride, aripiprazole, olanzapine, paliperidone Extended-Release (ER) and risperidone, compared to haloperidol, over a 1-year treatment period among people living in Spain with schizophrenia. The transition probabilities for assessed therapies were obtained from the systemic review and meta-analysis performed by National Institute for Health and Clinical Excellence (NICE). Results Paliperidone ER was the option that yielded more quality-adjusted life years (QALYs) gained per patient (0.7573). In addition, paliperidone ER was the least costly strategy (€3,062), followed by risperidone (€3,194), haloperidol (€3,322), olanzapine (€3,893), amisulpride (€4,247) and aripiprazole (€4,712). In the incremental cost-effectiveness (ICE) analysis of the assessed antipsychotics compared to haloperidol, paliperidone ER and risperidone were dominant options. ICE ratios for other medications were €23,621/QALY gained, €91,584/QALY gained and €94,558/QALY gained for olanzapine, amisulpride and aripiprazole, respectively. Deterministic sensitivity analysis showed that risperidone is always dominant when compared to haloperidol. Paliperidone ER is also dominant apart from the exception of the scenario with a 20% decrease in the probability of relapses. Conclusions Our findings may be of interest to clinicians and others interested in outcomes and cost of mental health services among patients with schizophrenia. Paliperidone ER and risperidone were shown to be dominant therapies compared to haloperidol in Spain. It is worthwhile to highlight that schizophrenia is a highly incapacitating disease and choosing the most appropriate drug and formulation for a particular patient is crucial. The availability of more accurate local epidemiological data on schizophrenia would allow a better adaptation of the model avoiding some of the assumptions taken in our work. Future research could be focused on this. PMID:22828390
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Hard, Marjie L; Wehr, Angela Y; Sadler, Brian M; Mills, Richard J; von Moltke, Lisa
2018-06-11
BACKGROUND AND OBJECTIVES: Aripiprazole lauroxil (AL), a long-acting injectable antipsychotic for the treatment of schizophrenia, requires 21 days of oral aripiprazole supplementation upon initiation (21-day initiation regimen). An alternative 1-day initiation regimen utilizing a nano-crystalline milled dispersion of AL (AL NCD ) plus a single 30 mg oral aripiprazole dose achieved aripiprazole concentrations associated with therapeutic doses of aripiprazole in the same time frame as the 21-day initiation regimen when starting AL (441 or 882 mg). A population pharmacokinetic (PopPK) model was developed to describe aripiprazole pharmacokinetics following administration of AL NCD , AL and oral aripiprazole, and evaluate dosing scenarios likely to be encountered in clinical practice. In total, 12,768 plasma aripiprazole concentrations from 343 patients (from 4 clinical studies) were included in the PopPK analysis and used to construct the model. Concomitant administration of the 1-day initiation regimen with all approved AL dosing regimens (441, 662, or 882 mg monthly, 882 mg every 6 weeks, or 1064 mg every 2 months) is predicted to achieve aripiprazole concentrations associated with therapeutic doses of AL using the 21-day initiation regimen within 4 days, maintaining these concentrations until the next AL dose. Administration of the first AL injection 10 days after the 1-day initiation regimen resulted in median aripiprazole concentrations just before the second dose of AL ≥ 77% of that when coadministered on the same day. Coadministration of AL with a single AL NCD injection was predicted to be effective in rapidly re-establishing concentrations associated with therapeutic doses of AL following dose delay. Model-based simulations demonstrate that the 1-day initiation regimen is suitable for starting treatment with all AL doses, allowing a window of ≤ 10 days between initiation and AL administration. AL NCD may also be used to re-establish concentrations associated with therapeutic doses of AL in conjunction with a delayed AL dose.
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Correll, Christoph U; Kohegyi, Eva; Zhao, Cathy; Baker, Ross A; McQuade, Robert; Salzman, Phyllis M; Sanchez, Raymond; Nyilas, Margaretta; Carson, William
2017-09-01
To evaluate the efficacy, safety, and tolerability of aripiprazole, a dopamine D 2 receptor partial agonist, as maintenance treatment in adolescent outpatients with schizophrenia. This was a multicenter, double-blind, placebo-controlled, randomized withdrawal design trial. Participants 13 to 17 years of age with a diagnosis of schizophrenia (DSM-IV-TR) were first cross-titrated from their other oral antipsychotic(s) (4-6 weeks), then stabilized (7-21 weeks) on oral aripiprazole 10 to 30 mg/d, and finally randomized 2:1 to continuation of oral aripiprazole or to placebo in a double-blind maintenance phase (≤52 weeks). The primary endpoint was time from randomization to exacerbation of psychotic symptoms/impending relapse. Safety and tolerability were assessed. Of 201 enrolled participants, 146 were randomized to aripiprazole (n = 98) or placebo (n = 48) in the double-blind maintenance phase. Treatment with aripiprazole was associated with a significantly longer time to exacerbation of psychotic symptoms/impending relapse compared with placebo (hazard ratio, 0.46 [95% CI = 0.24-0.88]; p = .016). Aripiprazole was associated with lower rates of serious treatment-emergent adverse events (TEAEs) versus placebo (3.1% versus 12.5%; p = .059) and severe TEAEs (2.0% versus 10.4%; p = .039). The rate of discontinuation due to TEAEs was lower with aripiprazole versus placebo (20.4% versus 39.6%, p = .014; number-needed-to-harm = 5.1). The incidences of extrapyramidal symptoms, weight gain, and somnolence were similar or lower with aripiprazole than with placebo, and no TEAEs related to elevated serum prolactin were reported. Based on Tanner staging, 27.6% of participants treated with aripiprazole and 16.7% of those who received placebo progressed one or two stages from baseline. Aripiprazole was observed to be safe and effective for the maintenance treatment of adolescents with schizophrenia. Efficacy and Safety Study of Oral Aripiprazole in Adolescents With Schizophrenia; http://clinicaltrials.gov/; NCT01149655. Copyright © 2017 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.
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Kaneta, Hiroo; Ukai, Wataru; Tsujino, Hanako; Furuse, Kengo; Kigawa, Yoshiyasu; Tayama, Masaya; Ishii, Takao; Hashimoto, Eri; Kawanishi, Chiaki
2017-09-01
Current antipsychotics reduce positive symptoms and reverse negative symptoms in conjunction with cognitive behavioral issues with the goal of restoring impaired occupational and social functioning. However, limited information is available on their influence on gliogenesis or their neurogenic properties in adult schizophrenia brains, particularly on GABAergic interneuron production. In the present study, we used young adult subventricular zone (SVZ)-derived progenitor cells expressing proteoglycan NG2 cultures to examine the oligodendrocyte and GABAergic interneuron genesis effects of several kinds of antipsychotics on changes in differentiation function induced by exposure to the NMDA receptor antagonist MK-801. We herein demonstrated that antipsychotics promoted or restored changes in the oligodendrocyte/GABAergic interneuron differentiation functions of NG2(+) cells induced by the exposure to MK-801, which was considered to be one of the drug-induced schizophrenia model. We also demonstrated that antipsychotics restored heat-shock protein (HSP) production in NG2(+) cells with differentiation impairment. The antipsychotics olanzapine, aripiprazole, and blonanserin, but not haloperidol increased HSP90 levels, which were reduced by the exposure to MK-801. Our results showed that antipsychotics, particularly those recently synthesized, exerted similar GABAergic interneuron genesis effects on NG2(+) neuronal/glial progenitor cells in the adult rat brain by increasing cellular HSP production, and also suggest that HSP90 may play a crucial role in the pathophysiology of schizophrenia and is a key target for next drug development. Copyright © 2017 Elsevier Ltd. All rights reserved.
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Aripiprazole-induced hypersensitivity pneumonitis.
Gunasekaran, Kulothungan; Murthi, Swetha; Jennings, Jeffrey; Lone, Nazir
2017-05-09
Aripiprazole is an atypical antipsychotic agent commonly used in the management of schizophrenia. Aripiprazole has not been reported to have an association with interstitial lung disease. We describe a case of a 36-year-old woman who began to experience respiratory issues shortly after starting aripiprazole and presented to us 4 years later with progressive exertional shortness of breath. High-resolution CT of the chest showed a bilateral ground glass pattern. Video-assisted thoracoscopy with biopsy revealed alveolar septal thickening and an inflammatory infiltrate composed mainly of lymphocytes, suggestive of chronic hypersensitivity pneumonitis. After discontinuing aripiprazole and initiating prednisolone therapy, the patient's pulmonary symptoms improved. This case highlights that aripiprazole can cause hypersensitivity pneumonitis in susceptible individuals. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
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Berrouiguet, Sofian; Barrigón, Maria Luisa; Brandt, Sara A; Ovejero-García, Santiago; Álvarez-García, Raquel; Carballo, Juan Jose; Lenca, Philippe; Courtet, Philippe; Baca-García, Enrique
2016-01-01
The emergence of electronic prescribing devices with clinical decision support systems (CDSS) is able to significantly improve management pharmacological treatments. We developed a web application available on smartphones in order to help clinicians monitor prescription and further propose CDSS. A web application (www.MEmind.net) was developed to assess patients and collect data regarding gender, age, diagnosis and treatment. We analyzed antipsychotic prescriptions in 4345 patients attended in five Psychiatric Community Mental Health Centers from June 2014 to October 2014. The web-application reported average daily dose prescribed for antipsychotics, prescribed daily dose (PDD), and the PDD to defined daily dose (DDD) ratio. The MEmind web-application reported that antipsychotics were used in 1116 patients out of the total sample, mostly in 486 (44%) patients with schizophrenia related disorders but also in other diagnoses. Second generation antipsychotics (quetiapine, aripiprazole and long-acting paliperidone) were preferably employed. Low doses were more frequently used than high doses. Long acting paliperidone and ziprasidone however, were the only two antipsychotics used at excessive dosing. Antipsychotic polypharmacy was used in 287 (26%) patients with classic depot drugs, clotiapine, amisulpride and clozapine. In this study we describe the first step of the development of a web application that is able to make polypharmacy, high dose usage and off label usage of antipsychotics visible to clinicians. Current development of the MEmind web application may help to improve prescription security via momentary feedback of prescription and clinical decision support system.
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Berrouiguet, Sofian; Barrigón, Maria Luisa; Brandt, Sara A.; Ovejero-García, Santiago; Álvarez-García, Raquel; Carballo, Juan Jose; Lenca, Philippe; Courtet, Philippe; Baca-García, Enrique
2016-01-01
Purpose The emergence of electronic prescribing devices with clinical decision support systems (CDSS) is able to significantly improve management pharmacological treatments. We developed a web application available on smartphones in order to help clinicians monitor prescription and further propose CDSS. Method A web application (www.MEmind.net) was developed to assess patients and collect data regarding gender, age, diagnosis and treatment. We analyzed antipsychotic prescriptions in 4345 patients attended in five Psychiatric Community Mental Health Centers from June 2014 to October 2014. The web-application reported average daily dose prescribed for antipsychotics, prescribed daily dose (PDD), and the PDD to defined daily dose (DDD) ratio. Results The MEmind web-application reported that antipsychotics were used in 1116 patients out of the total sample, mostly in 486 (44%) patients with schizophrenia related disorders but also in other diagnoses. Second generation antipsychotics (quetiapine, aripiprazole and long-acting paliperidone) were preferably employed. Low doses were more frequently used than high doses. Long acting paliperidone and ziprasidone however, were the only two antipsychotics used at excessive dosing. Antipsychotic polypharmacy was used in 287 (26%) patients with classic depot drugs, clotiapine, amisulpride and clozapine. Conclusions In this study we describe the first step of the development of a web application that is able to make polypharmacy, high dose usage and off label usage of antipsychotics visible to clinicians. Current development of the MEmind web application may help to improve prescription security via momentary feedback of prescription and clinical decision support system. PMID:27764107
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ERIC Educational Resources Information Center
Danov, Stacy E.; Tervo, Raymond; Meyers, Stephanie; Symons, Frank J.
2012-01-01
The atypical antipsychotic medication aripiprazole was evaluated using a randomized AB multiple baseline, double-blind, placebo-controlled design for the treatment of severe problem behavior with 4 children with intellectual and developmental disabilities. Functional analysis (FA) was conducted concurrent with the medication evaluation to…
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Liu, Yueying; Ni, Hong; Wang, Chunhong; Li, Lili; Cheng, Zaohuo; Weng, Zhen
2016-06-01
Aripiprazole, an atypical antipsychotic drug, has shown potential as a promising candidate for the treatment of Tourette's disorder (TD). However, the effectiveness and the tolerability profile of aripiprazole in the reduction of tics in children and adolescents with TD have not been systematically analyzed. This meta-analysis aimed to evaluate the effectiveness and tolerability of aripiprazole in children and adolescents with TD. We searched for clinical trials that investigated the effect of aripiprazole in children and adolescents with TD in PubMed and Web of Science. The outcomes of interest comprised the Yale Global Tic Severity Score (YGTSS) total tic scores and the Clinical Global Impressions Scale for Tic Severity (CGI-S) scores. The pooled effect size (ES) and 95% confidence interval (CI) were calculated to assess the effectiveness of aripiprazole in children and adolescents with TD. Ten studies were retrieved from 122 citations for the analysis, and in total, 302 patients (mean age, 11.6 years; median follow-up, 9 weeks) were included in the analysis. After synthesis of the data, the meta-analysis showed significantly greater improvement in the mean change in the YGTSS total tic scores (ES = -1.99, 95% CI = [-2.26]-[-1.72]; p = 0.001) and the mean CGI-S scores (ES = -2.34, 95% CI = [-2.96]-[-1.73]; p = 0.001) from pretreatment to posttreatment. Adverse events were reported in nine trials. Drowsiness (28.5%), nausea (20.2%), and headache (13.8%) were common adverse events. The use of aripiprazole is safe, and shows therapeutic effectiveness in children and adolescents with TD.
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ERIC Educational Resources Information Center
Cohen, David; Raffin, Marie; Canitano, Roberto; Bodeau, Nicolas; Bonnot, Olivier; Perisse, Didier; Consoli, Angele; Laurent, Claudine
2013-01-01
Second-generation antipsychotics (SGAs) induce frequent adverse effects in children and adolescents with each compound appearing to have a specific adverse effect profile. Aripiprazole and risperidone are FDA-approved medications for behavioral disturbances associated with autism and/or intellectual disabilities (ID) in children and adolescents.…
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Zhang, Chen; Chen, Mei-Juan; Wu, Guo-Jun; Wang, Zuo-Wei; Rao, Shun-Zeng; Zhang, Yi; Yi, Zheng-Hui; Yang, Wei-Min; Gao, Ke-Ming; Song, Li-Sheng
2016-11-01
Maintenance treatment of schizophrenia with antipsychotic medications has become a standard for the prevention of psychotic relapse. However, little is known about the effectiveness of antipsychotic drugs for maintenance treatment in "real-world" populations with schizophrenia. We carried out a prospective study to assess the effectiveness of the most frequently prescribed antipsychotic drugs in the maintenance treatment of schizophrenia from 2 community settings. This study was conducted from October 2011 to December 2014. All participants were diagnosed with schizophrenia according to DSM-IV, were treated with an antipsychotic monotherapy, and were registered in a case management program with monthly monitoring for 24 months. The primary outcome measure, Positive and Negative Syndrome Scale (PANSS), and the Clinical Global Impressions-Severity of Illness (CGI-S) and -Improvement (CGI-I) scales were used to evaluate symptom severity and treatment response. The Personal and Social Performance scale (PSP) was used to evaluate the patients' social functioning. The Medication Adherence Rating Scale (MARS) was used to assess medication adherence behavior. On the basis of antipsychotic used at baseline, patients were clustered into 7 groups: aripiprazole (n = 21), clozapine (n = 84), chlorpromazine (n = 61), olanzapine (n = 34), perphenazine (n = 21), quetiapine (n = 27), and risperidone (n = 99). Of the 347 patients enrolled in the study, 312 completed the 24-month follow-up. There were no significant differences among the treatment groups in the PANSS total and subscale scores or the CGI-S and CGI-I scores over 24 months (all P values > .05). There were also no significant differences in interactions between PSP scores and antipsychotic drugs (P = .17). The remission rates increased as the follow-time lapsed in all groups, but no significant difference was observed in remission rates at each time point among the 7 groups (P values > .05). At the endpoint, MARS total scores were over 6, but did not significantly differ among the studied drugs (P = .24). These findings suggest that antipsychotic drugs can achieve equivalent effectiveness in maintenance treatment of first-episode schizophrenia through a well-organized case management program and family participation. © Copyright 2016 Physicians Postgraduate Press, Inc.
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Yamashita, Satoko; Miyaoka, Tsuyoshi; Nagahama, Michiharu; Ieda, Masa; Tsuchie, Keiko; Wake, Rei; Horiguchi, Jun
2016-01-01
Paroxysmal perceptual alteration (PPA) is the occurrence of brief and recurrent episodes of perceptual changes. It is mainly caused by the treatment of schizophrenia patients with antipsychotics. However, diagnosis of PPA is not very prevalent among psychiatrists, partly due to underrecognition or misunderstanding that it is a worsening of psychiatric symptoms. If psychiatrists do not understand PPA, they cannot treat it appropriately, and the patient's quality of life is impaired. We present a case of PPA in catatonic schizophrenia that was successfully treated by switching to aripiprazole from risperidone. We suggest that the disappearance of PPA in our case was due to both discontinuing risperidone, which completely blocks D2 receptors, and replacing it with aripiprazole, which is characterized as a partial agonist of D2 receptors. Treatment of PPA will improve medication adherence and quality of life. It is important to recognize PPA as a possible side effect of treatment with antipsychotics.
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Bruins Slot, Liesbeth A; Palmier, Christiane; Tardif, Stéphanie; Cussac, Didier
2007-08-01
The effects of new generation antipsychotic drugs (APDs) targeting dopamine D(2) and serotonin 5-HT(1A) receptors were compared with typical and atypical APDs on phosphorylation of extracellular signal-regulated kinase 1/2 (ERK 1/2) and measures of G protein activation in CHO cell lines stably expressing the human dopamine D(3) receptor. The preferential dopamine D(3) agonists (+)-7-OH-DPAT and PD128907, like dopamine and quinelorane, efficaciously stimulated ERK 1/2 phosphorylation at dopamine D(3) receptors. In contrast, in [(35)S]GTPgammaS binding experiments, (+)-7-OH-DPAT exhibited partial agonist properties, while PD128907 and quinelorane maintained full agonist properties. The preferential dopamine D(3) ligand BP 897 and the antidyskinetic sarizotan partially activated ERK 1/2 phosphorylation while exerting no agonist activity on GTPgammaS binding, suggesting signal amplification at the MAP kinase level. Antipsychotics differed in their ability to inhibit both agonist-stimulated GTPgammaS binding and ERK 1/2 phosphorylation, but all typical and atypical compounds tested acted as dopamine D(3) receptor antagonists with the exception of n-desmethylclozapine, the active metabolite of clozapine, which partially activated dopamine D(3) receptor-mediated ERK 1/2 phosphorylation. Among the new generation dopamine D(2)/serotonin 5-HT(1A) antipsychotics, only F 15063 and SLV313 acted as pure dopamine D(3) receptor antagonists, bifeprunox was highly efficacious whereas SSR181507 and aripiprazole showed marked partial agonist properties for ERK 1/2 phosphorylation. In contrast, in the GTPgammaS binding study, aripiprazole was devoid of agonist properties and bifeprunox, and to an even lesser extent SSR181507, only weakly stimulated GTPgammaS binding. In summary, these findings underline the differences of dopamine D(3) properties of new generation antipsychotics which may need to be considered in understanding their diverse therapeutic actions.
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Ascher-Svanum, Haya; Furiak, Nicolas M; Lawson, Anthony H; Klein, Timothy M; Smolen, Lee J; Conley, Robert R; Culler, Steven D
2012-01-01
Although the use of innovative drug delivery systems, like orally disintegrating antipsychotic tablets (ODT), may facilitate medication adherence and help reduce the risk of relapse and hospitalization, no information is available about the comparative cost-effectiveness of standard oral tablets (SOT) vs ODT formulations in the treatment of schizophrenia. This study compared the cost-effectiveness of olanzapine ODT and olanzapine SOT in the usual treatment of outpatients with schizophrenia from a US healthcare perspective. The study also compared olanzapine ODT with risperidone and aripiprazole, two other atypical antipsychotics available in both ODT and SOT formulations. Published medical literature and a clinical expert panel were used to populate a 1-year Monte Carlo Micro-simulation model. The model captures clinical and cost parameters including adherence levels, treatment discontinuation by reason, relapse with and without inpatient hospitalization, quality-adjusted life years (QALYs), treatment-emergent adverse events, healthcare resource utilization, and associated costs. Key outcomes were total annual direct cost per treatment, QALY, and incremental cost-effectiveness (ICER) per 1 QALY gained. Based on model projections, olanzapine ODT therapy was more costly ($9808 vs $9533), but more effective in terms of a lower hospitalization rate (15% vs 16%) and better QALYs (0.747 vs 0.733) than olanzapine SOT therapy. Olanzapine ODT was more cost-effective than olanzapine SOT (ICER: $19,643), more cost-effective than risperidone SOT therapy (ICER: $39,966), and dominant (meaning less costly and more effective) than risperidone ODT and aripiprazole in ODT or SOT formulations. Lack of head-to-head randomized studies comparing the three studied atypical antipsychotics required making input assumptions that need further study. This micro-simulation found that the utilization of olanzapine ODT for the treatment of schizophrenia is predicted to be more cost-effective than any other ODT or SOT formulations of the studied atypical antipsychotic medications.
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Regional variation in physician adoption of antipsychotics: Impact on US Medicare expenditures
Donohue, Julie M.; Normand, Sharon-Lise T.; Horvitz-Lennon, Marcela; Men, Aiju; Berndt, Ernst R.; Huskamp, Haiden A.
2016-01-01
Background Regional variation in US Medicare prescription drug spending is driven by higher prescribing of costly brand-name drugs in some regions. This variation likely arises from differences in the speed of diffusion of newly-approved medications. Second-generation antipsychotics were widely adopted for treatment of severe mental illness and for several off-label uses. Rapid diffusion of new psychiatric drugs likely increases drug spending but its relationship to non-drug spending is unclear. The impact of antipsychotic diffusion on drug and medical spending is of great interest to public payers like Medicare, which finance a majority of mental health spending in the U.S. Aims We examine the association between physician adoption of new antipsychotics and antipsychotic spending and non-drug medical spending among disabled and elderly Medicare enrollees. Methods We linked physician-level data on antipsychotic prescribing from an all-payer dataset (IMS Health's Xponent™) to patient-level data from Medicare. Our physician sample included 16,932 U.S. psychiatrists and primary care providers with ≥10 antipsychotic prescriptions per year from 1997-2011. We constructed a measure of physician adoption of 3 antipsychotics introduced during this period (quetiapine, ziprasidone and aripiprazole) by estimating a shared frailty model of the time to first prescription for each drug. We then assigned physicians to one of 306 U.S. hospital referral regions (HRRs) and measured the average propensity to adopt per region. Using 2010 data for a random sample of 1.6 million Medicare beneficiaries, we identified 138,680 antipsychotic users. A generalized linear model with gamma distribution and log link was used to estimate the effect of region-level adoption propensity on beneficiary-level antipsychotic spending and non-drug medical spending adjusting for patient demographic and socioeconomic characteristics, health status, eligibility category, and whether the antipsychotic was for an on- vs. off-label use. Results In our sample, mean patient age was 62 years, 42% were male, and 86% had low-income. Half of antipsychotic users in Medicare had an on-label indication. The weighted average propensity to adopt the three new antipsychotics varied four-fold across HRRs. For every one standard deviation increase in the propensity to adopt there was a 5% increase in antipsychotic spending after adjusting for covariates (adjusted ratio of spending = 1.05, 95% CI 1.01-1.08, p= 0.005). Physician propensity to adopt new antipsychotics was not associated with non-drug medical spending (adjusted ratio 0.96, 95% CI 0.91-1.01, p<0.117). Discussion These findings suggest wide regional variation in physicians’ propensity to adopt new antipsychotic medications. While physician adoption of new antipsychotics was positively associated with antipsychotic expenditures, it was not associated with non-drug spending. Our analysis is limited to Medicare and may not generalize to other payers. Also, claims data do not allow the measurement of health outcomes, which would be important to evaluate when calculating the value of rapid vs. slow technology adoption. Implications for Health Policies This study will provide important insight on the relationship between the speed of adoption of new antipsychotic medications and drug and non-drug medical spending for payers and policymakers seeking to maximize the value of health care expenditures. PMID:27453458
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Emerging pharmacological therapies in schizophrenia: what's new, what's different, what's next?
Citrome, Leslie
2016-12-01
There are several new and emerging medication interventions for both the acute and maintenance treatment phases of schizophrenia. Recently approved are 2 new dopamine receptor partial agonists, brexpiprazole and cariprazine, as well as 2 new long-acting injectable antipsychotic formulations, aripiprazole lauroxil and 3-month paliperidone palmitate. Although differences in efficacy compared to other available choices are not expected, the new oral options offer different tolerability profiles that may be attractive for individual patients who have had difficulties with older medications. The new long-acting injectable options provide additional flexibility in terms of increasing the time interval between injections. In Phase III of clinical development is a novel antipsychotic, lumateperone (ITI-007), that appears to have little in the way of significant adverse effects. Deutetrabenazine and valbenazine are agents in Phase III for the treatment of tardive dyskinesia, a condition that can be found among persons receiving chronic antipsychotic therapy. On the horizon are additional injectable formulations of familiar antipsychotics, aripiprazole and risperidone, that may be more convenient than what is presently available.
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Hellings, Jessica A; Arnold, L Eugene; Han, Joan C
2017-04-01
Drug development and repurposing are urgently needed for individuals with autism spectrum disorders (ASD) and psychiatric comorbidity, which often presents as aggression and self-injury. Areas covered: We review dopamine antagonists, including classical and atypical, as well as unconventional antipsychotics in ASD. The older antipsychotic loxapine is discussed in terms of preliminary albeit limited evidence in ASD. Emerging promise of amitriptyline in ASD is discussed, together with promising BDNF effects of loxapine and amitriptyline. Expert opinion: In ASD, pharmacotherapy and specifically dopamine antagonist drugs are often prescribed for challenging behaviors including aggression. The novel antipsychotics risperidone and aripiprazole have received most study in ASD and are FDA-approved for irritability in children with ASD over age 5 years; individuals with ASD are prone to weight gain, Type II diabetes and associated side effects. Low dose loxapine has properties of classical and novel antipsychotics but importantly appears more weight neutral, and with promising use in adolescents and adults with ASD. Amitriptyline appears effective in ASD for irritability, aggression, gastrointestinal problems, and insomnia, in children, adolescents and adults however our adult data on amitriptyline in ASD is still in preparation for publication. Both loxapine and amitriptyline may stimulate BDNF; further studies are warranted.
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Interventions for tic disorders: An overview of systematic reviews and meta analyses.
Yang, Chunsong; Hao, Zilong; Zhu, Cairong; Guo, Qin; Mu, Dezhi; Zhang, Lingli
2016-04-01
We conducted a comprehensive search and the overview included 22 systematic reviews (SRs) for treating tic disorders (TDs). Three SRs indicated typical antipsychotics (i.e., haloperidol, pimozide) were efficacious in the reduction of tic severity compared with placebo but with poor tolerability. Six SRs assessed the efficacy of atypical antipsychotics and indicated that atypical antipsychotics (i.e., risperidone, aripiprazole) could significantly improved tic symptoms compared with placebo or typical antipsychotics with less AEs. Four SRs indicated alpha adrenergic agonists (i.e., clonidine, guanfacine) could improve tic symptoms. Two SRs assessed the efficacy of antiepileptic drugs and indicated topiramate was a promising therapy. Six SRs evaluated the efficacy of behavior therapy and showed habit reversal therapy (HRT) and exposure and response prevention (ERP) were effective. One SR evaluated the efficacy deep brain stimulation (DBS) and indicated DBS is a promising treatment option for severe cases of TS. In conclusion, RCTs directly comparing different pharmacological treatment options are scarce. In practice, typical and atypical antipsychotics are often considered firstly while other pharmacological medications are suggested as alternatives in the case of treatment failure or contradictory outcomes. Behavioral therapies can be used either alone or in combination with medication. Copyright © 2016. Published by Elsevier Ltd.
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Adler, Benjamin A; Wink, Logan K; Early, Maureen; Shaffer, Rebecca; Minshawi, Noha; McDougle, Christopher J; Erickson, Craig A
2015-01-01
Aggression, self-injurious behavior, and severe tantrums are impairing symptoms frequently experienced by individuals with autism spectrum disorders. Despite US Food and Drug Administration approval of two atypical antipsychotics targeting these symptoms in youth with autistic disorder, they remain frequently drug refractory. We define drug-refractory aggression, self-injurious behavior, and severe tantrums in people with autism spectrum disorders as behavioral symptoms requiring medication adjustment despite previous trials of risperidone and aripiprazole or previous trials of three psychotropic drugs targeting the symptom cluster, one of which was risperidone or aripiprazole. We reviewed the medical records of individuals of all ages referred to our clinic for autism spectrum disorder diagnostic evaluation, as well as pharmacotherapy follow-up notes for all people meeting autism spectrum disorder criteria, for drug-refractory symptoms. Among 250 consecutively referred individuals, 135 met autism spectrum disorder and enrollment criteria, and 53 of these individuals met drug-refractory symptom criteria. Factors associated with drug-refractory symptoms included age 12 years or older (p < 0.0001), diagnosis of autistic disorder (p = 0.0139), and presence of intellectual disability (p = 0.0273). This pilot report underscores the significance of drug-refractory aggression, self-injurious behavior, and severe tantrums; suggests the need for future study clarifying factors related to symptom development; and identifies the need for focused treatment study of this impairing symptom domain. © The Author(s) 2014.
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Atypical antipsychotics in the treatment of early-onset schizophrenia
Hrdlicka, Michal; Dudova, Iva
2015-01-01
Atypical antipsychotics (AAPs) have been successfully used in early-onset schizophrenia (EOS). This review summarizes the randomized, double-blind, controlled studies of AAPs in EOS, including clozapine, risperidone, olanzapine, aripiprazole, paliperidone, quetiapine, and ziprasidone. No significant differences in efficacy between AAPs were found, with the exception of clozapine and ziprasidone. Clozapine demonstrated superior efficacy in treatment-resistant patients with EOS, whereas ziprasidone failed to demonstrate efficacy in the treatment of EOS. Our review also focuses on the onset of action and weight gain associated with AAPs. The data on onset of action of AAPs in pediatric psychiatry are scanty and inconsistent. Olanzapine appears to cause the most significant weight gain in patients with EOS, while ziprasidone and aripiprazole seem to cause the least. PMID:25897226
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Genaro-Mattos, Thiago C; Tallman, Keri A; Allen, Luke B; Anderson, Allison; Mirnics, Karoly; Korade, Zeljka; Porter, Ned A
2018-06-15
While antipsychotic medications provide important relief from debilitating psychotic symptoms, they also have significant adverse side effects, which might have relevant impact on human health. Several research studies, including ours, have shown that commonly used antipsychotics such as haloperidol and aripiprazole affect cholesterol biosynthesis at the conversion of 7-dehydrocholesterol (7-DHC) to cholesterol. This transformation is promoted by the enzyme DHCR7 and its inhibition causes increases in plasma and tissue levels of 7-DHC. The inhibition of this enzymatic step by mutations in the Dhcr7 gene leads to Smith-Lemli-Opitz syndrome, a devastating human condition that can be replicated in rats by small molecule inhibitors of DHCR7. The fact that two compounds, brexpiprazole and cariprazine, that were recently approved by the FDA have substructural elements in common with the DHCR7 inhibitor aripiprazole, prompted us to evaluate the effect of brexpiprazole and cariprazine on cholesterol biosynthesis. We report that cariprazine affects levels of 7-DHC and cholesterol in cell culture incubations at concentrations as low as 5 nM. Furthermore, a common metabolite of cariprazine and aripiprazole, 2,3-(dichlorophenyl) piperazine, inhibits DHCR7 activity at concentrations comparable to those of the potent teratogen AY9944. The cell culture experiments were corroborated in mice in studies showing that treatment with cariprazine elevated 7-DHC in brain and serum. The consequences of sterol inhibition by antipsychotics in the developing nervous system and the safety of their use during pregnancy remains to be established. Copyright © 2018 Elsevier Inc. All rights reserved.
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2014-01-01
Background Signaling pathways outside dopamine D2 receptor antagonism may govern the variable clinical profile of antipsychotic drugs (APD) in schizophrenia. One postulated mechanism causal to APD action may regulate synaptic plasticity and neuronal connectivity via the extracellular signal-regulated kinase (ERK) cascade that links G-protein coupled receptors (GPCR) and ErbB growth factor signaling, systems disturbed in schizophrenia. This was based upon our finding that the low D2 receptor affinity APD clozapine induced initial down-regulation and delayed epidermal growth factor receptor (EGFR or ErbB1) mediated activation of the cortical and striatal ERK response in vivo distinct from olanzapine or haloperidol. Here we map whether the second generation atypical APDs aripiprazole and quetiapine affect the EGFR-ERK pathway and its substrates p90RSK and c-Fos in mouse brain, given their divergent agonist and antagonist properties on dopaminergic transmission, respectively. Results In prefrontal cortex, aripiprazole triggered triphasic ERK phosphorylation that was EGFR-independent but had no significant effect in striatum. Conversely quetiapine did not alter cortical ERK signaling but elevated striatal ERK levels in an EGFR-dependent manner. Induction of ERK by aripiprazole did not affect p90RSK signaling but quetiapine decreased RSK phosphorylation within 1-hour of administration. The transcription factor c-Fos by comparison was a direct target of ERK phosphorylation induced by aripiprazole in cortex and quetiapine in striatum with protein levels in temporal alignment with that of ERK. Conclusions These data indicate that aripiprazole and quetiapine signal to specific nuclear targets of ERK, which for quetiapine occurs via an EGFR-linked mechanism, possibly indicating involvement of this system in its action. PMID:24552586
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Patient-oriented randomisation: A new trial design applied in the Neuroleptic Strategy Study.
Schulz, Constanze; Timm, Jürgen; Cordes, Joachim; Gründer, Gerhard; Mühlbauer, Bernd; Rüther, Eckart; Heinze, Martin
2016-06-01
The 'gold standard' for clinical studies is a randomised controlled trial usually comparing specific treatments. If the scientific study expands to strategy comparison with each strategy including various treatments, the research problems are increasingly complicated. The strategy debate in the psychiatric community is the starting point for the development of our new design. It is widely accepted that second-generation antipsychotics are the therapy of choice in the treatment of schizophrenia. However, their general superiority over first-generation antipsychotics could not be demonstrated in recent randomised controlled trials. Furthermore, we are becoming increasingly aware that the experimental conditions of randomised controlled trials, as in the European First Episode Schizophrenia Trial and Clinical Antipsychotic Trials of Intervention Effectiveness Phase 1 studies, may be inappropriate for psychiatric treatments. The high heterogeneity in the patient population produces discrepancies between daily clinical perception and randomised controlled trials results. The patient-oriented approach in the Cost Utility of the Latest Antipsychotic drugs in Schizophrenia Study reflects everyday clinical practice. The results, however, are highly dependent on the physicians' preferences. The goal of the design described here is to take an intermediate path between randomised controlled trials and clinical studies such as Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study, combining the advantages of both study types. The idea is to randomise two treatment pairs each consisting of one first-generation antipsychotic and one second-generation antipsychotic in a first step and subsequently, to involve the investigators in deciding for a pair most appropriate to the patients' needs and then to randomise the allocation to one drug (first-generation antipsychotic or second-generation antipsychotic) of that chosen pair. This idea was first implemented in the clinical trial, the Neuroleptic Strategy Study, with a randomised design comparing efficacy and safety of two different strategies: either to use first-generation antipsychotics (haloperidol and flupentixol) or second-generation antipsychotics (olanzapine, aripiprazole and quetiapine) in patients suffering from schizophrenia. In the course of the Neuroleptic Strategy Study, feasibility of this design was demonstrated. All aspects of the new design were implemented: randomisation process, documentation of responses from investigators as well as patients and drug logistic experience. In implementing the design, furthermore, we could investigate its theoretical properties. The physicians' preferences for specific drugs used for the respective patients were analysed. The idea of patient-oriented randomisation can be generalised. In light of the heterogeneity and complexity of patient-drug interaction, this design should prove particularly useful. © The Author(s) 2016.
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Hard, Marjie L.; Mills, Richard J.; Sadler, Brian M.; Turncliff, Ryan Z.; Citrome, Leslie
2017-01-01
Abstract Background Aripiprazole lauroxil is an extended-release prodrug of aripiprazole for intramuscular injection, approved for schizophrenia treatment. We developed a population pharmacokinetic (PopPK) model to characterize aripiprazole lauroxil PK and evaluate dosing scenarios likely to be encountered in clinical practice. Methods Data from 616 patients with schizophrenia, collected from 5 clinical studies, were used to construct the PopPK model. The model was subsequently used to evaluate various dose levels and frequency and the impact of dosing delay on aripiprazole concentrations. Findings The results of the model indicate that aripiprazole is released into the systemic circulation after 5 to 6 days, and release continues for an additional 36 days. The slow increase in aripiprazole concentration after injection necessitates the coadministration of oral aripiprazole for 21 days with the first injection. Based on the PopPK model simulations, a dosing interval of 882 mg every 6 weeks results in aripiprazole concentrations that fall within the concentration range associated with the efficacious aripiprazole lauroxil dose range (441–882 mg dosed monthly). A 662-mg monthly dose also resulted in aripiprazole concentrations within the efficacious dose range. Aripiprazole lauroxil administration results in prolonged exposure, such that dose delays of 2 to 4 weeks, depending on the dose regimen, do not require oral aripiprazole supplementation upon resumption of dosing. Conclusions This PopPK model and model-based simulations were effective means for evaluating aripiprazole lauroxil dosing regimens and management of missed doses. Such analyses play an important role in determining the use of this long-acting antipsychotic in clinical practice. PMID:28350572
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Effects of antipsychotic drugs on insight in schizophrenia.
Bianchini, Oriana; Porcelli, Stefano; Nespeca, Claudia; Cannavò, Dario; Trappoli, Angela; Aguglia, Eugenio; De Ronchi, Diana; Serretti, Alessandro
2014-08-15
Lack of insight is predominant in schizophrenia though the causes are still unclear. The present study was carried on to investigate the effect of three Second Generation Antipsychotics (SGAs) and Haloperidol on insight and the associations among different clusters of symptoms and insight. Fifty-five patients have been recruited at the moment of pharmacological switch needed for psychotic exacerbation, from other antipsychotic drugs to Olanzapine, Aripiprazole, Ziprasidone and Haloperidol. Patients have been followed for 6 months and evaluated at baseline, after 3 months and after 6 months. Regarding the insight improvement, all SGAs resulted more effective than Haloperidol, while no difference was detected among different SGAs. Concerning psychopathology, all SGAs showed a better efficacy than Haloperidol, positive symptoms apart. All SGAs showed a similar efficacy on all domains, except for negative symptoms which resulted less responsive to ziprasidone and haloperidol. An association between improvement of insight and psychopathology was detected. Furthermore, insight appears to be related to psychopathology severity, particularly to negative symptoms. However, the observed different effectiveness of Ziprasidone on negative symptoms and insight suggests that these psychopathological features may be not strictly related and, thus, they may be sustained by different psychopathological processes. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
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Chen, Jing-Xu; Su, Yun-Ai; Bian, Qing-Tao; Wei, Li-He; Zhang, Rong-Zhen; Liu, Yan-Hong; Correll, Christoph; Soares, Jair C; Yang, Fu-De; Wang, Shao-Li; Zhang, Xiang-Yang
2015-08-01
Hyperprolactinemia is an unwanted adverse effect associated with several antipsychotics. The addition of partial dopamine receptor agonist aripiprazole may attenuate antipsychotic-induced hyperprolactinemia effectively. However, the ideal dosing regimen for this purpose is unknown. We aimed to evaluate the dose effects of adjunctive treatment with aripiprazole on prolactin levels and hyperprolactinemia in schizophrenia patients. Stable subjects 18-45 years old with schizophrenia and hyperprolactinemia (i.e., >24 ng/ml for females and >20 ng/ml for males) were randomly assigned to receive 8 weeks of placebo (n=30) or oral aripiprazole 5mg/day (n=30), 10mg/day (n=29), or 20mg/day (n=30) added on to fixed dose risperidone treatment. Serum prolactin levels were measured at baseline and after 2, 4 and 8 weeks; clinical symptoms and side effects were assessed at baseline and week 8 using the Positive and Negative Syndrome Scale, Clinical Global Impressions Severity scale, Barnes Akathisia Scale, Simpson-Angus Scale and UKU Side Effects Rating Scale. Of 119 randomized patients, 107 (89.9%) completed the 8-week study. At study end, all three aripiprazole doses resulted in significantly lower prolactin levels (beginning at week 2), higher response rates (≥30% prolactin reduction) and higher prolactin normalization rates than placebo. Effects were significantly greater in the 10 and 20mg/day groups than the 5mg/day group. No significant changes were observed in any treatment groups regarding psychopathology and adverse effect ratings. Adjunctive aripiprazole treatment was effective and safe for resolving risperidone-induced hyperprolactinemia, producing significant and almost maximal improvements by week 2 without significant effects on psychopathology and side effects. Copyright © 2015 Elsevier Ltd. All rights reserved.
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Bechdolf, Andreas; Müller, Hendrik; Stützer, Hartmut; Wagner, Michael; Maier, Wolfgang; Lautenschlager, Marion; Heinz, Andreas; de Millas, Walter; Janssen, Birgit; Gaebel, Wolfgang; Michel, Tanja Maria; Schneider, Frank; Lambert, Martin; Naber, Dieter; Brüne, Martin; Krüger-Özgürdal, Seza; Wobrock, Thomas; Riedel, Michael; Klosterkötter, Joachim
2011-09-01
Antipsychotics, cognitive behavioral therapy (CBT), and omega-3-fatty acids have been found superior to control conditions as regards prevention of psychosis in people at-risk of first-episode psychosis. However, no large-scale trial evaluating the differential efficacy of CBT and antipsychotics has been performed yet. In PREVENT, we evaluate CBT, aripiprazole, and clinical management (CM) as well as placebo and CM for the prevention of psychosis in a randomized, double-blind, placebo-controlled trial with regard to the antipsychotic intervention and a randomized controlled trial with regard to the CBT intervention with blinded ratings. The hypotheses are first that CBT and aripiprazole and CM are superior to placebo and CM and second that CBT is not inferior to aripiprazole and CM combined. The primary outcome is transition to psychosis. By November 2010, 156 patients were recruited into the trial. The subjects were substantially functionally compromised (Social and Occupational Functioning Assessment Scale mean score 52.5) and 78.3% presented with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition axis I comorbid diagnosis. Prior to randomization, 51.5% of the participants preferred to be randomized into the CBT arm, whereas only 12.9% preferred pharmacological treatment. First, assessments of audiotaped treatment sessions confirmed the application of CBT-specific skills in the CBT condition and the absence of those in CM. The overall quality rating of the CBT techniques applied in the CBT condition was good. When the final results of the trial are available, PREVENT will substantially expand the current limited evidence base for best clinical practice in people at-risk (prodromal) of first-episode psychosis.
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The Texas Medication Algorithm Project antipsychotic algorithm for schizophrenia: 2003 update.
Miller, Alexander L; Hall, Catherine S; Buchanan, Robert W; Buckley, Peter F; Chiles, John A; Conley, Robert R; Crismon, M Lynn; Ereshefsky, Larry; Essock, Susan M; Finnerty, Molly; Marder, Stephen R; Miller, Del D; McEvoy, Joseph P; Rush, A John; Saeed, Sy A; Schooler, Nina R; Shon, Steven P; Stroup, Scott; Tarin-Godoy, Bernardo
2004-04-01
The Texas Medication Algorithm Project (TMAP) has been a public-academic collaboration in which guidelines for medication treatment of schizophrenia, bipolar disorder, and major depressive disorder were used in selected public outpatient clinics in Texas. Subsequently, these algorithms were implemented throughout Texas and are being used in other states. Guidelines require updating when significant new evidence emerges; the antipsychotic algorithm for schizophrenia was last updated in 1999. This article reports the recommendations developed in 2002 and 2003 by a group of experts, clinicians, and administrators. A conference in January 2002 began the update process. Before the conference, experts in the pharmacologic treatment of schizophrenia, clinicians, and administrators reviewed literature topics and prepared presentations. Topics included ziprasidone's inclusion in the algorithm, the number of antipsychotics tried before clozapine, and the role of first generation antipsychotics. Data were rated according to Agency for Healthcare Research and Quality criteria. After discussing the presentations, conference attendees arrived at consensus recommendations. Consideration of aripiprazole's inclusion was subsequently handled by electronic communications. The antipsychotic algorithm for schizophrenia was updated to include ziprasidone and aripiprazole among the first-line agents. Relative to the prior algorithm, the number of stages before clozapine was reduced. First generation antipsychotics were included but not as first-line choices. For patients refusing or not responding to clozapine and clozapine augmentation, preference was given to trying monotherapy with another antipsychotic before resorting to antipsychotic combinations. Consensus on algorithm revisions was achieved, but only further well-controlled research will answer many key questions about sequence and type of medication treatments of schizophrenia.
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Aripiprazole for treating irritability in children & adolescents with autism: a systematic review
Ghanizadeh, Ahmad; Tordjman, Sylvie; Jaafari, Nematollah
2015-01-01
Background & objectives: No clear therapeutic benefits of antipsychotics have been reported for the treatment of behavioural symptoms in autism. This systematic review provides an assessment of evidence for treating irritability in autism by aripiprazole. Methods: The databases of MEDLINE/PubMed and Google Scholar were searched for relevant articles about the effect of aripiprazole in children with autism. The articles were searched according to the inclusion and exclusion criteria specifed for this review. All the double-blind, controlled, randomized, clinical trials examining the efficacy of aripiprazole for treating children and adolescents with autism were included. Results: From the 93 titles identified, 26 were irrelevant and 58 were evaluated for more details. Only five articles met the inclusive criteria. The evidence from precise randomized double blind clinical trials of aripiprazole for the treatment of autism in children and adolescents was convincing enough to recommend aripiprazole. Adverse effects were not very common and were usually mild. Interpretation & conclusions: Current evidence suggests that aripiprazole is as effective and safe as risperidone for treating irritability in autism. However, further studies with larger sample size and longer duration are required. PMID:26458342
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Aripiprazole for treating irritability in children & adolescents with autism: A systematic review.
Ghanizadeh, Ahmad; Tordjman, Sylvie; Jaafari, Nematollah
2015-09-01
No clear therapeutic benefits of antipsychotics have been reported for the treatment of behavioural symptoms in autism. This systematic review provides an assessment of evidence for treating irritability in autism by aripiprazole. The databases of MEDLINE/PubMed and Google Scholar were searched for relevant articles about the effect of aripiprazole in children with autism. The articles were searched according to the inclusion and exclusion criteria specifed for this review. All the double-blind, controlled, randomized, clinical trials examining the efficacy of aripiprazole for treating children and adolescents with autism were included. From the 93 titles identified, 26 were irrelevant and 58 were evaluated for more details. Only five articles met the inclusive criteria. The evidence from precise randomized double blind clinical trials of aripiprazole for the treatment of autism in children and adolescents was convincing enough to recommend aripiprazole. Adverse effects were not very common and were usually mild. Current evidence suggests that aripiprazole is as effective and safe as risperidone for treating irritability in autism. However, further studies with larger sample size and longer duration are required.
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Blonanserin extensively occupies rat dopamine D3 receptors at antipsychotic dose range.
Baba, Satoko; Enomoto, Takeshi; Horisawa, Tomoko; Hashimoto, Takashi; Ono, Michiko
2015-03-01
Antagonism of the dopamine D3 receptor has been hypothesized to be beneficial for schizophrenia cognitive deficits, negative symptoms and extrapyramidal symptoms. However, recent animal and human studies have shown that most antipsychotics do not occupy D3 receptors in vivo, despite their considerable binding affinity for this receptor in vitro. In the present study, we investigated the D3 receptor binding of blonanserin, a dopamine D2/D3 and serotonin 5-HT2A receptors antagonist, in vitro and in vivo. Blonanserin showed the most potent binding affinity for human D3 receptors among the tested atypical antipsychotics (risperidone, olanzapine and aripiprazole). Our GTPγS-binding assay demonstrated that blonanserin acts as a potent full antagonist for human D3 receptors. All test-drugs exhibited antipsychotic-like efficacy in methamphetamine-induced hyperactivity in rats. Treatment with blonanserin at its effective dose blocked the binding of [(3)H]-(+)-PHNO, a D2/D3 receptor radiotracer, both in the D2 receptor-rich region (striatum) and the D3 receptor-rich region (cerebellum lobes 9 and 10). On the other hand, the occupancies of other test-drugs for D3 receptors were relatively low. In conclusion, we have shown that blonanserin, but not other tested antipsychotics, extensively occupies D3 receptors in vivo in rats. Copyright © 2015 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. All rights reserved.
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Aripiprazole for autism spectrum disorders (ASD).
Hirsch, Lauren E; Pringsheim, Tamara
2016-06-26
Autism spectrum disorders (ASD) include autistic disorder, Asperger's disorder and pervasive developmental disorder - not otherwise specified (PDD-NOS). Antipsychotics have been used as a medication intervention for irritability related to ASD. Aripiprazole, a third-generation, atypical antipsychotic, is a relatively new drug that has a unique mechanism of action different from that of other antipsychotics. This review updates a previous Cochrane review on the safety and efficacy of aripiprazole for individuals with ASD, published in 2011 (Ching 2011). To assess the safety and efficacy of aripiprazole as medication treatment for individuals with ASD. In October 2015, we searched the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and seven other databases as well as two trial registers. We searched for records published in 1990 or later, as this was the year aripiprazole became available. Randomised controlled trials (RCTs) of aripiprazole (administered orally and at any dosage) versus placebo for treatment of individuals with a diagnosis of ASD. Two review authors independently collected, evaluated and analysed data. We performed meta-analysis for primary and secondary outcomes, when possible. We used the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach to rate the overall quality of the evidence. We included three trials in this review. Two were included in the previous published review, and the results of one, placebo-controlled discontinuation study were added to this review. Although we searched for studies across age groups, we found only studies conducted in children and youth. Included trials had low risk of bias across most domains. High risk of bias was seen in only one trial with incomplete outcome data. We judged the overall quality of the evidence for most outcomes to be moderate.Two RCTs with similar methods evaluated use of aripiprazole for a duration of eight weeks in 316 children/adolescents with ASD. Meta-analysis of study results revealed a mean improvement of -6.17 points on the Aberrant Behavior Checklist (ABC) - Irritability subscale (95% confidence intervals (CIs) -9.07 to -3.26, two studies, 308 children/adolescents, moderate-quality evidence), -7.93 points on the ABC - Hyperactivity subscale (95% CI -10.98 to -4.88, two studies, 308 children/adolescents, moderate-quality evidence) and -2.66 points on the ABC - Stereotypy subscale (95% CI -3.55 to -1.77, two studies, 308 children/adolescents, moderate-quality evidence) in children/adolescents taking aripiprazole relative to children/adolescents taking placebo. In terms of side effects, children/adolescents taking aripiprazole had a greater increase in weight, with a mean increase of 1.13 kg relative to placebo (95% CI 0.71 to 1.54, two studies, 308 children/adolescents, moderate-quality evidence), and had a higher risk ratio (RR) for sedation (RR 4.28, 95% CI 1.58 to 11.60, two studies, 313 children/adolescents, moderate-quality evidence) and tremor (RR 10.26, 95% CI 1.37 to 76.63, two studies, 313 children/adolescents, moderate-quality evidence). A randomised, placebo-controlled discontinuation study found that 35% of children/adolescents randomised to continue intervention with aripiprazole relapsed with respect to their symptoms of irritability, compared with 52% of children/adolescents randomised to placebo, for a hazard ratio of 0.57 (95% CI 0.28 to 1.12, 85 children/adolescents, low-quality evidence).All three included trials were supported by Bristol-Myers Squibb (Princeton, NJ) and Otsuka Pharmaceutical Company, Ltd. (Tokyo, Japan), with editorial support provided by Ogilvy Healthworld Medical Education and Bristol-Myers Squibb. Evidence from two RCTs suggests that aripiprazole can be effective as a short-term medication intervention for some behavioural aspects of ASD in children/adolescents. After a short-term medication intervention with aripiprazole, children/adolescents showed less irritability and hyperactivity and fewer stereotypies (repetitive, purposeless actions). However, notable side effects, such as weight gain, sedation, drooling and tremor, must be considered. One long-term, placebo discontinuation study found that relapse rates did not differ between children/adolescents randomised to continue aripiprazole versus children/adolescents randomised to receive placebo, suggesting that re-evaluation of aripiprazole use after a period of stabilisation in irritability symptoms is warranted. Studies included in this review used criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) (APA 2000) for ASD diagnosis; however, the diagnostic criteria for ASD changed significantly with release of the fifth edition of the DSM (DSM-5) in 2013 (APA 2013).
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Thase, Michael E.; Trivedi, Madhukar H.; Nelson, J. Craig; Fava, Maurizio; Swanink, Rene; Tran, Quynh-Van; Pikalov, Andrei; Yang, Huyuan; Carlson, Berit X.; Marcus, Ronald N.; Berman, Robert M.
2008-01-01
Background: Patients with major depressive disorder (MDD) who fail to achieve complete remission with antidepressant therapy may benefit from augmentation therapy with an atypical antipsychotic. Method: A pooled analysis was performed on 2 identical 14-week studies (8-week prospective antidepressant therapy treatment phase followed by 6-week randomized double-blind phase) evaluating the efficacy of adjunctive aripiprazole (2–20 mg/day) in DSM-IV-TR–defined MDD patients with an inadequate response to antidepressant therapy. Primary efficacy endpoint was the mean change in Montgomery-Asberg Depression Rating Scale (MADRS) total score from end of the prospective phase (week 8) to end of randomized phase (week 14, last observation carried forward). Subgroup analyses were performed. The key secondary endpoint was mean change in Sheehan Disability Scale (SDS) mean score. Results: At endpoint, mean change in MADRS total score was significantly greater with adjunctive aripiprazole (–8.7) than with adjunctive placebo (–5.7; p < .001). Except for a differential treatment-by-sex interaction, change in MADRS total scores were consistently greater with adjunctive aripiprazole than with adjunctive placebo, regardless of race, age, episode duration, prior antidepressant therapy response, number of historical treatment failures, severity of depressive symptoms, and antidepressant. At endpoint, MADRS remission rates were significantly greater with adjunctive aripiprazole than with placebo (25.7% vs. 15.4%; p < .001). Adjunctive aripiprazole also demonstrated significantly greater improvements in mean change from baseline in SDS total score than adjunctive placebo (–1.2 vs. –0.6; p = .001). Conclusion: Augmentation of antidepressant therapy with the atypical antipsychotic aripiprazole resulted in significant efficacy benefits across a range of subgroups of patients with MDD. Further study of a treatment-by-sex interaction is needed. Trial Registration: www.clinicaltrials.gov Identifiers: NCT00095823 and NCT00095758 PMID:19287552
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Jureidini, Jon N.; Parry, Peter I.; Spielmans, Glen I.; Healy, David
2011-01-01
Background Aripiprazole, a second-generation antipsychotic medication, has been increasingly used in the maintenance treatment of bipolar disorder and received approval from the U.S. Food and Drug Administration for this indication in 2005. Given its widespread use, we sought to critically review the evidence supporting the use of aripiprazole in the maintenance treatment of bipolar disorder and examine how that evidence has been disseminated in the scientific literature. Methods and Findings We systematically searched multiple databases to identify double-blind, randomized controlled trials of aripiprazole for the maintenance treatment of bipolar disorder while excluding other types of studies, such as open-label, acute, and adjunctive studies. We then used a citation search to identify articles that cited these trials and rated the quality of their citations. Our evidence search protocol identified only two publications, both describing the results of a single trial conducted by Keck et al., which met criteria for inclusion in this review. We describe four issues that limit the interpretation of that trial as supporting the use of aripiprazole for bipolar maintenance: (1) insufficient duration to demonstrate maintenance efficacy; (2) limited generalizability due to its enriched sample; (3) possible conflation of iatrogenic adverse effects of abrupt medication discontinuation with beneficial effects of treatment; and (4) a low overall completion rate. Our citation search protocol yielded 80 publications that cited the Keck et al. trial in discussing the use of aripiprazole for bipolar maintenance. Of these, only 24 (30%) mentioned adverse events reported and four (5%) mentioned study limitations. Conclusions A single trial by Keck et al. represents the entirety of the literature on the use of aripiprazole for the maintenance treatment of bipolar disorder. Although careful review identifies four critical limitations to the trial's interpretation and overall utility, the trial has been uncritically cited in the subsequent scientific literature. Please see later in the article for the Editors' Summary PMID:21559324
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[Antipsychotic Treatment of the Adult Patient in the Acute Phase of Schizophrenia].
Bohórquez Peñaranda, Adriana; Gómez Restrepo, Carlos; García Valencia, Jenny; Jaramillo González, Luis Eduardo; de la Hoz, Ana María; Arenas, Álvaro; Tamayo Martínez, Nathalie
2014-01-01
To determine the efficacy and safety of different antipsychotic drugs in the management of patients diagnosed with schizophrenia in the acute phase. To formulate evidence-based recommendations on the antipsychotic (AP) drug management strategies for the treatment of the adult diagnosed with schizophrenia in the acute phase. Clinical practice guidelines were prepared, using the guidelines of the Methodology Guide of the Ministry of Health and Social Protection, in order to identify, synthesise, and evaluate the evidence and formulate recommendations as regards the management and follow-up of adult patients diagnosed with schizophrenia. The evidence of the NICE 82 guideline was adopted and updated, which answered the question on the management of the acute phase of adults with a diagnosis of schizophrenia. The evidence and its level were presented to the Guideline Development Group (GDG) in order to formulate recommendations following the methodology proposed by the GRADE approach. Clozapine, olanzapine, risperidone, ziprasidone, amisulpride, paliperidone, haloperidol, quetiapine, and aripiprazole were more effective than placebo for the majority of psychotic symptoms and the abandonment of treatment, but asenapine was not. Paliperidone, risperidone, quetiapine, clozapine, and olanzapine showed significant increases in weight compared to placebo. Haloperidol, risperidone, ziprasidone, and paliperidone had a higher risk of extrapyramidal symptoms than placebo. There was a significant risk of sedation or drowsiness with, risperidone, haloperidol, ziprasidone, quetiapine, olanzapine, and clozapine in the comparisons with placebo. Of the results of the comparisons between AP, it was shown that clozapine and paliperidone had a clinically significant effect compared to haloperidol and quetiapine, respectively. Olanzapine and risperidone had a lower risk of abandoning the treatment in general, and due to adverse reactions in two comparisons of each one, haloperidol was the drug with more risk of abandoning due to adverse effects, followed by clozapine. Amisulpride, haloperidol and ziprasidone had favourable results as regards weight increase in several comparisons. Aripiprazole and paliperidone obtained a higher number of favourable results as regards sedation, and all the atypical drugs (except paliperidone) had a lower risk than the use of anti-parkinsonian drugs. Of the evidence from observational studies, it was found that, in subjects with risk factors for diabetes, such as age, hypertension, and dyslipidaemia, the initial treatment and current treatment with olanzapine, as well as current treatment with clozapine, may promote the development of this disease. Although it is imperative to prescribe an antipsychotic for treatment of the acute phase, the selection of the drug depends on the particular clinical condition of each patient and their collateral effects profile. Copyright © 2014 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.
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The Facts About Sexual (Dys)function in Schizophrenia: An Overview of Clinically Relevant Findings
de Boer, Marrit K.; Castelein, Stynke; Wiersma, Durk; Schoevers, Robert A.; Knegtering, Henderikus
2015-01-01
A limited number of studies have evaluated sexual functioning in patients with schizophrenia. Most patients show an interest in sex that differs little from the general population. By contrast, psychiatric symptoms, institutionalization, and psychotropic medication contribute to frequently occurring impairments in sexual functioning. Women with schizophrenia have a better social outcome, longer lasting (sexual) relationships, and more offspring than men with schizophrenia. Still, in both sexes social and interpersonal impairments limit the development of stable sexual relationships. Although patients consider sexual problems to be highly relevant, patients and clinicians not easily discuss these spontaneously, leading to an underestimation of their prevalence and contributing to decreased adherence to treatment. Studies using structured interviews or questionnaires result in many more patients reporting sexual dysfunctions. Although sexual functioning can be impaired by different factors, the use of antipsychotic medication seems to be an important factor. A comparison of different antipsychotics showed high frequencies of sexual dysfunction for risperidone and classical antipsychotics, and lower frequencies for clozapine, olanzapine, quetiapine, and aripiprazole. Postsynaptic dopamine antagonism, prolactin elevation, and α1-receptor blockade may be the most relevant factors in the pathogenesis of antipsychotic-induced sexual dysfunction. Psychosocial strategies to treat antipsychotic-induced sexual dysfunction include psychoeducation and relationship counseling. Pharmacological strategies include lowering the dose or switching to a prolactin sparing antipsychotic. Also, the addition of a dopamine agonist, aripiprazole, or a phosphodiesterase-5 inhibitor has shown some promising results, but evidence is currently scarce. PMID:25721311
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Gholampour, Hanieh; Moezi, Leila; Shafaroodi, Hamed
2017-10-15
Renal ischemia/reperfusion (I/R) injury is strongly related to morbidity and mortality. Oxidative stress, inflammation, and apoptosis play key roles in renal dysfunction following renal I/R. Aripiprazole is an atypical antipsychotic which used for the treatment of schizophrenia and bipolar disorder. Recent studies have reported aripiprazole as displaying certain anti-inflammatory effects. Regarding the underlying mechanisms of renal ischemia-reperfusion, therefore, nephroprotective effects might be predicted to be seen with aripiprazole. I/R injury was induced by bilateral clamping of the renal pedicles (45min) followed by reperfusion (24h). The mechanism of aripiprazole-mediated nephroprotection was explored by a combined use of aripiprazole and L-NAME (non-selective nitric oxide synthase inhibitor). Animals were given aripiprazole (2.5, 5, 10 and 20mg/kg) intraperitoneally, 30min before ischemia. L-NAME was administered before the aripiprazole injection. Serum creatinine and blood urea nitrogen were assessed after 24h of reperfusion. Serum levels of malondialdehyde (MDA), TNF-α and IL-1β were measured for rats treated with aripiprazole. The extent of necrosis was measured by the stereology method. Ischemia/reperfusion caused significant renal dysfunction and marked renal injury. Aripiprazole reduced creatinine and blood urea nitrogen. Serum levels of MDA, IL-1β and TNF-α were significantly lower in the aripiprazole group. Aripiprazole treatment also decreased the volume of kidney necrosis. The administration of L-NAME reversed the renoprotective effect of aripiprazole on BUN and creatinine, but enhanced the anti-necrotic effect of aripiprazole. The results show that a single dose of aripiprazole significantly improved renal function following ischemia/reperfusion injury - probably through the involvement of nitric oxide. Copyright © 2017 Elsevier B.V. All rights reserved.
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Majer, Istvan M; Gaughran, Fiona; Sapin, Christophe; Beillat, Maud; Treur, Maarten
2015-01-01
Treatment with long-acting injectable (LAI) antipsychotic medication is an important element of relapse prevention in schizophrenia. Recently, the intramuscular once-monthly formulation of aripiprazole received marketing approval in Europe and the United States for schizophrenia. This study aimed to compare aripiprazole once-monthly with other LAI antipsychotics in terms of efficacy, tolerability, and safety. A systematic literature review was conducted to identify relevant double-blind randomized clinical trials of LAIs conducted in the maintenance treatment of schizophrenia. MEDLINE, MEDLINE In-Process, Embase, the Cochrane Library, PsycINFO, conference proceedings, clinical trial registries, and the reference lists of key review articles were searched. The literature search covered studies dating from January 2002 to May 2013. Studies were required to have ≥24 weeks of follow-up. Patients had to be stable at randomization. Studies were not eligible for inclusion if efficacy of acute and maintenance phase treatment was not reported separately. Six trials were identified (0.5% of initially identified studies), allowing comparisons of aripiprazole once-monthly, risperidone LAI, paliperidone palmitate, olanzapine pamoate, haloperidol depot, and placebo. Data extracted included study details, study duration, the total number of patients in each treatment arm, efficacy, tolerability, and safety outcomes. The efficacy outcome contained the number of patients that experienced a relapse, tolerability outcomes included the number of patients that discontinued treatment due to treatment-related adverse events (AEs), and that discontinued treatment due to reasons other than AEs (e.g., loss to follow-up). Safety outcomes included the incidence of clinically relevant weight gain and extrapyramidal symptoms. Data were analyzed by applying a mixed treatment comparison competing risks model (efficacy) and using binary models (safety). There was no statistically significant difference between any study outcome, including the risk of relapse, the risk of discontinuations, and safety outcomes. Aripiprazole once-monthly is similarly efficacious to other LAIs with relatively low rates of discontinuation due to AEs and due to reasons other than AEs than other LAIs.
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[Antipsychotic-drug-induced hyperprolactinemia: physiopathology, clinical features and guidance].
Besnard, I; Auclair, V; Callery, G; Gabriel-Bordenave, C; Roberge, C
2014-02-01
Hyperprolactinemia is a frequent but neglected adverse effect observed in patients treated with antipsychotic-drugs. In this review, we summarize its physiopathogenetic mechanism, its clinical manifestations in men and women, and the way to manage it. Prolactin is a hormone secreted by lactotroph cells in the anterior pituitary. Its synthesis and release are under the control of peptides, steroids and neurotransmitters. The main inhibitory regulation is made by dopamine, which binds dopamine receptors D2 on the membrane of lactotroph cells. Antipsychotic-drugs block these receptors and thus remove the inhibitory effect of dopamine on prolactin secretion. All antipsychotic-drugs block D2 receptors and all can induce hyperprolactinemia. Nonetheless, it seems that the faster the antipsychotic-drug dissociates from D2 receptors, the lesser the increase of prolactin in the plasma. Another way to explain hyperprolactinemia is the ability of antipsychotic-drugs to cross the blood-brain barrier. The role of their metabolites should also be considered. For these reasons, one can distinguish prolactin-raising (conventional neuroleptics, amisulpride, risperidone) and prolactin-sparing (clozapine, aripiprazole, olanzapine) antipsychotics. An English study showed that 18% of men and 47% of women treated with antipsychotics for severe mental illness had a prolactin level above the normal range. Hyperprolactinemia is in fact more frequent in women than in men. Sometimes it is asymptomatic, but the higher the prolactin level is, the more patients have clinical manifestations. Some symptoms are due to the hypogonadism caused by prolactin, which disturbs hypothalamic-pituitary axis function, and others are due to direct effects on target tissues. Consequently, patients can suffer from sexual dysfunction, infertility, amenorrhea, gynecomastia or galactorrhoea. Data suggest that these symptoms are common, but patients don't mention them spontaneously and clinicians underestimate their prevalence. In the long-term, hypogonadism involves a premature bone loss in men and women. Klibanski and colleagues showed that this loss is significant only in women with hyperprolactinemia associated with amenorrhea. That suggests that prolactin is not directly responsible for this clinical feature. Nevertheless, prolactin seems to be involved in the development of breast cancer, but its role is unclear for prostate cancer. Our review promotes a check-up before beginning a treatment with antipsychotic agents. First, a baseline prolactin level should be measured. It should also include the research on previous treatment with antipsychotic-drugs and the assessment of adverse effects suggestive of hyperprolactinemia. Questioning should finally look for any contra-indication to antipsychotics. Monitoring during antipsychotic treatment has been studied by a group of international experts in psychiatry, medicine, toxicology and pharmacy who made a critical review of clinical guidance on hyperprolactinemia. Experts notify that it is important to check whether patients have any sexual dysfunction, such as loss of libido or menstrual irregularity, and galactorrhoea. Prolactin level should also be controlled after three months of stable dose treatment, or if any clinical feature of hyperprolactinemia appears. If a patient prescribed antipsychotic-drugs has a confirmed prolactin level above the normal range, it is necessary to exclude other causes of hyperprolactinemia. If antipsychotics are really involved, the management should be adapted with the prolactin level and the patient him/herself. To summarize, clinicians can decrease the dose of the antipsychotic or switch to a prolactin-sparing drug. Oral contraceptives can be added whether to prevent pregnancy or to prevent bone loss and osteoporosis. Finally, experts recommend reserving dopamine agonists to treat antipsychotic-induced hyperprolactinemia in very exceptional circumstances as it can worsen the mental illness. Copyright © 2013. Published by Elsevier Masson SAS.
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Second-generation antipsychotics for major depressive disorder and dysthymia.
Komossa, Katja; Depping, Anna M; Gaudchau, Andrea; Kissling, Werner; Leucht, Stefan
2010-12-08
Major depressive disorder (MDD) is a common condition with a lifetime prevalence of 15% to 18%, which leads to considerable suffering and disability. Some antipsychotics have been reported to induce remission in major depression, when added to an antidepressant. To evaluate the effects of second-generation antipsychotic (SGA) drugs (alone or augmentation) compared with placebo or antidepressants for people with MDD or dysthymia. The Cochrane Depression, Anxiety and Neurosis Group's controlled trial registers (CCDANCTR-Studies and CCDANCTR-References) were searched up to 21 July 2010. The author team ran complementary searches on clinicaltrials.gov and contacted key authors and drug companies. We included all randomised, double-blind trials comparing oral SGA treatment (alone or augmentation) with other forms of pharmaceutical treatment or placebo in people with MDD or dysthymia. We extracted data independently. For dichotomous data we calculated the odds ratio (OR) and 95% confidence interval (CI) on an intention-to-treat basis, and for continuous data the mean difference (MD), based on a random-effects model. We presented each comparison separately; we did not perform a pooled data analysis. We included 28 trials with 8487 participants on five SGAs: amisulpride, aripiprazole, olanzapine, quetiapine and risperidone.Three studies (1092 participants) provided data on aripiprazole augmentation in MDD. All efficacy data (response n = 1092, three RCTs, OR 0.48; 95% CI 0.37 to 0.63), (MADRS n = 1077, three RCTs, MD -3.04; 95% CI -4.09 to -2) indicated a benefit for aripiprazole but more side effects (weight gain, EPS) .Seven trials (1754 participants) reported data on olanzapine. Compared to placebo fewer people discontinued treatment due to inefficacy; compared to antidepressants there were no efficacy differences, olanzapine augmentation showed symptom reduction (MADRS n = 808, five RCTs, MD -2.84; 95% CI -5.48 to -0.20), but also more weight or prolactin increase.Quetiapine data are based on seven trials (3414 participants). Compared to placebo, quetiapine monotherapy (response n = 1342, three RCTs, OR 0.52; 95% CI 0.41 to 0.66) and quetiapine augmentation (response n = 937, two RCTs, OR 0.68; 95% CI 0.52 to 0.90) showed symptom reduction, but quetiapine induced more sedation.Four trials (637 participants) presented data on risperidone augmentation, response data were better for risperidone (n = 371, two RCTs, OR 0.57; 95% CI 0.36 to 0.89) but augmentation showed more prolactin increase and weight gain.Five studies (1313 participants) presented data on amisulpride treatment for dysthymia. There were some beneficial effects compared to placebo or antidepressants but tolerability was worse. Quetiapine was more effective than placebo treatment. Aripiprazole and quetiapine and partly also olanzapine and risperidone augmentation showed beneficial effects compared to placebo. Some evidence indicated beneficial effects of low-dose amisulpride for dysthymic people. Most SGAs showed worse tolerability.
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López-Muñoz, Francisco; Sim, Kang; Shen, Winston Wu; Huelves, Lorena; Moreno, Raquel; Molina, Juan de Dios; Rubio, Gabriel; Noriega, Concha; Pérez-Nieto, Miguel Ángel; Alamo, Cecilio
2014-01-01
A bibliometric study was carried out to ascertain the volume and impact of scientific literature published on second-generation antipsychotic drugs (SGAs) in Singapore from 1997 to 2011. A search of the EMBASE and MEDLINE databases was performed to identify articles originating from Singapore that included the descriptors 'atypic* antipsychotic*', 'second-generation antipsychotic*', 'clozapine', 'risperidone', 'olanzapine', 'ziprasidone', 'quetiapine', 'sertindole', 'aripiprazole', 'paliperidone', 'amisulpride', 'zotepine', 'asenapine', 'iloperidone', 'lurasidone', 'perospirone' and 'blonanserin' in the article titles. Certain bibliometric indicators of production and dispersion (e.g. Price's Law on the increase of scientific literature, and Bradford's Law) were applied, and the participation index of various countries was calculated. The bibliometric data was also correlated with some social and health data from Singapore, such as the total per capita expenditure on health and gross domestic expenditure on research and development. From 1997 to 2011, a total of 51 articles on SGAs in Singapore were published. Our results suggested non-fulfilment of Price's Law (r = 0.0648 after exponential adjustment vs. r = 0.2140 after linear adjustment). The most widely studied drugs were clozapine (21 articles), risperidone (16 articles) and olanzapine (8 articles). Division into Bradford zones yielded a nucleus occupied by the Journal of Clinical Psychopharmacology (6 articles) and the Singapore Medical Journal(4 articles). The analysed material was published in a total of 30 journals, with the majority from six journals. Four of these six journals have an impact factor greater than 2. Publications on SGAs in Singapore are still too few to confirm an exponential growth of scientific literature.
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Cost-Utility Analysis of Lurasidone Versus Aripiprazole in Adults with Schizophrenia.
Rajagopalan, Krithika; Trueman, David; Crowe, Lydia; Squirrell, Daniel; Loebel, Antony
2016-07-01
In 2014, lurasidone, an atypical antipsychotic, was approved for the treatment of schizophrenia in adults. It is an alternative treatment option to aripiprazole, and when compared with aripiprazole, lurasidone was associated with improved symptom reduction and reduced risk of weight gain and relapse. We conducted a cost-utility analysis of lurasidone versus aripiprazole from the perspective of healthcare services, using Scotland and Wales as specific case studies. A 10-year Markov model, incorporating a 6-week acute phase and a maintenance phase across three health states (discontinuation, relapse, death) was constructed. Six-week probabilities of discontinuation and adverse events were based on a published independent mixed-treatment comparison; long-term risks of relapse and discontinuation were from an indirect comparison. Costs included drug therapy, relapse, and outpatient, primary and residential care. Costs and benefits were discounted at 3.5 %. Utility estimates were taken from published literature, and cost effectiveness was expressed as total 10-year incremental costs and quality-adjusted life-years (QALYs). Lurasidone yielded a cost saving of £3383 and an improvement of 0.005 QALYs versus aripiprazole, in Scotland. Deterministic sensitivity analysis demonstrated that results were sensitive to relapse rates, while probabilistic sensitivity analysis suggested that lurasidone had the highest expected net benefit at willingness-to-pay thresholds of £20,000-30,000 per QALY. The probability that lurasidone was a cost-effective treatment strategy was approximately 75 % at all willingness-to-pay thresholds, with similar results being obtained for the Welsh analysis. Our analysis suggests that lurasidone would provide an effective, cost-saving alternative for the healthcare service in the treatment of adult patients with schizophrenia.
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Arenas Borrero, Álvaro Enrique; Gómez Restrepo, Carlos; Bohórquez Peñaranda, Adriana Patricia; Vélez Traslaviña, Ángela; Castro Díaz, Sergio Mario; Jaramillo González, Luis Eduardo; García Valencia, Jenny
2014-01-01
To determine the most adequate strategies for the prevention and treatment of the acute adverse effects of the use of antipsychotics. A clinical practice guideline was elaborated under the parameters of the Methodological Guide of the Ministerio de Salud y Protección Social to identify, synthesize and evaluate the evidence and make recommendations about the treatment and follow-up of adult patients with schizophrenia. A systematic literature search was carried out. The evidence was presented to the Guideline Developing Group and recommendations, employing the GRADE system, were produced. The non-pharmacological interventions such as nutritional counseling by a nutritionist, exercise and psychotherapy are effective in preventing weight gain with the use of antipsychotics. (Kg Weight reduction in DM of -3.05 (-4.16, -1.94)). The antipsychotic change from olanzapine to aripiprazole showed weight loss and decreased BMI (decreased weight in KG DM -3.21 (-9.03, -2.61). The use of beta blockers was ineffective in reducing akathisia induced by antipsychotic; using as outcome the 50% reduction of symptoms of akathisia comparing beta-blockers with placebo RR was 1.4 (0.59, 1.83). It is recommended to make psychotherapeutic accompaniment and nutrition management of overweight for patients with weight gain. If these alternatives are ineffective is suggested to change the antipsychotic or consider starting metformin. For the management of drug-induced akathisia it is recommended to decrease the dose of the drug and the addition of lorazepam. It is recommended using 5mg biperiden IM or trihexyphenidyl 5mg orally in case of secondary acute dystonia and for the treatment of antipsychotic-induced parkinsonism to decrease the dose of antipsychotic or consider using 2 - 4mg/day of biperiden or diphenhydramine 50mg once daily. Copyright © 2014 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.
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Boettger, Soenke; Jenewein, Josef; Breitbart, William
2015-08-01
The aim of this study was to compare the efficacy and side-effect profile of the typical antipsychotic haloperidol with that of the atypical antipsychotics risperidone, olanzapine, and aripiprazole in the management of delirium. The Memorial Delirium Assessment Scale (MDAS), the Karnofsky Performance Status (KPS) scale, and a side-effect rating were recorded at baseline (T1), after 2-3 days (T2), and after 4-7 days (T3). Some 21 cases were case-matched by age, preexisting dementia, and baseline MDAS scores, and subsequently analyzed. The baseline characteristics of the medication groups were not different: The mean age of the patients ranged from 64.0 to 69.6 years, dementia was present in between 23.8 and 28.6%, and baseline MDAS scores were 19.9 (haloperidol), 18.6 (risperidone), 19.4 (olanzapine), and 18.0 (aripiprazole). The doses of medication at T3 were 5.5 mg haloperidol, 1.3 mg risperidone, 7.1 mg olanzapine, and 18.3 mg aripiprazole. Over one week, the decline in MDAS scores between medications was equal, and no differences between individual MDAS scores existed at T2 or T3. After one week, the MDAS scores were 6.8 (haloperidol), 7.1 (risperidone), 11.7 (olanzapine), and 8.3 (aripiprazole). At T2, delirium resolution occurred in 42.9-52.4% of cases and at T3 in 61.9-85.7%; no differences in assessments between medications existed. Recorded side effects were extrapyramidal symptoms (EPSs) in haloperidol- and risperidone-managed patients (19 and 4.8%, respectively) and sedation with olanzapine (28.6%). Haloperidol, risperidone, aripiprazole, and olanzapine were equally effective in the management of delirium; however, they differed in terms of their side-effect profile. Extrapyramidal symptoms were most frequently recorded with haloperidol, and sedation occurred most frequently with olanzapine.
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Phelps, Thomas I.; Bondi, Corina O.; Mattiola, Vincent V.; Kline, Anthony E.
2016-01-01
Background Antipsychotic drugs (APDs) are used to manage traumatic brain injury (TBI)-induced behavioral disturbances, such as agitation and aggression. However, APDs exhibiting D2 receptor antagonism impede cognitive recovery after experimental TBI. Hence, empirical evaluation of APDs with different mechanistic actions is warranted. Aripiprazole (ARIP) is a D2 and 5-HT1A receptor agonist; pharmacotherapies with these properties enhance cognition after TBI. Objective To test the hypothesis that ARIP would increase behavioral performance and decrease histopathology after TBI. Methods Adult male rats were subjected to either a controlled cortical impact (CCI) or sham injury and then randomly assigned to ARIP (0.1 or 1.0 mg/kg) or VEH (1.0 mL/kg, saline vehicle) groups. Treatments began 24 hr after surgery and were administered once daily for 19 days. Motor (beam-balance/beam-walk) and cognitive (Morris water maze) performance was assessed on post-operative days 1-5 and 14-19, respectively, followed by quantification of hippocampal CA1/3 neuron survival and cortical lesion volume. Results Beam-balance was significantly improved in the CCI + ARIP (1.0 mg/kg) group vs. CCI + ARIP (0.1 mg/kg) and CCI + VEH [p<0.05]. Spatial learning and memory retention were significantly improved in the CCI + ARIP (0.1 mg/kg) group vs. the CCI + ARIP (1.0 mg/kg) and CCI + VEH groups [p<0.05]. Both doses of ARIP reduced lesion size and CA3 cell loss vs. VEH [p<0.05]. Importantly, neither dose of ARIP impeded functional recovery as previously reported with other APDs. Conclusion These findings support the hypothesis and endorse ARIP as a safer APD for alleviating behavioral disturbances after TBI. PMID:27225976
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Leukopenia and neutropenia induced by quetiapine.
Cowan, Colin; Oakley, Clare
2007-01-30
Leukopenia and neutropenia are recognised as side effects of antipsychotic medication, notably clozapine. A case is presented in which a female Caucasian patient who had previously developed these side effects with clozapine also developed them with quetiapine in conjunction with semisodium valproate. There was no such reaction to zuclopenthixol, sulpiride, olanzapine and aripiprazole. It is concluded that caution should be exercised when treating with quetiapine especially where there has been neutropenia with a previous antipsychotic agent.
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Salvador, Alexandre; Worbe, Yulia; Delorme, Cécile; Coricelli, Giorgio; Gaillard, Raphaël; Robbins, Trevor W; Hartmann, Andreas; Palminteri, Stefano
2017-07-24
The dopamine partial agonist aripiprazole is increasingly used to treat pathologies for which other antipsychotics are indicated because it displays fewer side effects, such as sedation and depression-like symptoms, than other dopamine receptor antagonists. Previously, we showed that aripiprazole may protect motivational function by preserving reinforcement-related signals used to sustain reward-maximization. However, the effect of aripiprazole on more cognitive facets of human reinforcement learning, such as learning from the forgone outcomes of alternative courses of action (i.e., counterfactual learning), is unknown. To test the influence of aripiprazole on counterfactual learning, we administered a reinforcement learning task that involves both direct learning from obtained outcomes and indirect learning from forgone outcomes to two groups of Gilles de la Tourette (GTS) patients, one consisting of patients who were completely unmedicated and the other consisting of patients who were receiving aripiprazole monotherapy, and to healthy subjects. We found that whereas learning performance improved in the presence of counterfactual feedback in both healthy controls and unmedicated GTS patients, this was not the case in aripiprazole-medicated GTS patients. Our results suggest that whereas aripiprazole preserves direct learning of action-outcome associations, it may impair more complex inferential processes, such as counterfactual learning from forgone outcomes, in GTS patients treated with this medication.
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Martinotti, Giovanni; Orsolini, Laura; Fornaro, Michele; Vecchiotti, Roberta; De Berardis, Domenico; Iasevoli, Felice; Torrens, Marta; Di Giannantonio, Massimo
2016-06-01
Among other approaches, the modulation of the dopaminergic pathway has been advocated in the therapeutic management of Alcohol Use Disorders (AUD). A potential avenue toward the modulation of the dopaminergic pathway across varying substance disorders seems to be provided by aripiprazole, a second-generation antipsychotic characterized by a peculiar pharmacodynamics signature. In this review, the authors provided a qualitative synthesis and a critical perspective on the efficacy of aripiprazole in relapse prevention and craving in AUD. A systematic search was carried out through MEDLINE/Embase/PsycINFO/Cochrane Library from inception until September 2015, combining free terms and MESH headings for the topics of AUD and aripiprazole as following: (((Alcohol use Disorder) OR (Alcohol use)) AND aripiprazole). Based both on a qualitative synthesis and a critical interpretation of the evidence, the authors submit that aripiprazole would promote alcohol abstinence and reduce the alcohol seeking behaviour possibly via dopaminergic and serotoninergic modulations at the fronto-subcortical circuits underpinning alcohol reward and craving, impulsive behaviour as well as reduce alcohol-related anxiety/low mood and anhedonia. However, due to the lack of published studies, a conclusive statement about any direct effect of aripiprazole in the prevention of craving and/or alcohol consumption is not possible.
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Varela, Fausto A.; Der-Ghazarian, Taleen; Lee, Ryan J.; Charntikov, Sergios; Crawford, Cynthia A.; McDougall, Sanders A.
2017-01-01
Aripiprazole is a second-generation antipsychotic that is increasingly being prescribed to children and adolescents. Despite this trend, little preclinical research has been done on the neural and behavioral actions of aripiprazole during early development. In the present study, young male and female Sprague-Dawley rats were pretreated with vehicle, haloperidol (1 mg/kg), or aripiprazole (10 mg/kg) once daily on postnatal days (PD) 10–20. After one, four, or eight days (i.e., on PD 21, PD 24, or PD 28), amphetamine-induced locomotor activity and stereotypy, as well as dorsal striatal D2 receptor levels, were measured in separate groups of rats. Pretreating young rats with aripiprazole or haloperidol increased D2 binding sites in the dorsal striatum. Consistent with these results, dopamine supersensitivity was apparent when aripiprazole- and haloperidol-pretreated rats were given a test day injection of amphetamine (2 or 4 mg/kg). Increased D2 receptor levels and altered behavioral responding persisted for at least eight days after conclusion of the pretreatment regimen. Contrary to what has been reported in adults, repeated aripiprazole treatment caused D2 receptor up-regulation and persistent alterations of amphetamine-induced behavior in young rats. These findings are consistent with human clinical studies showing that children and adolescents are more prone than adults to aripiprazole-induced side-effects, including extrapyramidal symptoms. PMID:24045880
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Aripiprazole added to Overweight and Obese Olanzapine-treated Schizophrenia Patients
Henderson, David C.; Fan, Xiaoduo; Copeland, Paul M.; Sharma, Bikash; Borba, Christina P; Boxill, Ryan; Freudenreich, Oliver; Cather, Corey; Evins, A. Eden; Goff, Donald C.
2015-01-01
Olanzapine treatment has been associated with clinically meaningful weight increases, hypertriglyceridemia, insulin resistance and diabetes mellitus. There are few options for olanzapine-responders who fail other antipsychotic agents. Aripiprazole is a potent (high-affinity) partial agonist at D2 and 5-HT1A receptors and a potent antagonist at 5-HT2A receptor and is associated with less weight gain than olanzapine. We report the results of a 10-week placebo controlled, double-blind crossover study that examined 15 mg/day aripiprazole's effects upon weight, lipids, glucose metabolism, and psychopathology in overweight and obese schizophrenia and schizoaffective disorder subjects treated with a stable dose of olanzapine. During the 4 weeks of aripiprazole treatment there were significant decreases in weight (p = .003) and BMI (p = .004) compared to placebo. Total serum cholesterol (p = .208), HDL-cholesterol (p = .99), HDL-2 (p=.08), HDL-3 (p=.495) and LDL- cholesterol (p=.665) did not change significantly comparing aripiprazole treatment to placebo treatment. However, total serum triglycerides (p = .001), total VLDL-cholesterol (p=.01), VLDL 1- &2-cholesterol (p=.012) decreased significantly during the aripiprazole treatment phase. VLDL-3-cholesterol tended lower during aripiprazole, but the decrease was not significant (p=.062). There was a decrease in c-reactive protein comparing aripiprazole treatment to placebo though it did not reach significance (p=.087). The addition of aripiprazole to a stable dose of olanzapine was well tolerated and resulted in significant improvements on several outcome measures that predict risk for medical morbidity. PMID:19512978
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Naylor, Jennifer C; Kilts, Jason D; Bradford, Daniel W; Strauss, Jennifer L; Capehart, Bruce P; Szabo, Steven T; Smith, Karen D; Dunn, Charlotte E; Conner, Kathryn M; Davidson, Jonathan R T; Wagner, Henry Ryan; Hamer, Robert M; Marx, Christine E
2015-05-01
Many individuals with post-traumatic stress disorder (PTSD) experience persistent symptoms despite pharmacological treatment with antidepressants. Several open-label monotherapy and adjunctive studies have suggested that aripiprazole (a second-generation antipsychotic) may have clinical utility in PTSD. However, there have been no randomized placebo-controlled trials of aripiprazole use for PTSD. We thus conducted a pilot randomized controlled trial of adjunctive aripiprazole versus placebo among Veterans with chronic PTSD serving in the US military since 11 September 2001 to assess the feasibility, safety, tolerability, and therapeutic potential of aripiprazole. Sixteen Veterans were randomized, and 14 completed at least 4 weeks of the study; 12 completed the entire 8-week trial. Outcome measures included the Clinician-Administered PTSD Scale (CAPS), PTSD Checklist, Beck Depression Inventory, Second Edition, and Positive and Negative Syndrome Scale scores. Aripiprazole was well-tolerated in this cohort, and improvements in CAPS, PTSD Checklist, Beck Depression Inventory, Second Edition, and Positive and Negative Syndrome Scale scores were as hypothesized. Although CAPS change scores did not reach statistical significance, aripiprazole outperformed placebo by 9 points on the CAPS in the last observation carried forward analysis compared with the placebo group (n = 7 per group), and by 20 points in the group randomized to aripiprazole that completed the entire study (n = 5) compared with the placebo group (n = 7). Results suggest promise for aripiprazole as an adjunctive strategy for the treatment of PTSD.
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Assié, Marie-Bernadette; Dominguez, Hélène; Consul-Denjean, Nathalie; Newman-Tancredi, Adrian
2006-09-01
Interaction with dopamine D2-like receptors plays a major role in the therapeutic effects of antipsychotic drugs. We examined in vivo dopamine D2 receptor occupancy of various established and potential antipsychotics in mouse striatum and olfactory tubercles 1 h after administration of the compound, using [3H]nemonapride as a ligand. All the compounds reduced in vivo binding of [3H]nemonapride in the striatum. When administered systemically, conventional antipsychotics, D2 antagonists, nemonapride (ID50: 0.034 mg/kg), eticlopride (0.047), haloperidol (0.11) and raclopride (0.11) potently inhibited [3H]nemonapride binding. The 'atypical' antipsychotics, risperidone (0.18), ziprasidone (0.38), aripiprazole (1.6), olanzapine (0.99), and clozapine (11.1) were less potent for occupying D2-like receptors. New compounds, displaying marked agonism at 5-HT1A receptors in addition to D2 receptor affinity, exhibited varying D2 receptor occupancy: bifeprunox (0.25), SLV313 (0.78), SSR181507 (1.6) and sarizotan (6.7). ID50 values for inhibition of [3H]nemonapride binding in the striatum correlated with those in the olfactory tubercles (r=0.95, P<0.0001). These values also correlated with previously-reported in vitro affinity of the compounds at rat D2 receptors (r=0.85, P=0.0001) and with inhibition of apomorphine-induced climbing in mice (r=0.79 P=0.0005). In contrast, there was no significant correlation between ID50 values herein and previously-reported ED50 values for catalepsy in mice. These data indicate that: (1) there is no difference in D2 receptor occupancy in limbic versus striatal regions between most classical and atypical or potential antipsychotics; and (2) high occupancy of D2 receptors can be dissociated from catalepsy, if the drugs also activate 5-HT1A receptors. Taken together, these data support the strategy of simultaneously targeting D2 receptor blockade and 5-HT1A receptor activation for new antipsychotics.
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Chen, Yen-Wen; Tseng, Ping-Tao
2016-09-15
Tardive syndrome is a troublesome complication secondary to the long-term usage of antipsychotic medication. At present, there is a lack of effective treatment for tardive syndrome. Aripiprazole has been used in the treatment of tardive syndrome, with some reports of a good response. However, other reports have suggested that tardive syndrome can actually be induced by aripiprazole. The aim of current study was to investigate whether aripiprazole is beneficial or harmful for the treatment of tardive syndrome in specific patients. We performed a thorough literature search via PubMed. We included all of the studies discussing the relationship between tardive syndrome and aripiprazole, either with regards to "inducing" or "improving" the disease. None of the included studies were well-designed clinical trials, and all were case reports or case series. A total of 26 articles were included in which aripiprazole induced tardive syndrome, and another 24 in which tardive syndrome was improved by aripiprazole treatment. In the "improved" group, there were significantly more cases of schizophrenia than in the "induced" group (p=0.002). However, there were significantly more cases with other miscellaneous diagnoses in the "induced" group than in the "improved" group (p=0.003). In addition, the cases in the "induced" group had a significantly longer duration of aripiprazole usage than those in the "improved" group (p=0.001). Current study is important for clinicians to pay attention to the risk of tardive syndrome when prescribing aripiprazole in patients with a diagnosis other than a psychiatric illness or in the long-term administration of aripiprazole.
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Kane, John M.; Zhao, Cathy; Johnson, Brian R.; Baker, Ross A.; Eramo, Anna; McQuade, Robert D.; Duca, Anna R.; Sanchez, Raymond; Peters-Strickland, Timothy
2015-01-01
Abstract Objective: To compare hospitalization rates in patients with schizophrenia treated prospectively with aripiprazole once-monthly 400 mg (AOM 400; an extended-release injectable suspension) vs the same patients’ retrospective rates with their prior oral anti-psychotic therapy. Research design and methods: Multi-center, open-label, mirror-image, naturalistic study in a community setting in North America. Patients who required a change in treatment and/or would benefit from long-acting injectable anti-psychotic therapy were treated prospectively for 6 months with AOM 400. Retrospective data on hospitalization rates were obtained. Clinical trial registration: ClinicalTrials.gov: NCT01432444. Main outcome measures: The proportion of patients with ≥1 psychiatric inpatient hospitalization with oral anti-psychotic therapy examined retrospectively (months –4 to –1 before oral conversion) and after switching to AOM 400 (months 4–6 after initiating AOM 400). Results: Psychiatric hospitalization rates were significantly lower when patients were treated with AOM 400 compared with oral anti-psychotic therapy both in the 3-month primary efficacy sample (2.7% [n = 9/336] vs 27.1% [n = 91/336], respectively; p < 0.0001) and in the total sample (6-month prospective rate: 8.8% [n = 38/433] vs 6-month retrospective rate: 38.1% [n = 165/433]; p < 0.0001). Discontinuations due to adverse events (AEs) during cross-titration were lower in patients cross-titrated on oral aripiprazole for >1 and <4 weeks (2.9% [n = 7/239]) compared with patients cross-titrated for ≤1 week (10.4% [n = 5/48]). The most common treatment-emergent AEs during the prospective treatment phase were insomnia (6.7% [n = 29/431]) and akathisia (6.5% [n = 28/431]). Patient-rated injection-site pain decreased from the first injection to the last visit. Conclusions: In a community setting, patients with schizophrenia demonstrated significantly lower psychiatric hospitalization rates after switching from their prior oral anti-psychotic therapy to AOM 400. Patients served as their own control, and thus an active control group was not included in this study. Confounding factors, such as insurance coverage and availability of hospital beds, were not examined here and deserve further consideration. PMID:25347448
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Solmi, Marco; Murru, Andrea; Pacchiarotti, Isabella; Undurraga, Juan; Veronese, Nicola; Fornaro, Michele; Stubbs, Brendon; Monaco, Francesco; Vieta, Eduard; Seeman, Mary V; Correll, Christoph U; Carvalho, André F
2017-01-01
Since the discovery of chlorpromazine (CPZ) in 1952, first-generation antipsychotics (FGAs) have revolutionized psychiatric care in terms of facilitating discharge from hospital and enabling large numbers of patients with severe mental illness (SMI) to be treated in the community. Second-generation antipsychotics (SGAs) ushered in a progressive shift from the paternalistic management of SMI symptoms to a patient-centered approach, which emphasized targets important to patients – psychosocial functioning, quality of life, and recovery. These drugs are no longer limited to specific Diagnostic and Statistical Manual of Mental Disorders (DSM) categories. Evidence indicates that SGAs show an improved safety and tolerability profile compared with FGAs. The incidence of treatment-emergent extrapyramidal side effects is lower, and there is less impairment of cognitive function and treatment-related negative symptoms. However, treatment with SGAs has been associated with a wide range of untoward effects, among which treatment-emergent weight gain and metabolic abnormalities are of notable concern. The present clinical review aims to summarize the safety and tolerability profile of selected FGAs and SGAs and to link treatment-related adverse effects to the pharmacodynamic profile of each drug. Evidence, predominantly derived from systematic reviews, meta-analyses, and clinical trials of the drugs amisulpride, aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, sertindole, ziprasidone, CPZ, haloperidol, loxapine, and perphenazine, is summarized. In addition, the safety and tolerability profiles of antipsychotics are discussed in the context of the “behavioral toxicity” conceptual framework, which considers the longitudinal course and the clinical and therapeutic consequences of treatment-emergent side effects. In SMI, SGAs with safer metabolic profiles should ideally be prescribed first. However, alongside with safety, efficacy should also be considered on a patient-tailored basis. PMID:28721057
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2013-01-01
Background It is desirable to establish evidence for the selection of antipsychotics from the viewpoint of recovery of social activity in individual patient with schizophrenia receiving medication. From this perspective, awareness of the importance of studies about drug effectiveness on treatment discontinuation rate, remission rate, and improvement in QOL has grown recently. In Western countries, numerous reports are available in effectiveness studies, which are related to olanzapine and risperidone primarily, whereas evidence for other second-generation antipsychotics (SGAs) is poor. In Japan, no effectiveness study has been reported: thus, it is desirable to collect data that will serve as evidence for selection of the 3 SGAs approved after olanzapine. Methods The present study was a long-term effectiveness study under healthcare setting in Japan. It was designed as an open-label, multicenter, randomized, comparative study involving 104-week oral treatment with 1 of the 3 drugs (aripiprazole, blonanserin, and paliperidone) in patients with schizophrenia aged 20 years or over who required antipsychotic medication or switching of the current medication to others for reasons such as lack of efficacy and intolerability. The primary endpoint is treatment discontinuation rate for any causes. The secondary endpoints include remission rate, improvement of social activity, alleviation, aggravation or recurrence of psychiatric symptoms, and safety. The target number of subjects was set at 300. Discussion Because this study is expected to yield evidence regarding the selection of antipsychotics for facilitating the recovery of social activity in patients with schizophrenia, it is considered highly valuable to perform this effectiveness study under ordinary healthcare setting in Japan. Trial registration UMIN Clinical Trials Registry 000007942 PMID:24090047
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Rauly-Lestienne, Isabelle; Boutet-Robinet, Elisa; Ailhaud, Marie-Christine; Newman-Tancredi, Adrian; Cussac, Didier
2007-10-01
5-HT(7) receptors are present in thalamus and limbic structures, and a possible role of these receptors in the pathology of schizophrenia has been evoked. In this study, we examined binding affinity and agonist/antagonist/inverse agonist properties at these receptors of a large series of antipsychotics, i.e., typical, atypical, and third generation compounds preferentially targeting D(2) and 5-HT(1A) sites. Adenylyl cyclase (AC) activity was measured in HEK293 cells stably expressing the human (h) 5-HT(7a) receptor isoform. 5-HT and 5-CT increased cyclic adenosine monophosphate level by about 20-fold whereas (+)-8-OH-DPAT, the antidyskinetic agent sarizotan, and the novel antipsychotic compound bifeprunox exhibited partial agonist properties at h5-HT(7a) receptors stimulating AC. Other compounds antagonized 5-HT-induced AC activity with pK (B) values which correlated with their pK (i) as determined by competition binding vs [(3)H]5-CT. The selective 5-HT(7) receptor ligand, SB269970, was the most potent antagonist. For antipsychotic compounds, the following rank order of antagonism potency (pK (B)) was ziprasidone > tiospirone > SSR181507 > or = clozapine > or = olanzapine > SLV-314 > SLV-313 > or = aripiprazole > or = chlorpromazine > nemonapride > haloperidol. Interestingly, pretreatment of HEK293-h5-HT(7a) cells with forskolin enhanced basal AC activity and revealed inverse agonist properties for both typical and atypical antipsychotics as well as for aripiprazole. In contrast, other novel antipsychotics exhibited diverse 5-HT(7a) properties; SLV-313 and SLV-314 behaved as quasi-neutral antagonists, SSR181507 acted as an inverse agonist, and bifeprunox as a partial agonist, as mentioned above. In conclusion, the differential properties of third generation antipsychotics at 5-HT(7) receptors may influence their antipsychotic profile.
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Robinson, Delbert G.; Gallego, Juan A.; John, Majnu; Petrides, Georgios; Hassoun, Youssef; Zhang, Jian-Ping; Lopez, Leonardo; Braga, Raphael J.; Sevy, Serge M.; Addington, Jean; Kellner, Charles H.; Tohen, Mauricio; Naraine, Melissa; Bennett, Natasha; Greenberg, Jessica; Lencz, Todd; Correll, Christoph U.; Kane, John M.; Malhotra, Anil K.
2015-01-01
Research findings are particularly important for medication choice for first-episode patients as individual prior medication response to guide treatment decisions is unavailable. We describe the first large-scale double-masked randomized comparison with first-episode patients of aripiprazole and risperidone, 2 commonly used first-episode treatment agents. One hundred ninety-eight participants aged 15–40 years with schizophrenia, schizophreniform disorder, schizoaffective disorder or psychotic disorder Not Otherwise Specified, and who had been treated in their lifetime with antipsychotics for 2 weeks or less were randomly assigned to double-masked aripiprazole (5–30mg/d) or risperidone (1–6mg/d) and followed for 12 weeks. Positive symptom response rates did not differ (62.8% vs 56.8%) nor did time to response. Aripiprazole-treated participants had better negative symptom outcomes but experienced more akathisia. Body mass index change did not differ between treatments but advantages were found for aripiprazole treatment for total and low-density lipoprotein cholesterol, fasting glucose, and prolactin levels. Post hoc analyses suggested advantages for aripiprazole on depressed mood. Overall, if the potential for akathisia is a concern, low-dose risperidone as used in this trial maybe a preferred choice over aripiprazole. Otherwise, aripiprazole would be the preferred choice over risperidone in most situations based upon metabolic outcome advantages and some symptom advantages within the context of similar positive symptom response between medications. PMID:26338693
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Maat, Arija; Cahn, Wiepke; Gijsman, Harm J; Hovens, Johannes E; Kahn, René S; Aleman, André
2014-04-01
To date, only few studies have examined the impact of medication on social cognition and none have examined the effects of aripiprazole in this respect. The goal of this 8-week, randomized, multicenter, open-label study was to examine the effects of aripiprazole and risperidone on social cognition and neurocognition in individuals with schizophrenia. Eighty schizophrenia patients (DSM-IV-TR) aged 16-50 years were administered multiple computerized measures of social cognition and neurocognition including reaction times at baseline and the end of week 8. Social functioning was mapped with the Social Functioning scale and Quality of Life scale. The study ran from June 2005 to March 2011. Scores on social cognitive and neurocognitive tests improved with both treatments, as did reaction time. There were few differences between the two antipsychotics on (social) cognitive test-scores. The aripiprazole group performed better (more correct items) on symbol substitution (P=.003). Aripiprazole was also superior to risperidone on reaction time for emotional working memory and working memory (P=.006 and P=.023, respectively). Improvements on these tests were correlated with social functioning. In conclusion, aripiprazole and risperidone showed a similar impact on social cognitive test-scores. However, aripiprazole treatment produced a greater effect on patients' processing speed compared to risperidone, with these improvements being associated with concurrent improvements in social functioning. Further research on the long-term effects of aripiprazole on cognition is warranted. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.
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Aripiprazole for Post-traumatic Stress Disorder: A Systematic Review.
Britnell, Sara R; Jackson, Anna D; Brown, Jamie N; Capehart, Bruce P
The aim of this study was to review the safety and efficacy of aripiprazole as monotherapy and adjunct therapy for the treatment of post-traumatic stress disorder (PTSD). A search of both MEDLINE (1956 to May 2017) and EMBASE (1957 to May 2017) was conducted using the terms "aripiprazole" and "post-traumatic stress disorder," "posttraumatic stress disorder," or "PTSD." Studies evaluating the primary endpoint of PTSD in patients taking aripiprazole as monotherapy or adjunct therapy were analyzed for relevance. Those that met the objective of this study were included for evaluation: 1 placebo-controlled trial; 4 open-label trials; and 1 retrospective chart review. In patients with a history of PTSD, aripiprazole resulted in significant improvements in the primary outcome, including Clinician-Administered PTSD Symptom Scale or PTSD Checklist-Military scores, in all but 1 study analyzed. Study durations ranged from 10 to 16 weeks. Initial doses of aripiprazole ranged from 2 to 15 mg daily that could be titrated up or down in the range of 2 to 30 mg daily based on efficacy and tolerability. Overall, aripiprazole was well tolerated with the most common treatment-related study discontinuations attributed to the adverse events of anxiety, insomnia, akathisia, asthenia, restlessness, and somnolence. Based on the reviewed literature, aripiprazole is a reasonable therapy option as monotherapy or adjunct therapy in patients with PTSD. Larger randomized controlled trials are needed to better understand the role of this atypical antipsychotic in patients with PTSD.
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Changes in biomarkers of bone turnover in an aripiprazole add-on or switching study.
Lodhi, Rohit J; Masand, Salaj; Malik, Amna; Shivakumar, Kuppuswami; McAllister, Victoria D M; O'Keane, Veronica; Young, Leah C; Heald, Adrian H; Sherwood, Roy A; Aitchison, Katherine J
2016-02-01
The association between mental illness and osteoporosis and fractures is particularly pronounced in psychotic disorders. Antipsychotic use has previously been described to affect bone density. A 52-week follow-up of patients switched to aripiprazole or with aripiprazole added on, conducting a specific analysis of markers of bone turnover: urinary NTX (a biomarker of bone resorption) and serum BSAP (a biomarker of bone formation). Baseline and serial measurements of bone markers NTX, BSAP and of hormones prolactin, oestrogen and testosterone were done at weeks 0 and 1, 2, 6, 12, 26 and 52, respectively. NTX concentration reduced over time but this did not reach significance in the whole group (log-NTX: β=-0.0012, p=0.142). For BSAP the addition of or replacement with aripiprazole produced a significant reduction (log-BSAP: β=-0.00039, p=0.002). Analysis with prolactin similarly showed a significant reduction (log-prolactin: β=-0.0024, p<0.001); other hormones did not change significantly. Sensitivity analysis to compare the switchers to aripiprazole versus the "add-on" showed that the former group had a significant reduction in NTX. We found that switching to aripiprazole was associated with changes in molecular biomarkers of bone resorption, indicating a more favourable profile for bone health. Copyright © 2015 Elsevier B.V. All rights reserved.
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Role of Dopamine 2 Receptor in Impaired Drug-Cue Extinction in Adolescent Rats.
Zbukvic, Isabel C; Ganella, Despina E; Perry, Christina J; Madsen, Heather B; Bye, Christopher R; Lawrence, Andrew J; Kim, Jee Hyun
2016-06-01
Adolescent drug users display resistance to treatment such as cue exposure therapy (CET), as well as increased liability to relapse. The basis of CET is extinction learning, which involves dopamine signaling in the medial prefrontal cortex (mPFC). This system undergoes dramatic alterations during adolescence. Therefore, we investigated extinction of a cocaine-associated cue in adolescent and adult rats. While cocaine self-administration and lever-alone extinction were not different between the two ages, we observed that cue extinction reduced cue-induced reinstatement in adult but not adolescent rats. Infusion of the selective dopamine 2 receptor (D2R)-like agonist quinpirole into the infralimbic cortex (IL) of the mPFC prior to cue extinction significantly reduced cue-induced reinstatement in adolescents. This effect was replicated by acute systemic treatment with the atypical antipsychotic aripiprazole (Abilify), a partial D2R-like agonist. These data suggest that adolescents may be more susceptible to relapse due to a deficit in cue extinction learning, and highlight the significance of D2R signaling in the IL for cue extinction during adolescence. These findings inspire new tactics for improving adolescent CET, with aripiprazole representing an exciting potential pharmacological adjunct for behavioral therapy. © The Author 2016. Published by Oxford University Press.
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Rummel-Kluge, Christine; Komossa, Katja; Schwarz, Sandra; Hunger, Heike; Schmid, Franziska; Lobos, Claudia Asenjo; Kissling, Werner; Davis, John M; Leucht, Stefan
2010-01-01
Objective The metabolic side effects of second-generation antipsychotics (SGA) are serious and have not been compared head to head in a meta-analysis. We conducted a meta-analysis of studies comparing the metabolic side effects of the following SGAs head-to-head: amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, sertindole, ziprasidone, zotepine. Method We searched the register of the Cochrane schizophrenia group (last search May 2007), supplemented by MEDLINE and EMBASE (last search January 2009) for randomized, blinded studies comparing the above mentioned SGA in the treatment of schizophrenia or related disorders. At least three reviewers extracted the data independently. The primary outcome was weight change. We also assessed changes of cholesterol and glucose. The results were combined in a meta-analysis. Results We included 48 studies with 105 relevant arms. Olanzapine produced more weight gain than all other second-generation antipsychotics except for clozapine where no difference was found. Clozapine produced more weight gain than risperidone, risperidone more than amisulpride, and sertindole more than risperidone. Olanzapine produced more cholesterol increase than aripiprazole, risperidone and ziprasidone. (No differences with amisulpride, clozapine and quetiapine were found). Quetiapine produced more cholesterol increase than risperidone and ziprasidone. Olanzapine produced more increase in glucose than amisulpride, aripiprazole, quetiapine, risperidone and ziprasidone; no difference was found with clozapine. Conclusions Some SGAs lead to substantially more metabolic side effects than other SGAs. When choosing an SGA for an individual patient these side effects with their potential cause of secondary diseases must be weighed against efficacy and characteristics of the individual patient. PMID:20692814
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Sun, Shawn X; Liu, Gordon G; Christensen, Dale B; Fu, Alex Z
2007-10-01
To review the literature addressing the economic outcomes of nonadherence in the treatment of schizophrenia, and to utilize the review results to provide an update on the economic impact of hospitalizations among schizophrenia patients related to antipsychotic nonadherence. A structured search of EMBASE, Ovid MEDLINE, PubMed and PsycINFO for years 1995-2007 was conducted to identify published English-language articles addressing the economic impact of antipsychotic nonadherence in schizophrenia. The following key words were used in the search: compliance, noncompliance, adherence, nonadherence, relapse, economic, cost, and schizophrenia. A bibliographic search of retrieved articles was performed to identify additional studies. For a study to be included, the date of publication had to be from 1/1/1995 to 6/1/2007, and the impact of nonadherence had to be measured in terms of direct healthcare costs or inpatient days. Subsequently, an estimate of incremental hospitalization costs related to antipsychotic non adherence was extrapolated at the US national level based on the reviewed studies (nonadherence rate and hospitalization rate) and the National Inpatient Sample of Healthcare Cost and Utilization Project (average daily hospitalization costs). Seven studies were identified and reviewed based on the study design, measurement of medication nonadherence, study setting, and cost outcome results. Despite the varied adherence measures across studies, all articles reviewed showed that antipsychotic nonadherence was related to an increase in hospitalization rate, hospital days or hospital costs. We also estimated that the national rehospitalization costs related to antipsychotic nonadherence was $1479 million, ranging from $1392 million to $1826 million in the US in 2005. The estimate of rehospitalization costs was restricted to schizophrenia patients from the Medicaid program. Additionally, the studies we reviewed did not capture the newer antipsychotic drugs (ziprasidone, aripiprazole and paliperidone). Thus, the nonadherence rates or rehospitalization rates might have changed after these new drugs came to the market, which could limit our cost estimation. Poor adherence to antipsychotic medications was consistently associated with higher risk of relapse and rehospitalization and higher hospitalization costs. To reduce the cost of hospitalizations among schizophrenia patients, it seems clear that efforts to increase medication adherence should be undertaken.
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Heusler, Peter; Newman-Tancredi, Adrian; Castro-Fernandez, Annabelle; Cussac, Didier
2007-03-01
The D(2) dopaminergic receptor represents a major target of antipsychotic drugs. Using the coupling of the human D(2long) (hD(2L)) receptor to G protein-coupled inward rectifier potassium (GIRK) channels in Xenopus laevis oocytes, we examined the activity of antipsychotic agents of different classes - typical, atypical, and a "new generation" of compounds, exhibiting a preferential D(2) and 5-HT(1A) receptor profile. When the hD(2L) receptor was coexpressed with GIRK channels, a series of reference compounds exhibited full agonist (dopamine, and quinpirole), partial agonist (apomorphine, (-)3-PPP, and (+)-UH232) or inverse agonist (raclopride, and L741626) properties. Sarizotan exhibited only very weak partial agonist action. At higher levels of receptor cRNA injected per oocyte, both partial agonist activity and inverse agonist properties were generally more pronounced. The inverse agonist action of L741626 was reversed by interaction with sarizotan, thus confirming the constitutive activity of wild-type hD(2L) receptors in the oocyte expression system. When antipsychotic agents were tested for their actions at the hD(2L) receptor, typical (haloperidol) as well as atypical (nemonapride, ziprasidone, and clozapine) compounds acted as inverse agonists. In contrast, among D(2)/5-HT(1A) antipsychotics, only SLV313 and F15063 behaved as inverse agonists, whilst the other members of this group (bifeprunox, SSR181507 and the recently marketed antipsychotic, aripiprazole) exhibited partial agonist properties. Thus, the X. laevis oocyte expression system highlights markedly different activity of antipsychotics at the hD(2L) receptor. These differential properties may translate to distinct therapeutic potential of these compounds.
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Pan, Bo; Lian, Jiamei; Huang, Xu-Feng; Deng, Chao
2016-05-01
The GABAA receptor is implicated in the pathophysiology of schizophrenia and regulated by PKA signalling. Current antipsychotics bind with D2-like receptors, but not the GABAA receptor. The cAMP-responsive element-binding protein 1 (CREB1) is also associated with PKA signalling and may be related to the positive symptoms of schizophrenia. This study investigated the effects of antipsychotics in modulating D2-mediated PKA signalling and its downstream GABAA receptors and CREB1. Rats were treated orally with aripiprazole (0.75 mg/kg, ter in die (t.i.d.)), bifeprunox (0.8 mg/kg, t.i.d.), haloperidol (0.1 mg/kg, t.i.d.) or vehicle for 1 week. The levels of PKA-Cα and p-PKA in the prefrontal cortex (PFC), nucleus accumbens (NAc) and caudate putamen (CPu) were detected by Western blots. The mRNA levels of Gabrb1, Gabrb2, Gabrb3 and Creb1, and their protein expression were measured by qRT-PCR and Western blots, respectively. Aripiprazole elevated the levels of p-PKA and the ratio of p-PKA/PKA in the NAc, but not the PFC and CPu. Correlated with this elevated PKA signalling, aripiprazole elevated the mRNA and protein expression of the GABAA (β-1) receptor and CREB1 in the NAc. While haloperidol elevated the levels of p-PKA and the ratio of p-PKA/PKA in both NAc and CPu, it only tended to increase the expression of the GABAA (β-1) receptor and CREB1 in the NAc, but not the CPu. Bifeprunox had no effects on PKA signalling in these brain regions. These results suggest that aripiprazole has selective effects on upregulating the GABAA (β-1) receptor and CREB1 in the NAc, probably via activating PKA signalling.
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Berger, Ariel; Edelsberg, John; Sanders, Kafi N; Alvir, Jose Ma J; Mychaskiw, Marko A; Oster, Gerry
2012-08-02
Schizophrenia and bipolar disorder are chronic debilitating disorders that are often treated with second-generation antipsychotic agents, such as aripiprazole, quetiapine, and ziprasidone. While patients who are hospitalized for schizophrenia and bipolar disorder often receive these agents at discharge, comparatively little information exists on subsequent patterns of pharmacotherapy. Using a database linking hospital admission records to health insurance claims, we identified all patients hospitalized for schizophrenia (ICD-9-CM diagnosis code 295.XX) or bipolar disorder (296.0, 296.1, 296.4-296.89) between January 1, 2001 and September 30, 2008 who received aripiprazole, quetiapine, or ziprasidone at discharge. Patients not continuously enrolled for 6 months before and after hospitalization ("pre-admission" and "follow-up", respectively) were excluded. We examined patterns of use of these agents during follow-up, including adherence with treatment (using medication possession ratios [MPRs] and cumulative medication gaps [CMGs]) and therapy switching. Analyses were undertaken separately for patients with schizophrenia and bipolar disorder, respectively. We identified a total of 43 patients with schizophrenia, and 84 patients with bipolar disorder. During the 6-month period following hospitalization, patients with schizophrenia received an average of 101 therapy-days with the second-generation antipsychotic agent prescribed at discharge; for patients with bipolar disorder, the corresponding value was 68 therapy-days. Mean MPR at 6 months was 55.1% for schizophrenia patients, and 37.3% for those with bipolar disorder; approximately one-quarter of patients switched to another agent over this period. Medication compliance is poor in patients with schizophrenia or bipolar disorder who initiate treatment with aripiprazole, quetiapine, or ziprasidone at hospital discharge.
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Rosenberg, David R.; Brooks, Beth Ann; Roberts, Mary W.; Diwadkar, Vaibhav A.
2012-01-01
Objective: There is general consensus that second-generation antipsychotics are at least as effective as and more tolerable than first-generation antipsychotics. We address questions of safety and tolerability in both the short-term and long-term use of these medications by reviewing the existing literature in youth and adults. Data Sources: A MEDLINE search was conducted via PubMed using the following keywords (in various combinations): typical antipsychotics, atypical antipsychotics, children, adolescents, side effects, weight gain, diabetes, metformin, metabolic syndrome, and CATIE. Only English-language articles published from 2000–2010 were included. The bibliographies of papers identified through MEDLINE searches were also reviewed. Results: Six adult studies were analyzed in detail. A summary of the data suggests that there may be a lower association of weight gain and diabetes with ziprasidone, aripiprazole, and haloperidol, while olanzapine, clozapine, quetiapine, and risperidone appear to be more highly associated. There may be less difference than originally thought concerning frequency of extrapyramidal side effects among these medications. All of these antipsychotics, including perphenazine, are similarly efficacious in treating psychosis, with the exception of clozapine, which demonstrates significantly more effectiveness. Although the studies on youth tend to be small (few subjects with large age ranges of 4 to 19 years) and short term in comparison to the adult studies, the data reviewed from 5 studies suggest that, in youth, olanzapine may be associated with the greatest weight gain, extrapyramidal side effects and metabolic changes are quite prevalent, and the antipsychotics studied seem to be similarly effective. Conclusions: Considering effectiveness, safety, and tolerability, this literature review suggests that in adults there may be a lower association of weight gain and diabetes with ziprasidone, aripiprazole, and haloperidol as compared with olanzapine, clozapine, quetiapine, and risperidone. Youth may be particularly sensitive to weight gain, especially with olanzapine, as well as extrapyramidal side effects and metabolic changes. The literature suggests similar effectiveness among the antipsychotics, perhaps with the exception of clozapine having greater effectiveness, at least in adults. PMID:23106030
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Mukundan, Anitha; Faulkner, Guy; Cohn, Tony; Remington, Gary
2010-12-08
Weight gain is common for people with schizophrenia and this has serious implications for a patient's health and well being. Switching strategies have been recommended as a management option. To determine the effects of antipsychotic medication switching as a strategy for reducing or preventing weight gain and metabolic problems in people with schizophrenia. We searched key databases and the Cochrane Schizophrenia Group's trials register (January 2005 and June 2007), reference sections within relevant papers and contacted the first author of each relevant study and other experts to collect further information. All clinical randomised controlled trials comparing switching of antipsychotic medication as an intervention for antipsychotic induced weight gain and metabolic problems with continuation of medication and/or other weight loss treatments (pharmacological and non pharmacological) in people with schizophrenia or schizophrenia-like illnesses. Studies were reliably selected, quality assessed and data extracted. For dichotomous data we calculated risk ratio (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis, based on a fixed-effect model. The primary outcome measures were weight loss, metabolic syndrome, relapse and general mental state. We included four studies for the review with a total of 636 participants. All except one study had a duration of 26 weeks or less. There was a mean weight loss of 1.94 kg (2 RCT, n = 287, CI -3.9 to 0.08) when switched to aripiprazole or quetiapine from olanzapine. BMI also decreased when switched to quetiapine (1 RCT, n = 129, MD -0.52 CI -1.26 to 0.22) and aripiprazole (1 RCT, n = 173, RR 0.28 CI 0.13 to 0.57) from olanzapine.Fasting blood glucose showed a significant decrease when switched to aripiprazole or quetiapine from olanzapine. (2 RCT, MD -2.53 n = 280 CI -2.94 to -2.11). One RCT also showed a favourable lipid profile when switched to aripiprazole but these measures were reported as percentage changes, rather than means with standard deviation.People are less likely to leave the study early if they remain on olanzapine compared to switching to quetiapine or aripiprazole.There was no significant difference in outcomes of mental state, global state, and adverse events between groups which switched medications and those that remained on previous medication. Three different switching strategies were compared and no strategy was found to be superior to the others for outcomes of weight gain, mental state and global state. Evidence from this review suggests that switching antipsychotic medication to one with lesser potential for causing weight gain or metabolic problems could be an effective way to manage these side effects, but the data were weak due to the limited number of trials in this area and small sample sizes. Poor reporting of data also hindered using some trials and outcomes. There was no difference in mental state, global state and other treatment related adverse events between switching to another medication and continuing on the previous one. When the three switching strategies were compared none of them had an advantage over the others in their effects on the primary outcomes considered in this review. Better designed trials with adequate power would provide more convincing evidence for using medication switching as an intervention strategy.
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Kishi, Taro; Matsuda, Yuki; Matsunaga, Shinji; Mukai, Tomohiko; Moriwaki, Masatsugu; Tabuse, Hideaki; Fujita, Kiyoshi; Iwata, Nakao
2016-01-01
There has been no direct comparison of aripiprazole and blonanserin for schizophrenia treatment. We conducted a 24-week, rater-masked, randomized trial of aripiprazole (6-30 mg/d) vs blonanserin (4-24 mg/d) in schizophrenia patients who were not taking any antipsychotic medication for more than 2 weeks before enrollment (UMIN000011194). The primary outcome measure for efficacy was improvement of Positive and Negative Syndrome Scale (PANSS) total score at week 24. Secondary outcomes were PANSS subscale scores, 21-item Hamilton Rating Scale for Depression (HAMD-21) score, response rate, discontinuation rate, and individual adverse events. Forty-four patients were recruited. The discontinuation rate was 86.4% in the aripiprazole group and 68.2% in the blonanserin treatment group. There was no significant difference in mean time to discontinuation between the groups. Although both treatment groups showed significant reductions in the PANSS total score, PANSS subscale scores, and HAMD-21 scores at week 24, the magnitudes of the changes did not differ between the groups. There were no significant differences in the incidences of adverse events including somnolence, extrapyramidal symptoms, prolactin-related adverse events, and weight change between the groups. Our results suggest similar efficacy and safety profiles of aripiprazole and blonanserin in the patients with schizophrenia. Double-blind controlled studies are needed to further explore the efficacy and safety of aripiprazole and blonanserin in schizophrenia.
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Ishigooka, Jun; Noda, Takamasa; Nishiyama, Kosuke; Tamaru, Noriko; Shima, Tomoko; Yamasaki, Yumiko; Tadori, Yoshihiro
2016-06-01
Aripiprazole once-monthly (AOM) was previously approved for treatment of schizophrenia as monthly injections in the gluteal muscle. The deltoid muscle provides a more accessible injection site. The present study was conducted in Japanese schizophrenia patients as a 24-week, open-label trial that assessed the pharmacokinetics and safety of 5 sequential doses of AOM 400 mg (AOM 400) once every 4 weeks administered in the deltoid muscle. Patients treated with an oral atypical antipsychotic (other than aripiprazole) continued to receive their pre-study medication up to 14 days after the first AOM 400 injection. The completion rate was 76.5% (n = 13/17). Mean aripiprazole plasma C(min) almost reached steady-state by the fourth AOM 400 injection. After the fifth AOM 400 injection, mean aripiprazole AUC(28d), C(max) and C(min) were 165 μg x h/ml, 331 ng/ml and 201 ng/ml, respectively, which were similar to previously published pharmacokinetic parameters after the fifth gluteal injection of AOM 400. The most common treatment-emergent adverse event (TEAE) was injection site pain (35.3%). Most TEAEs were classified as mild in intensity. In conclusion, the deltoid injection of AOM can be considered an alternative route of administration, as deltoid and gluteal injections are interchangeable in terms of aripiprazole plasma concentrations, with no additional safety issues.
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Dose Equivalents for Second-Generation Antipsychotic Drugs: The Classical Mean Dose Method
Leucht, Stefan; Samara, Myrto; Heres, Stephan; Patel, Maxine X.; Furukawa, Toshi; Cipriani, Andrea; Geddes, John; Davis, John M.
2015-01-01
Background: The concept of dose equivalence is important for many purposes. The classical approach published by Davis in 1974 subsequently dominated textbooks for several decades. It was based on the assumption that the mean doses found in flexible-dose trials reflect the average optimum dose which can be used for the calculation of dose equivalence. We are the first to apply the method to second-generation antipsychotics. Methods: We searched for randomized, double-blind, flexible-dose trials in acutely ill patients with schizophrenia that examined 13 oral second-generation antipsychotics, haloperidol, and chlorpromazine (last search June 2014). We calculated the mean doses of each drug weighted by sample size and divided them by the weighted mean olanzapine dose to obtain olanzapine equivalents. Results: We included 75 studies with 16 555 participants. The doses equivalent to 1 mg/d olanzapine were: amisulpride 38.3 mg/d, aripiprazole 1.4 mg/d, asenapine 0.9 mg/d, chlorpromazine 38.9 mg/d, clozapine 30.6 mg/d, haloperidol 0.7 mg/d, quetiapine 32.3mg/d, risperidone 0.4mg/d, sertindole 1.1 mg/d, ziprasidone 7.9 mg/d, zotepine 13.2 mg/d. For iloperidone, lurasidone, and paliperidone no data were available. Conclusions: The classical mean dose method is not reliant on the limited availability of fixed-dose data at the lower end of the effective dose range, which is the major limitation of “minimum effective dose methods” and “dose-response curve methods.” In contrast, the mean doses found by the current approach may have in part depended on the dose ranges chosen for the original trials. Ultimate conclusions on dose equivalence of antipsychotics will need to be based on a review of various methods. PMID:25841041
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Cleymans, Stijn; Morrens, Manuel; Bervoets, Chris
2017-06-01
The number of antipsychotic prescriptions are increasing rapidly worldwide, a trend which is mainly driven by the steep rise in second-generation antipsychotic (SGA) prescriptions. However, the success of SGA, compared with the older first-generation antipsychotics (FGAs), cannot be explained by evidence. Several studies concluded on equal efficacy of FGA and SGA on positive, negative and cognitive symptoms of schizophrenia. Next to that, the influence of the pharmaceutical industry on prescription behaviour has drawn considerable interest. Therefore, the relationship between antipsychotic prescription patterns and exposure to information directly provided by pharmaceutical companies was studied. A cross-sectional online survey, addressing psychiatrists, general practitioners (GPs) and trainees in Flanders, was carried out. Respondents were questioned about their prescription behaviour, opinion about efficacy of SGA versus FGA and the nature and frequency of their contact with the pharmaceutical industry. Using Spearman's rank correlations and χ 2 tests, the relationship between different variables and group differences were examined. Psychiatrists, GPs and trainees in Flanders clearly favour olanzapine and risperidone, followed by quetiapine and aripiprazole above all other agents. This behaviour is supported by the conviction that SGAs have superior efficacy and a more benign side effect profile, compared with FGA. Frequent contact with drug representatives is correlated with a preference of SGA over FGA. 41% of the respondents acknowledge to be influenced by the pharmaceutical industry, which is more than that previously reported. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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Aripiprazole inhibits polyI:C-induced microglial activation possibly via TRPM7.
Sato-Kasai, Mina; Kato, Takahiro A; Ohgidani, Masahiro; Mizoguchi, Yoshito; Sagata, Noriaki; Inamine, Shogo; Horikawa, Hideki; Hayakawa, Kohei; Shimokawa, Norihiro; Kyuragi, Sota; Seki, Yoshihiro; Monji, Akira; Kanba, Shigenobu
2016-12-01
Viral infections during fetal and adolescent periods, as well as during the course of schizophrenia itself have been linked to the onset and/or relapse of a psychosis. We previously reported that the unique antipsychotic aripiprazole, a partial D2 agonist, inhibits the release of tumor necrosis factor (TNF)-α from interferon-γ-activated rodent microglial cells. Polyinosinic-polycytidylic acid (polyI:C) has recently been used as a standard model of viral infections, and recent in vitro studies have shown that microglia are activated by polyI:C. Aripiprazole has been reported to ameliorate behavioral abnormalities in polyI:C-induced mice. To clarify the anti-inflammatory properties of aripiprazole, we investigated the effects of aripiprazole on polyI:C-induced microglial activation in a cellular model of murine microglial cells and possible surrogate cells for human microglia. PolyI:C treatment of murine microglial cells activated the production of TNF-α and enhanced the p38 mitogen-activated protein kinase (MAPK) pathway, whereas aripiprazole inhibited these responses. In addition, polyI:C treatment of possible surrogate cells for human microglia markedly increased TNF-α mRNA expression in cells from three healthy volunteers. Aripiprazole inhibited this increase in cells from two individuals. PolyI:C consistently increased intracellular Ca 2+ concentration ([Ca 2+ ] i ) in murine microglial cells by influx of extracellular Ca 2+ . We demonstrated that transient receptor potential in melastatin 7 (TRPM7) channels contributed to this polyI:C-induced increase in [Ca 2+ ] i . Taken together, these data suggest that aripiprazole may be therapeutic for schizophrenia by reducing microglial inflammatory reactions, and TRPM7 may be a novel therapeutic target for schizophrenia. Further studies are needed to validate these findings. Copyright © 2016 Elsevier B.V. All rights reserved.
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Jing, Yonghua; Kim, Edward; You, Min; Pikalov, Andrei; Tran, Quynh-Van
2009-06-01
Bipolar disorder has an associated economic burden due to its treatment, including medication and hospitalization costs as well as costs associated with treatment of comorbid conditions. This study compared healthcare costs in patients treated with a mood stabilizer and adjunctive aripiprazole versus adjunctive olanzapine, quetiapine, risperidone or ziprasidone. A retrospective propensity score-matched cohort study was conducted in the LabRx integrated claims database from January 2003 to December 2006. Patients (18-65 years) with bipolar disorder and 180 days of pre-index enrolment without atypical treatment and 90 days post-index enrolment were eligible. Mood stabilizer therapy was initiated prior to index atypical prescription. Generalized gamma regressions were used to compare the total healthcare costs of adjunctive aripiprazole treatment and treatment with adjunctive olanzapine, quetiapine, risperidone or ziprasidone. After controlling for differences in baseline characteristics and pre-index cost, psychiatric costs and subtotal psychiatric and general medical costs were higher for all adjunctive atypicals than adjunctive aripiprazole (p<0.001). Based on gamma regressions cost ratios, there was no significant difference in general medical costs between aripiprazole and ziprasidone, olanzapine, or quetiapine; risperidone general medical costs were 18% higher versus aripiprazole (p=0.041). Aripiprazole pharmacy costs were higher than quetiapine and risperidone (p<0.001) but not olanzapine or ziprasidone. Total healthcare costs were higher for ziprasidone, olanzapine, or risperidone (p<0.001) but not quetiapine. Methodological restriction of patients to those newly initiated on an atypical antipsychotic and incomplete medication history limit the generalizability of the findings. Adjunctive aripiprazole may have economic benefits over other atypicals in terms of lower psychiatric treatment costs than adjunctive olanzapine, quetiapine, risperidone or ziprasidone, and lower total healthcare costs than adjunctive olanzapine, risperidone or ziprasidone.
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Bradford, Andrea M; Savage, Kevin M; Jones, Declan N C; Kalinichev, Mikhail
2010-10-01
We evaluated locomotor hyperactivity induced in BALB/C mice by an N-methyl-D-aspartate receptor antagonist MK-801 as an assay for the detection of antipsychotic drugs. We assessed the effects of antipsychotic drugs to validate the assay (study 1), selective dopamine and serotonin ligands for pharmacological characterisation of the model (study 2) and a number of compounds with efficacy in models of schizophrenia to understand the predictive validity of the model (study 3). Adult males (n = 9/group) were pretreated with a test compound, habituated to locomotor activity cages before receiving MK-801 (0.32 mg/kg) and activity recorded for a further 75 or 120 min. In study 1, we tested haloperidol, clozapine, olanzapine, risperidone, ziprasidone, aripiprazole, sertindole and quetiapine. In study 2, we tested SCH23390 (D(1) antagonist), sulpiride (D(2)/D(3) antagonist), raclopride (D(2)/D(3) antagonist), SB-277011 (D(3) antagonist), L-745,870 (D(4) antagonist), WAY100635 (5-HT(1A) antagonist), 8-OH-DPAT (5-HT(1A) agonist), ketanserin (5-HT(2A)/5-HT(2C) antagonist) and SB-242084 (5-HT(2C) antagonist). In study 3, we tested xanomeline (M(1)/M(4) receptor agonist), LY379268 (mGluR2/3 receptor agonist), diazepam (GABA(A) modulator) and thioperamide (H(3) receptor antagonist). All antipsychotics suppressed MK-801-induced hyperactivity in a dose-dependent and specific manner. The effects of antipsychotics appear to be mediated via dopamine D(1), D(2) and 5-HT(2) receptors. Xanomeline, LY379268 and diazepam were active in this assay while thioperamide was not. MK-801-induced hyperactivity in BALB/C mice model of positive symptoms has shown predictive validity with novel compounds acing at M(1)/M(4), mGluR2/3 and GABA(A) receptors and can be used as a screening assay for detection of novel pharmacotherapies targeting those receptors.
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Liemburg, Edith J; van Es, Frank; Knegtering, Henderikus; Aleman, André
2017-10-03
Impaired function of prefrontal brain networks may be the source of both negative symptoms and neurocognitive problems in psychotic disorders. Whereas most antipsychotics may decrease prefrontal activation, the partial dopamine D2-receptor agonist aripiprazole is hypothesized to improve prefrontal function. This study investigated whether patients with a psychotic disorder would show stronger activation of prefrontal areas and associated regions after treatment with aripiprazole compared to risperidone treatment. In this exploratory pharmacological neuroimaging study, 24 patients were randomly assigned to either aripiprazole or risperidone. At baseline and after nine weeks treatment they underwent an interview and MRI session. Here we report on brain activation (measured with arterial spin labeling) during performance of two tasks, the Tower of London and the Wall of Faces. Aripiprazole treatment decreased activation of the middle frontal, superior frontal and occipital gyrus (ToL) and medial temporal and inferior frontal gyrus, putamen and cuneus (WoF), while activation increased after risperidone. Activation increased in the ventral anterior cingulate and posterior insula (ToL), and superior frontal, superior temporal and precentral gyrus (WoF) after aripiprazole treatment and decreased after risperidone. Both treatment groups had increased ventral insula activation (ToL) and middle temporal gyrus (WoF), and decreased occipital cortex, precuneus and caudate head activation (ToL) activation. In conclusion, patients treated with aripiprazole may need less frontal resources for planning performance and may show increased frontotemporal and frontostriatal reactivity to emotional stimuli. More research is needed to corroborate and extend these preliminary findings. Copyright © 2017 Elsevier Inc. All rights reserved.
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Sim, Juhyun; Kim, Eunmi; Yang, Wonkyung; Woo, Sanghee; In, Sangwhan
2017-05-01
In recent years, the inappropriate use of antipsychotics by young Korean men has become a social problem. As military service exemptions are given for mental illness, some men pose as mental health patients to avoid military service. In order to verify the authenticity of mental illnesses, we developed simultaneous analytical methods for the detection of 15 antipsychotics and 2 of their metabolites in hair using liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. The target drugs were modafinil, atomoxetine, aripiprazole, benztropine, buspirone, duloxetine, gabapentin, oxcarbazepine, topiramate, escitalopram, paliperidone, ziprasidone, lamotrigine, clonazepam, levetiracetam, and metabolites of oxcarbazepine and clonazepam. To remove possible contaminants on the hair surface, hair samples were washed twice with methanol and distilled water, and then were extracted with methanol overnight at 38°C. Desipramine-d 3 was used as an internal standard. LC-MS/MS analysis was performed on an Agilent 1290 Infinity UHPLC coupled to an AB Sciex Qtrap ® 5500 MS/MS. The total chromatographic run time was 14min. The following validation parameters were evaluated: selectivity, linearity, limit of detection (LOD), limit of quantification (LOQ), precision, accuracy, matrix effect, and recovery. The LOD and LOQ values for all analytes, except modafinil, ranged from 0.2 to 10pg/mg hair and from 0.2 to 20pg/mg hair, respectively. Good linearity was achieved for most of the analytes in the range of 20-200pg/mg hair. The method showed acceptable precision and accuracy, which were less than 15%, as well as satisfactory matrix effects and recoveries. Furthermore, this method was also applied to the analysis of rat hair samples. The study in rats showed that the concentrations of atomoxetine and aripiprazole in pigmented hair were significantly higher than those in non-pigmented hair. However, no significant difference was observed in the concentration of topiramate between pigmented and non-pigmented hair. This method will be useful in monitoring the inappropriate use of antipsychotics in suspects posing as mental health patients. However, further research is necessary before applying this method to authentic hair samples from mental health patients. Copyright © 2017 Elsevier B.V. All rights reserved.
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Almost All Antipsychotics Result in Weight Gain: A Meta-Analysis
Bak, Maarten; Fransen, Annemarie; Janssen, Jouke; van Os, Jim; Drukker, Marjan
2014-01-01
Introduction Antipsychotics (AP) induce weight gain. However, reviews and meta-analyses generally are restricted to second generation antipsychotics (SGA) and do not stratify for duration of AP use. It is hypothesised that patients gain more weight if duration of AP use is longer. Method A meta-analysis was conducted of clinical trials of AP that reported weight change. Outcome measures were body weight change, change in BMI and clinically relevant weight change (7% weight gain or loss). Duration of AP-use was stratified as follows: ≤6 weeks, 6–16 weeks, 16–38 weeks and >38 weeks. Forest plots stratified by AP as well as by duration of use were generated and results were summarised in figures. Results 307 articles met inclusion criteria. The majority were AP switch studies. Almost all AP showed a degree of weight gain after prolonged use, except for amisulpride, aripiprazole and ziprasidone, for which prolonged exposure resulted in negligible weight change. The level of weight gain per AP varied from discrete to severe. Contrary to expectations, switch of AP did not result in weight loss for amisulpride, aripiprazole or ziprasidone. In AP-naive patients, weight gain was much more pronounced for all AP. Conclusion Given prolonged exposure, virtually all AP are associated with weight gain. The rational of switching AP to achieve weight reduction may be overrated. In AP-naive patients, weight gain is more pronounced. PMID:24763306
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Almost all antipsychotics result in weight gain: a meta-analysis.
Bak, Maarten; Fransen, Annemarie; Janssen, Jouke; van Os, Jim; Drukker, Marjan
2014-01-01
Antipsychotics (AP) induce weight gain. However, reviews and meta-analyses generally are restricted to second generation antipsychotics (SGA) and do not stratify for duration of AP use. It is hypothesised that patients gain more weight if duration of AP use is longer. A meta-analysis was conducted of clinical trials of AP that reported weight change. Outcome measures were body weight change, change in BMI and clinically relevant weight change (7% weight gain or loss). Duration of AP-use was stratified as follows: ≤6 weeks, 6-16 weeks, 16-38 weeks and >38 weeks. Forest plots stratified by AP as well as by duration of use were generated and results were summarised in figures. 307 articles met inclusion criteria. The majority were AP switch studies. Almost all AP showed a degree of weight gain after prolonged use, except for amisulpride, aripiprazole and ziprasidone, for which prolonged exposure resulted in negligible weight change. The level of weight gain per AP varied from discrete to severe. Contrary to expectations, switch of AP did not result in weight loss for amisulpride, aripiprazole or ziprasidone. In AP-naive patients, weight gain was much more pronounced for all AP. Given prolonged exposure, virtually all AP are associated with weight gain. The rational of switching AP to achieve weight reduction may be overrated. In AP-naive patients, weight gain is more pronounced.
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An update of safety of clinically used atypical antipsychotics.
Orsolini, L; Tomasetti, C; Valchera, A; Vecchiotti, R; Matarazzo, I; Vellante, F; Iasevoli, F; Buonaguro, E F; Fornaro, M; Fiengo, A L C; Martinotti, G; Mazza, M; Perna, G; Carano, A; De Bartolomeis, A; Di Giannantonio, M; De Berardis, D
2016-10-01
The atypical antipsychotic (APs) drugs have become the most widely used agents to treat a variety of psychoses because of their superiority with regard to safety and tolerability profile compared to conventional/'typical' APs. We aimed at providing a synthesis of most current evidence about the safety and tolerability profile of the most clinically used atypical APs so far marketed. Qualitative synthesis followed an electronic search made inquiring of the following databases: MEDLINE, Embase, PsycINFO and the Cochrane Library from inception until January 2016, combining free terms and MESH headings for the topics of psychiatric disorders and all atypical APs as following: ((safety OR adverse events OR side effects) AND (aripiprazole OR asenapine OR quetiapine OR olanzapine OR risperidone OR paliperidone OR ziprasidone OR lurasidone OR clozapine OR amisulpride OR iloperidone)). A critical issue in the treatment with atypical APs is represented by their metabolic side effect profile (e.g. weight gain, lipid and glycaemic imbalance, risk of diabetes mellitus and diabetic ketoacidosis) which may limit their use in particular clinical samples. Electrolyte imbalance, ECG abnormalities and cardiovascular adverse effects may recommend a careful baseline and periodic assessments.
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Kishi, Taro; Matsuda, Yuki; Matsunaga, Shinji; Mukai, Tomohiko; Moriwaki, Masatsugu; Tabuse, Hideaki; Fujita, Kiyoshi; Iwata, Nakao
2016-01-01
Objective There has been no direct comparison of aripiprazole and blonanserin for schizophrenia treatment. We conducted a 24-week, rater-masked, randomized trial of aripiprazole (6−30 mg/d) vs blonanserin (4−24 mg/d) in schizophrenia patients who were not taking any antipsychotic medication for more than 2 weeks before enrollment (UMIN000011194). Methods The primary outcome measure for efficacy was improvement of Positive and Negative Syndrome Scale (PANSS) total score at week 24. Secondary outcomes were PANSS subscale scores, 21-item Hamilton Rating Scale for Depression (HAMD-21) score, response rate, discontinuation rate, and individual adverse events. Results Forty-four patients were recruited. The discontinuation rate was 86.4% in the aripiprazole group and 68.2% in the blonanserin treatment group. There was no significant difference in mean time to discontinuation between the groups. Although both treatment groups showed significant reductions in the PANSS total score, PANSS subscale scores, and HAMD-21 scores at week 24, the magnitudes of the changes did not differ between the groups. There were no significant differences in the incidences of adverse events including somnolence, extrapyramidal symptoms, prolactin-related adverse events, and weight change between the groups. Conclusion Our results suggest similar efficacy and safety profiles of aripiprazole and blonanserin in the patients with schizophrenia. Double-blind controlled studies are needed to further explore the efficacy and safety of aripiprazole and blonanserin in schizophrenia. PMID:27932884
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Atypical antipsychotics for psychosis in adolescents.
Kumar, Ajit; Datta, Soumitra S; Wright, Stephen D; Furtado, Vivek A; Russell, Paul S
2013-10-15
Schizophrenia often presents in adolescence, but current treatment guidelines are based largely on studies of adults with psychosis. Over the past decade, the number of studies on treatment of adolescent-onset psychosis has increased. The current systematic review collates and critiques evidence obtained on the use of various atypical antipsychotic medications for adolescents with psychosis. To investigate the effects of atypical antipsychotic medications in adolescents with psychosis. We reviewed in separate analyses various comparisons of atypical antipsychotic medications with placebo or a typical antipsychotic medication or another atypical antipsychotic medication or the same atypical antipsychotic medication but at a lower dose. We searched the Cochrane Schizophrenia Group Register (October 2011), which is based on regular searches of BIOSIS, CENTRAL, CINAHL, EMBASE, MEDLINE and PsycINFO. We inspected references of all identified studies and contacted study authors and relevant pharmaceutical companies to ask for more information. We included all relevant randomised controlled trials (RCTs) that compared atypical antipsychotic medication with placebo or another pharmacological intervention or with psychosocial interventions, standard psychiatric treatment or no intervention in children and young people aged 13 to 18 years with a diagnosis of schizophrenia, schizoaffective disorder, acute and transient psychoses or unspecified psychosis. We included studies published in English and in other languages that were available in standardised databases. Review authors AK and SSD selected the studies, rated the quality of the studies and performed data extraction. For dichotomous data, we estimated risk ratios (RRs) with 95% confidence intervals (CIs) using a fixed-effect model. When possible, for binary data presented in the 'Summary of findings' table, we calculated illustrative comparative risks. We summated continuous data using the mean difference (MD). Risk of bias was assessed for included studies. We included 13 RCTs, with a total of 1112 participants. We found no data on service utilisation, economic outcomes, behaviour or cognitive response. Trials were classified into the following groups. 1. Atypical antipsychotics versus placebo: Only two studies compared one atypical antipsychotic medication with placebo. In one study, the number of non-responders treated with olanzapine was not different from the number treated with placebo (1 RCT, n = 107, RR 0.84, 95% CI 0.65 to 1.10); however, significantly more (57% vs 32%) people left the study early (1 RCT, n = 107, RR 0.56, 95% CI 0.36 to 0.87) from the placebo group compared with the olanzapine group. With regard to adverse effects, young people treated with aripiprazole had significantly lower serum cholesterol compared with those given placebo (1 RCT, n = 302, RR 3.77, 95% CI 1.88 to 7.58). 2. Atypical antipsychotics versus typical antipsychotics: When the findings of all five trials comparing atypical antipsychotic medications with a typical antipsychotic medication were collated, no difference in the mean end point Brief Psychiatric Rating Scale (BPRS) score was noted between the two arms (5 RCTs, n = 236, MD -1.08, 95% CI -3.08 to 0.93). With regard to adverse effects, the mean end point serum prolactin concentration was much higher than the reference range for treatment with risperidone, olanzapine and molindone in one of the studies. However, fewer adolescents who were receiving atypical antipsychotic medications left the study because of adverse effects (3 RCTs, n = 187, RR 0.65, 95% CI 0.36 to 1.15) or for any reason (3 RCTs, n = 187, RR 0.62, 95% CI 0.39 to 0.97).3. One atypical antipsychotic versus another atypical antipsychotic: The mean end point BPRS score was not significantly different for people who received risperidone compared with those who received olanzapine; however, the above data were highly skewed. Overall no difference was noted in the number of people leaving the studies early because of any adverse effects between each study arm in the three studies comparing olanzapine and risperidone (3 RCTs, n = 130, RR 1.15, 95% CI 0.44 to 3.04). Specific adverse events were not reported uniformly across the six different studies included in this section of the review; therefore it was difficult to do a head-to-head comparison of adverse events for different atypical antipsychotic medications.4. Lower-dose atypical antipsychotic versus standard/higher-dose atypical antipsychotic: Three studies reported comparisons of lower doses of the atypical antipsychotic medication with standard/higher doses of the same medication. One study reported better symptom reduction with a standard dose of risperidone as compared with a low dose (1 RCT, n = 257, RR -8.00, 95% CI -13.75 to -2.25). In another study, no difference was reported in the number of participants not achieving remission between the group receiving 10 mg/d and those who received 30 mg/d of aripiprazole (1 RCT, n = 196, RR 0.84, 95% CI 0.48 to 1.48). Similarly in the other study, authors reported no statistically significant difference in clinical response between the two groups receiving lower-dose (80 mg/d) and higher-dose (160 mg/d) ziprasidone, as reflected by the mean end point BPRS score (1 RCT, n = 17, MD -4.40, 95% CI -19.20 to 10.40). No convincing evidence suggests that atypical antipsychotic medications are superior to typical medications for the treatment of adolescents with psychosis. However, atypical antipsychotic medications may be more acceptable to young people because fewer symptomatic adverse effects are seen in the short term. Little evidence is available to support the superiority of one atypical antipsychotic medication over another, but side effect profiles are different for different medications. Treatment with olanzapine, risperidone and clozapine is often associated with weight gain. Aripiprazole is not associated with increased prolactin or with dyslipidaemia. Adolescents may respond better to standard-dose as opposed to lower-dose risperidone, but for aripiprazole and ziprasidone, lower doses may be equally effective. Future trials should ensure uniform ways of reporting.
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Klewe, Ib V.; Nielsen, Søren M.; Tarpø, Louise; Urizar, Eneko; Dipace, Concetta; Javitch, Jonathan A.; Gether, Ulrik; Egebjerg, Jan; Christensen, Kenneth V.
2013-01-01
Drugs acting at dopamine D2-like receptors play a pivotal role in the treatment of both schizophrenia and Parkinson’s disease. Recent studies have demonstrated a role for G-protein independent D2 receptor signaling pathways acting through β-arrestin. In this study we describe the establishment of a Bioluminescence Resonance Energy Transfer (BRET) assay for measuring dopamine induced recruitment of human β-arrestin2 to the human dopamine D2 receptor. Dopamine, as well as the dopamine receptor agonists pramipexole and quinpirole, acted as full agonists in the assay as reflected by their ability to elicit marked concentration dependent increases in the BRET signal signifying β-arrestin2 recruitment to the D2 receptor. As expected from their effect on G-protein coupling and cAMP levels mediated through the D2 receptor RNPA, pergolide, apomorphine, ropinirole, bromocriptine, 3PPP, terguride, aripiprazole, SNPA all acted as partial agonists with decreasing efficacy in the BRET assay. In contrast, a wide selection of typical and atypical anti-psychotics was incapable of stimulating β-arrestin2 recruitment to the D2 receptor. Moreover, we observed that haloperidol, sertindole, olanzapine, clozapine and ziprasidone all fully inhibited the dopamine induced β-arrestin2 recruitment to D2 receptor (short variant) in a concentration dependent manner. We conclude that most anti-psychotics are incapable of stimulating β-arrestin2 recruitment to the dopamine D2 receptor, in accordance with their antagonistic properties at the level of G-protein coupling. PMID:18455202
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Myxedema coma associated with combination aripiprazole and sertraline therapy.
Church, Chelsea O; Callen, Erin C
2009-12-01
To describe a case of myxedema coma (MC) associated with combination aripiprazole and sertraline therapy. A 41-year-old male presented to the emergency department with confusion, right-sided numbness and tingling, slurred speech, dizziness, and facial edema. His blood pressure was 160/113 mm Hg, with a pulse of 56 beats/min and temperature of 35.4 degrees C. Initial abnormal laboratory values included creatine kinase (CK) 439 U/L; serum creatinine 1.6 mg/dL; aspartate aminotransferase 85 U/L; and alanine aminotransferase 35 U/L. Repeat cardiac markers revealed an elevated CK level of 3573 U/L with a CK-MB of 24 ng/mL. Thyroid function tests showed thyroid-stimulating hormone 126.4 microIU/mL and free thyroxine 0.29 ng/dL. Home medications of unknown duration were sertraline 200 mg and aripiprazole 20 mg daily. He was admitted to the intensive care unit and initially treated with intravenous levothyroxine and dexamethasone. By hospital day 4, the patient was clinically stable and discharged to home. Myxedema coma, the most significant form of hypothyroidism (HT), is a rare but potentially fatal condition. The known precipitating causes of MC were ruled out in this patient, which left his home medications as the likely cause. Cases of HT caused by certain atypical antipsychotics and antidepressants are found in the literature, but none was reported with aripiprazole therapy. There are also no reported cases of sertraline or aripiprazole inducing MC. Use of the Naranjo probability scale indicates that the combination of aripiprazole and sertraline was a probable inducer of MC in this patient. Due to the widespread use of psychotropic medications, clinicians should be reminded of the rare, yet life-threatening, occurrence of MC when treating patients, especially with combination therapies such as sertraline and aripiprazole.
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Turner, Erick H.; Knoepflmacher, Daniel; Shapley, Lee
2012-01-01
Background Publication bias compromises the validity of evidence-based medicine, yet a growing body of research shows that this problem is widespread. Efficacy data from drug regulatory agencies, e.g., the US Food and Drug Administration (FDA), can serve as a benchmark or control against which data in journal articles can be checked. Thus one may determine whether publication bias is present and quantify the extent to which it inflates apparent drug efficacy. Methods and Findings FDA Drug Approval Packages for eight second-generation antipsychotics—aripiprazole, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, risperidone long-acting injection (risperidone LAI), and ziprasidone—were used to identify a cohort of 24 FDA-registered premarketing trials. The results of these trials according to the FDA were compared with the results conveyed in corresponding journal articles. The relationship between study outcome and publication status was examined, and effect sizes derived from the two data sources were compared. Among the 24 FDA-registered trials, four (17%) were unpublished. Of these, three failed to show that the study drug had a statistical advantage over placebo, and one showed the study drug was statistically inferior to the active comparator. Among the 20 published trials, the five that were not positive, according to the FDA, showed some evidence of outcome reporting bias. However, the association between trial outcome and publication status did not reach statistical significance. Further, the apparent increase in the effect size point estimate due to publication bias was modest (8%) and not statistically significant. On the other hand, the effect size for unpublished trials (0.23, 95% confidence interval 0.07 to 0.39) was less than half that for the published trials (0.47, 95% confidence interval 0.40 to 0.54), a difference that was significant. Conclusions The magnitude of publication bias found for antipsychotics was less than that found previously for antidepressants, possibly because antipsychotics demonstrate superiority to placebo more consistently. Without increased access to regulatory agency data, publication bias will continue to blur distinctions between effective and ineffective drugs. Please see later in the article for the Editors' Summary PMID:22448149
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Youssef, Nagy A; Marx, Christine E; Bradford, Daniel W; Zinn, Sandra; Hertzberg, Michael A; Kilts, Jason D; Naylor, Jennifer C; Butterfield, Marian I; Strauss, Jennifer L
2012-07-01
Emerging data suggest that second-generation antipsychotics such as aripiprazole may be effective in the treatment of post-traumatic stress disorder (PTSD). However, few clinical trials have used aripiprazole in PTSD, and data are limited on its use in Veterans with PTSD. The objective of this pilot trial was to investigate the safety and efficacy of aripiprazole in Veterans with PTSD. Ten individuals (five men and five women) meeting the Diagnostic and statistical manual of mental disorders, 4th ed., PTSD criteria participated in this 12-week, open-label, flexibly dosed monotherapy trial. The dose range of aripiprazole was 5-30 mg/day, titrated to tolerability and clinical response. The primary outcome measure was the Clinician-Administered PTSD Scale. Additional outcomes included the Short PTSD Rating Interview, the Treatment Outcome PTSD Scale (Top-8), the Davidson Trauma Scale, the Positive and Negative Syndrome Scale, the Beck Depression Inventory-Fast Screen, and Clinical Global Impressions-Improvement. Eight participants completed the study, and aripiprazole was generally well tolerated and associated with a significant improvement in PTSD symptoms, as measured by the Clinician-Administered PTSD Scale (primary outcome measure) and by the Short PTSD Rating Interview, the Treatment Outcome PTSD Scale, and the Davidson Trauma Scale. An improvement was also observed on all three Positive and Negative Syndrome Scale subscales and the Beck Depression Inventory-Fast Screen, and the average Clinical Global Impressions-Improvement ratings indicated that patients were 'much improved'. These promising initial results merit further investigation in a larger, randomized-controlled trial.
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Gao, Keming; Kemp, David E; Fein, Elizabeth; Wang, Zuowei; Fang, Yiru; Ganocy, Stephen J; Calabrese, Joseph R
2011-08-01
To estimate the number needed to treat to harm (NNTH) for discontinuation due to adverse events with atypical antipsychotics relative to placebo during the treatment of bipolar depression, major depressive disorder (MDD), and generalized anxiety disorder (GAD). English-language literature published and cited in MEDLINE from January 1966 to May 2009 was searched with the terms antipsychotic, atypical antipsychotic, generic and brand names of atypical antipsychotics, safety, tolerability, discontinuation due to adverse events, somnolence, sedation, weight gain, akathisia, or extrapyramidal side effect; and bipolar depression, major depressive disorder, or generalized anxiety disorder; and randomized, placebo-controlled clinical trial. This search was augmented with a manual search. Studies with a cumulative sample of ≥ 100 patients were included. The NNTHs for discontinuation due to adverse events, somnolence, sedation, ≥ 7% weight gain, and akathisia relative to placebo were estimated with 95% confidence intervals to reflect the magnitude of variance. Five studies in bipolar depression, 10 studies in MDD, and 4 studies in GAD were identified. Aripiprazole and olanzapine have been studied in bipolar depression and refractory MDD. Only quetiapine extended release (quetiapine-XR) has been studied in 3 psychiatric conditions with different fixed dosing schedules. For aripiprazole, the mean NNTH for discontinuation due to adverse events was 14 in bipolar depression, but was not significantly different from placebo in MDD. For olanzapine, the mean NNTHs were 24 in bipolar depression and 9 in MDD. The risk for discontinuation due to adverse events during quetiapine-XR treatment appeared to be associated with dose. For quetiapine-XR 300 mg/d, the NNTHs for discontinuation due to adverse events were 9 for bipolar depression, 8 for refractory MDD, 9 for MDD, and 5 for GAD. At the same dose of quetiapine-XR, patients with GAD appeared to have a lower tolerability than those with bipolar depression or MDD. Due to flexible dosing, the risk for discontinuation due to adverse events in the treatment of bipolar depression, MDD, or GAD with other atypical antipsychotics could not be compared. © Copyright 2011 Physicians Postgraduate Press, Inc.
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Schuster, Jean-Pierre; Raucher-Chéné, Delphine; Lemogne, Cédric; Rouillon, Frédéric; Gasquet, Isabelle; Leguay, Denis; Gierski, Fabien; Azorin, Jean-Michel; Limosin, Frédéric
2012-10-01
Although weight gain is one of the most widely studied adverse effects of second-generation antipsychotics, only relatively few studies have specifically evaluated the long-term effect of switching antipsychotic medication on body weight. We aimed to evaluate the impact of switching antipsychotics on body mass index (BMI) during a 6-month follow-up period in a large cohort of patients with schizophrenia. Data came from a 6-month prospective naturalistic survey in 6007 patients with schizophrenia. We prospectively studied the effect on BMI of initiating or switching antipsychotic medication after 6 months of treatment among 3801 patients with schizophrenia in a real-life setting. Patients who were being treated with clozapine or olanzapine at baseline were more likely to experience a decrease in BMI during the follow-up period than the patients who were being treated with a conventional antipsychotic (odds ratio, 2.25 and 1.68, respectively). Patients treated with aripiprazole and, to a lesser extent, those treated with risperidone were more likely to experience a decrease in BMI during follow-up than patients treated with conventional antipsychotics (odds ratio, 2.96 and 2.06, respectively). Our findings suggest that switching antipsychotics could be an effective strategy for reducing or preventing weight gain.
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Bergmann, F; Zacher, A; Nass, A; Urban, R; Werner, C; Spevakné-Göröcs, T; Kungel, M; Ebrecht, M; Modell, S
2009-05-01
Aripiprazole (ABILIFY) is an effective antipsychotic used in a dose range from 10 to 30 mg, administered once daily. Soon after its approval in Germany for treatment of schizophrenia, a 12-month post-marketing surveillance study was initiated that included 1 096 patients cared for by 408 office-based psychiatrists and/or neurologists in private practice. The aim was to gain further insights into safety and efficacy of aripiprazole in an outpatient real-life setting focusing on general health, well-being and psychosocial functioning. Efficacy was rated by using standard CGI, SF-12 and SIWM-PsySo instruments for severity of disease, physical and mental health outcomes and psychosocial state, respectively. Safety was evaluated according to the reports of adverse events. Mean total daily dose of aripiprazole increased from 15.4 mg at the visit after 1 month to 17.6 mg at the visits after 6 to 12 months, the most frequently administered maintenance dose being 15 mg. Within the observation period significant improvements of CGI, SF-12 and SIWM-PsySo scores over time versus baseline values were observed (p<0.001) when starting with or switching to aripiprazole. Physicians observed improvements in 80.7% of the patients at endpoint; in 62% of the patients the disease state was considered "much" or "very much" improved. Aripiprazole was overall well tolerated; 19.9% of patients discontinued treatment after 12 months. Adverse effects in general were moderate to mild and corresponded to the known tolerability profile of aripiprazole. Psychotic side effects reported were probably due to a recurrence of the underlying schizophrenic disorder. The results indicate that aripiprazole may be an efficacious and safe treatment option for pre-treated patients with schizophrenia also in a naturalistic psychiatrist/neurologist practice setting with effects on health and psychosocial functioning and a comparably low dropout rate.
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Kishi, Taro; Matsui, Yuki; Matsuda, Yuki; Katsuki, Asuka; Hori, Hikaru; Yanagimoto, Hiroko; Sanada, Kenji; Morita, Kiichiro; Yoshimura, Reiji; Shoji, Yoshihisa; Hagi, Katsuhiko; Iwata, Nakao
2018-03-07
We conducted an updated systematic review and meta-analysis of randomized controlled trials (RCTs) comparing blonanserin with other antipsychotics (amisulpride, aripiprazole, haloperidol, paliperidone, and risperidone). Weighted mean difference (WMD), risk ratio, and number needed to harm (NNH) with 95% confidence intervals (95% CIs) were calculated using random-effects model. Ten RCTs (n = 1521) were included in this study. Blonanserin was superior to aripiprazole in improvement of Positive and Negative Syndrome Scale total scores (WMD = -10.62, 95% CI = -17.67 to -3.560, p = 0.003). Blonanserin was associated with a higher incidence of all-cause discontinuation (RR = 1.373, 95% CI = 1.088-1.734, p = 0.008, NNH = 11), akathisia, extrapyramidal disorder, and agitation/excitement and a lower risk of hyperprolactinemia compared with risperidone + paliperidone. The current meta-analytic study did not update the comparison of blonanserin vs. haloperidol because there were no new RCTs. Our results suggest that the efficacy of blonanserin for schizophrenia is comparable with that of other antipsychotics, and blonanserin seems to be well tolerated. © Georg Thieme Verlag KG Stuttgart · New York.
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De Nayer, A; De Hert, M; Scheen, A; Van Gaal, L; Peuskens, J
2007-01-01
The current literature supports that schizophrenia (and bipolar disorders) appear to be associated with a higher prevalence of type 2 diabetes. Because of the silent nature of diabetes mellitus, and the fact that schizophrenic patients are not screened comprehensively for the disease, the true prevalence of hyperglycemia and diabetes may be substantially underestimated. Notably, it has been suggested that schizophrenia as such carries an increased risk, as certain characteristics of schizophrenic patients such as unhealthy life style promote the diabetes risk. This risk may be increased by antipsychotic drug treatment, as was already suggested for first-generation antipsychotics (FGA). The amount of literature on the association of SGA and metabolic disorders is much larger however, although well-controlled prospective data are sparse. Reports comprise abnormal glucose regulation, exacerbation of existing type 1 and 2 diabetes, new-onset pseudo-type 1 or type 2 diabetes, diabetic ketoacidosis, coma and death. In large-scale studies (mostly retrospective), reviews and meta-analyses, the association was not found for all drugs. According to recent reviews, the risk of developing diabetes was highest for clozapine and olanzapine, followed by quetiapine and risperidone. The hierarchy of liability of weight gain, or differential effects on insulin resistance was also in the described order. Apart from disturbances in glucose metabolism, further frequent metabolic abnormalities in schizophrenic patients on SGA include features of the metabolic syndrome. Antipsychotics such as clozapine and olanzapine have also been associated with hypertriglyceridemia, while agents such as haloperidol, risperidone and ziprasidone were associated with reductions in plasma triglycerides. Amisulpride, aripiprazole and ziprasidone seem to carry the lowest risk for weight gain, diabetes and effects on insulin resistance. As a consequence, there is a shift in attention toward physical health monitoring in patients with mental health disorders. The APA and ADA as well a British working group have recently published the findings on SGA and metabolic abnormalities in a joint statement (table I).
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Comparative effect of antipsychotics on risk of self-harm among patients with schizophrenia.
Ma, C-H; Chang, S-S; Tsai, H-J; Gau, S S-F; Chen, I-M; Liao, S-C; Chien, Y-L; Hsieh, M H; Wu, C-S
2018-04-01
To investigate the association of different antipsychotic treatments with hospitalization due to self-harm among patients with schizophrenia. This retrospective cohort study was based on Taiwan's universal health insurance database. Patients aged 15-45 years with a newly diagnosed schizophrenic disorder in 2001-2012 were included. The study outcome was the first hospitalization due to self-harm or undetermined injury after the diagnosis of schizophrenic disorders. The exposure status of antipsychotics was modeled as a time-dependent variable. The analyses were stratified by antipsychotic dosage based on defined daily dose (DDD). Among 70 380 patients with a follow-up of 500 355 person-years, 2272 self-harm hospitalization episodes were identified. Compared with none or former use, current use of several second-generation antipsychotics with a dose of one DDD or above, including amisulpride, aripiprazole, clozapine, risperidone, and sulpiride, was associated with decreased risk of self-harm hospitalization, with clozapine showing the strongest effect (adjusted rate ratio = 0.26, 95% confidence interval 0.15-0.47). The protective effect on self-harm may vary across different antipsychotics. Further studies are needed to replicate the findings. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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Mintzer, Jacobo E; Tune, Larry E; Breder, Christopher D; Swanink, René; Marcus, Ronald N; McQuade, Robert D; Forbes, Andy
2007-11-01
To assess the efficacy and safety of aripiprazole for psychosis associated with Alzheimer dementia (AD). In this double-blind, multicenter study, 487 institutionalized patients with psychosis associated with AD were randomized to placebo or aripiprazole, 2, 5 or 10 mg/day. Primary efficacy assessment was the mean change from baseline to week 10 on the Neuropsychiatric Inventory-Nursing Home (NPI-NH) version Psychosis Subscale score. Secondary measures included NPI-NH Total, Clinical Global Impression-Severity of Illness (CGI-S), Brief Psychiatric Rating Scale (BPRS) Core and Total, and the Cohen-Mansfield Agitation Inventory (CMAI) scores. Aripiprazole 10 mg/day showed significantly greater improvements (mean change [2 x SD]) than placebo on the NPI-NH Psychosis Subscale (-6.87 [8.6] versus -5.13 [10.0]; F = 6.29, df = 1, 422, p = 0.013 by analysis of covariance [ANCOVA]); CGI-S (-0.72 [1.8] versus -0.46 [1.6]; F = 4.68, df = 1, 419, p = 0.031 [ANCOVA]); BPRS Total (-7.12 [18.4] versus -4.17 [21.6]; F = 4.72, df = 1, 399, p = 0.030 [ANCOVA]); BPRS Core (-3.07 [6.9] versus -1.74 [7.8]; F = 7.30, df = 1, 407, p = 0.007 [ANCOVA]); CMAI (-10.96 [22.6] versus -6.64 [28.6]; F = 5.23, df = 1, 410, p = 0.023 [ANCOVA]), and NPI-NH Psychosis response rate (65 versus 50%; chi(2) = 5.52, df = 1, p = 0.019 [CMH]). Aripiprazole 5 mg/day showed significant improvements versus placebo on BPRS and CMAI scores. Aripiprazole 2 mg/day was not efficacious. Cerebrovascular adverse events were reported: aripiprazole 2 mg/day, N = 1; 5 mg/day, N = 2; 10 mg/day, N = 4; placebo, N = 0. No deaths in any group (aripiprazole 2 mg/day, 3%; 5 mg/day, 2%; 10 mg/day, 7%; placebo, 3%) were considered to be treatment-related. Aripiprazole 10 mg/day was efficacious and safe for psychosis associated with AD, significantly improving psychotic symptoms, agitation, and clinical global impression. However, clinicians should be aware of the safety considerations of atypical antipsychotic uses in this population.
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Detection of Cases of Noncompliance to Drug Treatment in Patient Forum Posts: Topic Model Approach
Foulquié, Pierre; Texier, Nathalie; Faviez, Carole; Burgun, Anita; Schück, Stéphane
2018-01-01
Background Medication nonadherence is a major impediment to the management of many health conditions. A better understanding of the factors underlying noncompliance to treatment may help health professionals to address it. Patients use peer-to-peer virtual communities and social media to share their experiences regarding their treatments and diseases. Using topic models makes it possible to model themes present in a collection of posts, thus to identify cases of noncompliance. Objective The aim of this study was to detect messages describing patients’ noncompliant behaviors associated with a drug of interest. Thus, the objective was the clustering of posts featuring a homogeneous vocabulary related to nonadherent attitudes. Methods We focused on escitalopram and aripiprazole used to treat depression and psychotic conditions, respectively. We implemented a probabilistic topic model to identify the topics that occurred in a corpus of messages mentioning these drugs, posted from 2004 to 2013 on three of the most popular French forums. Data were collected using a Web crawler designed by Kappa Santé as part of the Detec’t project to analyze social media for drug safety. Several topics were related to noncompliance to treatment. Results Starting from a corpus of 3650 posts related to an antidepressant drug (escitalopram) and 2164 posts related to an antipsychotic drug (aripiprazole), the use of latent Dirichlet allocation allowed us to model several themes, including interruptions of treatment and changes in dosage. The topic model approach detected cases of noncompliance behaviors with a recall of 98.5% (272/276) and a precision of 32.6% (272/844). Conclusions Topic models enabled us to explore patients’ discussions on community websites and to identify posts related with noncompliant behaviors. After a manual review of the messages in the noncompliance topics, we found that noncompliance to treatment was present in 6.17% (276/4469) of the posts. PMID:29540337
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Blankenship, Kelly; Erickson, Craig A; Stigler, Kimberly A; Posey, David J; McDougle, Christopher J
2011-01-01
Aripiprazole was recently US FDA-approved to treat irritability in children and adolescents with autistic disorder aged 6–17 years. There are currently only two psychotropics approved by the FDA to treat irritability in the autistic population. This drug profile will discuss available studies of aripiprazole in individuals with pervasive developmental disorders, two of which led to its recent FDA approval. We will discuss the efficacy, as well as the safety and tolerability of the drug documented in these studies. In addition, the chemistry, pharmacokinetics, metabolism and mechanism of action of aripiprazole will be reviewed. PMID:21359119
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Klingerman, Candice M; Stipanovic, Michelle E; Bader, Mohammad; Lynch, Christopher J
2014-03-01
Some second-generation antipsychotics (SGAs) increase insulin resistance and fat oxidation, but counter intuitively they do not activate lipolysis. This seems unsustainable for meeting energy demands. Here, we measured dose-dependent effects of SGAs on rates of oxygen consumption (VO2), respiratory exchange ratio (RER), and physical activity in C57BL/6J mice. The role of H1-histamine receptors and consequences of blocking fat oxidation were also examined. Olanzapine, risperidone, and clozapine (2.5-10mg/kg) elicited rapid drops in dark-cycle RER (~0.7) within minutes, whereas aripiprazole exerted only modest changes. Higher doses of olanzapine decreased VO2, and this was associated with accumulation of glucose in plasma. Clozapine and risperidone also lowered VO2, in contrast to aripiprazole, whereas all decreased physical activity. Astemizole and terfenadine had no significant effects on RER, VO2, or physical activity. The VO2 and RER effects appear independent of sedation/physical activity or H1-receptors. CPT-1 inhibitors can enhance muscle glucose utilization and prevent fat oxidation. However, after etomoxir (2 × 30 mg/kg), a low dose of olanzapine that did not significantly affect VO2 by itself caused precipitous drops in VO2 and body temperature, leading to death within hours or a moribund state requiring euthanasia. One 30 mg/kg dose of either etomoxir or 2-tetradecylglycidate followed by olanzapine, risperidone, or clozapine, but not aripiprazole, dramatically lowered VO2 and body temperature. Thus, mice treated with some SGAs shift their fuel utilization to mostly fat but are unable to either switch back to glucose or meet their energy demands when either higher doses are used or when fat oxidation is blocked.
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Lynch, Christopher J.
2014-01-01
Some second-generation antipsychotics (SGAs) increase insulin resistance and fat oxidation, but counter intuitively they do not activate lipolysis. This seems unsustainable for meeting energy demands. Here, we measured dose-dependent effects of SGAs on rates of oxygen consumption (VO2), respiratory exchange ratio (RER), and physical activity in C57BL/6J mice. The role of H1-histamine receptors and consequences of blocking fat oxidation were also examined. Olanzapine, risperidone, and clozapine (2.5–10mg/kg) elicited rapid drops in dark-cycle RER (~0.7) within minutes, whereas aripiprazole exerted only modest changes. Higher doses of olanzapine decreased VO2, and this was associated with accumulation of glucose in plasma. Clozapine and risperidone also lowered VO2, in contrast to aripiprazole, whereas all decreased physical activity. Astemizole and terfenadine had no significant effects on RER, VO2, or physical activity. The VO2 and RER effects appear independent of sedation/physical activity or H1-receptors. CPT-1 inhibitors can enhance muscle glucose utilization and prevent fat oxidation. However, after etomoxir (2 × 30mg/kg), a low dose of olanzapine that did not significantly affect VO2 by itself caused precipitous drops in VO2 and body temperature, leading to death within hours or a moribund state requiring euthanasia. One 30mg/kg dose of either etomoxir or 2-tetradecylglycidate followed by olanzapine, risperidone, or clozapine, but not aripiprazole, dramatically lowered VO2 and body temperature. Thus, mice treated with some SGAs shift their fuel utilization to mostly fat but are unable to either switch back to glucose or meet their energy demands when either higher doses are used or when fat oxidation is blocked. PMID:23328157
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Augmentation treatment in major depressive disorder: focus on aripiprazole
Nelson, J Craig; Pikalov, Andrei; Berman, Robert M
2008-01-01
Major depressive disorder (MDD) is a disabling psychiatric condition for which effective treatment remains an outstanding need. Antidepressants are currently the mainstay of treatment for depression; however, almost two-thirds of patients will fail to achieve remission with initial treatment. As a result, a range of augmentation and combination strategies have been used in order to improve outcomes for patients. Despite the popularity of these approaches, limited data from double-blind, randomized, placebo-controlled studies are available to allow clinicians to determine which are the most effective augmentation options or which patients are most likely to respond to which options. Recently, evidence has shown that adjunctive therapy with atypical antipsychotics has the potential for beneficial antidepressant effects in the absence of psychotic symptoms. In particular, aripiprazole has shown efficacy as an augmentation option with standard antidepressant therapy in two, large, randomized, double-blind studies. Based on these efficacy and safety data, aripiprazole was recently approved by the FDA as adjunctive therapy for MDD. The availability of this new treatment option should allow more patients with MDD to achieve remission and, ultimately, long-term, successful outcomes. PMID:19183784
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Effects of antipsychotics and reference monoaminergic ligands on marble burying behavior in mice.
Bruins Slot, Liesbeth A; Bardin, Laurent; Auclair, Agnès L; Depoortere, Ronan; Newman-Tancredi, Adrian
2008-03-01
Antipsychotics constitute efficacious augmenting agents in the treatment of anxiety disorders, including refractory obsessive-compulsive disorder. We examined the effects of 36 compounds, including typical, atypical and novel antipsychotics with dual dopamine D2/5-hydroxytryptamine 1A (D2/5-HT1A) actions on marble burying behavior in mice, a putative preclinical test for anxiety disorders. One hour after drug administration, male NMRI mice were placed individually in cages containing 20 marbles, and the total number of marbles buried after 30 min was counted. The selective serotonin reuptake inhibitors, citalopram (2.5-40 mg/kg), fluoxetine (2.5-10 mg/kg) and the benzodiazepine diazepam (2.5-10 mg/kg), reduced the number of buried marbles. The atypical antipsychotic, clozapine (0.16-10 mg/kg), but not its congener olanzapine, was effective in this test. Haloperidol, a typical antipsychotic, also reduced the number of buried marbles, albeit not in a dose-dependent manner. The atypical risperidone was partially active (0.16-0.63 mg/kg), as was the benzamide derivative, amisulpride, albeit at high (10-40 mg/kg) doses. Among the 'third-generation' antipsychotics possessing combined D2/5-HT1A properties, bifeprunox was active at 0.0025 mg/kg, whereas SLV313 and aripiprazole were active only at the highest doses (2.5 and 10 mg/kg, respectively). SSR181507, F15063 and the antidyskinetic agent, sarizotan, were without any effect. Among a series of receptor subtype-selective ligands, only the 5-HT1A agonist, (+)-8-OH-DPAT (0.63-2.5 mg/kg) and the 5-HT2A/2B/2C antagonist, ritanserin (0.63-2.5 mg/kg) were active. Among novel antipsychotics with dual D2/5-HT1A properties, only bifeprunox was able to potently reduce the number of buried marbles. Inhibition of marble burying behavior may result from the interplay of several receptor systems, including 5-HT2 receptor blockade, dopamine D2 partial agonism and serotonin 5-HT1A agonism.
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Aripiprazole-induced transient myopia: A rare entity.
Praveen Kumar, K V; Chiranjeevi, P; Alam, Md Shahid
2018-01-01
Aripiprazole is a new drug for the treatment of adults with schizophrenia. Ocular side effects of aripiprazole are very rare. Review of literature revealed few cases of aripiprazole-induced myopia. We report a rare case of aripiprazole-induced transient myopia. A 22-year-old female patient presented to the department of psychiatry with worsening of symptoms of schizophrenia and was started on aripiprazole. She presented with complaints of blurring of vision in both eyes for 1 week which started on the 3rd day following the use of aripiprazole. Anterior segment examination revealed a shallow anterior chamber and narrow angles. Intraocular pressure was normal. A diagnosis of aripiprazole-induced acute myopia was made and the treating psychiatrist was advised to stop the medication. At 2-week follow-up, the unaided visual acuity improved to 20/20 in both the eyes. Ophthalmologists should be aware of the myopic shift that may occur as an ocular side effect with aripiprazole.
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Brott, David A; Diamond, Melody; Campbell, Pam; Zuvich, Andy; Cheatham, Letitia; Bentley, Patricia; Gorko, Mary Ann; Fikes, James; Saye, JoAnne
2013-01-01
Drug-induced glucose dysregulation and insulin resistance have been associated with weight gain and potential induction and/or exacerbation of diabetes mellitus in the clinic suggesting they may be safety biomarkers when developing antipsychotics. Glucose and insulin have also been suggested as potential efficacy biomarkers for some oncology compounds. The objective of this study was to qualify a medium throughput rat in vivo acute Intravenous Glucose Tolerance Test (IVGTT) for predicting compounds that will induce altered blood glucose and/or insulin levels. Acute and sub-chronic studies were performed to qualify an acute IVGTT model. Double cannulated male rats (Han-Wistar and Sprague-Dawley) were administered vehicle, olanzapine, aripiprazole or other compounds at t=-44min for acute studies and at time=-44min on the last day of dosing for sub-chronic studies, treated with dextrose (time=0min; i.v.) and blood collected using an automated Culex® system for glucose and insulin analysis (time=-45, -1, 2, 10, 15, 30, 45, 60, 75, 90, 120, 150 and 180min). Olanzapine significantly increased glucose and insulin area under the curve (AUC) values while aripiprazole AUC values were similar to control, in both acute and sub-chronic studies. All atypical antipsychotics evaluated were consistent with literature references of clinical weight gain. As efficacy biomarkers, insulin AUC but not glucose AUC values were increased with a compound known to have insulin growth factor-1 (IGF-1) activity, compared to control treatment. These studies qualified the medium throughput acute IVGTT model to more quickly screen compounds for 1) safety - the potential to elicit glucose dysregulation and/or insulin resistance and 2) efficacy - as a surrogate for compounds affecting the glucose and/or insulin regulatory pathways. These data demonstrate that the same in vivo rat model and assays can be used to predict both clinical safety and efficacy of compounds. © 2013.
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Effect of aripiprazole lauroxil on agitation and hostility in patients with schizophrenia.
Citrome, Leslie; Du, Yangchun; Risinger, Robert; Stankovic, Srdjan; Claxton, Amy; Zummo, Jacqueline; Bose, Anjana; Silverman, Bernard L; Ehrich, Elliot W
2016-03-01
This study aimed to evaluate the effects of aripiprazole lauroxil on hostility and aggressive behavior in patients with schizophrenia. Patients aged 18-70 years with a diagnosis of schizophrenia and currently experiencing an acute exacerbation or relapse were randomized to intramuscular (IM) aripiprazole lauroxil 441 mg (n=207), 882 mg (n=208), or placebo (n=207) for 12 weeks. In post-hoc analyses, hostility and aggression were assessed by the Positive and Negative Syndrome Scale (PANSS) Hostility item (P7) and a specific antihostility effect was assessed by adjusting for positive symptoms of schizophrenia, somnolence, and akathisia. The PANSS excited component score [P4 (Excitement), P7 (Hostility), G4 (Tension), G8 (Uncooperativeness), and G14 (Poor impulse control)], and the Personal and Social Performance scale disturbing and aggressive behavior domain were also assessed. Of the 147 patients who received aripiprazole lauroxil 882 mg and with a baseline PANSS Hostility item P7 more than 1, there was a significant (P<0.05) improvement versus placebo on the PANSS Hostility item P7 score by mixed-model repeated-measures at the end of the study, which remained significant when PANSS-positive symptoms and somnolence or akathisia were included as additional covariates. The proportion with PANSS Hostility item P7 more than 1 at endpoint was significantly (P<0.05) lower with aripiprazole lauroxil versus placebo (53.6, 46.1, and 66.3% for 441, 882 mg, and placebo). A significant (P<0.05) improvement was found with aripiprazole lauroxil versus placebo for change from baseline in the PANSS excited component score. The proportion of patients with aggressive behavior on the Personal and Social Performance scale was significantly (P<0.05) lower for aripiprazole lauroxil: 30.0% for 441 mg versus 44.1% for placebo (P=0.006) and 22.2% for 881 mg (P<0.001 versus placebo). Treatment with aripiprazole lauroxil resulted in decreases in agitation and hostility in patients with schizophrenia and this antihostility effect appears to be independent of a general antipsychotic effect.
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Teff, Karen L; Rickels, Michael R; Grudziak, Joanna; Fuller, Carissa; Nguyen, Huong-Lan; Rickels, Karl
2013-09-01
Atypical antipsychotic (AAP) medications that have revolutionized the treatment of mental illness have become stigmatized by metabolic side effects, including obesity and diabetes. It remains controversial whether the defects are treatment induced or disease related. Although the mechanisms underlying these metabolic defects are not understood, it is assumed that the initiating pathophysiology is weight gain, secondary to centrally mediated increases in appetite. To determine if the AAPs have detrimental metabolic effects independent of weight gain or psychiatric disease, we administered olanzapine, aripiprazole, or placebo for 9 days to healthy subjects (n = 10, each group) under controlled in-patient conditions while maintaining activity levels. Prior to and after the interventions, we conducted a meal challenge and a euglycemic-hyperinsulinemic clamp to evaluate insulin sensitivity and glucose disposal. We found that olanzapine, an AAP highly associated with weight gain, causes significant elevations in postprandial insulin, glucagon-like peptide 1 (GLP-1), and glucagon coincident with insulin resistance compared with placebo. Aripiprazole, an AAP considered metabolically sparing, induces insulin resistance but has no effect on postprandial hormones. Importantly, the metabolic changes occur in the absence of weight gain, increases in food intake and hunger, or psychiatric disease, suggesting that AAPs exert direct effects on tissues independent of mechanisms regulating eating behavior.
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Sobiś, Jarosław; Rykaczewska-Czerwińska, Monika; Świętochowska, Elżbieta; Gorczyca, Piotr
2015-04-01
Weight gain and metabolic abnormalities occur in chronic schizophrenia patients treated with atypical antipsychotics. The purpose of the study was to evaluate changes in serum levels of C-reactive protein (CRP), insulin and cytokines (IL-6, TNF-α, IL-1β, IFN-γ, sTNF-R1, IL-12, IL-23, IL-1Ra, TGF-β1, IL-4, and IL-10) after switching to aripiprazole. Cytokine, hsCRP and insulin measurements were performed in patients (n=17) on day 0 and day 28 of the study using standard ELISA assays. The psychopathological status was assessed using PANSS. WC and BMI were measured and calculated, respectively. We observed high clinical efficacy in aripiprazole linked to a 2.7% weight loss. There were statistically significant reductions in PANSS scores and body parameters (p<0.001). After 28 days we detected a significant reduction in hsCRP (p<0.001), insulin (p<0.001), IL-1β, IL-6, TNF-α, sTNF-R1, IL-12, IL-23, IL-1Ra, TGF-β1, IL-4 (p<0.001), IFN-γ (p<0.05) and a significant elevation of IL-10 (p<0.001). There was a significant negative correlation between IL-10 levels and PANSS positive, negative and total scores after the study (p=0.022, p=0.003, p=0.008, respectively). Aripiprazole limits inflammatory processes by enhancing anti-inflammatory signaling. Aripiprazole also reduces the risk of metabolic abnormalities. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.
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Miura, Itaru; Takeuchi, Satoshi; Katsumi, Akihiko; Mori, Azuma; Kanno, Keiko; Yang, Qiaohui; Mashiko, Hirobumi; Numata, Yoshihiko; Niwa, Shin-Ichi
2012-02-01
The Taq1A polymorphism in the dopamine D2 receptor (DRD2) gene could be related to the response to antipsychotics. We examined the effects of the Taq1A polymorphism on the plasma monoamine metabolites during the treatment of schizophrenia with aripiprazole, a DRD2 partial agonist. Thirty Japanese patients with schizophrenia were treated with aripiprazole for 6 weeks. We measured plasma levels of homovanillic acid (pHVA) and 3-methoxy-4hydroxyphenylglycol (pMHPG) before and after treatment. The Taq1A polymorphism was genotyped with polymerase chain reaction. Aripiprazole improved the acute symptoms of schizophrenia and decreased pHVA in responders (P = 0.023) but not in nonresponders (P = 0.28). Although A1 allele carriers showed a tendency to respond to aripiprazole (61.5%) compared to A1 allele noncarriers (29.4%) (P = 0.078), there was not statistically significant difference in the response between the 2 genotype groups. There were significant effect for response (P = 0.013) and genotype × response interaction (P = 0.043) on the change of pHVA. The changes of pHVA differ between responders and nonresponders in A1 allele carriers but not in A1 allele noncarriers. There were no genotype or response effects or genotype × response interaction on the changes of the plasma levels of 3-methoxy-4hydroxyphenylglycol. Our preliminary results suggest that Taq1A polymorphism may be partly associated with changes in pHVA during acute schizophrenia.
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Lamberti, Marco; Siracusano, Rosamaria; Italiano, Domenico; Alosi, Norma; Cucinotta, Francesca; Di Rosa, Gabriella; Germanò, Eva; Spina, Edoardo; Gagliano, Antonella
2016-08-01
Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are frequently overlapping neurodevelopmental disorders. Individuals in whom the disorders are comorbid show more severe impairment because of deficits in the processing of social situations, adaptive functioning, and executive control than individuals with either disorder alone. This open-label pilot study aimed to evaluate and compare the efficacy and tolerability of risperidone and aripiprazole for treating ADHD symptoms in patients with both ASD and ADHD over the course of 24 weeks of treatment. Patients (n = 44) were randomly assigned to start treatment with risperidone (22 patients) or aripiprazole (22 patients). Children were evaluated before starting treatment (T0), and after 12 weeks (T1) and 24 weeks (T2) of treatment. At each visit, specific psychiatric clinical scales were administered to assess the efficacy of the two drugs. The mean age was 8.4 ± 2.9 years in the aripiprazole group and 7.8 ± 2.3 years in the risperidone group. A total of 37 children (29 boys and 8 girls) completed the study (18 in the aripiprazole group and 19 in the risperidone group). Aripiprazole and risperidone appeared to have similar benefits in terms of efficacy and tolerability, although there were slight differences between the two drugs. Both groups showed a significant improvement in ADHD symptoms after 24 weeks of treatment (ADHD Rating Scale, Conners Parent Rating Scale-Hyperactivity, and Clinical Global Improvement-Severity Scale). No significant difference between the two drugs on any parameters at 24 weeks were found. Prolactin levels were decreased in the aripiprazole group. Both drugs were well tolerated, with no serious adverse events detected. Our study confirms the efficacy of both aripiprazole and risperidone in ameliorating ADHD symptoms of children also presenting with ASD.
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Kim, Yunjeong; Jeon, Ji-Young; Chung, Young-Chul; Kim, Min-Gul
2015-12-01
The main objective of this study was to compare the pharmacokinetic properties and relative bioavailability of two 15-mg aripiprazole formulations (an orally disintegrating tablet [ODT] as the test drug and a conventional tablet as the reference drug) in healthy middle-aged Korean subjects. This study was conducted in a population of healthy middle-aged Korean subjects as a randomized, open-label, single-dose, 2-sequence, 2-period crossover trial. After administration of a single dose of a 15-mg aripiprazole standard tablet with 240 mL water or an aripiprazole 15-mg ODT without water, blood samples were collected at specific time intervals from 0 to 240 hours. Concentrations of aripiprazole in plasma were analyzed by using a LC-MS/MS method of detection. Data on the pharmacokinetic parameters were recorded, and the 90% CIs of the ratios of the geometric means of the parameters were determined from the logarithmically transformed data by using an ANOVA model. Thirty-nine healthy middle-aged Korean subjects were enrolled (mean age, 52.7 years; mean height, 167 cm; mean weight, 67.6 kg); 33 participants completed the study (29 male subjects and 4 female subjects). The 90% CIs of the geometric means ratio (test drug/reference drug) of Cmax, AUC0-last, and AUC0-∞ values were 0.95 to 1.14, 0.98 to 1.09, and 0.97 to 1.08, respectively. All of the subjects who experienced adverse events recovered without sequelae, and no serious adverse events were observed. The aripiprazole pharmacokinetics was similar for the ODT and standard tablet of 15-mg aripiprazole in these healthy middle-aged Korean subjects. The aripiprazole ODT formulation is therefore expected to offer a convenient alternative for patients who have difficulty swallowing tablets without water. The study was registered at http://cris.nih.go.kr (registration number: KCT0001677). Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.
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Mercer, Deanna; Douglass, Alan B; Links, Paul S
2009-04-01
The objective of our study was to complete separate meta-analyses of randomized controlled trials of mood stabilizers, antidepressants and antipsychotics to determine whether these medications are efficacious for depression and anger symptoms in borderline personality disorder (BPD). Studies were obtained from OVID Medline, Cochrane Central Register of Controlled Trials, and PsychInfo. References of all original papers and reviews were searched for additional studies. Index terms included: BPD, randomized controlled trials, drug therapy, medication, and treatment. Studies were included if they were randomized double-blind placebo-controlled trials, published in a peer reviewed journal, had a majority of patients with BPD or included patients with BPD where anger was a target of treatment. Preference was given to studies using outcome measures that were well known, validated, objective, and based on intent-to-treat data. Where available, measures of anger that incorporated verbal and other indirect forms of aggression were utilized. The StatsDirect meta-analysis program was used to calculate an effect size and 95% confidence interval for each study. Mood stabilizers, with the exception of divalproic acid, were found to have a large pooled effect size (-1.75, 95% CI = -2.77 to -0.74) for anger. Divalproic acid and carbamazepine had a moderate effect on depression. Antidepressants had a moderate effect on anger reduction, but a small effect on depression. Antipsychotics had a moderate effect on anger; however aripiprazole had a much larger effect-size than other antipsychotics. Antipsychotics did not have an effect for depression. Sources of variation between studies included length of treatment (5-24 weeks), drop out rates (5% to 65%), proportion of patients in psychotherapy (0-100%) and with comorbid mood disorders (0-100%). Unfortunately most studies excluded patients with alcohol and substance abuse, suicidality, and self-harm behaviors. This may limit the ability to generalize our findings to usual clinical practice.
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Oliveira-Lima, A J; Marinho, Eav; Santos-Baldaia, R; Hollais, A W; Baldaia, M A; Talhati, F; Ribeiro, L T; Wuo-Silva, R; Berro, L F; Frussa-Filho, R
2017-02-06
We have previously demonstrated that treatment with ziprasidone and aripiprazole selectively inhibit the development of behavioral sensitization to cocaine in mice. We now investigate their effects on a counter-conditioning strategy in mice and the importance of the treatment environment for this phenomenon. Evaluate the context-specificity of ziprasidone and aripiprazole on conditioned locomotion to cocaine and cocaine-induced hyperlocomotion and behavioral sensitization in a counter-conditioning strategy in mice. Animals were sensitized with saline or cocaine injections in the open-field apparatus in a 15-day intermittent treatment and subsequently treated with vehicle, 5mg/kg ziprasidone or 0.1mg/kg aripiprazole paired to the open-field or the home-cage for 4 alternate days. Mice were then challenged with saline and cocaine in the open-field apparatus on subsequent days. While treatment with ziprasidone decreased spontaneous locomotion and conditioned locomotion alike, treatment with aripiprazole specifically attenuated the expression of conditioned hyperlocomotion to cocaine. Ziprasidone and aripiprazole had no effects on cocaine-induced conditioned hyperlocomotion observed during saline challenge after drug withdrawal. Treatment with either ziprasidone or aripiprazole when previously given in the cocaine-paired environment attenuated the subsequent expression of behavioral sensitization to cocaine. Animals treated with aripiprazole in the open-field, but not in the home-cage, showed a blunted response to cocaine when receiving a cocaine challenge for the first time. Both neuroleptic drugs showed a context-dependent effectiveness in attenuating long-term expression of cocaine-induced behavioral sensitization when administered in the cocaine-associated environment, with aripiprazole also showing effectiveness in blocking the expression of acute cocaine effects. Copyright © 2016. Published by Elsevier Inc.
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[Drug Abuse Comorbidity in Bipolar Disorder].
Ortiz, Óscar Medina
2012-06-01
Drug use among patients with bipolar disorder is greater than the one observed in the general population; psychotic episodes are likely to occur after consumption. This has implications in the prevention, etiology, management, and treatment of the disease. Bipolar disorder pathology is likely to have positive response to pharmacological treatment. Therefore, identifying the strategies with better results to be applied in these patients is fundamental for psychiatrists and primary care physicians. Review literature in order to determine the prevalence and characteristics of drug abuse in patients with bipolar disorder and establish the pharmacological strategies that have produced better results. Literature review. A great variety of studies demonstrate the relationship between bipolar disorder and drug use disorder. These patients are hospitalized more frequently, have an earlier onset of the disease, and present a larger number of depressive episodes and suicide attempts which affect the course of the disease. The drug with better results in the treatment of these patients is Divalproate. Satisfactory results have been also obtained with other mood stabilizers such as carbamazepine, lamotrigine, and the antipsychotic aripiprazole. Substance abuse is present in a large number of patients with bipolar disorder. The Divalproate is the drug that has shown better results in the studies. Copyright © 2012 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.
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Hard, Marjie L; Mills, Richard J; Sadler, Brian M; Wehr, Angela Y; Weiden, Peter J; von Moltke, Lisa
2017-07-01
Aripiprazole lauroxil (AL) is a long-acting injectable medication approved for the treatment of schizophrenia. Current AL regimens are 441 mg, 662 mg, and 882 mg administered monthly (every 4 weeks [q4wk]), or 882 mg administered every 6 weeks (q6wk). We examined the feasibility of a 2-month (every 8 weeks [q8wk]) dosing interval of AL in a phase I open-label pharmacokinetic study investigating AL 1064 mg administered q8wk for 24 weeks, followed by 20 weeks of safety and pharmacokinetic measurements (ClinicalTrials.gov ID: NCT02320032). Second, a population pharmacokinetic model (referred to as the 2MPopPK model) was generated using data collected from the present trial, as well as data obtained from earlier studies. The phase I study included patients with schizophrenia or schizoaffective disorder maintained on an oral antipsychotic (n = 140) who were assigned to one of three groups: AL 441 mg q4wk, AL 882 mg q6wk, or AL 1064 mg q8wk, with a total of seven, five, or four injections administered, respectively. No oral aripiprazole lead-in supplementation was administered and patients continued on maintenance oral antipsychotics. Pharmacokinetic samples were collected at various time points during the 24-week study period and the 20-week follow-up period. Plasma concentrations obtained from the phase I study were analyzed using non-compartmental methods. Additionally, the data were combined with data collected from prior studies to develop the 2MPopPK model. Following the final injection of AL in the phase I study, maximum aripiprazole concentrations were achieved 24.4-35.2 days after the last dose and persisted for the duration of the study. The mean C avg,ss values were 125.8 ng/ml, 131.1 ng/ml, and 140.7 ng/ml for the 441 mg q4wk, 882 mg q6wk, and 1064 mg q8wk doses, respectively. The mean elimination half-life of aripiprazole following the last dose was 53.9 days for the 1064 mg dose, 55.1 days for the 882 mg dose, and 57.2 days for the 441 mg dose. The 2MPopPK dataset included 14,524 aripiprazole concentrations from 700 patients with schizophrenia. The duration of absorption of aripiprazole was estimated as 43 days (95% confidence interval [CI] 42-45 days), which was preceded by a 3.2-day lag time (95% CI 3.0-3.5 days) for a total duration of input into the systemic circulation of 46 days following intramuscular administration of AL. Multiple-dose simulations showed that the 1064 mg q8wk regimen provides aripiprazole concentrations within the concentration range associated with 441 mg and 882 mg q4wk doses previously demonstrated to be efficacious in a phase III study. These data from the phase I study and the 2MPopPK model support the suitability of using the AL 1064 mg dose as a 2-month (q8wk) dose interval option for the treatment of schizophrenia.
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Prolonged QRS Widening After Aripiprazole Overdose.
Mazer-Amirshahi, Maryann; Porter, Robert; Dewey, Kayla
2018-05-05
Aripiprazole is an atypical antipsychotic with a long half-life. Overdose can result in protracted somnolence and cardiac disturbances, particularly QT interval prolongation. This is a single case report of a 14-year-old boy who took an overdose of aripiprazole and developed QRS widening. A 14-year-old boy intentionally ingested 20 tablets of aripiprazole (5 mg). He was brought to the emergency department when his ingestion was discovered. The patient's vital signs were as follows: temperature, 37.7°C; heart rate, 108 beats/min; blood pressure, 138/98 mm Hg; and respirations, 16 breaths/min. Activated charcoal was administered within 90 minutes of ingestion. Initial electrocardiogram (EKG) showed sinus tachycardia, with a QRS of 138 ms and QT interval of 444 ms. QRS duration was 90 ms on an EKG performed 3 months earlier. A bolus of sodium bicarbonate was administered, and the patient was transferred to the pediatric intensive care unit. Repeat EKG demonstrated a QRS of 156 ms, and a sodium bicarbonate infusion was initiated. The patient continued to have QRS prolongation for the next 8 days, reaching a peak of 172 ms 3 days postingestion. Despite aggressive treatment with sodium bicarbonate, there was persistent QRS prolongation; however, the patient did not have any dysrhythmias and remained hemodynamically stable. The patient was discharged 9 days postingestion when the QRS duration normalized to 82 ms. Genetic testing revealed that the patient was a CYP2D6 poor metabolizer. This case suggests that aripiprazole toxicity may possibly be associated with QRS prolongation without associated dysrhythmias or cardiovascular compromise. In addition, toxicity may be prolonged in patients who are CYP2D6 poor metabolizers.
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Rhee, Taeho Greg; Mohamed, Somaia; Rosenheck, Robert A
A recent moderately long-term study found an antipsychotic to be more effective than an antidepressant as the next-step treatment of unresponsive major depressive disorder (MDD). It is thus timely to examine recent trends in the pharmacoepidemiology of antipsychotic treatment of MDD. Data from the 2006-2015 National Ambulatory Medical Care Survey, nationally representative samples of office-based outpatient visits in adults with MDD (ICD-9-CM codes 296.20-296.26 and 296.30-296.36) (n = 4,044 unweighted), were used to estimate rates of antipsychotic prescribing over these 10 years. Multivariable logistic regression analysis identified demographic and clinical factors independently associated with antipsychotic use in MDD. Antipsychotic prescribing for MDD increased from 18.5% in 2006-2007 to 24.9% in 2008-2009 and then declined to 18.9% in 2014-2015. Visits with adults 75 years or older showed the greatest decline from 27.0% in 2006-2007 to 10.7% in 2014-2015 (OR for overall trend = 0.73; 95% CI, 0.56-0.95). The most commonly prescribed antipsychotic agents were aripiprazole, olanzapine, quetiapine, and risperidone. Antipsychotic prescription was associated with being black or Hispanic, having Medicare among adults under 65 years or Medicaid as a primary source of payment, and receiving mental health counseling, 3 or more concomitant medications, and diagnosis of cannabis use disorder (P < .01). Antipsychotics, prescribed for about one-fifth of adults with MDD, increased and then declined from 2006 to 2015, reflecting, first, FDA approval and then concern about adverse effects in the elderly. Future research should track evolving trends following the publication of evidence of greater long-term effectiveness of antipsychotic than antidepressant next-step therapy in adults with MDD. © Copyright 2018 Physicians Postgraduate Press, Inc.
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Tadori, Yoshihiro; Forbes, Robert A; McQuade, Robert D; Kikuchi, Tetsuro
2011-10-15
Aripiprazole is the first dopamine D(2)/D(3) receptor partial agonist successfully developed and ultimately approved for treatment of a broad spectrum of psychiatric and neurological disorders. Aripiprazole's dopamine D(2) and serotonin 5-HT(1A) receptor partial agonist activities have been postulated to confer clinical efficacy without marked sedation, and a relatively favorable overall side-effect profile. Using aripiprazole's unique profile as a benchmark for new dopamine partial agonist development may facilitate discovery of new antipsychotics. We conducted an in vitro comparative analysis between aripiprazole, and its human metabolite OPC-14857 (7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl)butoxy)-2(1H)-quinolinone)); RGH-188 (trans-1-[4-[2-[4-(2,3-dichlorophenyl)piperazine-1-yl]ethyl]cyclohexyl]-3,3-dimethylurea), and its metabolite didesmethyl-RGH-188 (DDM-RGH-188); as well as bifeprunox, sarizotan, N-desmethylclozapine (NDMC; clozapine metabolite), and SDZ 208-912 (N-[(8α)-2-chloro-6-methylergolin-8-yl]-2,2-dimethylpropanamide). In vitro pharmacological assessment included inhibition of forskolin-stimulated cAMP accumulation and the reversal of dopamine-induced inhibition in clonal Chinese hamster ovary cell lines expressing D(2S), D(2L), D(3) Ser-9 and D(3) Gly-9 for human dopamine receptors. All test compounds behaved as dopamine D(2)/D(3) receptor partial agonists. Aripiprazole's intrinsic activity at dopamine D(2S) and D(2L) receptors was similar to that of OPC-14857 and RGH-188; lower than that of dopamine and bifeprunox; and higher than that of DDM-RGH-188, SDZ 208-912, sarizotan, and NDMC. Aripiprazole's intrinsic activity at dopamine D(3) Ser-9 and D(3) Gly-9 receptors was similar to that of OPC-14857 and sarizotan; lower than that of dopamine, bifeprunox, RGH-188 and DDM-RGH-188; and higher than that of SDZ 208-912 and NDMC. A consolidated assessment of these findings may help defining the most appropriate magnitude of intrinsic activity at dopamine D(2)/D(3) receptors for clinical efficacy and safety. Copyright © 2011 Elsevier B.V. All rights reserved.
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Detection of Cases of Noncompliance to Drug Treatment in Patient Forum Posts: Topic Model Approach.
Abdellaoui, Redhouane; Foulquié, Pierre; Texier, Nathalie; Faviez, Carole; Burgun, Anita; Schück, Stéphane
2018-03-14
Medication nonadherence is a major impediment to the management of many health conditions. A better understanding of the factors underlying noncompliance to treatment may help health professionals to address it. Patients use peer-to-peer virtual communities and social media to share their experiences regarding their treatments and diseases. Using topic models makes it possible to model themes present in a collection of posts, thus to identify cases of noncompliance. The aim of this study was to detect messages describing patients' noncompliant behaviors associated with a drug of interest. Thus, the objective was the clustering of posts featuring a homogeneous vocabulary related to nonadherent attitudes. We focused on escitalopram and aripiprazole used to treat depression and psychotic conditions, respectively. We implemented a probabilistic topic model to identify the topics that occurred in a corpus of messages mentioning these drugs, posted from 2004 to 2013 on three of the most popular French forums. Data were collected using a Web crawler designed by Kappa Santé as part of the Detec't project to analyze social media for drug safety. Several topics were related to noncompliance to treatment. Starting from a corpus of 3650 posts related to an antidepressant drug (escitalopram) and 2164 posts related to an antipsychotic drug (aripiprazole), the use of latent Dirichlet allocation allowed us to model several themes, including interruptions of treatment and changes in dosage. The topic model approach detected cases of noncompliance behaviors with a recall of 98.5% (272/276) and a precision of 32.6% (272/844). Topic models enabled us to explore patients' discussions on community websites and to identify posts related with noncompliant behaviors. After a manual review of the messages in the noncompliance topics, we found that noncompliance to treatment was present in 6.17% (276/4469) of the posts. ©Redhouane Abdellaoui, Pierre Foulquié, Nathalie Texier, Carole Faviez, Anita Burgun, Stéphane Schück. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 14.03.2018.
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Ishida, Takayuki; Obara, Yoshihito; Kamei, Chiaki
2009-09-01
We studied the effects of antipsychotics and a hypnotic on sleep disturbance in schizophrenia using an animal model of the disease. Electrodes for the electroencephalogram (EEG) and electromyogram (EMG) were chronically implanted into the cortex and the dorsal neck muscle of rats. EEG and EMG were recorded with an electroencephalograph for 6 h (10:00 - 16:00). SleepSign ver. 2.0 was used for EEG and EMG analysis. Haloperidol and olanzapine had an antagonizing effect on the increases in sleep latency and total awake time and the decrease in total non-rapid eye movement (NREM) sleep time induced by MK-801. Olanzapine also antagonized the decrease in total rapid eye movement (REM) sleep time induced by MK-801. Aripiprazole antagonized only the increase in sleep latency induced by MK-801, whereas, risperidone, quetiapine, and flunitrazepam had no effect in the changes of sleep-wake pattern induced by MK-801. Olanzapine increased delta activity and decreased beta activity during NREM sleep. In contrast, flunitrazepam had an opposite effect. It was clarified that haloperidol and olanzapine were effective for decrease of sleep time in this animal model of schizophrenia. In addition, aripiprazole showed a sleep-inducing effect in schizophrenia model rat. On the other hand, flunitrazepam showed no beneficial effect on sleep disturbance in schizophrenia model rat.
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Comai, Stefano; Tau, Michael; Pavlovic, Zoran; Gobbi, Gabriella
2012-04-01
Patients experiencing mental disorders are at an elevated risk for developing aggressive behavior. In the past 10 years, the psychopharmacological treatment of aggression has changed dramatically owing to the introduction of atypical antipsychotics on the market and the increased use of anticonvulsants and lithium in the treatment of aggressive patients.This review (second of 2 parts) uses a translational medicine approach to examine the neurobiology of aggression, discussing the major neurotransmitter systems implicated in its pathogenesis (serotonin, glutamate, norepinephrine, dopamine, and γ-aminobutyric acid) and the neuropharmacological rationale for using atypical antipsychotics, anticonvulsants, and lithium in the therapeutics of aggressive behavior. A critical review of all clinical trials using atypical antipsychotics (aripiprazole, clozapine, loxapine, olanzapine, quetiapine, risperidone, ziprasidone, and amisulpride), anticonvulsants (topiramate, valproate, lamotrigine, and gabapentin), and lithium are presented. Given the complex, multifaceted nature of aggression, a multifunctional combined therapy, targeting different receptors, seems to be the best strategy for treating aggressive behavior. This therapeutic strategy is supported by translational studies and a few human studies, even if additional randomized, double-blind, clinical trials are needed to confirm the clinical efficacy of this framework.
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Ye, Na; Song, Zilan; Zhang, Ao
2014-01-01
Psychiatric disorders like schizophrenia and neurodegenerative diseases like Parkinson's disease are associated with poly-factorial pathogenic mechanisms, with several neurotransmitter systems closely involved. In addition to the cerebral dopaminergic (DA) system, the serotoninergic (5-HT) system also plays a crucial role in regulating psychoemotional, cognitive and motor functions in the central nervous system (CNS). Among the large 5-HT receptor family, accumulating data have revealed new insights into the therapeutic benefit of the 5-HT1A receptor in treating various CNS disorders, especially schizophrenia and Parkinson's disease. The present review discusses the advance of dual agents with mixed actions at the dopamine D2 and serotonin 5-HT1A receptors in the treatment of these diseases. Aripiprazole was the only marketed drug with dual D2 and 5-HT1A profile. It is a partial D2 and 5-HT1A receptor agonist and has been prescribed as an atypical antipsychotical drug. Two other drugs Cariprazine and Pardoprunox are being investigated in clinic. Most of the other candidate compounds, including Bifeprunox, Sarizotan, Mazapertine succinate, PF-217830, and Adoprazine were discontinued due to either non-optimal pharmacokinetic properties or insufficient therapeutical efficacy. Although much effort has been done to highlight the advantages of the 5-HT1A and D2 dual approach, it has to be pointed out that many of these drugs showed poly-pharmacological profile by targeting many other receptors and/or transporters besides the D2 and 5-HT1A receptors. In this regard, 'pure' compounds exclusively acting on the D2 and 5-HT1A receptors are highly needed to further validate this approach. Meanwhile, safety concerns and in vivo pharmacokinetic alerts should also be implanted to the drug design art early.
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Girardi, Paolo; Del Casale, Antonio; Rapinesi, Chiara; Kotzalidis, Georgios D; Splendori, Francesca; Verzura, Claudio; Trovini, Giada; Sorice, Serena; Carrus, Dario; Mancinelli, Iginia; Comparelli, Anna; De Filippis, Sergio; Francomano, Antonio; Ballerini, Andrea; Marcellusi, Andrea; Mennini, Francesco S; Ducci, Giuseppe; Sani, Gabriele; Pompili, Maurizio; Brugnoli, Roberto
2018-05-01
Long-acting injectable (LAI) antipsychotics can improve medication adherence and reduce hospitalisation rates compared with oral treatments. Paliperidone palmitate (PAL) and aripiprazole monohydrate (ARI) LAI treatments were associated with improvements in global functioning in patients with schizophrenia. The objective of this study was to assess the predictive factors of better overall functioning in patients with chronic schizophrenia and schizoaffective disorder treated with PAL and ARI. Enrolled were 143 (97 males, 46 females, mean age 38.24 years, SD = 12.65) patients with a diagnosis of schizophrenia or schizoaffective disorder, whom we allocated in two groups (PAL and ARI treatments). We assessed global functioning, amount of oral medications, adherence to oral treatment, and number of hospitalisations before LAI introduction and at assessment time point. Longer treatment time with LAIs (p < .001), lower number of oral drugs (p < .001), and hospitalisations (p = .002) before LAI introduction, and shorter duration of illness (p = .038) predicted better Global Assessment of Functioning scores in the whole sample (R 2 = 0.337). Early administration and longer duration of ARI or PAL treatments could play a significant role in improving global functioning of patients with schizophrenia and schizoaffective disorder. Better improvement in functioning could be achieved with ARI in young individuals with recent illness onset and PAL in patients at risk for recurrent hospitalisations. Copyright © 2018 John Wiley & Sons, Ltd.
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Population pharmacokinetics of aripiprazole in healthy Korean subjects.
Jeon, Ji-Young; Chae, Soo-Wan; Kim, Min-Gul
2016-04-01
Aripiprazole is widely used to treat schizophrenia and bipolar disorder. This study aimed to develop a combined population pharmacokinetic model for aripiprazole in healthy Korean subjects and to identify the significant covariates in the pharmacokinetic variability of aripiprazole. Aripiprazole plasma concentrations and demographic data were collected retrospectively from previous bioequivalence studies that were conducted in Chonbuk National University Hospital. Informed consent was obtained from subjects for cytochrome P450 (CYP) genotyping. The population pharmacokinetic parameters of aripiprazole were estimated using nonlinear mixed-effect modeling with first-order conditional estimation with interaction method. The effects of age, sex, weight, height, and CYP genotype were assessed as covariates. A total of 1,508 samples from 88 subjects in three bioequivalence studies were collected. The two-compartment model was adopted, and the final population model showed that the CYP2D6 genotype polymorphism, height and weight significantly affect aripiprazole disposition. The bootstrap and visual predictive check results were evaluated, showing that the accuracy of the pharmacokinetic model was acceptable. A population pharmacokinetic model of aripiprazole was developed for Korean subjects. CYP2D6 genotype polymorphism, weight, and height were included as significant factors affecting aripiprazole disposition. The population pharmacokinetic parameters of aripiprazole estimated in the present study may be useful for individualizing clinical dosages and for studying the concentration-effect relationship of the drug.
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Grover, Sandeep; Dutt, Alakananda; Chakrabarty, Kaustav; Kumar, Vineet
2012-01-01
Non-catatonic mutism in schizophrenia has been described less frequently in literature. We describe the case of a young male who presented with non-catatonic mutism, secondary to first rank symptoms, which was refractory to adequate antipsychotic trials (quetiapine, risperidone, aripiprazole, ziprasidone, and trifluperazine) and responded to a combination of electroconvulsive therapy (ECT) and neuroleptics partially. However, when the ECT was continued in the continuation phase, the patient started speaking. PMID:23766583
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Chanachev, Aleksandar; Ansermot, Nicolas; Crettol Wavre, Séverine; Nowotka, Ute; Stamatopoulou, Maria-Eleni; Conus, Philippe; Eap, Chin B
2011-01-01
There exist many case reports and studies on the antipsychotic augmentation by aripirazole in partial responders to clozapine, the most seem to be finding a slight difference in the PANSS and CGI scores after the aripirazole addition. The results of our report are compatible with those of other studies but, we have found a considerable antianxiety action in both of the cases. The 5HT1A agonism of aripirazole could be hypothesized as mechanism contributing to this effect.
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Neural Basis for the Ability of Atypical Antipsychotic Drugs to Improve Cognition in Schizophrenia
Sumiyoshi, Tomiki; Higuchi, Yuko; Uehara, Takashi
2013-01-01
Cognitive impairments are considered to largely affect functional outcome in patients with schizophrenia, other psychotic illnesses, or mood disorders. Specifically, there is much attention to the role of psychotropic compounds acting on serotonin (5-HT) receptors in ameliorating cognitive deficits of schizophrenia. It is noteworthy that atypical antipsychotic drugs (AAPDs), e.g., clozapine, melperone, risperidone, olanzapine, quetiapine, aripiprazole, perospirone, blonanserin, and lurasidone, have variable affinities for these receptors. Among the 5-HT receptor subtypes, the 5-HT1A receptor is attracting particular interests as a potential target for enhancing cognition, based on preclinical and clinical evidence. The neural network underlying the ability of 5-HT1A agonists to treat cognitive impairments of schizophrenia likely includes dopamine, glutamate, and gamma-aminobutyric acid neurons. A novel strategy for cognitive enhancement in psychosis may be benefited by focusing on energy metabolism in the brain. In this context, lactate plays a major role, and has been shown to protect neurons against oxidative and other stressors. In particular, our data indicate chronic treatment with tandospirone, a partial 5-HT1A agonist, recover stress-induced lactate production in the prefrontal cortex of a rat model of schizophrenia. Recent advances of electrophysiological measures, e.g., event-related potentials, and their imaging have provided insights into facilitative effects on cognition of some AAPDs acting directly or indirectly on 5-HT1A receptors. These findings are expected to promote the development of novel therapeutics for the improvement of functional outcome in people with schizophrenia. PMID:24137114
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Cai, H L; Jiang, P; Tan, Q Y; Dang, R L; Tang, M M; Xue, Y; Deng, Y; Zhang, B K; Fang, P F; Xu, P; Xiang, D X; Li, H D; Yao, J K
2017-01-01
Schizophrenia (SZ) is considered to be a multifactorial brain disorder with defects involving many biochemical pathways. Patients with SZ show variable responses to current pharmacological treatments of SZ because of the heterogeneity of this disorder. Stress has a significant role in the pathophysiological pathways and therapeutic responses of SZ. Atypical antipsychotic drugs (AAPDs) can modulate the stress response of the hypothalamic–pituitary–adrenal (HPA) axis and exert therapeutic effects on stress by targeting the prefrontal cortex (PFC) and hippocampus. To evaluate the effects of AAPDs (such as clozapine, risperidone and aripiprazole) on stress, we compared neurochemical profile variations in the PFC and hippocampus between rat models of chronic unpredictable mild stress (CUMS) for HPA axis activation and of long-term dexamethasone exposure (LTDE) for HPA axis inhibition, using an ultraperformance liquid chromatography–mass spectrometry (UPLC–MS/MS)-based metabolomic approach and a multicriteria assessment. We identified a number of stress-induced biomarkers comprising creatine, choline, inosine, hypoxanthine, uric acid, allantoic acid, lysophosphatidylcholines (LysoPCs), phosphatidylethanolamines (PEs), corticosterone and progesterone. Specifically, pathway enrichment and correlation analyses suggested that stress induces oxidative damage by disturbing the creatine–phosphocreatine circuit and purine pathway, leading to excessive membrane breakdown. Moreover, our data suggested that the AAPDs tested partially restore stress-induced deficits by increasing the levels of creatine, progesterone and PEs. Thus, the present findings provide a theoretical basis for the hypothesis that a combined therapy using adenosine triphosphate fuel, antioxidants and omega-3 fatty acids as supplements may have synergistic effects on the therapeutic outcome following AAPD treatment. PMID:28509906
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Jakobsen, Klaus Damgaard; Bruhn, Christina Hedegaard; Pagsberg, Anne-Katrine; Fink-Jensen, Anders; Nielsen, Jimmi
2016-10-01
Aripiprazole is a partial dopamine agonist with only minor neurological and psychiatric adverse effects, making it a potential first-line drug for the treatment of psychiatric disorders. However, the evidence of its use in children and adolescents is rather sparse. The aim of this case study is to discuss adverse drug reaction (ADR) reports concerning aripiprazole-associated neurological and psychiatric events in children and adolescents. The ADR report database at Danish Medicines Agency was searched for all ADRs involving children and adolescents (<18 years) reported by the search term [aripiprazole] AND all spontaneous reports since the introduction of aripiprazole in 2003 until December 31, 2015. Nineteen case reports were included in the study and included both patients with psychotic disorders (PS group) and nonpsychotic disorders (non-PS group). The PS group consisted of 5 patients with schizophrenia and psychoses, not otherwise specified; and the non-PS group consisted of fourteen cases including autism spectrum disorders, attention deficit and hyperactivity disorder, obsessive-compulsive disorder, and Tourette syndrome. The main reported adverse effects in the non-PS group were chronic insomnia, Parkinsonism, behavioral changes psychoses, and weight gain, whereas the adverse effects in the PS group was predominantly anxiety, convulsions, and neuroleptic malignant syndrome. Although aripiprazole is considered safe and well tolerated in children and adolescents, severe adverse events as neuroleptic malignant syndrome, extreme insomnia, and suicidal behavior has been reported to health authorities. Clinicians should pay attention to these possible hazards when prescribing aripiprazole to this vulnerable group of patients.
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[Pharmacotherapy for conduct disorder in children and adolescents].
Levy, Tomer; Bloch, Yuval
2012-07-01
Conduct disorder (CD) is a common disorder which is typified by a variety of behavioral problems and aggression. Treating CD is a challenge in the field of child and adolescent psychiatry. The use of drugs for this indication is broad despite the lack of systematic knowledge on this subject. This paper aims to review research data available on the efficacy of the different medication classes and agents for CD and to specify the considerations that should be taken accordingly. Trials on the pharmacotherapy of CD in children and adolescents are reviewed from the PubMed database (dated from 1980 until today). Trials of antipsychotics, lithium, anti-epileptics, stimulants, alfa-2 agonists and beta-blockers were found. The use of typical antipsychotics is accompanied by major side-effects. Research on risperidone, the most investigated agent, shows it to be effective. Limited research with positive results is also available on quetiapine, olanzapine and aripiprazole. Trials of lithium yield contradictory results. Few trials with valproate suggest it to be effective for this indication. There is evidence showing the efficacy of stimulants but substance abuse is a potential risk in this population. The results for other agents are very few. There are few well controlled studies of the pharmacotherapy of conduct disorder in children and adolescents. The most proven efficacy is for the atypical antipsychotics. Valproate or lithium may be possible second or third alternatives, based on some supporting evidence. When Attention-Deficit/Hyperactivity Disorder is diagnosed, stimulant use should be considered. Given the adverse effects profile of these agents on the one hand, and the developmental risks of avoiding medication on the other hand, a risk-benefit analysis should be conducted for each patient and adverse effects should be monitored carefully. More research is needed to broaden and deepen the knowledge on this subject.
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Cordes, J; Sinha-Röder, A; Kahl, K G; Malevani, J; Thuenker, J; Lange-Asschenfeldt, C; Hauner, H; Agelink, M W; Klimke, A
2008-12-01
Extensive, selective literature review of 2500 articles from the last years (up to December 2007) predominantly from Medline and Cochrane, using as search terms "antipsychotic or schizophrenia or individual drug names (amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, ziprasidone)" and the terms "BMI, weight gain, metabolic syndrome, diabetes, lipid(s), cholesterol, triglycerides" was conducted. Regardless of the advantages ascribed to atypical antipsychotics and the special effectiveness of clozapine in patients resistant to therapy and at risk for suicide, the probability of weight gain is considerably increased for some of these substances. Patients with schizophrenia have a considerably reduced life expectancy associated with an increased prevalence of cardiovascular risk factors. There is a lack of practical guidelines integrated into clinical psychiatric care for the management of cardiovascular risk factors. The monitoring of patients treated with atypics, which has been recommended in the APA/ADA Consensus Paper in light of these facts, is insufficiently established in clinical practice. A regular monitoring can convey self control and motivation to the patient. In the case of corresponding risk constellations further decisions regarding indication and therapy have to be considered. Especially patients with a high cardiovascular risk profile are highly recommended to participate in a weight-management program for prevention purposes. Such a special program should include elements of dietetic treatment and behaviour and exercise therapy. First controlled studies suggest an effective prevention of weight gain and metabolic changes when applying such a structured program. The practice oriented step by step concept presented here is meant to provide points of reference for the implementation of required medical and psychoeducative measures facilitating the management of weight and further cardiovascular risk factors in the context of psychiatric care in patients with schizophrenia.
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Lui, Kingwai; Randhawa, Gagandeep; Totten, Vicken; Smith, Adam E.; Raese, Joachim
2016-01-01
Objective: Metabolic syndrome is a common underdiagnosed condition among psychiatric patients exacerbated by second-generation antipsychotics, with the exception of aripiprazole and ziprasidone. This study evaluated the prescribing and treating behavior with regard to antipsychotics and metabolic syndrome of psychiatrists before and after implementation of a mandatory admission order set and electronic notification of results. Method: Baseline data from 9,100 consecutive psychiatric admissions to a mental health hospital (July 2013–July 2014) were compared to postintervention data (July 2014–January 2015), which included 1,499 consecutive patient records. The intervention initiated standardized admission testing with electronic notification to psychiatrists when patients met metabolic syndrome criteria (according to Axis III of the DSM-IV). Charts were examined for inclusion of this diagnosis at discharge and for treatment changes. Results: At baseline, only 2.4% of patients (n = 214) were evaluated for metabolic syndrome. Of these, 34.5% (0.8% of the total sample) met metabolic syndrome criteria. Only 15 patients (0.16%) were comprehensively treated. No chart listed metabolic syndrome under Axis III of the DSM-IV. After the intervention, the diagnosis of patients meeting the criteria for metabolic syndrome increased from 0% to 29.3%. Less than 3% of patients were switched to drugs with a more benign metabolic profile. All patients who continued on second-generation antipsychotics had metabolic retesting. Thirty-eight experienced a significant and rapid increase in triglyceride levels after only 3 to 17 days. Conclusions: Mandatory intake testing increases the number of patients evaluated for metabolic syndrome. Electronic alerts increase the inclusion of metabolic syndrome among discharge diagnoses but rarely affect prescribing practices. PMID:27247842
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Edwards, Natalie C; Locklear, Julie C; Rupnow, Marcia F T; Diamond, Ronald J
2005-01-01
The availability of long-acting risperidone injection may increase adherence and lead to improved clinical and economic outcomes for individuals with schizophrenia. The objective of this study was to assess the cost effectiveness of long-acting risperidone, oral risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, and haloperidol depot in patients with schizophrenia over 1 year from a healthcare system perspective. Published medical literature, unpublished data from clinical trials and a consumer health database, and a clinical expert panel were utilized to populate a decision analytical model comparing the seven treatment alternatives. The model captured rates of patient compliance, the rates, frequency and duration of relapse, incidence of adverse events, and healthcare resource utilization and associated costs. Primary outcomes were expressed in terms of percentage of patients relapsing per year, number of relapse days per year (number and duration of relapses per patient per year), and total direct 2003 medical cost per patient per year. On the basis of model projections, the proportions of patients experiencing a relapse requiring hospitalization in 1 year were 66% for haloperidol depot, 41% for oral risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole, and 26% for long-acting risperidone, whereas the proportions of patients with an exacerbation not requiring hospitalization were 60% for haloperidol depot, 37% for oral risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole, and 24% for long-acting risperidone. The mean number of days of relapse requiring hospitalization per patient per year were 28 for haloperidol depot, 18 for oral risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole, and 11 for long-acting risperidone, whereas the mean number of days of exacerbation not requiring hospitalization were eight for haloperidol depot, five for oral risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole, and three for long-acting risperidone. This would translate into direct medical cost savings with long-acting risperidone compared with oral risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, and haloperidol depot of US dollars 161, 1425, 508, 259, 1068, and 8224, respectively. These findings were supported by sensitivity analyses. The utilization of long-acting risperidone is predicted to result in better clinical outcomes and lower total healthcare costs than its comparators, oral risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, and haloperidol depot. Long-acting risperidone may therefore be a cost saving therapeutic option for patients with schizophrenia.
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Movement disorders and chronic psychosis
Morgante, Francesca
2017-01-01
Abstract Purpose of review: To discuss selected peer-reviewed research articles published between 2014 and 2016 and highlight 5 clinically relevant messages related to hyperkinetic and hypokinetic movement disorders in patients with chronic psychosis. Recent findings: A recent population-based study complemented data from clinical trials in showing increased risk of developing extrapyramidal symptoms with antipsychotic use. A community service–based longitudinal study showed that dopamine transporter imaging could help identify subgroups of patients with parkinsonism associated with antipsychotics with a progressive course, potentially manageable with l-dopa. Data from recent noteworthy clinical trials showed that a new VMAT-2 inhibitor and, for pharmacologically refractory tardive dyskinesia, deep brain stimulation of the globus pallidus internus are promising interventions. Finally, a population-based study has confirmed that hyperkinesias (encompassing chorea, dystonia, and stereotypies) may be early predictors of psychosis even in childhood and adolescence. Summary: Movement disorders associated with new-generation antipsychotics, including widely used agents (e.g., aripiprazole), are not rare occurrences. Better monitoring is needed to assess their true effect on patients' quality of life and functioning and to prevent underascertainment. PMID:29185545
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Han, Tae Hwan; Kim, Do Yeon; Park, Dong Woo; Moon, Jin-Hwa
2017-01-01
Transient bulbar palsy without involvement of the facial or extraocular muscles is a rare presentation. It is considered a form of cranial polyneuropathy, a variant of Guillain-Barré syndrome that is related to the autoimmune mechanisms induced by preceding infections or vaccinations. However, drug-induced cranial polyneuropathy has not previously been reported. We describe a boy with isolated bulbar palsy and positive serum antiganglioside antibodies during aripiprazole treatment. This 12-year-old boy was admitted with a seven-day history of dysarthria, tongue discomfort, and tinnitus. Three weeks before symptom onset, aripiprazole was added to the patient's medications for attention-deficit hyperactivity disorder. On examination, he showed curtaining of the pharyngeal wall, tongue fasciculation and deviation, and a weak gag reflex. Cranial magnetic resonance imaging suggested lower cranial nerve involvement. Serum anti-GM1 IgG and anti-GD1b IgG antibodies were positive. After stopping aripiprazole, his bulbar symptoms improved. However, on readministration of aripiprazole seven weeks later, dysarthria recurred and again resolved after stopping the drug. We describe the first patient with anti-GM1 IgG and anti-GD1b IgG antibodies-associated transient cranial polyneuropathy presenting as isolated bulbar palsy. These findings could be an adverse effect of aripiprazole treatment. Copyright © 2016 Elsevier Inc. All rights reserved.
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Hegde, Aditya; Kalyani, Bangalore G; Arumugham, Shyam Sundar; Narayanaswamy, Janardhanan C; Math, Suresh Bada; Reddy, Y C Janardhan
2017-03-01
To study the effectiveness and tolerability of aripiprazole augmentation in patients with highly treatment-resistant obsessive-compulsive disorder (OCD) in a real-world scenario. We conducted a chart review of patients who were initiated on aripiprazole augmentation at a specialty OCD clinic in India between 2004 and 2014. Primary outcome measure was all-cause discontinuation. 23 patients were eligible for analysis. Patients had not achieved symptom remission despite a mean of over 3 prior SRI trials. Aripiprazole was continued to be used in seven patients (30%) at the time of last follow-up. Thirteen patients (57%) discontinued the drug due to side effects, and three patients (13%) discontinued aripiprazole citing no improvement. Six patients (26%) were noted to have ≥25% reduction on the Yale-Brown Obsessive-Compulsive Scale. The study demonstrated, in a real-world setting, that aripiprazole may be a useful augmenting agent in a proportion of patients with highly treatment-resistant OCD. However, side effects may lead to premature discontinuation in many of them.
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Chanachev, Aleksandar; Ansermot, Nicolas; Crettol Wavre, Séverine; Nowotka, Ute; Stamatopoulou, Maria-Eleni; Conus, Philippe; Eap, Chin B.
2011-01-01
There exist many case reports and studies on the antipsychotic augmentation by aripirazole in partial responders to clozapine, the most seem to be finding a slight difference in the PANSS and CGI scores after the aripirazole addition. The results of our report are compatible with those of other studies but, we have found a considerable antianxiety action in both of the cases. The 5HT1A agonism of aripirazole could be hypothesized as mechanism contributing to this effect. PMID:22937411
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Aripiprazole maintenance increases smoked cocaine self-administration in humans
Rubin, Eric; Foltin, Richard W.
2011-01-01
Rationale Partial dopamine receptor agonists have been proposed as candidate pharmacotherapies for cocaine dependence. Objective This 42-day, within-subject, human laboratory study assessed how maintenance on aripiprazole, a partial D2 receptor agonist, influenced smoked cocaine self-administration, cardiovascular measures, subjective effects, and cocaine craving in nontreatment-seeking, cocaine-dependent volunteers. Methods In order to achieve steady-state concentrations, participants (n=8 men) were administered placebo and aripiprazole (15 mg/day) capsules in counter-balanced order for 21 days. A smoked cocaine dose–response curve (0, 12, 25, 50 mg) was determined twice under placebo and aripiprazole maintenance. Sessions comprised a “sample” trial, when participants smoked the cocaine dose available that session, and five choice trials, when they responded on a progressive-ratio schedule of reinforcement to receive the cocaine dose or receive $5.00. Results Cocaine’s reinforcing, subjective, and cardiovascular effects were dose-dependent. Aripiprazole significantly increased cocaine (12, 25 mg) self-administration. Following a single administration of cocaine (25 mg), aripiprazole decreased ratings of how much participants would pay for that dose. Following repeated cocaine (50 mg) self-administration, aripiprazole decreased ratings of cocaine quality, craving, and good drug effect as compared to placebo. Conclusions These data suggest that aripiprazole may have increased self-administration to compensate for a blunted subjective cocaine effect. Overall, the findings do not suggest aripiprazole would be useful for treating cocaine dependence. PMID:21373790
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Nagai, Goyo; Mihara, Kazuo; Nakamura, Akifumi; Nemoto, Kenji; Kagawa, Shoko; Suzuki, Takeshi; Kondo, Tsuyoshi
2017-02-01
It has been suggested that a plasma trough concentration of aripiprazole plus its active metabolite, dehydroaripiprazole of 225 ng/mL is a threshold for a good therapeutic response in the treatment of acutely exacerbated patients with schizophrenia. The present study investigated whether or not an optimal dose of aripiprazole could be predicted from these concentrations at week 1. The subjects were 26 inpatients with schizophrenia, who received aripiprazole once a day for 3 weeks. The daily doses were 12 mg for the first week and 24 mg for the next 2 weeks. No other drugs except biperiden and flunitrazepam were coadministered. Blood samples were taken at weeks 1 and 3 after the treatment. Plasma concentrations of aripiprazole and dehydroaripiprazole were measured using liquid chromatography with mass-spectrometric detection. There was a significant linear relationship between the plasma concentrations of aripiprazole plus dehydroaripiprazole at weeks 1 (x) and 3 (y) (P < 0.001). Regression equation was y = 2.580x + 34.86 (R = 0.698). Based on the equation, a nomogram to estimate an optimal dose of aripiprazole could be constructed. The present study suggests that an optimal dose of aripiprazole for the treatment of patients with schizophrenia can be predicted from the plasma concentrations of the sum of the 2 compounds at week 1.
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Pagsberg, Anne Katrine; Tarp, Simon; Glintborg, Dorte; Stenstrøm, Anne Dorte; Fink-Jensen, Anders; Correll, Christoph Ulrich; Christensen, Robin
2017-03-01
To determine the comparative efficacy and safety of antipsychotics for youth with early-onset schizophrenia using network meta-analytic methods combining direct and indirect trial data. The authors systematically searched MEDLINE, the Cochrane Library, and clinicaltrials.gov and selected randomized controlled trials allocating youth with schizophrenia spectrum disorders to a (non-clozapine) antipsychotic versus placebo or another antipsychotic. Major efficacy outcomes were Positive and Negative Syndrome Scale (PANSS) total and positive symptoms. Major safety outcomes were weight, plasma triglyceride levels, extrapyramidal symptoms, akathisia, and all-cause discontinuation. Sixteen additional outcomes were analyzed. A random-effects arm-based network meta-analysis was applied, and consistency was assessed by pairwise meta-analysis. Confidence in PANSS total estimates was assessed by applying the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Twelve 6- to 12-week trials (N = 2,158; 8-19 years old; 61% boys) involving 8 antipsychotics (aripiprazole, asenapine, paliperidone, risperidone, quetiapine, olanzapine, molindone, and ziprasidone) were analyzed. PANSS total symptom change was comparable among antipsychotics (low- to moderate-quality evidence), except ziprasidone (very low- to low-quality evidence), and all antipsychotics were superior to placebo (low- to high-quality evidence), except ziprasidone and asenapine (low- to moderate-quality evidence). PANSS positive changes and additional efficacy outcomes were comparable among antipsychotics. Weight gain was primarily associated with olanzapine; extrapyramidal symptoms and akathisia were associated with molindone; and prolactin increased with risperidone, paliperidone, and olanzapine. Serious adverse events, discontinuation of treatment, sedation, insomnia, or change in triglycerides did not differ among antipsychotics. This network meta-analysis showed comparable efficacy among antipsychotics for early-onset schizophrenia, except that efficacy appeared inferior for ziprasidone and unclear for asenapine. Adverse reaction profiles varied substantially among the investigated antipsychotics and were largely consistent with prior findings in adults. Protocol registration information-Antipsychotic Treatment for Children With Schizophrenia Spectrum Disorders: Network Meta-Analysis of Randomised Trials; https://www.crd.york.ac.uk/PROSPERO/; CRD42013006676. Copyright © 2017 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.
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Tadokoro, Shigenori; Okamura, Naoe; Sekine, Yoshimoto; Kanahara, Nobuhisa; Hashimoto, Kenji; Iyo, Masaomi
2012-01-01
Background: Long-term treatment of schizophrenia with antipsychotics is crucial for relapse prevention, but a prolonged blockade of D2 dopamine receptors may lead to the development of supersensitivity psychosis. We investigated the chronic effects of aripiprazole (ARI) on dopamine sensitivity. Methods: We administered ARI (1.5 mg/kg/d), haloperidol (HAL; 0.75 mg/kg/d), or vehicle (VEH) via minipump for 14 days to drug-naive rats or to rats pretreated with HAL (0.75 mg/kg/d) or VEH via minipump for 14 days. On the seventh day following treatment cessation, we examined the effects of the treatment conditions on the locomotor response to methamphetamine and on striatal D2 receptor density (N = 4-10/condition/experiment). Results: Chronic treatment with HAL led to significant increases in locomotor response and D2 receptor density, compared with the effects of chronic treatment with either VEH or ARI; there were no significant differences in either locomotor response or D2 density between the VEH- and ARI-treated groups. We also investigated the effects of chronic treatment with HAL, ARI, or VEH preceded by HAL or VEH treatment on locomotor response and D2 density. ANOVA analysis indicated that the rank ordering of groups for both locomotor response and D2 density was HAL-HAL > HAL-VEH > HAL-ARI > VEH-VEH. Conclusions: Chronic treatment with ARI prevents development of dopamine supersensitivity and potentially supersensitivity psychosis, suggesting that by reducing excessive sensitivity to dopamine and by stabilizing sensitivity for an extended period of time, ARI may be helpful for some patients with treatment-resistant schizophrenia. PMID:21402722
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Simon, N; Azorin, J-M
2015-04-01
Drug manufacturer seeking authorization to bring a newly medicinal compound to the market (Market Authorization Application) have to undertake various studies, each of them providing a specific report. It is however essential to know how to pool results in order to understand the behavior of the drug in all the situations likely to be encountered in clinical practice. The exploitation of these data is now carried out through pharmacometric analyzes which aim at quantifying the exposure and the response of a drug over time. These methods (named "population approach") are based on non-linear mixed effects model and therefore, on the identification of a mathematical model. A first step is to model the variations in concentrations over time by integrating the physio-pathological characteristics of the patients. At this stage, the Bayesian analysis is essential to identify and select the factors of interindividual variability. This pharmacokinetic (PK) modeling allows us to obtain the prescribed dose for each patient, but also their exposure. The second step consists in defining the relationship between exposure and effect: pharmacodynamic (PD) modeling. In psychiatry, the response can be the receptors' occupancy rate or the evolution of a clinical score (BPRS, PANSS…) over time. The final PK-PD model defines the target exposure, that is to say, the concentration values required to achieve maximum effect on the score studied without risking over-exposure. Ultimately, a Monte Carlo simulation will be conducted which will test the expected response for different doses and will facilitate a rational choice in dosage. Assessing the process behind the transition from an oral to a long-acting injectable form of an active ingredient such as aripiprazole can be done by following the same protocol. A 10- to 30-mg per day therapeutic range has thus been identified. The model incorporates all the identified factors of variability of aripiprazole (drug interactions and genetic polymorphism of the P450 2D6 cytochrome) and showed that with an injectable sustained release form, a monthly dose of 400mg would allow 90% of patients to gain exposure in the therapeutic range. In case of a drug inhibition and/or of a slow metabolizing profile, dosage adjustment is necessary. Copyright © 2015 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.
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Antipsychotics and associated risk of out-of-hospital cardiac arrest.
Weeke, P; Jensen, A; Folke, F; Gislason, G H; Olesen, J B; Fosbøl, E L; Wissenberg, M; Lippert, F K; Christensen, E F; Nielsen, S L; Holm, E; Kanters, J K; Poulsen, H E; Køber, L; Torp-Pedersen, C
2014-10-01
Antipsychotic drugs have been associated with sudden cardiac death, but differences in the risk of out-of-hospital cardiac arrest (OHCA) associated with different antipsychotic drug classes are not clear. We identified all OHCAs in Denmark (2001-2010). The risk of OHCA associated with antipsychotic drug use was evaluated by conditional logistic regression analysis in case-time-control models. In total, 2,205 (7.6%) of 28,947 OHCA patients received treatment with an antipsychotic drug at the time of the event. Overall, treatment with any antipsychotic drug was associated with OHCA (odds ratio (OR) = 1.53, 95% confidence interval (CI): 1.23-1.89), as was use with typical antipsychotics (OR = 1.66, CI: 1.27-2.17). By contrast, overall, atypical antipsychotic drug use was not (OR = 1.29, CI: 0.90-1.85). Two individual typical antipsychotic drugs, haloperidol (OR = 2.43, CI: 1.20-4.93) and levomepromazine (OR = 2.05, CI: 1.18-3.56), were associated with OHCA, as was one atypical antipsychotic drug, quetiapine (OR = 3.64, CI: 1.59-8.30).
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Wang, Shuai; Wei, Yan-Zhao; Yang, Jian-Hong; Zhou, Yu-Ming; Cheng, Yu-Hang; Yang, Chao; Zheng, Yi
2017-08-01
The aims are to evaluate the efficacy and safety of aripiprazole for tic disorders (TDs) in children and adolescents. We searched PubMed, Embase, PsychINFO, Cochrane database as well as Chinese databases of CNKI, VIP, CBM and Wanfang from the database inception to October 2016, and 17 full-text studies (N=1305) were included in our article. The meta-analysis of 10 studies (N=817) showed that there was no significant difference in the reduction of total YGTSS score between aripiprazole and other drugs, and meta-analysis of 7 studies (n=324) which used tic symptom control ≧30% as outcome measure showed that there was no significant difference between aripiprazole and other treatments. The most common AEs of aripiprazole were the drowsiness, nausea/vomiting and increased appetite, and meta analysis which used the TESS scale as the outcome measurement showed that there was a significant difference between aripiprazole and haloperidol. In conclusion, these data provide moderate quality evidence that aripiprazole could be an effective and safe treatment option for TDs, and results from further trials are urgently needed to extend this evidence base. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.
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Haloperidol versus second-generation antipsychotics in the long-term treatment of schizophrenia.
Buoli, Massimiliano; Kahn, René S; Serati, Marta; Altamura, A Carlo; Cahn, Wiepke
2016-07-01
The purpose of the study was to compare antipsychotic monotherapies in terms of time to discontinuation in a sample of schizophrenia patients followed-up for 36 months. Two hundred and twenty schizophrenia patients, treated with antipsychotic monotherapy and followed-up in psychiatric outpatient clinics of Universities of Milan and Utrecht were included in the study. A survival analysis (Kaplan-Meier) of the 36-month follow-up period was performed to compare the single treatment groups. End-point was considered as discontinuation of treatment for recurrence, side effects or non-compliance. Patients treated with haloperidol discontinued more than the other groups (Breslow: risperidone p < 0.001, olanzapine p < 0.001, quetiapine p = 0.002, clozapine p < 0.001, aripiprazole p = 0.002). Lack of efficacy (recurrence) was a more frequent reason for discontinuation in the haloperidol group than in the olanzapine group (p < 0.05). Extrapyramidal side effects (EPS) were more frequent in the haloperidol group than with olanzapine (p < 0.05). The olanzapine group presented more frequently weight gain than the other groups, without reaching statistical significance. Patients treated with atypical antipsychotics appear to continue pharmacotherapy longer than patients treated with haloperidol. In addition, atypical antipsychotics seem to be more protective against recurrences than haloperidol. However, these results should be cautiously interpreted in the light of potential confounder factors such as duration of illness. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.
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Johnson, Gary R.; Chen, Peijun; Hicks, Paul B.; Davis, Lori L.; Yoon, Jean; Gleason, Theresa C.; Vertrees, Julia E.; Weingart, Kimberly; Tal, Ilanit; Scrymgeour, Alexandra; Lawrence, David D.; Planeta, Beata; Thase, Michael E.; Huang, Grant D.; Zisook, Sidney; Rao, Sanjai D.; Pilkinton, Patricia D.; Wilcox, James A.; Iranmanesh, Ali; Sapra, Mamta; Jurjus, George; Michalets, James P.; Aslam, Muhammed; Beresford, Thomas; Anderson, Keith D.; Fernando, Ronald; Ramaswamy, Sriram; Kasckow, John; Westermeyer, Joseph; Yoon, Gihyun; D’Souza, D. Cyril; Larson, Gunnar; Anderson, William G.; Klatt, Mary; Fareed, Ayman; Thompson, Shabnam I.; Carrera, Carlos J.; Williams, Solomon S.; Juergens, Timothy M.; Albers, Lawrence J.; Nasdahl, Clifford S.; Villarreal, Gerardo; Winston, Julia L.; Nogues, Cristobal A.; Connolly, K. Ryan; Tapp, Andre; Jones, Kari A.; Khatkhate, Gauri; Marri, Sheetal; Suppes, Trisha; LaMotte, Joseph; Hurley, Robin; Mayeda, Aimee R.; Niculescu, Alexander B.; Fischer, Bernard A.; Loreck, David J.; Rosenlicht, Nicholas; Lieske, Steven; Finkel, Mitchell S.; Little, John T.
2017-01-01
Importance Less than one-third of patients with major depressive disorder (MDD) achieve remission with their first antidepressant. Objective To determine the relative effectiveness and safety of 3 common alternate treatments for MDD. Design, Setting, and Participants From December 2012 to May 2015, 1522 patients at 35 US Veterans Health Administration medical centers who were diagnosed with nonpsychotic MDD, unresponsive to at least 1 antidepressant course meeting minimal standards for treatment dose and duration, participated in the study. Patients were randomly assigned (1:1:1) to 1 of 3 treatments and evaluated for up to 36 weeks. Interventions Switch to a different antidepressant, bupropion (switch group, n = 511); augment current treatment with bupropion (augment-bupropion group, n = 506); or augment with an atypical antipsychotic, aripiprazole (augment-aripiprazole group, n = 505) for 12 weeks (acute treatment phase) and up to 36 weeks for longer-term follow-up (continuation phase). Main Outcomes and Measures The primary outcome was remission during the acute treatment phase (16-item Quick Inventory of Depressive Symptomatology-Clinician Rated [QIDS-C16] score ≤5 at 2 consecutive visits). Secondary outcomes included response (≥50% reduction in QIDS-C16 score or improvement on the Clinical Global Impression Improvement scale), relapse, and adverse effects. Results Among 1522 randomized patients (mean age, 54.4 years; men, 1296 [85.2%]), 1137 (74.7%) completed the acute treatment phase. Remission rates at 12 weeks were 22.3% (n = 114) for the switch group, 26.9% (n = 136)for the augment-bupropion group, and 28.9% (n = 146) for the augment-aripiprazole group. The augment-aripiprazole group exceeded the switch group in remission (relative risk [RR], 1.30 [95% CI, 1.05-1.60]; P = .02), but other remission comparisons were not significant. Response was greater for the augment-aripiprazole group (74.3%) than for either the switch group (62.4%; RR, 1.19 [95% CI, 1.09-1.29]) or the augment-bupropion group (65.6%; RR, 1.13 [95% CI, 1.04-1.23]). No significant treatment differences were observed for relapse. Anxiety was more frequent in the 2 bupropion groups (24.3% in the switch group [n = 124] vs 16.6% in the augment-aripiprazole group [n = 84]; and 22.5% in augment-bupropion group [n = 114]). Adverse effects more frequent in the augment-aripiprazole group included somnolence, akathisia, and weight gain. Conclusions and Relevance Among a predominantly male population with major depressive disorder unresponsive to antidepressant treatment, augmentation with aripiprazole resulted in a statistically significant but only modestly increased likelihood of remission during 12 weeks of treatment compared with switching to bupropion monotherapy. Given the small effect size and adverse effects associated with aripiprazole, further analysis including cost-effectiveness is needed to understand the net utility of this approach. Trial Registration clinicaltrials.gov Identifier: NCT01421342 PMID:28697253
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Mohamed, Somaia; Johnson, Gary R; Chen, Peijun; Hicks, Paul B; Davis, Lori L; Yoon, Jean; Gleason, Theresa C; Vertrees, Julia E; Weingart, Kimberly; Tal, Ilanit; Scrymgeour, Alexandra; Lawrence, David D; Planeta, Beata; Thase, Michael E; Huang, Grant D; Zisook, Sidney; Rao, Sanjai D; Pilkinton, Patricia D; Wilcox, James A; Iranmanesh, Ali; Sapra, Mamta; Jurjus, George; Michalets, James P; Aslam, Muhammed; Beresford, Thomas; Anderson, Keith D; Fernando, Ronald; Ramaswamy, Sriram; Kasckow, John; Westermeyer, Joseph; Yoon, Gihyun; D'Souza, D Cyril; Larson, Gunnar; Anderson, William G; Klatt, Mary; Fareed, Ayman; Thompson, Shabnam I; Carrera, Carlos J; Williams, Solomon S; Juergens, Timothy M; Albers, Lawrence J; Nasdahl, Clifford S; Villarreal, Gerardo; Winston, Julia L; Nogues, Cristobal A; Connolly, K Ryan; Tapp, Andre; Jones, Kari A; Khatkhate, Gauri; Marri, Sheetal; Suppes, Trisha; LaMotte, Joseph; Hurley, Robin; Mayeda, Aimee R; Niculescu, Alexander B; Fischer, Bernard A; Loreck, David J; Rosenlicht, Nicholas; Lieske, Steven; Finkel, Mitchell S; Little, John T
2017-07-11
Less than one-third of patients with major depressive disorder (MDD) achieve remission with their first antidepressant. To determine the relative effectiveness and safety of 3 common alternate treatments for MDD. From December 2012 to May 2015, 1522 patients at 35 US Veterans Health Administration medical centers who were diagnosed with nonpsychotic MDD, unresponsive to at least 1 antidepressant course meeting minimal standards for treatment dose and duration, participated in the study. Patients were randomly assigned (1:1:1) to 1 of 3 treatments and evaluated for up to 36 weeks. Switch to a different antidepressant, bupropion (switch group, n = 511); augment current treatment with bupropion (augment-bupropion group, n = 506); or augment with an atypical antipsychotic, aripiprazole (augment-aripiprazole group, n = 505) for 12 weeks (acute treatment phase) and up to 36 weeks for longer-term follow-up (continuation phase). The primary outcome was remission during the acute treatment phase (16-item Quick Inventory of Depressive Symptomatology-Clinician Rated [QIDS-C16] score ≤5 at 2 consecutive visits). Secondary outcomes included response (≥50% reduction in QIDS-C16 score or improvement on the Clinical Global Impression Improvement scale), relapse, and adverse effects. Among 1522 randomized patients (mean age, 54.4 years; men, 1296 [85.2%]), 1137 (74.7%) completed the acute treatment phase. Remission rates at 12 weeks were 22.3% (n = 114) for the switch group, 26.9% (n = 136)for the augment-bupropion group, and 28.9% (n = 146) for the augment-aripiprazole group. The augment-aripiprazole group exceeded the switch group in remission (relative risk [RR], 1.30 [95% CI, 1.05-1.60]; P = .02), but other remission comparisons were not significant. Response was greater for the augment-aripiprazole group (74.3%) than for either the switch group (62.4%; RR, 1.19 [95% CI, 1.09-1.29]) or the augment-bupropion group (65.6%; RR, 1.13 [95% CI, 1.04-1.23]). No significant treatment differences were observed for relapse. Anxiety was more frequent in the 2 bupropion groups (24.3% in the switch group [n = 124] vs 16.6% in the augment-aripiprazole group [n = 84]; and 22.5% in augment-bupropion group [n = 114]). Adverse effects more frequent in the augment-aripiprazole group included somnolence, akathisia, and weight gain. Among a predominantly male population with major depressive disorder unresponsive to antidepressant treatment, augmentation with aripiprazole resulted in a statistically significant but only modestly increased likelihood of remission during 12 weeks of treatment compared with switching to bupropion monotherapy. Given the small effect size and adverse effects associated with aripiprazole, further analysis including cost-effectiveness is needed to understand the net utility of this approach. clinicaltrials.gov Identifier: NCT01421342.
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Auclair, Agnès L; Galinier, Alexandra; Besnard, Joël; Newman-Tancredi, Adrian; Depoortère, Ronan
2007-07-01
Prepulse inhibition (PPI) of the startle reflex has been extensively studied because it is disrupted in several psychiatric diseases, most notably schizophrenia. In rats, and to a lesser extent, in humans, PPI can be diminished by dopamine (DA) D(2)/D(3) and serotonin 5-HT(1A) receptor agonists. A novel class of potential antipsychotics (SSR181507, bifeprunox, and SLV313) possess partial agonist/antagonist properties at D(2) receptors and various levels of 5-HT(1A) activation. It thus appeared warranted to assess, in Sprague-Dawley rats, the effects of these antipsychotics on basal PPI. SSR181507, sarizotan, and bifeprunox decreased PPI, with a near-complete abolition at 2.5-10 mg/kg; SLV313 had a significant effect at 0.16 mg/kg only. Co-treatment with the 5-HT(1A) receptor antagonist WAY100,635 (0.63 mg/kg) showed that the 5-HT(1A) agonist activity of SSR181507 was responsible for its effect. By contrast, antipsychotics with low affinity and/or efficacy at 5-HT(1A) receptors, such as aripiprazole (another DA D(2)/D(3) and 5-HT(1A) ligand), and established typical and atypical antipsychotics (haloperidol, clozapine, risperidone, olanzapine, quetiapine, and ziprasidone) had no effect on basal PPI (0.01-2.5 to 2.5-40 mg/kg). The present data demonstrate that some putative antipsychotics with pronounced 5-HT(1A) agonist activity, coupled with partial agonist activity at DA D(2) receptors, markedly diminish PPI of the startle reflex in rats. These data raise the issue of the influence of such compounds on sensorimotor gating in humans.
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Kishi, Taro; Ikuta, Toshikazu; Matsunaga, Shinji; Matsuda, Yuki; Oya, Kazuto; Iwata, Nakao
2017-01-01
The relative efficacy and tolerability of antipsychotics for schizophrenia are considerably well studied. This study aimed to examine whether previous findings could be replicated in a genetically distinct and homogenous group (ie, Japanese patients with schizophrenia) and whether previous findings could be extended to a broader range of antipsychotics with previously unclear relative efficacy and tolerability. Bayesian network meta-analysis was performed in which randomized trials comparing any of the following interventions were included: second-generation antipsychotics, haloperidol, or placebo. The primary outcomes for efficacy and acceptability were the response rate and all-cause discontinuation. The secondary outcomes included the improvement of Positive and Negative Syndrome Scale scores, discontinuation because of adverse events, and individual adverse events. Eighteen relevant studies were identified (total n=3,446; aripiprazole =267, blonanserin =285, clozapine =47, clocapramine =295, haloperidol =857, mosapramine =493, olanzapine =179, paliperidone =136, perospirone =146, placebo =138, quetiapine =212, and risperidone =338; mean study duration =8.33±1.41 weeks). In primary outcomes, olanzapine and paliperidone showed efficacy than placebo, and olanzapine and paliperidone showed superior acceptability compared with placebo. There were differences in the incidences of individual adverse events (the best antipsychotic: extrapyramidal symptoms = olanzapine, hyperprolactinemia- related symptoms = quetiapine, sedation = paliperidone, and weight change = blonanserin) among antipsychotics. Although the current analysis exclusively included Japanese patients with schizophrenia, no remarkable differences were observed in efficacy and safety compared with previous meta-analyses. Diverse hierarchies in safety outcomes also support the implication that individual risk expectations for adverse events can guide clinical decisions. However, the sample size was relatively limited. Additional efficacy and safety data are required to fully obtain a conclusive understanding.
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Kishi, Taro; Ikuta, Toshikazu; Matsunaga, Shinji; Matsuda, Yuki; Oya, Kazuto; Iwata, Nakao
2017-01-01
Background The relative efficacy and tolerability of antipsychotics for schizophrenia are considerably well studied. This study aimed to examine whether previous findings could be replicated in a genetically distinct and homogenous group (ie, Japanese patients with schizophrenia) and whether previous findings could be extended to a broader range of antipsychotics with previously unclear relative efficacy and tolerability. Methods Bayesian network meta-analysis was performed in which randomized trials comparing any of the following interventions were included: second-generation antipsychotics, haloperidol, or placebo. The primary outcomes for efficacy and acceptability were the response rate and all-cause discontinuation. The secondary outcomes included the improvement of Positive and Negative Syndrome Scale scores, discontinuation because of adverse events, and individual adverse events. Results Eighteen relevant studies were identified (total n=3,446; aripiprazole =267, blonanserin =285, clozapine =47, clocapramine =295, haloperidol =857, mosapramine =493, olanzapine =179, paliperidone =136, perospirone =146, placebo =138, quetiapine =212, and risperidone =338; mean study duration =8.33±1.41 weeks). In primary outcomes, olanzapine and paliperidone showed efficacy than placebo, and olanzapine and paliperidone showed superior acceptability compared with placebo. There were differences in the incidences of individual adverse events (the best antipsychotic: extrapyramidal symptoms = olanzapine, hyperprolactinemia- related symptoms = quetiapine, sedation = paliperidone, and weight change = blonanserin) among antipsychotics. Conclusion Although the current analysis exclusively included Japanese patients with schizophrenia, no remarkable differences were observed in efficacy and safety compared with previous meta-analyses. Diverse hierarchies in safety outcomes also support the implication that individual risk expectations for adverse events can guide clinical decisions. However, the sample size was relatively limited. Additional efficacy and safety data are required to fully obtain a conclusive understanding. PMID:28553116
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Patil, Payal Hasmukhlal; Wankhede, Pooja R; Mahajan, H S; Zawar, Laxmikant
2018-01-04
The fundamental objective of current study was to encapsulate Ari-piprazole (ARP) within Pluronic F127 micelles to improve its aqueous solubility. The recent patents on Ar-ipiprazole (JP2013136621) and micelles (WO2016004369A1) facilitated selection of drug and polymer. The drug-laden micelles were fabricated using thin-film hydration technique. Optimization of the micellar formulation was done by using response surface method (RSM). The Pluronic F127 concentration of 150 mg and 75 rpm rotational speed of rotary evaporator were found to be optimized conditions for formulating micelles. The prepared batches were further characterized for PDI (polydispersity index), zeta potential, % DLC (% Drug loading content), % EE (% Entrapment Efficiency) and % drug release study; results of these parameters were found to be 0.228, −4.04 mV and 76.50 % and 18.56 % respectively. It was observed from the In vitro release study that 97.37 ± 1.81 % drug had released from micelles after 20 hrs which were found about thrice as compared to that of pure drug. The optimized ARP micellar for-mulation was characterized using DSC (Differential Scanning Colorimetry), FT-IR (Fourier Trans-formed Infrared Spectroscopy), P-XRD (Powdered X-ray Diffraction Study) and TEM (Transmission Electronic Microscopy) studies. ARP-loaded micelles displayed a hydrodynamic diameter of 170.3 nm and a sphere-shaped morphology as determined by dynamic light scattering as well as TEM study. It is concluded that the prepared polymeric micellar system has an excellent potential to be used as a delivery carrier for Aripiprazole with increased solubility. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
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Angelopoulos, Elias; Theleritis, Christos; Economou, Marina; Georgatou, Korina; Papageorgiou, Charalambos C; Tsaltas, Eleftheria
2017-07-01
In the recent study by Verhoeven and Egger, 2015 and the recent letter to the editor by Boot et al. 2015 an emphasis is given to the best possible pharmacological treatment of 22q11-2 Deletion-Syndrome related psychoses. We would like to present the case of a 23-year old Cypriot patient with 22q11.2 deletion syndrome who fulfilled criteria for treatment resistant schizophrenia (TRS). He was sequentially treated with aripiprazole, risperidone, olanzapine, haloperidol and a combination treatment with olanzapine and haloperidol. Clozapine was the only antipsychotic medication that has improved his condition. © Georg Thieme Verlag KG Stuttgart · New York.
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Aripiprazole for the maintenance treatment of bipolar I disorder: A review.
McIntyre, Roger S
2010-01-01
Bipolar disorder is a chronic neuropsychiatric syndrome associated with substantial rates of recurrence, interepisodic dysfunction, comorbidity, and premature mortality. Metabolic comorbidity (eg, overweight, obesity, metabolic syndrome) differentially affects individuals with bipolar disorder and contributes to increased illness-associated morbidity and mortality (ie, cardiovascular disease). Few pharmacologic agents have been approved by the US Food and Drug Administration for the maintenance treatment of bipolar disorder. This paper discusses the metabolic profile of aripiprazole and reviews pivotal registration trials of aripiprazole for the maintenance treatment of adults with bipolar I disorder. MEDLINE was searched for English-language articles published between January 1995 and November 2009. The key search term was aripiprazole, combined with bipolar disorder and maintenance treatment. The review was limited to randomized, controlled registration trials, supplemented by poster presentations involving the registration-trial data sets. Three studies of the efficacy and tolerability of aripiprazole monotherapy in the maintenance treatment of bipolar I disorder were identified by the literature search: a 26-week, randomized, double-blind study and its 74-week extension phase (for a total of 100 weeks of double-blind treatment), and a randomized, double-blind comparison of aripiprazole with placebo and lithium (internal comparator) for up to 12 weeks. After 100 weeks of double-blind treatment, aripiprazole had a minimal effect on body composition and did not disrupt metabolic parameters compared with placebo. The mean (SD) weight change was 0.4 (0.8) kg with aripiprazole and -1.9 (0.8) kg with placebo (P = NS). A clinically significant (> or =7%) increase in weight occurred in 20% of the aripiprazole group and 5% of the placebo group (P = 0.01). Extrapyramidal symptoms were reported in 22% of the aripiprazole group and 15% of the placebo group. The identified trials of aripiprazole primarily enrolled patients during a manic state; no maintenance trials of combination therapy or trials enrolling individuals presenting with an acute depressive episode were identified. The available evidence supports the efficacy and tolerability of aripiprazole in the maintenance treatment of bipolar disorder. The placebo-subtracted differences in body composition and metabolic parameters suggest utility for aripiprazole in the long-term treatment of bipolar disorder. 2010 Excerpta Medica Inc. All rights reserved.
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Tempest, Michael; Sapin, Christophe; Beillat, Maud; Robinson, Paul; Treur, Maarten
2015-12-01
Schizophrenia is a severe and debilitating psychiatric disorder. Pharmacological interventions aim to ameliorate symptoms and reduce the risk of relapse and costly hospitalisation. Despite the established efficacy of antipsychotic medication, compliance to treatment is poor, particularly with oral formulation. The emergence of long acting injectable (LAI) antipsychotic formulations in recent years has aimed to counteract the poor compliance rates observed and optimise long term patient outcomes. To estimate the cost-effectiveness of aripiprazole once-monthly 400mg (AOM 400) vs. risperidone long acting injectable (RLAI), paliperidone long acting injectable (PLAI) and olanzapine long acting injectable (OLAI) in the maintenance treatment of chronic, stable schizophrenia patients in the United Kingdom. A Markov model was developed to emulate the treatment pathway of a hypothetical cohort of patients initiating maintenance treatment with LAI antipsychotics. The economic analysis was conducted from a National Health Service (NHS) and Personal Social Services (PSS) perspective over a 10 year time horizon. Efficacy and safety probabilities were derived from mixed treatment comparisons (MTCs) where possible. Analyses were conducted assuming pooled dosing from randomised clinical trials included in the MTCs. The model estimates that AOM 400 improves clinical outcomes by reducing relapses per patient comparative to other LAIs over the model time horizon (2.38, 2.53, 2.70, and 2.67 for AOM 400, RLAI, PLAI and OLAI respectively). In the deterministic analysis, AOM 400 dominated PLAI and OLAI; an incremental cost-effectiveness ratio (ICER) of GBP 3,686 per QALY gained was observed against RLAI. Results from the univariate sensitivity analyses highlighted the probability and cost of relapse as main drivers for cost-effectiveness. In the probabilistic sensitivity analysis, AOM 400 demonstrated a marginally higher probability of being cost-effective (51%) than RLAI, PLAI and OLAI (48%, 1% and 0%, respectively) at a willingness to pay threshold of GBP 20,000. The model was built to accommodate results of an adjusted MTC analysis. Furthermore the model effectively captures repercussions of deteriorating compliance to treatment by incorporating three levels of compliance with elevated risks of relapse for partial compliance and non-compliance. Limitations of the analysis include the limited number of studies incorporated in the MTC, the extrapolation of short term clinical data and the exclusion of the wider societal burden. Comparative to other atypical antipsychotics, AOM 400 represents value for money in the maintenance treatment of chronic, stable schizophrenia; however, in light of the PSA findings and comparable cost-effectiveness (i.e. against RLAI), the product profile and wider benefits of the respective treatments must be taken into account when prescribing antipsychotics. Future research should assess the use of LAI antipsychotics earlier in the disease course of schizophrenia to see whether improved compliance and outcomes shortly following the onset of psychosis has the potential to alter the disease trajectory. Moreover it should be assessed whether changes in the disease trajectory can alleviate cost and resource pressures placed on national health services.
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[Guidelines for the prescription of mood stabilizers for adolescents: A literature review].
Munch, G; Godart, N
2017-10-01
Adolescence is a unique phase of the human developmental process. In adolescents, psychotropic medications may have different efficacy and tolerance profiles compared to those at other stages of the lifespan. Mood stabilizers are a complex pharmacological category including lithium, some anticonvulsants, and some second generation antipsychotics. Focusing on this class of pharmacological agents, we aim to answer the following questions: in which indications and according to which modalities should mood stabilizers be prescribed during adolescence? Information was sought from the websites of the French Haute Autorité de santé (HAS) and Agence nationale de sécurité du médicament et des produits de santé (ANSM), the American Food and Drug Administration (FDA) and the British National Institute for Health and Clinical Excellence (NICE). Guidelines from the American Academy of Child and Adolescent Psychiatry (AACAP) were also reviewed. Additional articles were found using PubMed and Google Scholar. We assumed that guidelines published by a national institute were the most relevant, second information from medical academies, then literature reviews, and finally single studies. Practical prescription data were also sought from the French Vidal Drug Dictionary. For bipolar disorder in adolescents, lithium has been the first drug licensed in France (from the age of 16) and in the USA (from the age of 12), with indications for acute mania and preventive treatment. Benefits for impulsive and self-aggressive behaviour disorders (especially relevant in case of borderline personality disorder) have also been documented, although lithium has not been licensed in any country for those indications. Extended-release tablets are usually used, at doses targeting for a lithiemia between 0.8 and 1.2mEq/L 12hours after last intake. Because of a narrow therapeutic window and potential side effects (especially nephrotoxicity), lithium prescription requires regular blood tests and good treatment compliance. None of the anticonvulsants has been licensed by a national drug administration as a mood stabilizer in adolescents. However, the AACAP recommends valproate as a first line treatment for mania, even though the NICE and the ANSM caution that valproate should not be used by women of child bearing age. Besides its teratogenic and endocrine side effects, valproate exposes one to the risk of hepatic toxicity. That is why regular liver function tests should be prescribed when valproate is chosen. According to the AACAP, carbamazepine (which is licensed for the treatment of mania in adults) is not a first line treatment for adolescents. Indeed, no clinical study has demonstrated its efficacy on manic episodes in adolescents. Moreover, carbamazepine exposes one to the risk of agranulocytosis. Lamotrigine has not been approved for adolescents, but some studies suggest its efficacy for bipolar depression (often a treatment-resistant phase) in this age group. Major side effects are the risk of Lyell or Stevens-Johnsons syndrome (which usually occur within the first eight weeks of treatment). There is no need for biological tests, just clinical monitoring. Pharmacological interactions between lamotrigine and oral contraceptives require caution. Finally, the use of some second generation antipsychotics for bipolar disorder in adolescents has been approved by national drug administrations. In France, only aripiprazole is licensed for acute mania (from the age of 13). In the USA, aripiprazole is licensed from the age of 10 for acute mania and preventive treatment, while risperidone and quetiapine are licensed from the age of 10 for acute mania, and olanzapine is licensed from the age of 13 for acute mania. The AACAP recommends second generation antipsychotics as a first line treatment for bipolar disorder. Moreover, the AACAP and the NICE recommend second generation antipsychotics for behavioural disorders in adolescents. Recommended doses are usually lower and titration slower than for adults. As in adults, adverse effects are metabolic, motor and cognitive disorders. Moreover, hyperprolactinemia, sedation and weight gain are more frequent than in adults. Epidemiologic data for prescription of mood stabilizers in adolescents only partially concord with recommendations from drug administrations and scientific societies. On the one hand, there is a trend toward preferential prescription of second generation antipsychotics, on the other hand lithium is hardly prescribed to adolescents, less often than anticonvulsants. Thus, without approval from any drug administration, the anticonvulsants are often preferred to lithium (because of lithium's potential risks due to noncompliance or voluntary poisoning) and to second generation antipsychotics (because of their tolerance profile). Nevertheless, for prescribers it is a complex matter to compare side effects: the frequency and intensity of adverse effects is quite variable from one mood stabilizer to another, and such a thing as an expected value is therefore hard to define. Regardless of the medication chosen, compliance and therapeutic alliance are major issues. Compliance is especially low during adolescence (less than 40% according to a study on bipolar disorder). This lack of compliance has multiple determinants: poor acceptance or misunderstanding of the psychiatric disorder, indirect effects of bad relationships with parents and more generally adults, but also reckless behaviour or death wishes. Improving therapeutic alliance appears as a major challenge for health practitioners dealing with youth. One interesting path of research could be the therapeutic education programs using humanistic communication techniques (addressing both adolescents and their parents) which have already produced encouraging results. Copyright © 2016. Published by Elsevier Masson SAS.
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Psychotic and Bipolar Disorders: Antipsychotic Drugs.
Holder, Sarah D; Edmunds, Alaina L; Morgan, Sherri
2017-04-01
Antipsychotic drugs block dopamine receptors and are used to manage psychosis as well as other mental illnesses that may or may not have psychotic features, such as bipolar disorders and major depressive disorder. First-generation antipsychotic drugs are more likely to cause adverse effects such as extrapyramidal symptoms and tardive dyskinesia. Adverse effects of second-generation antipsychotic drugs typically are related to metabolic abnormalities such as weight gain, abnormal blood glucose levels, and elevated lipid levels. Neuroleptic malignant syndrome is a rare but serious adverse effect of antipsychotic drugs that causes mental status changes, hyperthermia, and generalized rigidity. Timely diagnosis is essential due to a high risk of related morbidities if the syndrome remains untreated. Some adverse effects of antipsychotics can be identified and managed so that patients can continue beneficial therapy while minimizing the physiologic consequences. Patients taking antipsychotic drugs should be monitored regularly for adverse effects. Antipsychotics are also associated with potential drug interactions, the most lethal being prolongation of the QT interval, which can lead to fatal arrhythmias. Antipsychotic drugs can be used in special populations, such as pregnant women, children, and elderly patients, per recommendation from a mental health subspecialist. Written permission from the American Academy of Family Physicians is required for reproduction of this material in whole or in part in any form or medium.
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The prefrontal cortex: a target for antipsychotic drugs.
Artigas, F
2010-01-01
At therapeutic doses, classical antipsychotic drugs occupy a large proportion of subcortical dopamine D2 receptors, whereas atypical antipsychotics preferentially occupy cortical 5-HT(2) receptors. However, the exact cellular and network basis of their therapeutic action is not fully understood. To review the mechanism of action of antipsychotic drugs with a particular emphasis on their action in the prefrontal cortex (PFC). The PFC controls a large number of higher brain functions altered in schizophrenia. Histological studies indicate the presence of a large proportion of PFC neurons expressing monoaminergic receptors sensitive to the action of atypical- and to a lesser extentclassical antipsychotic drugs. Functional studies also indicate that both drug families act at PFC level. Atypical antipsychotic drugs likely exert their therapeutic activity by a preferential action on PFC neurons, thus modulating the PFC output to basal ganglia circuits. Classical antipsychotics also interact with these PFC targets in addition to blocking massively striatal D2 receptors.
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Beresford, Thomas; Buchanan, Jennifer; Thumm, Elizabeth Brie; Emrick, Chad; Weitzenkamp, David; Ronan, Patrick J
2017-12-01
Co-occurring schizophrenia spectrum disorder and International Statistical Classification of Diseases, 10th Revision cocaine dependence present a particularly destructive constellation that is often difficult to treat. Both conditions raise dopamine transmission effects in the brain. Traditional neuroleptics block dopamine receptors, whereas aripiprazole modulates dopamine activity as an agonist/antagonist. We tested whether dopamine modulation is superior to dopamine blocking in dual-diagnosis patients. In a randomized, double-blind, comparison design, cocaine-dependent schizophrenic subjects actively using cocaine received either aripiprazole or perphenazine in an 8-week trial. Primary outcome targeted cocaine-free urine sample proportions, whereas cocaine craving scores were a secondary variable. Subjects (N = 44) randomized (n = 22 per group) did not differ at baseline. The proportion of cocaine-free urine samples did not differ by medication group. Contrasting weeks 3 to 5 vs 6 to 8 revealed significant late reductions in craving with aripiprazole. On the respective 5-point subscales, craving intensity decreased by 1.53 ± 0.43 (P < 0.0005) points, craving frequency by 1.4 ± 0.40 (P > 0.0004) points, and craving duration by 1.76 ± 0.44 (P > 0.0001) points. A drug effect of aripiprazole on craving items appeared at week 6 of treatment, on average, and was not seen before that length of drug exposure. The data suggest that dopamine modulation reduces cocaine cravings but requires an acclimation period. To understand the mechanism of action better, a trial of depot aripiprazole may be useful. Clinically, a reduction in craving potentially offers a clearer focus for ongoing behavioral treatment. It may also offer a longer-term treatment effect with respect to the severity of relapse.
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Belmonte, Carmen; Ochoa, Dolores; Román, Manuel; Cabaleiro, Teresa; Talegón, Maria; Sánchez-Rojas, Sergio Daniel; Abad-Santos, Francisco
2016-12-01
The aim of this study was the evaluation of the possible relationship between pharmacokinetics and the safety of aripiprazole as well as its influence on blood pressure (BP), heart rate (HR), and corrected QT (QTc) interval. The study population comprised 157 healthy volunteers from 6 bioequivalence clinical trials. Subjects were administered a single 10-mg oral dose of each formulation separated by a 28-day washout period. Plasma concentrations were measured using high-performance liquid chromatography coupled to mass spectrometry. Blood pressure was measured at the following times: predose and 0.5, 2, 4, 6, and 8 hours postdose. An electrocardiogram was recorded at predose, 4, and 8 hours postdose. Area under the curve (AUC), maximum plasma concentration, half-life, and distribution volume corrected for weight were higher in women. Aripiprazole treatment produced a decrease of BP (9.3 mm Hg on systolic and 6.2 mm Hg on diastolic pressure) and an increase in HR (12.1 beats per minute) and QTc interval (9.1 milliseconds). There were sex differences in BP, HR, and QTc interval. Women and subjects with higher AUC and maximum plasma concentration values were more prone to experience adverse drug reactions and gastrointestinal adverse reactions. The AUC was related with systolic BP and diastolic BP decrease and HR increase but there was no relationship between aripiprazole concentrations and QTc increase. Aripiprazole decreases BP and increases HR and QTc interval. Pharmacokinetics, pharmacodynamics, and safety of aripiprazole are affected by sex. There is a directly proportional relationship between pharmacokinetic parameters and adverse drug reactions and effect on BP and HR.
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Mohamed, Somaia; Rosenheck, Robert A; Lin, Haiqun; Swartz, Marvin; McEvoy, Joseph; Stroup, Scott
2015-07-01
No large-scale randomized trial has compared the effect of different second-generation antipsychotic drugs and any first-generation drug on alcohol, drug and nicotine use in patients with schizophrenia. The Clinical Antipsychotic Trial of Intervention Effectiveness study randomly assigned 1432 patients formally diagnosed with schizophrenia to four second-generation antipsychotic drugs (olanzapine, risperidone quetiapine, and ziprasidone) and one first-generation antipsychotic (perphenazine) and followed them for up to 18 months. Secondary outcome data documented cigarettes smoked in the past week and alcohol and drug use severity ratings. At baseline, 61% of patients smoked, 35% used alcohol, and 23% used illicit drugs. Although there were significant effects of time showing reduction in substance use over the 18 months (all p < 0.0001), this study found no evidence that any antipsychotic was robustly superior to any other in a secondary analysis of data on substance use outcomes from a large 18-month randomized schizophrenia trial.
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Chavant, Francois; Favrelière, Sylvie; Lafay-Chebassier, Claire; Plazanet, Caroline; Pérault-Pochat, Marie-Christine
2011-12-01
To investigate putative associations of reports of memory disorders and suspected drugs. We used the case/noncase method in the French PharmacoVigilance Database (FPVD). Cases were reports of memory loss in the FPVD between January 2000 and December 2009. Noncases were all other reports during the same period. To assess the association between memory impairment and drug intake, we calculated an odds ratio with its 95% confidence interval. Among the 188,284 adverse drug reactions recorded, we identified 519 cases of memory loss. The sex ratio was 0.6 and the median age was 54 years (range 4-93). The maximal number of cases occurred between 40-49 and 50-59 years. Evolution was favourable in 63% of the cases. We found significant odds ratios for benzodiazepines (alprazolam, bromazepam, prazepam, clonazepam etc.), benzodiazepine-like hypnotics (zolpidem and zopiclone), antidepressants (fluoxetine, paroxetine and venlafaxine), analgesics (morphine, nefopam and tramadol), anticonvulsants (topiramate, pregabalin, levetiracetam etc.), antipsychotics (aripiprazole and lithium) and other drugs, such as trihexyphenidyl, ciclosporin and isotretinoin. Our study confirmed an association between memory disorders and some drugs, such as benzodiazepines and anticonvulsants. However, other drugs, such as benzodiazepine-like hypnotics, newer anticonvulsants, serotonin reuptake inhibitor antidepressants, isotretinoin and ciclosporin were significantly associated with memory disorders, although this was not described or poorly described in the literature. Taking account of the limits of this study in the FPVD (under-reporting, notoriety bias etc.), the case/noncase method allows assessment and detection of associations between exposure to drugs and a specific adverse drug reaction, such as memory disorders, and could thus generate signals and orientate us to further prospective studies to confirm such associations. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.
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Cameron, Chris; Zummo, Jacqueline; Desai, Dharmik N; Drake, Christine; Hutton, Brian; Kotb, Ahmed; Weiden, Peter J
Aripiprazole lauroxil (AL) is a long-acting injectable atypical antipsychotic recently approved for treatment of schizophrenia on the basis of a large-scale trial of two doses of AL versus placebo. There are no direct-comparison studies with paliperidone palmitate (PP; long-acting antipsychotic used most often in acute settings) for the acute psychotic episode. To indirectly compare efficacy and safety of the pivotal AL study with all PP studies meeting indirect comparison criteria. Systematic searches of MEDLINE, Embase, Cochrane CENTRAL, PsycINFO, ClinicalTrials.gov, International Clinical Trials Registry Platform, and gray literature were performed to identify randomized controlled trials of PP with similar designs to the AL trial. Bayesian network meta-analysis compared treatments with respect to symptom response and tolerability issues including weight gain, akathisia, parkinsonism, and likelihood of treatment-emergent adverse events. Three appropriate PP studies were identified for indirect comparison. Both doses of AL (441 mg and 882 mg monthly) were used and compared with two efficacious doses of PP (156 mg and 234 mg monthly). All four active-treatment conditions were associated with comparable reductions in acute symptoms (Positive and Negative Syndrome Scale) versus placebo and were of similar magnitude (range of mean difference -8.12 to -12.01, with overlapping 95% credible intervals). Between-group comparisons of active-treatment arms were associated with summary estimates of magnitude near 0. No clinically meaningful differences in selected safety or tolerability parameter incidence were found between active treatments. These results suggest that both AL and PP are effective for treatment of adults experiencing acute exacerbation of schizophrenia. Copyright © 2017 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.
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Zimbroff, Dan; Warrington, Lewis; Loebel, Antony; Yang, Ruoyong; Siu, Cynthia
2007-11-01
We compared the efficacy and safety of ziprasidone and aripiprazole in the treatment of acutely ill patients with schizophrenia. Patients were randomized to receive double-blind treatment with ziprasidone (80-160 mg/day), or aripiprazole (10-30 mg/day) for up to 4 weeks. Primary efficacy measures were the Clinical Global Impression of Severity scale (CGI-S) and Brief Psychiatric Rating Scale (BPRSd) total (derived from the Positive and Negative Syndrome Scale). Noninferiority for ziprasidone (N=125) relative to aripiprazole (N=128) was established for CGI-S score (P=0.007), but was not confirmed for BPRSd total score (P=0.248). Effect sizes for within-group improvement, however, were robust for both ziprasidone and aripiprazole (effect size range 1.0-1.1 for CGI-S; and range 1.1-1.2 for BPRSd total). A mixed model repeated measures analysis of BPRSd total score favored ziprasidone at day 4 compared with aripiprazole (P=0.04), with no significant differences between treatment groups at other visits (P=0.001 for interaction between treatment and visit). No statistically significant difference was found in CGI-S score between groups across all visits. Our findings suggest that ziprasidone and aripiprazole exhibit similar efficacy and tolerability profiles in the treatment of acute schizophrenia. Differences between the two drugs in the onset of therapeutic effect warrant further investigation.
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Küçükköse, Mustafa; Kabukçu Başay, Bürge
2017-01-01
Autism spectrum disorders (ASD) are neuropsychiatric disorders characterized by impairment in social interactions, in verbal and non-verbal communication, and restricted and stereotyped patterns of interest and behavior within the first 3 years of life. Pharmacologic interventions may be needed for the treatment of temper tantrums, aggression, hyperactivity, and stereotypes in children with ASD. The approval of aripiprazole by the United States Food and Drug Administration (USFDA) for the treatment of temper tantrums in children and adolescents with ASD has gained increased interest for the use in these patients. Aripiprazole is a partial agonist for the dopamine D2, serotonin 5-HT1A receptors, and an antagonist for 5HT2A receptors. Because aripiprazole is a partial agonist, it has been is speculated that aripiprazole has a protective effect for extrapyramidal side effects, movement disorders, and metabolic problems. But the increased use in children and adolescents is associated with an increase in the number of case reports related with such problems. Nevertheless, our review of the literature uncovered limited data regarding the association between acute dystonia and aripiprazole use in ASD children under five years of age is. In this paper, we present two cases of autistic spectrum disorder children with ages under 5 years that developed acute dystonia taking aripiprazole.
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Citrome, Leslie
2009-09-01
Pharmaceutical product labeling as approved by regulatory agencies include statements of adverse event risk. Product labels include descriptive statements such as whether events are uncommon or rare, as well as percentage occurrence for more common events. In addition tables are provided with the frequencies of the latter events for both product and placebo as observed in clinical trials. Competing products are not mentioned in a specific drug's product labeling but indirect comparisons can be made using the corresponding label information for the alternate product. Two types of tools are easily used for this purpose: absolute measures such as number needed to harm (NNH), and relative measures such as relative risk increase (RRI). The calculations for both of these types of quantitative measures are presented using as examples the oral first-line second-generation antipsychotic medications. Among three sample outcomes selected a priori, akathisia, weight gain, and discontinuation from a clinical trial because of an adverse reaction, there appears to be differences among the different antipsychotics versus placebo. Aripiprazole was associated with the highest risk for akathisia, particularly when used as adjunctive treatment of major depressive disorder (NNH 5, 95% CI 4-7; RRI 525%, 95% CI 267%-964%). Although insufficient information was available in product labeling to calculate the CI, olanzapine was associated with the highest risk for weight gain of at least 7% from baseline (NNH 6, RRI 640% for adults; NNH 4, RRI 314% for adolescents), and quetiapine for the indication of bipolar depression was associated with the highest risk of discontinuation from a clinical trial because of an adverse reaction (NNH 8, RRI 265% for 600 mg/d; NNH 15, RRI 137% for 300 mg/d). In conclusion, with certain limitations, it is possible for the clinician to extract information from medication product labeling regarding the frequency with which certain adverse reactions can be expected. This supplements, but does not replace, information reported directly in clinical trial reports.
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Aripiprazole (intramuscular) for psychosis-induced aggression or agitation (rapid tranquillisation).
Ostinelli, Edoardo G; Jajawi, Salwan; Spyridi, Styliani; Sayal, Kamlaj; Jayaram, Mahesh B
2018-01-08
People experiencing psychosis may become aggressive. Antipsychotics, such as aripiprazole in intramuscular form, can be used in such situations. To evaluate the effects of intramuscular aripiprazole in the treatment of psychosis-induced aggression or agitation (rapid tranquillisation). On 11 December 2014 and 11 April 2017, we searched the Cochrane Schizophrenia Group's Study-based Register of Trials which is based on regular searches of CINAHL, BIOSIS, AMED, Embase, PubMed, MEDLINE, PsycINFO, and registries of clinical trials. All randomised controlled trials (RCTs) that randomised people with psychosis-induced aggression or agitation to receive either intramuscular aripiprazole or another intramuscular intervention. We independently inspected citations and, where possible, abstracts, ordered papers and re-inspected and quality assessed these. We included studies that met our selection criteria. At least two review authors independently extracted data from the included studies. We chose a fixed-effect model. We analysed dichotomous data using risk ratio (RR) and the 95% confidence intervals (CI). We analysed continuous data using mean differences (MD) and their CIs. We assessed risk of bias for included studies and used GRADE to create 'Summary of findings' tables. Searching found 63 records referring to 21 possible trials. We could only include three studies, all completed over the last decade, with 885 participants, of which 707 were included for quantitative analyses in this systematic review. Due to limited comparisons, small size of trials and a paucity of investigated and reported 'pragmatic' outcomes, evidence was mostly graded as low or very low quality. No trials reported useful data for one of our primary outcomes of tranquil or asleep by 30 minutes. Economic outcomes were also not reported in the trials.When compared with placebo, fewer people in the aripiprazole group needed additional injections compared to the placebo group (2 RCTs, n = 382, RR 0.69, 95% CI 0.56 to 0.85, very low-quality evidence). Clinically important improvement in agitation at two hours favoured the aripiprazole group (2 RCTs, n = 382, RR 1.50, 95% CI 1.17 to 1.92, very low-quality evidence). The numbers of non-responders after the first injection also favoured aripiprazole (1 RCT, n = 263, RR 0.49, 95% CI 0.34 to 0.71, low-quality evidence). Although no effect was found, more people in the aripiprazole compared to the placebo group experienced adverse effects (1 RCT, n = 117, RR 1.51, 95% CI 0.93 to 2.46, very low-quality evidence).Aripiprazole required more injections compared to haloperidol (2 RCTs, n = 477, RR 1.28, 95% CI 1.00 to 1.63, very low-quality evidence), with no significant difference in agitation (2 RCTs, n = 477, RR 0.94, 95% CI 0.80 to 1.11, very low-quality evidence), and similar non-responders after first injection (1 RCT, n = 360, RR 1.18, 95% CI 0.78 to 1.79, low-quality evidence). Aripiprazole and haloperidol did not differ when taking into account the overall number of people that experienced at least one adverse effect (1 RCT, n = 113, RR 0.91, 95% CI 0.61 to 1.35, very low-quality evidence).Compared to aripiprazole, olanzapine was better at reducing agitation (1 RCT, n = 80, RR 0.77, 95% CI 0.60 to 0.99, low-quality evidence) and had a more favourable effect on global state change scores (1 RCT, n = 80, MD 0.58, 95% CI 0.01 to 1.15, low-quality evidence), both at two hours. No differences were found in terms of experiencing at least one adverse effect during the 24 hours after treatment (1 RCT, n = 80, RR 0.75, 95% CI 0.45 to 1.24, very low-quality evidence). However, participants allocated to aripiprazole experienced less somnolence (1 RCT, n = 80, RR 0.25, 95% CI 0.08 to 0.82, low-quality evidence). The available evidence is of poor quality but there is some evidence aripiprazole is effective compared to placebo and haloperidol, but not when compared to olanzapine. However, considering that evidence comes from only three studies, caution is required in generalising these results to real-world practice. This review firmly highlights the need for more high-quality trials on intramuscular aripiprazole in the management of people with acute aggression or agitation.
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Kishi, Taro; Matsuda, Yuki; Iwata, Nakao
2014-01-01
The present study aimed to evaluate cardiometabolic risks [weight gain, blood lipid levels (total cholesterol and triglycerides), blood glucose levels, hemoglobin A1c (HbA1c) levels, and corrected QT interval (QTc) prolongation] associated with the use of blonanserin and perospirone versus other antipsychotics in the management of patients with schizophrenia. We conducted a systematic review and meta-analysis of patient data from randomized controlled trials comparing blonanserin or perospirone with other antipsychotics. In total, 4 blonanserin studies (n = 1080) were identified [vs. risperidone (2 studies, n = 508); vs. haloperidol (2 studies, n = 572)]. Blonanserin produced less weight gain compared with risperidone (weighted mean difference = -0.86, 95% confidence intervals = -1.36 to -0.36, p = 0.0008; 2 studies, 480 patients). However, no significant differences were observed in blood lipid, glucose, and HbA1c levels or QTc prolongation between blonanserin and risperidone or haloperidol. For perospirone studies, 5 studies [562 adult patients with schizophrenia randomized to perospirone (n = 256), olanzapine (n = 20), quetiapine (n = 28), risperidone (n = 53), aripiprazole (n = 49), haloperidol (n = 75), or mosapramine (n = 81)] were identified. Perospirone did not differ from other antipsychotics with regard to weight gain and total cholesterol levels. Our results suggest that blonanserin is associated with a lower of weight gain compared with other antipsychotics. Because the number of studies was small, additional controlled clinical trials with larger number of patients are indicated.
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Savoy, Yvette E.; Ashton, Michael A.; Miller, Matthew W.; Nedza, Frank M.; Spracklin, Douglas K.; Hawthorn, Mark H.; Rollema, Hans; Matos, F. Fatima; Hajos-Korcsok, Eva
2010-01-01
Atypical antipsychotic treatment has been associated with serious metabolic adverse events, such as glucose dysregulation and development of type 2 diabetes. As part of our studies on possible underlying mechanisms, we investigated the acute effects of various typical and atypical antipsychotics on plasma glucose and insulin in FVB/N mice, a strain that showed a more pronounced hyperglycemic response to clozapine than C57BL/6 and CD-1 mice. Acute administration of high doses of clozapine, olanzapine, quetiapine, perphenazine, or chlorpromazine significantly increased plasma glucose by 100%–140% above basal levels without significant effects on insulin levels. In contrast, risperidone reduced plasma glucose (−30%) and markedly enhanced plasma insulin levels. Doses of ziprasidone that gave 50-fold higher free plasma concentrations than therapeutic plasma levels, as well as high doses of aripiprazole and haloperidol, did not significantly alter either glucose or insulin levels. Clozapine- and olanzapine-induced hyperglycemia occurred at free plasma concentrations that were within, or one order of magnitude above, the range of therapeutic plasma levels. Pretreatment with either the ganglionic blocker hexamethonium, or the α2 adrenergic receptor antagonist yohimbine, blocked the clozapine- and chlorpromazine-induced increase in glucose levels. Taken together, these results suggest that typical and atypical antipsychotics with known metabolic liability produce acute hyperglycemia in mice and that this effect is likely driven by activation of the sympathetic autonomic nervous system via a central mechanism. PMID:18703666
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Takekita, Yoshiteru; Fabbri, Chiara; Kato, Masaki; Nonen, Shinpei; Sakai, Shiho; Sunada, Naotaka; Koshikawa, Yosuke; Wakeno, Masataka; Okugawa, Gaku; Kinoshita, Toshihiko; Serretti, Alessandro
2015-06-01
Individual differences in serotonin 1A (5-HT1A) receptor may result in variable response to antipsychotics with 5-HT1A receptor partial agonism. We investigated the relationship between 5-HT1A receptor gene (HTR1A) single nucleotide polymorphisms (SNPs) and efficacy of antipsychotics with 5-HT1A receptor partial agonism in Japanese patients with schizophrenia. Perospirone or aripiprazole was administered to 100 patients with schizophrenia in a randomized controlled study. Candidate SNPs were rs6295 (which affects HTR1A expression and function), rs1364043, rs878567, and rs10042486. Efficacy at week 12 of treatment was evaluated using the Positive and Negative Syndrome Scale (PANSS) 5-factor subscales (excitement/hostility, depression/anxiety, cognition, positive, and negative). Rs1364043 T allele was correlated with the percent change in the PANSS 5-factor negative score (P < 0.01). Haplotype analysis showed that the rs10042486-rs6295-rs1364043 T-C-G haplotype was correlated with worse negative score improvement (haplotype frequency, 0.675; P = 0.014), and the relatively rare T-G-T haplotype correlated with better efficacy (haplotype frequency, 0.05; P = 0.031). This is the first study to show that rs10042486-rs6295-rs1364043 HTR1A variants may be correlated with the improvement of the PANSS 5-factor negative score during treatment with 5-HT1A partial agonist antipsychotics. Studies with larger sample sizes and in different ethnic groups are warranted.
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Mohamed, Somaia; Johnson, Gary R; Vertrees, Julia E; Guarino, Peter D; Weingart, Kimberly; Young, Ilanit Tal; Yoon, Jean; Gleason, Theresa C; Kirkwood, Katherine A; Kilbourne, Amy M; Gerrity, Martha; Marder, Stephen; Biswas, Kousick; Hicks, Paul; Davis, Lori L; Chen, Peijun; Kelada, AlexandraMary; Huang, Grant D; Lawrence, David D; LeGwin, Mary; Zisook, Sidney
2015-10-30
Because two-thirds of patients with Major Depressive Disorder do not achieve remission with their first antidepressant, we designed a trial of three "next-step" strategies: switching to another antidepressant (bupropion-SR) or augmenting the current antidepressant with either another antidepressant (bupropion-SR) or with an atypical antipsychotic (aripiprazole). The study will compare 12-week remission rates and, among those who have at least a partial response, relapse rates for up to 6 months of additional treatment. We review seven key efficacy/effectiveness design decisions in this mixed "efficacy-effectiveness" trial. Copyright © 2015. Published by Elsevier Ireland Ltd.
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Druais, Sylvain; Doutriaux, Agathe; Cognet, Magali; Godet, Annabelle; Lançon, Christophe; Levy, Pierre; Samalin, Ludovic; Guillon, Pascal
2016-04-01
French clinical recommendations suggest prescribing long-acting injectable (LAI) antipsychotics to patients with a maintenance treatment indication in schizophrenia. Despite this, and due to their relatively high acquisition and administration costs, LAIs are still underused in clinical practice in France, thus highlighting the need for pharmacoeconomic evaluations. Our objective was to estimate the cost effectiveness of paliperidone LAI (or paliperidone palmitate), a once-monthly second-generation LAI antipsychotic, compared with the most common antipsychotic medications for the maintenance treatment of schizophrenia in France. A Markov model was developed to simulate the progression of a cohort of schizophrenic patients through four health states (stable treated, stable non-treated, relapse and death) and to consider up to three lines of treatment to account for changes in treatment management. Paliperidone LAI was compared with risperidone LAI, aripiprazole LAI, olanzapine LAI, haloperidol LAI (or haloperidol decanoate) and oral olanzapine. Costs, quality-adjusted life-years (QALYs) and number of relapses were assessed over 5 years based on 3-month cycles with a discount rate of 4% and from a French health insurance perspective. Patients were considered to be stabilised after a schizophrenic episode and would enter the model at an initiation phase, followed by a prevention of relapse phase if successful. Data (e.g. relapse or discontinuation rates) for the initiation phase came from randomised clinical trials, whereas relapse rates in the prevention phase were derived from hospitalisation risks based on real-life French data to capture adherence effects. Safety and utility data were derived from international publications. Additionally, costs were retrieved from French health insurance databases and publications. Finally, expert opinion was used for validation purposes or in case of gaps in data. The robustness of results was assessed through deterministic and probabilistic sensitivity analyses. All LAI antipsychotics were found to have similar costs over 5 years: approximatively €55,000, except for paliperidone LAI which had a discounted cost of €50,880. Oral olanzapine was less costly than LAIs (i.e. €50,379 after 5 years) but was associated with fewer QALYs gained and relapses avoided. Paliperidone LAI dominated aripiprazole LAI, olanzapine LAI and haloperidol LAI in terms of costs per QALY, and it was associated with slightly fewer QALYs when compared with risperidone LAI (i.e. 3.763 vs 3.764). This resulted in a high incremental cost-effectiveness ratio (ICER) (i.e. €4,770,018 per QALY gained) for risperidone LAI compared with paliperidone LAI. Paliperidone LAI was more costly than olanzapine oral but associated with more QALYs (i.e. ICER of €2411 per QALY gained for paliperidone LAI compared with oral olanzapine). Paliperidone LAI had a probability of being the optimal strategy in more than 50% of cases for a willingness-to-pay threshold of €8000 per QALY gained. This analysis, to the best of our knowledge, is the first of its kind to assess the cost effectiveness of antipsychotics based on French observational data. Paliperidone LAI appeared to be a cost-effective option in the treatment of schizophrenia from the French health insurance perspective.
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Sevak, Rajkumar J.; Vansickel, Andrea R.; Stoops, William W.; Glaser, Paul E. A.; Hays, Lon R.; Rush, Craig R.
2013-01-01
Methamphetamine is thought to produce its behavioral effects by releasing dopamine (DA), serotonin (5-HT) and norepinephrine. Results from animal studies support this notion, while results from human laboratory studies have not consistently demonstrated the importance of monoamine systems in the behavioral effects of methamphetamine. Human laboratory procedures of drug-discrimination are well suited to assess neuropharmacological mechanisms of the training drug by studying pharmacological manipulation. In this human laboratory study, six participants with a history of recreational stimulant use learned to discriminate 10 mg oral methamphetamine. After acquiring the discrimination (i.e., ≥80% correct responding on 4 consecutive sessions), the effects of a range of doses of methamphetamine (0, 2.5, 5, 10 and 15 mg), alone and in combination with 0 and 20 mg aripiprazole (a partial agonist at D2 and 5-HT1A receptors), were assessed. Methamphetamine alone functioned as a discriminative stimulus, produced prototypical stimulant-like subject-rated drug effects (e.g., increased ratings of Good Effects, Talkative-Friendly, and Willing to Pay For) and elevated cardiovascular indices. These effects were generally a function of dose. Aripiprazole alone did not occasion methamphetamine-appropriate responding or produce subject-rated effects, but modestly impaired performance. Administration of aripiprazole significantly attenuated the discriminative-stimulus and cardiovascular effects of methamphetamine, as well as some of the subject-rated drug effects. These results indicate that monoamine systems likely play a role in the behavioral effects of methamphetamine in humans. Moreover, given the concordance between past results with d-amphetamine and the present findings, d-amphetamine can likely serve as a model for the pharmacological effects of methamphetamine. PMID:21694622
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Paradoxes of evidence in Russian addiction medicine.
Mendelevich, V D; Zalmunin, K Yu
2015-01-01
For many years, clinical protocols for treatment of drug abuse patients and treatment standards in Russian Federation were not grounded on the principles of evidence-based medicine [1]. Recommendations for use of certain drugs were not accompanied by any indication of the level of credibility of the evidence supporting it. The appearance in 2014 of such indications in clinical recommendations can be considered a significant step forward for the science of addiction medicine [2]. To compare Russian evidence and practice in addiction medicines with international standards. Situation and literature analysis. The analysis shows that in the wording of recommendations on the use of medicines, some were subject of serious methodological errors. For some drugs globally there is high quality evidence supporting effects of certain drugs globally, but this is not recognized in Russia. As a result, Russian standards of clinical care for the treatment of dependency syndrome are radically different to the standards of therapy, presented in the WHO recommendations. This is due both to the disregard of the meta-analyses presented in the Cochrane reviews and also to the specific bioethical preferences in drug treatment in Russia.It is known that there is no convincing data on the effectiveness and safety of antipsychotics in the treatment of alcohol dependence syndrome [3]. 13 randomized trials with a double blind placebo-controlled design involving 1593 patients assessing effects of amisulpride, aripiprazole, flupentixolum dekonoat, olanzapine, quetiapine, tiapride showed that antipsychotics do not result in abstinence, do not reduce abuse and do not stop craving in alcoholic patients: "Antipsychotics should not be used in patients with a primary diagnosis of dependence. Appointment of antipsychotics for the treatment of substance abuse disorders are contraindicated, since not only does it not improve the condition of patients, but it can even worsen the course of the disease, leading to a reduction in the duration and quality of the remission, and is fraught with serious side effects that threaten the health of patients."SSRI antidepressants indirectly improve the results of treatment of comorbid alcoholism in depressed patients, without affecting alcohol dependence per se. Also, there is currently no convincing evidence of the efficacy of anticonvulsants in the treatment of dependence syndrome, particularly alcohol.Despite the fact that traditional psychotherapeutic interventions remain widespread in practice, and treatment of alcohol dependence syndrome showed high efficiency, there is no convincing evidence for long-term benefits as opposed to short-term benefits.The Cochrane Review with data based on 146 scientific studies involving 21,404 patients confirmed the effectiveness of opioid receptor agonists in treatment of opioid dependence. This therapy showed a statistically significant reduction in the use of illegal drugs, HIV transmission and risky sexual behavior, and was significantly more effective compared to the conventional maintenance therapy with opioid receptor antagonists. In countries, where law prohibits prescribing and use of opioid agonists for opioid dependence treatment, the drugs of choice are antagonists.A meta-analysis of thirteen randomized placebo-controlled trials of oral form of naltrexone (1158 subjects), did not show any advantages of this type of treatment both for management and prevention of relapse compared with placebo [4]. Special studies also showed no inclination to reduce the use of opiates in patients receiving naltrexone [5]. However, studies carried out in Russia, showed the best results for daily intake of naltrexone after detoxification, which increased the duration of remission [6]. It was noted that the effect is associated with higher levels of adherence and family support in the examined population.An overview based on controlled clinical studies on the use of antipsychotic drugs (neuroleptics) in patients dependent on opioids revealed no evidence of effectiveness of this approach. It was concluded that the use of antipsychotics is justified only in the presence of co-morbid psychiatric problems in patients [7]. In a recent meta-analytic review on the use of atypical antipsychotics for off-label indications (off-label), there was a lack of data to support the effectiveness of their use in substance abuse [8, 9]. The effectiveness of anticonvulsants in the treatment of opioid dependence syndrome has not been proven.In connection with the above puzzling fact, for Russian standards of treatment (clinical guidelines) the level of credibility of the effectiveness of antipsychotics and antidepressants in treatment of substance abuse is assessed as A or B. This paradox raises the question of the methodology for determining the level of credibility of evidence. It should be noted that Russian recommendations for inclusion of certain drugs and therapies are based on sufficient consensus of experts rather than on the results of meta-analyses [2]. This fact casts doubt on credibility and validity of scientific recommendations. Thus, one may say that Russian addiction medicine is not based on evidence, which is, in our view, erroneous and may impair the quality of care.
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Penzner, Julie B.; Dudas, Melissa; Saito, Ema; Olshanskiy, Vladimir; Parikh, Umesh H.; Kapoor, Sandeep; Chekuri, Raja; Gadaleta, Dominick; Avedon, Jennifer; Sheridan, Eva M.; Randell, Jane; Malhotra, Anil K.; Kane, John M.
2009-01-01
Abstract Background Second-generation antipsychotics (SGAs) are associated with weight gain, metabolic abnormalities, sedation/sleep disturbance, and prolactin abnormalities, especially in youths. Although stimulants have opposing dopamine receptor and adverse effects, it is unclear whether stimulant co-treatment counteracts the therapeutic or side effects of antipsychotics. Methods This was a naturalistic cohort study including 153 antipsychotic trials in youths aged 4–19 (mean, 11.3 ± 3.0) years, started on an SGA for clinically significant aggression or oppositionality associated with oppositional defiant disorder, conduct disorder, disruptive behavior disorder not otherwise specified (NOS), impulse control disorder NOS, intermittent explosive disorder, Tourette's disorder, autistic disorder, and pervasive developmental disorder NOS. Patients underwent fasting assessments of body composition, lipids, glucose, insulin, prolactin, sedation, and general efficacy at baseline, weeks 4, 8, and 12, comparing patients co-prescribed stimulants (n = 71) with those not co-prescribed stimulants (n = 82). Results Patients received risperidone (33.3%), aripiprazole (29.4%), quetiapine (18.4%), olanzapine (11.8%), ziprasidone (5.9%), or clozapine (0.7%). With and without adjustment for differences in baseline variables (sex, prior stimulant use, primary Diagnostic and Statistical Manual of Mental Disorders, 4th edition [DSM-IV] disorders, co-morbid attention-deficit/hyperactivity disorder [ADHD], present in 46.3% of youths not receiving stimulants, and some body composition parameters), patients on versus off stimulants did not differ on any of the assessed outcomes (all p values ≥ 0.1). Conclusions In contrast to guidelines, stimulant use did not precede or accompany antipsychotic use during the current episode of aggression/oppositionality in almost half of those youths who had aggressive/oppositional behavior and a DSM-IV diagnosis of ADHD. At the clinically prescribed doses, stimulant co-treatment of SGAs did not seem to significantly reduce antipsychotic effects on body composition, metabolic parameters, prolactin, sedation, and broad efficacy. PMID:19877981
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Kishi, Taro; Hirota, Tomoya; Matsunaga, Shinji; Iwata, Nakao
2016-07-01
We performed an updated meta-analysis of antipsychotic treatment in patients with delirium, based on a previous meta-analysis published in 2007. Included in this study were randomised, placebo-controlled or usual care (UC) controlled trials of antipsychotics in adult patients with delirium. Our primary outcome measure was response rate at the study end point. The secondary outcome measures included improvement of severity of delirium, Clinical Global Impression-Severity Scale (CGI-S), time to response (TTR), discontinuation rate and individual adverse effects. The risk ratio (RR), the number-needed-to-treat/harm (NNT/NNH), 95% CIs and standardised mean difference (SMD), were calculated. We identified 15 studies (mean duration: 9.8 days) for the systematic review (total n=949, amisulpride=20, aripiprazole=8, chlorpromazine=13, haloperidol=316, intramuscular olanzapine or haloperidol injection=62, olanzapine=144, placebo=75, quetiapine=125, risperidone=124, UC=30 and ziprasidone=32), 4 of which were conference abstracts and unpublished. When pooled as a group, antipsychotics were superior to placebo/UC in terms of response rate (RR=0.22, NNT=2), delirium severity scales scores (SMD=-1.27), CGI-S scores (SMD=-1.57) and TTR (SMD=-1.22). The pooled antipsychotic group was associated with a higher incidence of dry mouth (RR=13.0, NNH=5) and sedation (RR=4.59, NNH=5) compared with placebo/UC. Pooled second-generation antipsychotics (SGAs) were associated with shorter TTR (SMD=-0.27) and a lower incidence of extrapyramidal symptoms (RR=0.31, NNH=7) compared with haloperidol. Our results suggested that SGAs have a benefit for the treatment of delirium with regard to efficacy and safety compared with haloperidol. However, further study using larger samples is required. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
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Anand, Ravi; Hartman, Richard; Graham, Stephen; Forrest, Emma; Faravelli, Laura
2017-01-01
Abstract Background: Increasing evidence implicates hippocampal hyperactivity and glutamatergic (Glu) dysfunction in the dysregulation of excitatory and inhibitory circuits leading to positive/negative symptoms and cognitive deficits associated with schizophrenia (SCZ). Existing antipsychotic drugs that target dopaminergic/serotoninergic (DA/5-HT) transmission are associated with a large proportion of patients experiencing inadequate therapeutic benefit. Evenamide, a new, highly selective, voltage-gated Na+ channel antagonist, reduces hyperexcitability, inhibits Glu release, and shows antipsychotic efficacy in multiple animal models of psychiatric disease in monotherapy and as an add-on to 1st and 2nd generation antipsychotics. Addition of evenamide to marketed antipsychotics would lead to reduction of hippocampal hyperactivity and Glu dysfunction, with modulation of mesolimbic and mesocortical DA/5-HT activity, thus providing unique benefits. Methods: This double-blind, 28-day, placebo-controlled, Phase 2 study evaluated safety, tolerability, and preliminary evidence of efficacy of evenamide as an add-on to a stable dose of risperidone or aripiprazole in SCZ outpatients. Selected patients (CGI-Severity of mild to moderately severe; PANSS total score <80) received placebo or evenamide (15–25 mg bid). Dose escalation from 15–20 to 25 mg bid was done weekly in an inpatient setting, based on tolerability. These doses are associated with plasma levels that overlap exposures (>20 ng/ml) measured at effective doses in animal models. Evaluations of vital signs, ECGs, extra-pyramidal symptom (EPS), and laboratory tests were performed weekly, and plasma levels of evenamide were measured at each dose level to determine PK–PD relationships. Preliminary evidence of efficacy was assessed by changes from baseline on the PANSS total score, CGI-Severity and Change, and the Strauss-Carpenter Level of Functioning scale. Results: Ninety patients were randomized at 5 centers (United States-2; India-3). Most patients tolerated evenamide, based on an absence of severe side-effects, as well as the high proportion of patients able to achieve and maintain the highest dose level. There are no reports of EPS, sedation, weight gain, cardiac changes, or sexual dysfunction. Conclusion: Despite the lack of interactions with DA/5-HT systems, evenamide improves positive/negative symptoms in preclinical models of psychiatric diseases, independent of the stimulus used to produce the perturbation. The combination of evenamide as an add-on to marketed antipsychotics in patients showing inadequate response would combine reduction of aberrant electrical activity and Glu transmission, with blockade of 5HT2/D2 receptors, thus producing a novel therapeutic option. Results from the Phase II trial will be presented.
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Ahmed, Zia; Subhan, Fazal; Ahmed, Saba; Abdur Rasheed, Qazi; Ahmed, Sagheer; Shahid, Muhammad; Farooq, Saeed
2016-09-01
A vast majority of psychiatric patients are effectively treated with combination of drugs to improve efficacy and adherence, but due to limited research and development in fixed dose combination (FDC) in psychiatry, these products are not commonly available. The aim of this study is to prepare cost effective FDC tablets containing aripiprazole and divalproex sodium. Two batches of fixed dose combination tablets, FDC1 and FDC2, were successfully prepared using wet granulation technique. Furthermore, aripiprazole tablets A1 and A2 and divalproex tablets D1 were also formulated as reference to compare the in vitro availability profile. An accurate and simple isocratic HPLC method was established and validated for the simultaneous quantification of aripiprazole and valproic acid in the FDC tablets. A reversed-phase C18 (250 × 4.6 mm) column in isocratic mode was used. The mobile phase consisted of acetonitrile and 0.32% KH2PO4 (60:40, v/v), flow rate was set at 1.0 mL/min and the detection was performed at 210 nm. Average percent recoveries of aripiprazole and valproic acid were 96.0 and 95.5%, respectively, meeting the official requirements. The newly developed FDC product may be used for the better therapeutic outcomes of combined use of aripiprazole and valproic acid, which may improve patient adherence.
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3D printed orodispersible films with Aripiprazole.
Jamróz, Witold; Kurek, Mateusz; Łyszczarz, Ewelina; Szafraniec, Joanna; Knapik-Kowalczuk, Justyna; Syrek, Karolina; Paluch, Marian; Jachowicz, Renata
2017-11-30
Three dimensional printing technology is gaining in importance because of its increasing availability and wide applications. One of the three dimensional printing techniques is Fused Deposition Modelling (FDM) which works on the basis of hot melt extrusion-well known in the pharmaceutical technology. Combination of fused deposition modelling with preparation of the orodispersible film with poorly water soluble substance such as aripiprazole seems to be extra advantageous in terms of dissolution rate. 3D printed as well as casted films were compared in terms of physicochemical and mechanical properties. Moreover, drug-free films were prepared to evaluate the impact of the extrusion process and aripiprazole presence on the film properties. X-ray diffractometry and thermal analyses confirmed transition of aripiprazole into amorphous state during film preparation using 3D printing technique. Amorphization of the aripiprazole and porous structure of printed film led to increased dissolution rate in comparison to casted films, which, however have slightly better mechanical properties due to their continuous structure. It can be concluded that fused deposition modelling is suitable technique and polyvinyl alcohol is applicable polymer for orodispersible films preparation. Copyright © 2017 Elsevier B.V. All rights reserved.
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Psychotropic Polypharmacy in Patients with Dementia: Prevalence and Predictors.
Nørgaard, Ane; Jensen-Dahm, Christina; Gasse, Christiane; Hansen, Elsebet Steno; Waldemar, Gunhild
2017-01-01
Antipsychotics and other psychotropics are frequently used to treat neuropsychiatric symptoms in patients with dementia, even though the evidence for effect is limited. Concerns have been raised about the safety of antipsychotics, but concomitant use of multiple psychotropic drug classes (psychotropic polypharmacy) may also pose a risk for patients. To investigate the prevalence and predictors associated with use of psychotropic polypharmacy in patients with dementia. A population-based study using nationwide registers. Patients with dementia were identified among all Danish residents ≥65 years on January 1, 2012. Data on prescriptions and comorbidity was included in the analysis. Overlapping prescriptions for different psychotropic drug classes were used to determine psychotropic polypharmacy. A multivariable logistic regression analysis was conducted to evaluate factors independently associated with the prescription of other psychotropic drug classes among patients already using antipsychotics. Among all patients registered with dementia (34,553), 25.3% (8,728) used ≥2 psychotropic drugs. Among patients treated with antipsychotics 75.8% (5,403) used at least one other psychotropic drug during the antipsychotic treatment period. Nursing home residency, number of non-psychotropic medications used in 2011, and prior psychiatric diagnosis were associated with psychotropic polypharmacy among antipsychotic drug users. The most frequent combination of psychotropic drugs was antipsychotics and antidepressants. Concomitant use of psychotropic drugs was frequent in dementia patients. Patients living in nursing homes had the highest risk of receiving a combination of antipsychotics and other psychotropic drugs. Concomitant use of psychotropics may cause adverse events, and potential consequences for patients' safety call for further investigation.
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Sudden cardiac death secondary to antidepressant and antipsychotic drugs
Sicouri, Serge; Antzelevitch, Charles
2008-01-01
A number of antipsychotic and antidepressant drugs are known to increase the risk of ventricular arrhythmias and sudden cardiac death. Based largely on a concern over QT prolongation and the development of life-threatening arrhythmias, a number of antipsychotic drugs have been temporarily or permanently withdrawn from the market or their use restricted. Some antidepressants and antipsychotics have been linked to QT prolongation and the development of Torsade de pointes arrhythmias, whereas others have been associated with a Brugada syndrome phenotype and the development of polymorphic ventricular arrhythmias. This review examines the mechanisms and predisposing factors underlying the development of cardiac arrhythmias, and sudden cardiac death, associated with antidepressant and antipsychotic drugs in clinical use. PMID:18324881
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Auclair, Agnès L; Kleven, Mark S; Besnard, Joël; Depoortère, Ronan; Newman-Tancredi, Adrian
2006-09-01
The dopamine D1/D2 agonist apomorphine (0.63 mg/kg) disrupted prepulse inhibition (PPI) of acoustic startle in rats, a model of sensorimotor gating deficits observed in schizophrenia. All current antipsychotics, which antagonize D2 receptors, prevent this apomorphine-induced deficit. A novel class of antipsychotics possesses, in addition to D2 antagonist property, various levels of 5-HT1A agonist activity. Considering that the latter itself produces PPI deficits, it appeared necessary to assess the potential of this novel class of antipsychotics to reverse apomorphine-PPI deficits. Potent D2 antagonists, like haloperidol (0.63-2.5 mg/kg), risperidone (0.63-10 mg/kg), and olanzapine (0.63-40 mg/kg) prevented apomorphine PPI disruption. The atypical antipsychotics, clozapine (40 mg/kg), nemonapride (0.01-2.5 mg/kg), ziprasidone (10 mg/kg), and aripiprazole (0.01 and 10 mg/kg), which all exhibit 5-HT1A agonist properties, reversed PPI deficits at some doses only, whereas the anti-dyskinetic agent sarizotan (0.16-10 mg/kg), an efficacious 5-HT1A agonist, did not. New generation antipsychotics with marked 5-HT1A agonist properties, such as SLV313 and SSR181507 (0.0025-10 mg/kg and 0.16-10 mg/kg, respectively) did not reverse these deficits whereas bifeprunox (0.04-2.5 mg/kg) did. To reveal the contribution of 5-HT1A agonist properties in the lack of effects of SLV313 and SSR181507, we pretreated rats with the 5-HT1A antagonist WAY100635 (0.63 mg/kg). Under these conditions, significant reversal of PPI deficit was observed, indicating that D2 antagonist properties of SLV313 and SSR181507 are now sufficient to overcome the disruptive effects of apomorphine. To summarize, antipsychotics possessing agonist efficacy at 5-HT1A receptors exhibit diverse profiles against apomorphine-induced PPI deficits, depending on the balance between D2 and 5-HT1A activities, suggesting that they may display distinct activity on some aspects of gating deficits in schizophrenic patients.
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Li, Kun-Yan; Zhou, Yan-Gang; Ren, Hua-Yi; Wang, Feng; Zhang, Bi-Kui; Li, Huan-De
2007-05-01
The ultra-performance liquid chromatography-electrospray tandem mass spectrometry (UPLC-ESI-MS/MS) method has been developed to perform the determination of quetiapine, perospirone, aripiprazole and quetiapine sulfoxide in in vitro samples in less than 3 min. The UPLC separation was carried out using an Acquity UPLC BEH C18 column (100 mm x 2.1mm i.d., 1.7 microm particle size) that provided high efficiency and resolution in combination with high linear velocities. The UPLC system was coupled to a Waters Micromass Quattro Premier XE tandem quadrupole mass spectrometer. This system permits high-speed data acquisition without peak intensity degradation, and produces sharp and narrow chromatographic peaks (w(h) about 2.5s) of compounds. The determination was performed in multiple reaction monitoring (MRM) mode. The quantification parameters of the developed method were established, obtaining instrumental LODs lower than 0.005 microg/l and a repeatability at a low concentration level lower than 10% CV (n=10). Finally, the method was successfully applied to the analysis of atypical antipsychotics and some metabolites in in vitro samples.
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de Kuijper, G M; Hoekstra, P J
2017-10-01
People with intellectual disability (ID) frequently use antipsychotic drugs on an off-label base, often for many years. Physicians' decisions to discontinue these drugs not only depend on patient characteristics, like the presence of mental or behavioural disorders, but also on environmental factors, such as inappropriate living circumstances, and on attitudes, knowledge and beliefs of staff, clients and their representatives towards the effects of antipsychotic drug use. In this study, we therefore investigated the influence of participant and setting-related factors on decisions of physicians not to discontinue off-label prescribed antipsychotics. The study took place in living facilities of six service providers for people with ID spread over the Netherlands and staffed with support professionals, nurses, behavioural scientist and physicians and was part of an antipsychotics discontinuation trial. ID physicians had to decide whether the off-label use of antipsychotics could be discontinued. Medical and pharmaceutical records were used to establish the prevalence of antipsychotic drug use in the study population, along with duration of use and whether the use was off-label. Reasons of physicians not to discontinue the prescription of antipsychotics in those participants who used off-label antipsychotics for more than a year were collected and categorised as related to participant or setting characteristics, including lack of consent to discontinue, and staff members, participants or their legal representatives. Of the 3299 clients of the service providers, 977 used one or more antipsychotic drugs. The prevalence of antipsychotic drug use was 30%. Reasons for use were in 5% of cases, a chronic psychotic disorder classified according to Diagnostic System Mental Disorders, Fourth Edition, criteria, in 25%, present or past (suspected) non-schizophrenia-related psychotic symptoms and in 69%, challenging behaviours. Overall, physicians were willing to discontinue their prescriptions in 51% of cases, varying from 22% to 87% per service provider. The odds for decisions of physicians to discontinue off-label prescriptions varied from 0.19 to 13.95 per service provider. The variables 'a living situation with care and support' and 'challenging behaviour' were associated with a higher chance of discontinuation. The main reasons for decisions not to discontinue were concerns for symptoms of restlessness, the presence of an autism spectrum disorder, previously unsuccessful attempts to discontinue and objections against discontinuation of legal representatives. Reasons for physicians' decisions not to discontinue the off-label use of antipsychotics varied largely between the service providers. The prevalence of antipsychotic drug use for off-label indications in people with ID remains high. The results of this study indicate that there is a large variation in clinical practice of physicians regarding discontinuation of long-term antipsychotic drug prescriptions, which may be partially related to environmental factors as setting culture and attitudes of staff towards off-label antipsychotic drug use in persons with ID. © 2017 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.
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Impact of regulatory measures on antipsychotics drug consumption in Castilla y León, Spain.
Martín Arias, L H; Treceño Lobato, C; Pérez García, S; García Ortega, P; Sáinz Gil, M; Sanz Fadrique, R; Carvajal García-Pando, A
2016-12-01
Antipsychotics are currently used to treat different diseases; even some off-labelled conditions are treated with this medication. Consumption and cost of antipsychotic drugs sharply increased in Spain after second-generation drugs were marketed; several regulatory measures were adopted to curb this trend. The aim of this study was to examine the impact of these measures upon the use and cost of antipsychotics. Study of drug use (SDU) from 1995 to 2012. Consumption and cost data were obtained from the CONCYLIA database; this database contains the retail community pharmacies sales of medicinal products reimbursed by the National Health System in Castilla y León (Spain). Data are presented as defined daily doses per 1000 inhabitants per day (DID) and day treatment cost (DTC). First-generation antipsychotics prescriptions gradually decreased from 3.0 to 1.8 DID; meanwhile, prescriptions for second-generation antipsychotics considerably increased from 0.3 to 9.9 DID. The use of risperidone dropped after the marketing of its structural derivative paliperidone with a similar efficacy but with a substantially higher cost per day. In 2011 and thereafter, patients in Spain began to pay a part of the medications cost, but this did not decrease antipsychotics consumption. Global cost of antipsychotics only began to fall after measures were adopted to lower the price of medicines because of the economic collapse in Spain after May 2010. Several health policy measures have tried to reduce antipsychotics consumption in Spain, special ways of dispensing, marketing of generic drugs and special economic measures for patients. These measures eventually failed to avoid the increase in antipsychotics use. The cost only dropped when lowering prescription drug prices took place. Copyright © 2016 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.
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ERIC Educational Resources Information Center
de Kuijper, G.; Hoekstra, P.; Visser, F.; Scholte, F. A.; Penning, C.; Evenhuis, H.
2010-01-01
Background: We investigated antipsychotic drug prescription practice of Dutch ID physicians, studying prevalence of antipsychotic drug use, reasons for prescription and the relationship between these reasons and patient characteristics. Methods: A cross-sectional study of medical and pharmaceutical records in a population living in residential…
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Multiple neurotoxic effects of haloperidol resulting in neuronal death.
Nasrallah, Henry A; Chen, Alexander T
2017-08-01
Several published studies have reported an association between antipsychotic medications, especially first-generation agents, and a decline in gray matter volume. This prompted us to review the possible neurotoxic mechanisms of first-generation antipsychotics (FGAs), especially haloperidol, which has been widely used over the past several decades. A PubMed search was conducted using the keywords haloperidol, antipsychotic, neurotoxicity, apoptosis, oxidative stress, and neuroplasticity. No restrictions were placed on the date of the articles or language. Studies with a clearly described methodology were included. Animal, cell culture, and human tissue studies were identified. Thirty reports met the criteria for the search. All studies included haloperidol; a few also included other FGAs (fluphenazine and perphenazine) and/or second-generation agents (SGAs) (aripiprazole, paliperidone, and risperidone). A neurotoxic effect of haloperidol and other FGAs was a common theme across all studies. Minimal (mainly at high doses) or no neurotoxic effects were noted in SGAs. A review of the literature suggests that haloperidol exerts measurable neurotoxic effects at all doses via many molecular mechanisms that lead to neuronal death. A similar effect was observed in 2 other FGAs, but the effect in SGAs was much smaller and occurred mainly at high doses. A stronger binding to serotonin 5HT-2A receptors than to dopamine D2 receptors may have a neuroprotective effect among SGAs. Further studies are warranted to confirm these findings.
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Osser, David N; Roudsari, Mohsen Jalali; Manschreck, Theo
2013-01-01
This article is an update of the algorithm for schizophrenia from the Psychopharmacology Algorithm Project at the Harvard South Shore Program. A literature review was conducted focusing on new data since the last published version (1999-2001). The first-line treatment recommendation for new-onset schizophrenia is with amisulpride, aripiprazole, risperidone, or ziprasidone for four to six weeks. In some settings the trial could be shorter, considering that evidence of clear improvement with antipsychotics usually occurs within the first two weeks. If the trial of the first antipsychotic cannot be completed due to intolerance, try another until one of the four is tolerated and given an adequate trial. There should be evidence of bioavailability. If the response to this adequate trial is unsatisfactory, try a second monotherapy. If the response to this second adequate trial is also unsatisfactory, and if at least one of the first two trials was with risperidone, olanzapine, or a first-generation (typical) antipsychotic, then clozapine is recommended for the third trial. If neither trial was with any these three options, a third trial prior to clozapine should occur, using one of those three. If the response to monotherapy with clozapine (with dose adjusted by using plasma levels) is unsatisfactory, consider adding risperidone, lamotrigine, or ECT. Beyond that point, there is little solid evidence to support further psychopharmacological treatment choices, though we do review possible options.
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Santos, GM; Das, M; Santos, DM; Huffaker, S; Matheson, T; Gasper, J; Vittinghoff, E; Colfax, GN
2012-01-01
Aims To test aripiprazole for efficacy in decreasing use in methamphetamine-dependent adults, compared to placebo. Design Participants were randomized to receive 12 weeks of aripiprazole or placebo, with a 3 month follow-up and a platform of weekly 30-minute substance abuse counseling. Setting The trial was conducted from January 2009 to March 2012 at the San Francisco Department of Public Health. Participants Ninety actively-using, methamphetamine-dependent, sexually active, adults were recruited from community venues. Measurements The primary outcome was regression estimated reductions in weekly methamphetamine-positive urines. Secondary outcomes were study medication adherence (by self-report and medication event monitoring systems [MEMS]), sexual risk behavior, and abstinence from methamphetamine. Findings Participant mean age was 38.7 years, 87.8% were male, 50.0% white, 18.9% African-American, and 16.7% Latino. Eighty-three percent of follow-up visits and final visits were completed. By intent-to-treat, participants assigned to aripiprazole had similar reductions in methamphetamine-positive urines as participants assigned to placebo (RR 0.88, 95% CI 0.66–1.19, P=0.41). Urine positivity declined from 73%(33/45 participants) to 45%(18/40) in the placebo arm, and from 77% (34/44) to 44% (20/35) in the aripiprazole arm. Adherence by MEMS and self-report was 42% and 74%, respectively, with no significant difference between arms (MEMS P=0.31; self-report P=0.17). Most sexual risk behaviors declined similarly among participants in both arms (all P>0.05). There were no serious adverse events related to study drug, although participants randomized to aripiprazole reported more akathisia, fatigue, and drowsiness (P<0.05). Conclusion Compared with placebo, aripiprazole did not significantly reduce methamphetamine use among actively-using, dependent adults. PMID:23186131
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Shin, Sangho; Kim, Seoyoung; Seo, Seongho; Lee, Jae Sung; Howes, Oliver D; Kim, Euitae; Kwon, Jun Soo
2018-04-24
Aripiprazole's effects on cognitive function in patients with schizophrenia are unclear because of the difficulty in disentangling specific effects on cognitive function from secondary effects due to the improvement in other schizophrenic symptoms. One approach to address this is to use an intermediate biomarker to investigate the relationship between the drug's effect on the brain and change in cognitive function. This study aims to investigate aripiprazole's effect on working memory by determining the correlation between dopamine D2/3 (D2/3) receptor occupancy and working memory of patients with schizophrenia. Seven patients with schizophrenia participated in the study. Serial positron emission tomography (PET) scans with [ 11 C]raclopride were conducted at 2, 26, and 74 h after the administration of aripiprazole. The subjects performed the N-back task just after finishing the [ 11 C]raclopride PET scan. The mean (±SD) D2/3 receptor occupancies were 66.9 ± 6.7% at 2 h, 65.0 ± 8.6% at 26, and 57.7 ± 11.2% at 74 h after administering aripiprazole. Compared with performance on the zero-back condition, performance in memory-loaded conditions (one-, two-, and three-back conditions) was significantly related to D2/3 receptor occupancy by aripiprazole (error rate: ß = -2.236, t = -6.631, df = 53.947, and p = 0.001; reaction time: ß = -9.567, t = -2.808, df = 29.967, and p = 0.009). Although the sample size was relatively small, these results suggest that aripiprazole as a dopamine-partial agonist could improve cognitive function in patients with schizophrenia.
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Cheon, Eun-Jin; Lee, Kwang-Hun; Park, Young-Woo; Lee, Jong-Hun; Koo, Bon-Hoon; Lee, Seung-Jae; Sung, Hyung-Mo
2017-04-01
The purpose of this study was to compare the efficacy and safety of aripiprazole versus bupropion augmentation in patients with major depressive disorder (MDD) unresponsive to selective serotonin reuptake inhibitors (SSRIs). This is the first randomized, prospective, open-label, direct comparison study between aripiprazole and bupropion augmentation. Participants had at least moderately severe depressive symptoms after 4 weeks or more of SSRI treatment. A total of 103 patients were randomized to either aripiprazole (n = 56) or bupropion (n = 47) augmentation for 6 weeks. Concomitant use of psychotropic agents was prohibited. Montgomery Asberg Depression Rating Scale, 17-item Hamilton Depression Rating scale, Iowa Fatigue Scale, Drug-Induced Extrapyramidal Symptoms Scale, Psychotropic-Related Sexual Dysfunction Questionnaire scores were obtained at baseline and after 1, 2, 4, and 6 weeks of treatment. Overall, both treatments significantly improved depressive symptoms without causing serious adverse events. There were no significant differences in the Montgomery Asberg Depression Rating Scale, 17-item Hamilton Depression Rating scale, and Iowa Fatigue Scale scores, and response rates. However, significant differences in remission rates between the 2 groups were evident at week 6 (55.4% vs 34.0%, respectively; P = 0.031), favoring aripiprazole over bupropion. There were no significant differences in adverse sexual events, extrapyramidal symptoms, or akathisia between the 2 groups. The present study suggests that aripiprazole augmentation is at least comparable to bupropion augmentation in combination with SSRI in terms of efficacy and tolerability in patients with MDD. Both aripiprazole and bupropion could help reduce sexual dysfunction and fatigue in patients with MDD. Aripiprazole and bupropion may offer effective and safe augmentation strategies in patients with MDD who are unresponsive to SSRIs. Double-blinded trials are warranted to confirm the present findings.
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Kolotkin, Ronette L; Corey-Lisle, Patricia K; Crosby, Ross D; Kan, Hong J; McQuade, Robert D
2008-12-01
This is a secondary analysis of clinical trial data collected in 12 European countries. We examined changes in weight and weight-related quality of life among community patients with schizophrenia treated with aripiprazole (ARI) versus standard of care (SOC), consisting of other marketed atypical antipsychotics (olanzapine, quetiapine, and risperidone). Five-hundred and fifty-five patients whose clinical symptoms were not optimally controlled and/or experienced tolerability problems with current medication were randomized to ARI (10-30 mg/day) or SOC. Weight and weight-related quality of life (using the IWQOL-Lite) were assessed at baseline, and weeks 8, 18 and 26. Random regression analysis across all time points using all available data was used to compare groups on changes in weight and IWQOL-Lite. Meaningful change from baseline was also assessed. Participants were 59.7% male, with a mean age of 38.5 years (SD 10.9) and mean baseline body mass index of 27.2 (SD 5.1). ARI participants lost an average of 1.7% of baseline weight in comparison to a gain of 2.1% by SOC participants (p<0.0001) at 26 weeks. ARI participants experienced significantly greater increases in physical function, self-esteem, sexual life, and IWQOL-Lite total score. At 26 weeks, 20.7% of ARI participants experienced meaningful improvements in IWQOL-Lite score, versus 13.5% of SOC participants. A clinically meaningful change in weight was also associated with a meaningful change in quality of life (p<0.001). A potential limitation of this study was its funding by a pharmaceutical company. Compared to standard of care, patients with schizophrenia treated with aripiprazole experienced decreased weight and improved weight-related quality of life over 26 weeks. These changes were both statistically and clinically significant.
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Atypical Antipsychotic Drugs and the Risk of Sudden Cardiac Death
Ray, Wayne A.; Chung, Cecilia P.; Murray, Katherine T.; Hall, Kathi; Stein, C. Michael
2009-01-01
Background Users of typical antipsychotics have increased risk of serious ventricular arrhythmias and sudden cardiac death. However, less is known regarding the cardiac safety of the atypical antipsychotic drugs, which have largely replaced the older agents in clinical practice. Methods We calculated the adjusted incidence of sudden cardiac death among current users of antipsychotics in a retrospective cohort of Tennessee Medicaid enrollees. The primary analysis included 44,218 and 46,089 baseline users of single typical and atypical drugs, respectively, and 186,600 matched nonuser controls. To assess residual confounding related to antipsychotic indication, we performed a secondary analysis of antipsychotic users with no baseline diagnosis of schizophrenia or related psychoses, propensity-score matched with nonusers. Results Current users of both typical and atypical antipsychotics had greater rates of sudden cardiac death than did nonusers of any antipsychotic, with adjusted incidence-rate ratios (IRRs) of 2.00 (95% CI, 1.69–2.35) and 2.27 (1.89–2.73), respectively. Former antipsychotic users had no significantly increased risk (IRR = 1.13 [0.98–1.30]). For both classes of drugs, the risk for current users increased significantly with dose. For typical antipsychotics the IRRs increased from 1.31 (0.97–1.77) for low doses to 2.42 (1.91–3.06) for high doses (p<.001). For atypical agents the IRRs increased from 1.59 (1.03–2.46) for low doses to 2.86 (2.25–3.65) for high doses (p=.015). The IRR for atypical vs typical antipsychotics was 1.14 (.93–1.39). Similar findings were present in the propensity-score matched cohort. Conclusion Current users of both typical and atypical antipsychotics had a similar, dose-related increased risk of sudden cardiac death. PMID:19144938
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Repurposing psychiatric drugs as anti-cancer agents.
Huang, Jing; Zhao, Danwei; Liu, Zhixiong; Liu, Fangkun
2018-04-10
Cancer is a major public health problem and one of the leading contributors to the global disease burden. The high cost of development of new drugs and the increasingly severe burden of cancer globally have led to increased interest in the search and development of novel, affordable anti-neoplastic medications. Antipsychotic drugs have a long history of clinical use and tolerable safety; they have been used as good targets for drug repurposing. Being used for various psychiatric diseases for decades, antipsychotic drugs are now reported to have potent anti-cancer properties against a wide variety of malignancies in addition to their antipsychotic effects. In this review, an overview of repurposing various psychiatric drugs for cancer treatment is presented, and the putative mechanisms for the anti-neoplastic actions of these antipsychotic drugs are reviewed. Copyright © 2018 Elsevier B.V. All rights reserved.
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Lipid profile in antipsychotic drug users: A comparative study
Roohafza, Hamidreza; Khani, Azam; Afshar, Hamid; Garakyaraghi, Mohammad; Amirpour, Afshin; Ghodsi, Basir
2013-01-01
BACKGROUND Schizophrenic patients who receive antipsychotic drugs may be highly prone to metabolic disorders such as weight gain, dyslipidemia, and insulin resistance. The objective of the present study was to compare the effect of atypical and conventional antipsychotics on lipid profile. METHODS 128 schizophrenic patients were enrolled into the study. Patients were divided into two groups. One group had received one type of atypical antipsychotic drug, and, the other, one type of conventional antipsychotic drug. They were considered as atypical and conventional groups. Moreover, both groups had not used any other antipsychotic drugs during the past year. Demographic data and food frequency questionnaire were completed by the participants. Serum triglyceride, total cholesterol (TC), high-density lipoprotein and low-density lipoprotein (LDL) cholesterols, and apolipoprotein A and B (Apo B) were tested by blood sample drawing after 12 hours of fasting through the antecubital vein. Student’s t-test was used to compare atypical and conventional groups. RESULTS There was no significant difference in age, gender, duration of illness, period of drug consumption, and age at onset of illness in the two groups. Patients in the atypical group used clozapine and risperidone (46.9%) more than olanzapine. In the conventional group 81.3% of patients used phenothiazines. Comparison between lipid profile in the conventional and atypical groups showed a significantly higher mean in TC (P = 0.01), LDL (P = 0.03), and Apo B (P = 0.01) in conventional group than the atypical group. CONCLUSION In schizophrenic patients, the level of lipid profile had been increased in both atypical and conventional antipsychotic users, especially conventional users, so the effect of antipsychotic drugs should be investigated periodically. PMID:23766777
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A critical assessment of antipsychotic drug monitoring.
Waraska, J; Nagle, J D
1987-06-01
Analytic problems associated with monitoring antipsychotic drug levels have largely been resolved. Despite the establishment of target values for some drugs, the clinical utility of such levels remains to be determined.
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Kishi, Taro; Matsuda, Yuki; Iwata, Nakao
2014-01-01
Background The present study aimed to evaluate cardiometabolic risks [weight gain, blood lipid levels (total cholesterol and triglycerides), blood glucose levels, hemoglobin A1c (HbA1c) levels, and corrected QT interval (QTc) prolongation] associated with the use of blonanserin and perospirone versus other antipsychotics in the management of patients with schizophrenia. Method We conducted a systematic review and meta-analysis of patient data from randomized controlled trials comparing blonanserin or perospirone with other antipsychotics. Results In total, 4 blonanserin studies (n = 1080) were identified [vs. risperidone (2 studies, n = 508); vs. haloperidol (2 studies, n = 572)]. Blonanserin produced less weight gain compared with risperidone (weighted mean difference = −0.86, 95% confidence intervals = −1.36 to −0.36, p = 0.0008; 2 studies, 480 patients). However, no significant differences were observed in blood lipid, glucose, and HbA1c levels or QTc prolongation between blonanserin and risperidone or haloperidol. For perospirone studies, 5 studies [562 adult patients with schizophrenia randomized to perospirone (n = 256), olanzapine (n = 20), quetiapine (n = 28), risperidone (n = 53), aripiprazole (n = 49), haloperidol (n = 75), or mosapramine (n = 81)] were identified. Perospirone did not differ from other antipsychotics with regard to weight gain and total cholesterol levels. Conclusions Our results suggest that blonanserin is associated with a lower of weight gain compared with other antipsychotics. Because the number of studies was small, additional controlled clinical trials with larger number of patients are indicated. PMID:24505373
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Do antipsychotic drugs affect brain structure? A systematic and critical review of MRI findings.
Navari, S; Dazzan, P
2009-11-01
The potential effects of antipsychotic drugs on brain structure represent a key factor in understanding neuroanatomical changes in psychosis. This review addresses two issues: (1) do antipsychotic medications induce changes in total or regional human brain volumes and (2) do such effects depend on antipsychotic type? A systematic review of studies reporting structural brain magnetic resonance imaging (MRI) measures: (1) directly in association with antipsychotic use; and (2) in patients receiving lifetime treatment with antipsychotics in comparison with drug-naive patients or healthy controls. We searched Medline and EMBASE databases using the medical subject heading terms: 'antipsychotics' AND 'brain' AND (MRI NOT functional). The search included studies published up to 31 January 2007. Wherever possible, we reported the effect size of the difference observed. Thirty-three studies met our inclusion criteria. The results suggest that antipsychotics act regionally rather than globally on the brain. These volumetric changes are of a greater magnitude in association with typical than with atypical antipsychotic use. Indeed, there is evidence of a specific effect of antipsychotic type on the basal ganglia, with typicals specifically increasing the volume of these structures. Differential effects of antipsychotic type may also be present on the thalamus and the cortex, but data on these and other brain areas are more equivocal. Antipsychotic treatment potentially contributes to the brain structural changes observed in psychosis. Future research should take into account these potential effects, and use adequate sample sizes, to allow improved interpretation of neuroimaging findings in these disorders.
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2010-01-01
Background Atypical antipsychotic drugs have been reported to cause fewer incidences of extrapyramidal side effects (EPS) than typical antipsychotic drugs, but adverse events such as akathisia have been observed even with atypical antipsychotic drugs. Although understanding of the pathophysiology of akathisia remains limited, it seems that a complex interaction of several neurotransmitter systems plays a role in its pathophysiology. The endoplasmic reticulum protein sigma-1 receptors have been shown to regulate a number of neurotransmitter systems in the brain. Methods We report on five cases in which monotherapy of the selective serotonin reuptake inhibitor and sigma-1 receptor agonist fluvoxamine was effective in ameliorating the akathisia of patients with schizophrenia treated with the new atypical antipsychotic drug blonanserin. Results The global score on the Barnes Akathisia Scale in five patients with schizophrenia treated with blonanserin rapidly decreased after fluvoxamine treatment. Conclusion Doctors should consider that fluvoxamine may be an alternative approach in treating akathisia associated with atypical antipsychotic drugs. PMID:20416096
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Furuse, Tsutomu; Hashimoto, Kenji
2010-04-24
Atypical antipsychotic drugs have been reported to cause fewer incidences of extrapyramidal side effects (EPS) than typical antipsychotic drugs, but adverse events such as akathisia have been observed even with atypical antipsychotic drugs. Although understanding of the pathophysiology of akathisia remains limited, it seems that a complex interaction of several neurotransmitter systems plays a role in its pathophysiology. The endoplasmic reticulum protein sigma-1 receptors have been shown to regulate a number of neurotransmitter systems in the brain. We report on five cases in which monotherapy of the selective serotonin reuptake inhibitor and sigma-1 receptor agonist fluvoxamine was effective in ameliorating the akathisia of patients with schizophrenia treated with the new atypical antipsychotic drug blonanserin. The global score on the Barnes Akathisia Scale in five patients with schizophrenia treated with blonanserin rapidly decreased after fluvoxamine treatment. Doctors should consider that fluvoxamine may be an alternative approach in treating akathisia associated with atypical antipsychotic drugs.
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Thiol Disulfide Homeostasis in Schizophrenic Patients Using Atypical Antipsychotic Drugs
Ersan, Etem Erdal; Aydin, Hüseyin; Erdoğan, Serpil; Erşan, Serpil; Alişik, Murat; Bakir, Sevtap; Erel, Özcan; Koç, Derya
2018-01-01
Objective Schizophrenia is a severe, debilitating mental disorder characterized by behavioral abnormalities. Although several studies have investigated the role of oxidative stress and the effects of antipsychotic drugs on oxidative markers in schizophrenia, adequate information is not available on these issues. The aim of this study is to determine the changes in oxidative status and thiol disulfide homeostasis in schizophrenic patients using atypical antipsychotic drugs. Methods Thirteen schizophrenic patients using atypical antipsychotic drugs and 30 healthy controls were included this study. The concentrations of total oxidant status (TOS), total antioxidant status (TAS), native thiol, total thiol, and disulfide levels were determined in the study population. Results The TAS (p=0.001), total thiol, and native thiol levels (p<0.001) were higher in the patients compared to the controls, whereas the TOS and disulfide levels were lower in the patients than in the controls (p<0.001). Conclusion These results may suggest that atypical antipsychotic drugs have a useful therapeutic effect by reducing oxidative stress via the inhibition of the formation of disulfide bonds. The study population number was one of the limitations of this study. Therefore, further studies are needed to establish the association between thiol disulfide homeostasis in schizophrenic patients using atypical antipsychotic drugs. PMID:29397665
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Studies of phase transitions in the aripiprazole solid dosage form.
Łaszcz, Marta; Witkowska, Anna
2016-01-05
Studies of the phase transitions in an active substance contained in a solid dosage form are very complicated but essential, especially if an active substance is classified as a BCS Class IV drug. The purpose of this work was the development of sensitive methods for the detection of the phase transitions in the aripiprazole tablets containing initially its form III. Aripiprazole exhibits polymorphism and pseudopolymorphism. Powder diffraction, Raman spectroscopy and differential scanning calorimetry methods were developed for the detection of the polymorphic transition between forms III and I as well as the phase transition of form III into aripiprazole monohydrate in tablets. The study involved the initial 10 mg and 30 mg tablets, as well as those stored in Al/Al blisters, a triplex blister pack and HDPE bottles (with and without desiccant) under accelerated and long term conditions. The polymorphic transition was not observed in the initial and stored tablets but it was visible on the DSC curve of the Abilify(®) 10 mg reference tablets. The formation of the monohydrate was observed in the diffractograms and Raman spectra in the tablets stored under accelerated conditions. The monohydrate phase was not detected in the tablets stored in the Al/Al blisters under long term conditions. The results showed that the Al/Al blisters can be recommended as the packaging of the aripiprazole tablets containing form III. Copyright © 2015 Elsevier B.V. All rights reserved.
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Novel antipsychotics: issues and controversies. Typicality of atypical antipsychotics.
Stip, E
2000-01-01
The typicality of atypical antipsychotic drugs remains debatable. Preclinical studies and findings from randomized, controlled and open trials of clozapine, olanzapine, risperidone, quetiapine, sertindole, ziprasidone and a substituted benzamide were examined. A MEDLINE search was conducted using key words, including "extrapyramidal side effects," "cognition," "schizophrenia" and the generic drug names. Over 140 articles from peer-reviewed journals were reviewed, some of which were based on a meta-analysis. New-generation neuroleptic agents were found to have greater efficacy on the negative symptoms of schizophrenia and to cause fewer unwanted extrapyramidal side effects (EPS) than the traditional antipsychotic drugs. On one hand, atypical neuroleptic agents could be strictly defined as any neuroleptic agent with antipsychotic effects at a dosage that does not cause extrapyramidal side effects. Thus, clozapine is regarded as the "standard" atypical antipsychotic drug. On the other hand, typicality is about dimension rather than category, and we suggest the use of the term "spectrum of atypicality." For example, an emphasis is placed on quetiapine to illustrate where a new compound fits in this spectrum. Although dose-related, atypicality may be more a question of prescription attitude than of a specific characteristic of a compound. The degree to which a new compound is clinically superior to another atypical antipsychotic drug, in terms of improving positive, negative or affective symptoms, cognitive function and long-term outcome, will require further a priori hypotheses based on conceptual frameworks that are clinically meaningful. In addition, the results from industry-sponsored trials should be more comparable to those obtained from investigator-leading trials. Finally, the patient characteristics that define a patient's response to a specific antipsychotic drug are unknown. PMID:10740987
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Starace, Fabrizio; Mungai, Francesco; Barbui, Corrado
2018-01-01
In mental healthcare, one area of major concern identified by health information systems is variability in antipsychotic prescribing. While most studies have investigated patient- and prescriber-related factors as possible reasons for such variability, no studies have investigated facility-level characteristics. The present study ascertained whether staffing level is associated with antipsychotic prescribing in community mental healthcare. A cross-sectional analysis of data extracted from the Italian national mental health information system was carried out. For each Italian region, it collects data on the availability and use of mental health facilities. The rate of individuals exposed to antipsychotic drugs was tested for evidence of association with the rate of mental health staff availability by means of univariate and multivariate analyses. In Italy there were on average nearly 60 mental health professionals per 100,000 inhabitants, with wide regional variations (range 21 to 100). The average rate of individuals prescribed antipsychotic drugs was 2.33%, with wide regional variations (1.04% to 4.01%). Univariate analysis showed that the rate of individuals prescribed antipsychotic drugs was inversely associated with the rate of mental health professionals available in Italian regions (Kendall's tau -0.438, p = 0.006), with lower rates of antipsychotic prescriptions in regions with higher rates of mental health professionals. After adjustment for possible confounders, the total availability of mental health professionals was still inversely associated with the rate of individuals exposed to antipsychotic drugs. The evidence that staffing level was inversely associated with antipsychotic prescribing indicates that any actions aimed at decreasing variability in antipsychotic prescribing need to take into account aspects related to the organization of the mental health system.
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Polić-Vižintin, Marina; Tripković, Ingrid; Štimac, Danijela; Šostar, Zvonimir; Orban, Mirjana
2016-12-01
The aim was to determine distribution and trends in the outpatient utilization of antipsychotics to evaluate the rationality of antipsychotic drug prescribing during the ten year period. The epidemiological method of descriptive and analytical observation was used. Data on drug utilization from Zagreb Municipal Pharmacy were used to calculate the number of defined daily doses (DDD) and DDD per 1000 inhabitants per day (DDD/TID) using the World Health Organization Anatomical-Therapeutic-Chemical methodology. The ratio of typical versus atypical antipsychotics served as an indicator on assessing the rationality of the utilization. Data on the use of anticholinergics in the treatment of neuroleptic side effects were also included. Outpatient utilization of antipsychotics showed a declining pattern from 14.17 in 2001 to 8.42 DDD/TID in 2010. The utilization of atypical antipsychotics increased by 60% (from 3.68 to 5.89 DDD/TID), while the utilization of typical antipsychotics decreased by 76% (from 10.49 to 2.53 DDD/TID). The drugs showing the largest increase were olanzapine (from 1.21 to 2.78 DDD/TID) and quetiapine (from 0 to 0.68 DDD/TID). The typical/atypical antipsychotic ratio changed from 1:0.4 in 2001 to 1:2.3 in 2010. A 2.3-fold decrease was recorded in the utilization of anticholinergics (from 2.05 to 0.91 DDD/TID). Total consumption of neuroleptics significantly decreased. A decrease was also recorded in the utilization of anticholinergics. Study results pointed to two favorable features, i.e. low use of typical antipsychotics and the ratio of typical and atypical antipsychotics. Implementation of the new clinical guidelines for nervous system disorders and updating of the list of reimbursable drugs with the addition of new ones contributed to the observed improvement in the prescribing patterns during the study period. Using the WHO ATC/DDD methodology and rationality indicators in the assessment of trends in the outpatient utilization of psychopharmaceuticals over a ten-year period proved efficient in the evaluation of prescribing rationality.
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ERIC Educational Resources Information Center
Paton, C.; Flynn, A.; Shingleton-Smith, A.; McIntyre, S.; Bhaumik, S.; Rasmussen, J.; Hardy, S.; Barnes, T.
2011-01-01
Background: Antipsychotics are perceived to be over-used in the management of behavioural problems in people with an intellectual disability (ID). Published guidelines have set good practice standards for the use of these drugs for behavioural indications. We sought to identify the range of indications for which antipsychotic drugs are prescribed…
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Zhu, Xiuqing; Hu, Jinqing; Sun, Bin; Deng, Shuhua; Wen, Yuguan; Chen, Weijia; Qiu, Chang; Shang, Dewei; Zhang, Ming
2018-04-01
This study aims to compare the prevalence of unlicensed and off-label use of antipsychotics among child and adolescent psychiatric outpatients with guidelines proposed by the China Food and Drug Administration (CFDA) and the U.S. Food and Drug Administration (FDA), and to identify factors associated with inconsistencies between the two regulations. A retrospective analysis of 29,326 drug prescriptions for child and adolescent outpatients from the Affiliated Brain Hospital of Guangzhou Medical University was conducted. Antipsychotics were classified as "unlicensed" or "off-label use" according to the latest pediatric license information registered by the CFDA and the FDA or the package inserts of antipsychotics authorized by the CFDA or the FDA for the treatment of pediatric mental and behavioral disorders, respectively. Binary logistic regression analysis was performed to assess factors associated with inconsistencies between the two regulations. The total unlicensed use, according to the CFDA analysis, was higher than that found in the FDA analysis (74.14% vs. 22.04%, p < 0.001). However, the total off-label use, according to the FDA analysis, was higher than that found in the CFDA analysis (46.53% vs. 15.77%, p < 0.001). Antipsychotic drug classes, age group, number of diagnoses, and diagnosis of schizophrenia and schizotypal and delusional disorders were associated with inconsistent unlicensed use. Antipsychotic drug classes, age group, number of prescribed psychotropic drugs, gender, diagnosis of schizophrenia and schizotypal and delusional disorders, diagnosis of mood [affective] disorders, diagnosis of mental retardation, and diagnosis of psychological development disorders were associated with inconsistent off-label use. The difference in prevalence of total unlicensed and off-label use of antipsychotics between the two regulations was statistically significant. This inconsistency could be partly attributed to differences in pediatric license information and package inserts of antipsychotics. The results indicate a need for further clinical pediatric studies and better harmonization between agencies regarding antipsychotic used in pediatrics.
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Moore, Thomas J; Glenmullen, Joseph; Mattison, Donald R
2014-12-01
Severe impulse control disorders involving pathological gambling, hypersexuality, and compulsive shopping have been reported in association with the use of dopamine receptor agonist drugs in case series and retrospective patient surveys. These agents are used to treat Parkinson disease, restless leg syndrome, and hyperprolactinemia. To analyze serious adverse drug event reports about these impulse control disorders received by the US Food and Drug Administration (FDA) and to assess the relationship of these case reports with the 6 FDA-approved dopamine receptor agonist drugs. We conducted a retrospective disproportionality analysis based on the 2.7 million serious domestic and foreign adverse drug event reports from 2003 to 2012 extracted from the FDA Adverse Event Reporting System. Cases were selected if they contained any of 10 preferred terms in the Medical Dictionary for Regulatory Activities (MedDRA) that described the abnormal behaviors. We used the proportional reporting ratio (PRR) to compare the proportion of target events to all serious events for the study drugs with a similar proportion for all other drugs. We identified 1580 events indicating impulse control disorders from the United States and 21 other countries:710 fordopamine receptor agonist drugs and 870 for other drugs. The dopamine receptor agonist drugs had a strong signal associated with these impulse control disorders (n = 710; PRR = 277.6, P < .001). The association was strongest for the dopamine agonists pramipexole (n = 410; PRR = 455.9, P < .001) and ropinirole (n = 188; PRR = 152.5, P < .001), with preferential affinity for the dopamine D3 receptor. A signal was also seen for aripiprazole, an antipsychotic classified as a partial agonist of the D3 receptor (n = 37; PRR = 8.6, P < .001). Our findings confirm and extend the evidence that dopamine receptor agonist drugs are associated with these specific impulse control disorders. At present, none of the dopamine receptor agonist drugs approved by the FDA have boxed warnings as part of their prescribing information. Our data, and data from prior studies, show the need for more prominent warnings.
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Fraguas, David; Correll, Christoph U; Merchán-Naranjo, Jessica; Rapado-Castro, Marta; Parellada, Mara; Moreno, Carmen; Arango, Celso
2011-08-01
To review data on efficacy and safety of second-generation antipsychotics (SGAs) in children and adolescents with psychotic and bipolar spectrum disorders. Medline/PubMed/Google Scholar search for studies comparing efficacy and/or tolerability: (i) between two or more SGAs; (ii) between SGAs and placebo; and (iii) between at least one SGA and one first-generation antipsychotic (FGA). The review focused on three major side-effect clusters: 1. body weight, body mass index, and cardiometabolic parameters, 2. prolactin levels, and 3. neuromotor side effects. In total, 34 studies with 2719 children and adolescents were included. Studies lasted between 3 weeks and 12 months, with most studies (79.4%) lasting 3 months or less. Nine studies (n=788) were conducted in patients with schizophrenia, 6 (n=719) in subjects with bipolar disorder, and 19 (n=1212) in a mixed population. Data on efficacy showed that, except for clozapine being superior for refractory schizophrenia, there were no significant differences between SGAs. By contrast, safety assessments showed relevant differences between SGAs. Mean weight gain ranged from 3.8 kg to 16.2 kg in patients treated with olanzapine (n=353), from 0.9 kg to 9.5 kg in subjects receiving clozapine (n=97), from 1.9 kg to 7.2 kg in those on risperidone (n=571), from 2.3 kg to 6.1 kg among patients taking quetiapine (n=133), and from 0 kg to 4.4 kg in those treated with aripiprazole (n=451). Prolactin levels increased the most in subjects on risperidone (mean change ranging from 8.3 ng/mL to 49.6 ng/mL), followed by olanzapine (-1.5 ng/mL to +13.7 ng/mL). Treatment with aripiprazole was associated with decreased prolactin levels, while clozapine and quetiapine were found to be mostly neutral. With respect to neuromotor side effects, SGAs were associated with less parkinsonism and akathisia than FGAs. Most of the studies comparing neuromotor side effects between SGAs found no significant differences. SGAs do not behave as a homogeneous group in children and adolescents with psychotic and mood disorders. Except for clozapine, the heterogeneity within the SGA group is mainly due to differences in the rates and severity of adverse events, especially regarding weight gain as a proxy for the risk of cardiometabolic disturbances. Published by Elsevier B.V.
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O’Callaghan, Matthew J; Bay-Richter, Cecilie; O’Tuathaigh, Colm MP; Heery, David M; Waddington, John L; Moran, Paula M
2014-01-01
Whether the dopamine Drd-2 receptor is necessary for the behavioural action of antipsychotic drugs is an important question, as Drd-2 antagonism is responsible for their debilitating motor side effects. Using Drd-2 null mice (Drd2 -/-) it has previously been shown that Drd-2 is not necessary for antipsychotic drugs to reverse D-amphetamine disruption of latent inhibition (LI), a behavioural measure of learning to ignore irrelevant stimuli. Weiner’s ‘two-headed’ model indicates that antipsychotics not only reverse LI disruption, ‘disrupted LI’, but also potentiate LI when low/absent in controls, ‘persistent’ LI. We investigated whether antipsychotic drugs haloperidol or clozapine potentiated LI in wild-type controls or Drd2 -/-. Both drugs potentiated LI in wild-type but not in Drd2-/- mice, suggesting moderation of this effect of antipsychotics in the absence of Drd-2. Haloperidol potentiated LI similarly in both Drd1-/- and wild-type mice, indicating no such moderation in Drd1-/-. These data suggest that antipsychotic drugs can have either Drd-2 or non-Drd-2 effects on learning to ignore irrelevant stimuli, depending on how the abnormality is produced. Identification of the non-Drd-2 mechanism may help to identify novel non-Drd2 based therapeutic strategies for psychosis. PMID:25122042
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Risperidone versus other atypical antipsychotics for schizophrenia
Komossa, Katja; Rummel-Kluge, Christine; Schwarz, Sandra; Schmid, Franziska; Hunger, Heike; Kissling, Werner; Leucht, Stefan
2014-01-01
Background In many countries of the industrialised world second-generation (“atypical”) antipsychotics (SGAs) have become the first line drug treatment for people with schizophrenia. The question as to whether and if so how much the effects of the various SGAs differ is a matter of debate. In this review we examined how the efficacy and tolerability of risperidone differs from that of other SGAs. Objectives To evaluate the effects of risperidone compared with other atypical antipsychotics for people with schizophrenia and schizophrenia-like psychosis. Search methods 1. Electronic searching We searched the Cochrane Schizophrenia Group Trials Register (April 2007) which is based on regular searches of BIOSIS, CENTRAL, CINAHL, EMBASE, MEDLINE and PsycINFO. 2. Reference searching We inspected the references of all identified studies for more trials. 3. Personal contact We contacted the first author of each included study for missing information. 4. Drug companies We contacted the manufacturers of all atypical antipsychotics included for additional data. Selection criteria We included all randomised, blinded trials comparing oral risperidone with oral forms of amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, sertindole, ziprasidone or zotepine in people with schizophrenia or schizophrenia-like psychosis. Data collection and analysis We extracted data independently. For dichotomous data we calculated risk ratio (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a random-effects model. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. For continuous data, we calculated mean differences (MD), again based on a random-effects model. Main results The review currently includes 45 blinded RCTs with 7760 participants. The number of RCTs available for each comparison varied: four studies compared risperidone with amisulpride, two with aripiprazole, 11 with clozapine, 23 with olanzapine, eleven with quetiapine, two with sertindole, three with ziprasidone and none with zotepine. Attrition from these studies was high (46.9%), leaving the interpretation of results problematic. Furthermore, 60% were industry sponsored, which can be a source of bias. There were few significant differences in overall acceptability of treatment as measured by leaving the studies early. Risperidone was slightly less acceptable than olanzapine, and slightly more acceptable than ziprasidone in this regard. Risperidone improved the general mental state (PANSS total score) slightly less than olanzapine (15 RCTs, n = 2390, MD 1.94 CI 0.58 to 3.31), but slightly more than quetiapine (9 RCTs, n = 1953, MD −3.09 CI −5.16 to −1.01) and ziprasidone (3 RCTs, n = 1016, MD −3.91 CI −7.55 to −0.27). The comparisons with the other SGA drugs were equivocal. Risperidone was also less efficacious than olanzapine and clozapine in terms of leaving the studies early due to inefficacy, but more efficacious than ziprasidone in the same outcome. Risperidone produced somewhat more extrapyramidal side effects than a number of other SGAs (use of antiparkinson medication versus clozapine 6 RCTs, n = 304, RR 2.57 CI 1.47 to 4.48, NNH 6 CI 33 to 3; versus olanzapine 13 RCTs, n = 2599, RR 1.28 CI 1.06 to 1.55, NNH 17 CI 9 to 100; versus quetiapine 6 RCTs, n = 1715, RR 1.98 CI 1.16 to 3.39, NNH 20 CI 10 to 100; versus ziprasidone 2 RCTs, n = 822, RR 1.42 CI 1.03 to 1.96, NNH not estimable; parkinsonism versus sertindole 1 RCT, n = 321, RR 4.11 CI 1.44 to 11.73, NNH 14 CI 100 to 8). Risperidone also increased prolactin levels clearly more than all comparators, except for amisulpride and sertindole for which no data were available. Other adverse events were less consistently reported, but risperidone may well produce more weight gain and/or associated metabolic problems than amisulpride (weight gain: 3 RCTs, n = 585, MD 0.99 CI 0.37 to 1.61), aripiprazole (cholesterol increase: 1 RCT, n = 83, MD 22.30 CI 4.91 to 39.69) and ziprasidone (cholesterol increase 2 RCTs, n = 767, MD 8.58 CI 1.11 to 16.04) but less than clozapine (weight gain 3 RCTs n = 373, MD −3.30 CI −5.65 to −0.95), olanzapine (weight gain 13 RCTs, n = 2116, MD −2.61 CI −3.74 to −1.48), quetiapine (cholesterol increase: 5 RCTs, n = 1433, MD −8.49 CI −12. 23 to −4.75) and sertindole (weight gain: 2 RCTs, n = 328, MD −0.99 CI −1.86 to −0.12). It may be less sedating than clozapine and quetiapine, lengthen the QTc interval less than sertindole (QTc change: 2 RCTs, n = 495, MD −18.60 CI −22.37 to 14.83), produce fewer seizures than clozapine (2 RCTs, n = 354, RR 0.22 CI 0.07 to 0.70, NNT 14 CI 8 to 33) and less sexual dysfunction in men than sertindole (2 RCTs, n = 437, RR 0.34 CI 0.16 to 0.76, NNT 13 CI 8 to 33). Authors’ conclusions Risperidone seems to produce somewhat more extrapyramidal side effects and clearly more prolactin increase than most other SGAs. It may also differ from other compounds in efficacy and in the occurrence of other adverse effects such as weight gain, metabolic problems, cardiac effects, sedation and seizures. Nevertheless, the large proportion of participants leaving studies early and incomplete reporting of outcomes makes it difficult to draw firm conclusions. Further large trials, especially comparing risperidone with those other new drugs for which only a few RCTs are available, are needed. PMID:21249678
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2011-01-01
Background When treating schizophrenia, improving patients' productivity level is a major goal considering schizophrenia is a leading cause of functional disability. Productivity level has been identified as the most preferred treatment outcome by patients with schizophrenia. However, little has been done to systematically investigate productivity levels in schizophrenia. We set out to better understand the change in productivity level among chronically ill patients with schizophrenia treated with olanzapine compared with other antipsychotic medications. We also assessed the links between productivity level and other clinical outcomes. Methods This post hoc analysis used data from 6 randomized, double-blind clinical trials of patients with schizophrenia or schizoaffective disorder, with each trial being of approximately 6 months duration. Change in productivity level was compared between olanzapine-treated patients (HGBG, n = 172; HGHJ, n = 277; HGJB, n = 171; HGLB, n = 281; HGGN, n = 159; HGDH, n = 131) and patients treated with other antipsychotic medications (separately vs. haloperidol [HGGN, n = 97; HGDH, n = 132], risperidone [HGBG, n = 167; HGGN, n = 158], quetiapine [HGJB, n = 175], ziprasidone [HGHJ, n = 271] and aripiprazole [HGLB, n = 285]). Productivity was defined as functional activities/work including working for pay, studying, housekeeping and volunteer work. Productivity level in the prior 3 months was assessed on a 5-point scale ranging from no useful functioning to functional activity/work 75% to 100% of the time. Results Chronically ill patients treated with olanzapine (OLZ) experienced significantly greater improvement in productivity when compared to patients treated with risperidone (RISP) (OLZ = 0.22 ± 1.19, RISP = -0.03 ± 1.17, p = 0.033) or ziprasidone (ZIP) (OLZ = 0.50 ± 1.38, ZIP = 0.25 ± 1.27, p = 0.026), but did not significantly differ from the quetiapine, aripiprazole or haloperidol treatment groups. Among first episode patients, OLZ therapy was associated with greater improvements in productivity levels compared to haloperidol (HAL), during the acute phase (OLZ = -0.31 ± 1.59, HAL = -0.69 ± 1.56, p = 0.011) and over the long-term (OLZ = 0.10 ± 1.50, HAL = -0.32 ± 1.91, p = 0.008). Significantly more chronically ill and first episode patients treated with olanzapine showed moderately high (>50%-75% of the time) and high levels of productivity (>75%-100% of the time) at endpoint, when compared to risperidone or haloperidol-treated patients (p < .05), respectively. Higher productivity level was associated with significantly higher study completion rates and better scores on the positive, negative, disorganized thoughts, hostility and depression subscales of the Positive and Negative Symptom Scale (PANSS). Conclusions Some antipsychotic medications significantly differed in beneficial impact on productivity level in the long-term treatment of patients with schizophrenia. Findings further highlight the link between clinical and functional outcomes, showing significant associations between higher productivity, lower symptom severity and better persistence on therapy. Trial Registration clinicaltrials.gov identifier NCT00088049; NCT00036088 PMID:21586165
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Trends in prescriptions and costs of drugs for mental disorders in England, 1998-2010.
Ilyas, Stephen; Moncrieff, Joanna
2012-05-01
Increasing rates of prescriptions for antidepressants, antipsychotics and stimulants have been reported from various countries. To examine trends in prescriptions and the costs of all classes of psychiatric medication in England. Data from the Prescription Cost Analysis 1998-2010 was examined, using linear regression analysis to examine trends. Prescriptions of drugs used for mental disorders increased by 6.8% (95% CI 6.3-7.4) per year on average, in line with other drugs, but made up an increasing proportion of all prescription drug costs (P = 0.001). There were rising trends in prescriptions of all classes of psychiatric drugs, except anxiolytics and hypnotics (which did not change). Antidepressant prescriptions increased by 10% (95% CI 9.0-11) per year on average, and antipsychotics by 5.1% (95% CI 4.3-5.9). Antipsychotics overtook antidepressants as the most costly class of psychiatric medication, with costs rising 22% (95% CI 17-27) per year. Rising prescriptions may be partly explained by longer-term treatment and increasing population. Nevertheless, it appears that psychiatric drugs make an increasing contribution to total prescription drug costs, with antipsychotics becoming the most costly. Low-dose prescribing of some antipsychotics is consistent with other evidence that their use may not be restricted to those with severe mental illness.
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Sheehan, Rory; Horsfall, Laura; Strydom, André; Osborn, David; Walters, Kate; Hassiotis, Angela
2017-08-03
To measure the incidence of movement side effects of antipsychotic drugs in adults with intellectual disability and compare rates with adults without intellectual disability. Cohort study using data from The Health Improvement Network. UK primary care. Adults with intellectual disability prescribed antipsychotic drugs matched to a control group of adults without intellectual disability prescribed antipsychotic drugs. New records of movement side effect including acute dystonias, akathisia, parkinsonism, tardive dyskinaesia and neuroleptic malignant syndrome. 9013 adults with intellectual disability and a control cohort of 34 242 adults without intellectual disability together contributed 148 709 person-years data. The overall incidence of recorded movement side effects was 275 per 10 000 person-years (95% CI 256 to 296) in the intellectual disability group and 248 per 10 000 person-years (95% CI 237 to 260) in the control group. The incidence of any recorded movement side effect was significantly greater in people with intellectual disability compared with those without (incidence rate ratio 1.30, 95% CI 1.18 to 1.42, p<0.001, after adjustment for potential confounders), with parkinsonism and akathisia showing the greatest difference between the groups. Neuroleptic malignant syndrome, although occurring infrequently, was three times more common in people with intellectual disability-prescribed antipsychotic drugs (incidence rate ratio 3.03, 95% CI 1.26 to 7.30, p=0.013). Differences in rates of movement side effects between the groups were not due to differences in the proportions prescribed first and second-generation antipsychotic drugs. This study provides evidence to substantiate the long-held assumption that people with intellectual disability are more susceptible to movement side effects of antipsychotic drugs. Assessment for movement side effects should be integral to antipsychotic drug monitoring in people with intellectual disability. Regular medication review is essential to ensure optimal prescribing in this group. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
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Tournier, Marie; Bégaud, Bernard; Cougnard, Audrey; Auleley, Guy-Robert; Deligne, Jean; Blum-Boisgard, Claudine; Thiébaut, Anne C M; Verdoux, Hélène
2012-07-01
• Metabolic disturbances represent a well-known side effect of second generation antipsychotics. However, studies comparing second generation antipsychotic drugs (SGAPs) and first generation antipsychotic drugs (FGAPs) through administrative databases have shown contrasting findings, which may be attributable to methodological differences. • The definition of antipsychotic exposure impacts on the association between antipsychotics and metabolic risk in studies carried out through administrative databases. • Considering cumulative exposure to antipsychotics or including patients exposed to an antipsychotic drug for months or years is likely to over-represent patients who tolerate the drug well with a depletion of susceptible effects. • Antipsychotic drug exposure is a time-varying determinant and episodes of no use, past use and current use should be distinguished over the study period to avoid any misclassification bias that might lead to misleading findings. To assess the influence of three definitions of antipsychotic exposure on the comparison between first generation (FGAP) and second generation (SGAP) antipsychotic drugs and 'conventional' mood stabilizers towards the risk of metabolic events using (i) a dichotomous measure (exposed/non-exposed over the follow-up), (ii) a categorical measure taking into account the chronology of exposure at the time of the metabolic event (current, recent and no use) and (iii) a continuous measure (cumulative duration). A historical fixed cohort was identified from the 2004-2006 claims database of the French health insurance programme for self-employed workers, including 3172 patients aged 18 years and over who used conventional mood stabilizers over a 3 month period. A metabolic event was defined as an incident dispensing of an anti-diabetic or lipid-lowering drug. A metabolic event occurred in 367 patients (11.6%). At least one FGAP had been prescribed in 29% of patients who did not develop a metabolic event and in 22% of patients who developed a metabolic event. In addition, at least one SGAP had been prescribed in 12% of patients who did not develop a metabolic event and in 7% of patients who developed a metabolic event. Compared with conventional mood stabilizers, the risk of a metabolic event was negatively associated with exposure to SGAPs over the follow-up period (HR 0.53, 95% CI 0.34, 0.82, P= 0.004), positively associated with recent, but not current, exposure to SGAPs (HR 2.1, 95% CI 1.2, 3.7, P= 0.006) and not associated with cumulative duration of SGAPs (HR 1.001, 95% CI 0.999, 1.003, P= 0.20). The definition of exposure to antipsychotics in epidemiological studies exploring their metabolic impact is of paramount importance in understanding this association. Different definitions can lead to opposite and seemingly nonsensical results. Not taking into account past exposure, in order to minimize the depletion of susceptible effects, may lead to absurd results. © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.
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[Creativity and antipsychotic drugs].
Murry, P; Torrecuadrada, J L
1997-09-01
For the authors, the creative abilities of a schizophrenic patient are indicators of the therapeutic efficacy of an antipsychotic treatment and the incidence of adverse effects. The new antipsychotic drugs available, unlike conventional neuroleptics, show enhanced efficacy and do not exacerbate the negative symptoms. They may even alleviate them. With regard to clozapine, the authors illustrate the foregoing by two examples of a favorable course in two patients. Clozapine induced an indisputable clinical improvement and hence the opportunity for undeniable artistic activity. Lastly, the new antipsychotics contribute to changing the image that we have of schizophrenic patients.
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Efficacy and safety of novel antipsychotics: a critical review.
Balestrieri, Matteo; Vampini, Claudio; Bellantuono, Cesario
2000-10-01
Efficacy and safety of novel antipsychotic (AP) drugs (amisulpride, olanzapine, quetiapine, ziprasidone and zotepine) have been reviewed. Data on their antipsychotic efficacy and side effects profile have been evaluated only on the basis of controlled trials so far published. Overall, all these drugs have shown an antipsychotic efficacy on positive symptoms of schizophrenia similar to that of the conventional AP drugs. On negative symptoms, all novel AP drugs, except quetiapine and ziprasidone, demonstrated a better efficacy than haloperidol. Long-term efficacy of these AP drugs in the maintenance treatment of schizophrenia needs to be explored by further, better-designed, epidemiological studies. The safety profile shows that the novel AP drugs are generally well-tolerated and induce significantly less acute extrapyramidal side effects in comparison with haloperidol. Some methodological flaws in the experimental design of the clinical trials analysed are discussed. Although these novel AP drugs have potential clinical advantages, a number of relevant questions still remain to be addressed, in order to establish the impact of these drugs in the overall treatment of schizophrenia. Copyright 2000 John Wiley & Sons, Ltd.
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Effects of the Antipsychotic Drug, Haloperidol, on Reproduction in the Fathead Minnow
Haloperidol is a butyrophenone antipsychotic drug used for the treatment of human hyperactive and manic disorders, agitation, and schizophrenia. The drug is thought to act through antagonism of dopaminergic receptors. We have studied a variety of endocrine-disrupting chemicals wi...
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Impact of Modafinil Add-on with Atypical Anti-psychotics on Excessive Daytime Drowsiness
Prasuna, P Lakshmi; Sudhakar, TP
2015-01-01
Background: Atypical antipsychotic drugs are known to cause many side effects which include daytime drowsiness. So many add on drugs are tried to reduce the same. Materials and Methods: 72 patients who were on atypical antipsychotic drugs were randomly assigned to either Modafinil or placebo and were followed for a period of 12 weeks. Daytime drowsiness, was taken at baseline, week 3, and at week 12 by using VAS, EDD scales. Results: The results were analyzed and showed that the Modafinil add on therapy significantly reduced the daytime Drowsiness. Conclusions: Modafinil could be a potential candidate in selected group of patients to decrease some of the unwanted adverse events like daytime drowsiness produced by atypical antipsychotics. PMID:26702168
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Agarwal, Sri Mahavir; Bose, Anushree; Shivakumar, Venkataram; Narayanaswamy, Janardhanan C; Chhabra, Harleen; Kalmady, Sunil V; Varambally, Shivarama; Nitsche, Michael A; Venkatasubramanian, Ganesan; Gangadhar, Bangalore N
2016-01-30
Transcranial direct current stimulation (tDCS) has generated interest as a treatment modality for schizophrenia. Dopamine, a critical pathogenetic link in schizophrenia, is also known to influence tDCS effects. We evaluated the influence of antipsychotic drug type (as defined by dopamine D2 receptor affinity) on the impact of tDCS in schizophrenia. DSM-IV-TR-diagnosed schizophrenia patients [N=36] with persistent auditory hallucinations despite adequate antipsychotic treatment were administered add-on tDCS. Patients were divided into three groups based on the antipsychotic's affinity to D2 receptors. An auditory hallucinations score (AHS) was measured using the auditory hallucinations subscale of the Psychotic Symptom Rating Scales (PSYRATS). Add-on tDCS resulted in a significant reduction inAHS. Antipsychotic drug type had a significant effect on AHS reduction. Patients treated with high affinity antipsychotics showed significantly lesser improvement compared to patients on low affinity antipsychotics or a mixture of the two. Furthermore, a significant sex-by-group interaction occurred; type of medication had an impact on tDCS effects only in women. Improvement differences could be due to the larger availability of the dopamine receptor system in patients taking antipsychotics with low D2 affinity. Sex-specific differences suggest potential estrogen-mediated effects. This study reports a first-time observation on the clinical utility of antipsychotic drug type in predicting tDCS effects in schizophrenia. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
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Metabolic syndrome in drug-naïve and drug-free patients with schizophrenia and in their siblings.
Enez Darcin, Aslı; Yalcin Cavus, Sercin; Dilbaz, Nesrin; Kaya, Hasan; Dogan, Eylem
2015-08-01
We tested the hypothesis that metabolic disturbances in people with schizophrenia exist as a part of the schizophrenic syndrome, even when the antipsychotic drug effect is eliminated. We aimed to determine the prevalence of metabolic syndrome among patients with schizophrenia who were antipsychotic drug-naive or drug-free and their siblings for comparison with healthy controls. One-hundred-two patients with schizophrenia (drug-naïve or drug-free), 64 siblings and 70 age-matched healthy subjects were recruited for this case-control study. Metabolic syndrome was assessed based on Adult Treatment Panel (ATP) III, adapted ATP III and International Diabetes Federation criteria. Student's t-tests, chi-squared tests, Kruskal-Wallis tests and Bonferroni corrections were used as appropriate. The diagnoses of metabolic syndrome and metabolic disturbances as a subsyndromal state were found to be significantly more frequent in patients and their siblings than in the controls. Low levels of high-density lipoprotein cholesterol and disturbances in blood pressure put the patient group at risk for metabolic syndrome even before they were exposed to antipsychotic drugs. Although antipsychotic drugs have consistently been related to disturbances of glucose and lipid metabolism in patients with schizophrenia, this study showed that patients with schizophrenia and their siblings are already at a high risk for metabolic syndrome independent of any antipsychotic effects. These individuals should be monitored regularly following a diagnosis of schizophrenia. Copyright © 2015 Elsevier B.V. All rights reserved.
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Antipsychotic Drug Side Effects for Persons with Intellectual Disability
ERIC Educational Resources Information Center
Matson, Johnny L.; Mahan, Sara
2010-01-01
Antipsychotic drugs are the most frequently prescribed of the psychotropic drugs among the intellectually disabled (ID) population. Given their widespread use, efforts to systematically assess and report side effects are warranted. Specific scaling methods such as the "Matson Evaluation of Side Effects" ("MEDS"), the "Abnormal Inventory Movement…
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Ruiu, Stefania; Casu, Maria Antonietta; Casu, Gianluca; Piras, Sara; Marchese, Giorgio
2012-08-01
Controlled-release formulations of atypical antipsychotics have recently been introduced into clinical practice. Clinical studies have indicated that these new therapies induce meaningful improvements in the functioning and quality of life of schizophrenic individuals. The present analysis makes an attempt to address the clinical relevance of these studies and their contribution to the understanding of the mechanisms of action of these new drugs. A Medline search was done using the keywords 'antipsychotic', 'plasma level', 'quality of life' and 'functioning'. After reviewing the literature, it seems that symptom control and side effects may play a role in modulating the functioning and quality of life of schizophrenic individuals treated with controlled-release formulations of atypical antipsychotics. The analysis also highlights that these new drugs may possess peculiarities and similarities in regulating patient functioning. However, the low number of clinical analyses that have focused on these aspects of antipsychotic therapy limits the interpretation of the results. Additional comparative clinical trials are needed to evaluate how the pharmacokinetic/pharmacodynamic properties of antipsychotic drugs may modulate the functioning and quality of life of schizophrenic individuals, as well as to establish whether new clinical benefits may come from the use of these drugs in schizophrenia therapy.
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Use of antipsychotic medication and suicidality--the Northern Finland Birth Cohort 1966.
Rissanen, Ina; Jääskeläinen, Erika; Isohanni, Matti; Koponen, Hannu; Joukamaa, Matti; Alaräisänen, Antti; Miettunen, Jouko
2012-09-01
In addition to psychoses, antipsychotic drugs are nowadays also prescribed for other psychiatric disturbances, such as mood disorders. We wanted to find out whether there is any association between the use of antipsychotic drugs and suicidality in cases of psychotic and non-psychotic disorders. Our sample was the population-based Northern Finland 1966 Birth Cohort. Information on the use of prescribed drugs was collected in 1997 from the nationwide medication register and with a postal questionnaire (N = 8218). The presence of suicidal ideation was assessed cross-sectionally using the Symptom Check List-25 questionnaire. We studied associations between suicidal ideation, adjusted for symptoms of depression and anxiety, and antipsychotic medication in different diagnostic groups (schizophrenia, other psychosis and no psychosis). Individuals receiving antipsychotic medication (n = 70, 0.9%) had in general more suicidal ideation regardless of diagnostic group, although the associations diminished when taking other symptoms into account. There were no statistically significant differences between those taking typical and atypical antipsychotics. In the non-psychotic group, higher antipsychotic doses were associated with more suicidal ideation even when adjusted for symptoms of depression and anxiety (p < 0.05). In the cases of schizophrenia or other forms of psychosis, no such associations were observed. Our results suggest that one should take suicidal ideation into account when prescribing antipsychotic medication, especially for off-label use. Copyright © 2012 John Wiley & Sons, Ltd.
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Diener, Jonathan T.; Kohn, Arlene E.; Li, Lang; Erickson, Craig A.; Posey, David J.; McDougle, Christopher J.
2009-01-01
Abstract Objective The aim of this study was to determine the effectiveness and tolerability of aripiprazole for irritability in pervasive developmental disorder not otherwise specified (PDD-NOS) and Asperger's disorder. Method This is a 14-week, prospective, open-label investigation of aripiprazole in 25 children and adolescents diagnosed with PDD-NOS or Asperger's disorder. Primary outcome measures included the Clinical Global Impressions–Improvement (CGI-I) scale and the Irritability subscale of the Aberrant Behavior Checklist (ABC-I). Results Twenty-five subjects, ages 5–17 years (mean 8.6 years) received a mean final aripiprazole dosage of 7.8 mg/day (range 2.5–15 mg/day). Full-scale intelligence quotient (IQ) scores ranged from 48 to 122 (mean 84). Twenty-two (88%) of 25 subjects were responders in regard to interfering symptoms of irritability, including aggression, self-injury, and tantrums, with a final CGI-I of 1 or 2 (very much or much improved) and a 25% or greater improvement on the ABC-I. The final mean CGI-I was 1.6 (p ≤ 0.0001). ABC-I scores ranged from 18 to 43 (mean 29) at baseline, whereas scores at week 14 ranged from 0 to 27 (mean 8.1) (p ≤ 0.001). Aripiprazole was well tolerated. Mild extrapyramidal symptoms (EPS) were reported in 9 subjects. Age- and sex-normed body mass index (BMI) increased from a mean value of 20.3 at baseline to 21.1 at end point (p ≤ 0.04). Prolactin significantly decreased from a mean value of 9.3 at baseline to 2.9 at end point (p ≤ 0.0001). No subject exited the study due to a drug-related adverse event. Conclusions These preliminary data suggest that aripiprazole may be effective and well tolerated for severe irritability in pediatric patients with PDD-NOS or Asperger's disorder. Larger-scale placebo-controlled studies are needed to elucidate the efficacy and tolerability of aripiprazole in this understudied population. PMID:19519261
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Physical Health and Drug Safety in Individuals with Schizophrenia
Kelly, Martina; Urness, Doug; Teehan, Michael; Ismail, Zahinoor; Gardner, David
2017-01-01
Background: While antipsychotic medications are the mainstay of therapy for individuals with schizophrenia and psychotic disorders, their use is associated with adverse effects on physical health that require the attention and care of prescribers. Methods: We used the ADAPTE process to adapt existing guideline recommendations from the National Institute for Health and Care Excellence (NICE) and Scottish Intercollegiate Guidelines Network (SIGN) guidelines on the dosing of antipsychotics and antipsychotic polypharmacy, screening for adverse effects of antipsychotics, and management of metabolic and extrapyramidal side effects to the Canadian context. Results: Prescribers are encouraged to use the lowest effective dose and to avoid the routine use of multiple antipsychotics. Scheduled monitoring of body mass index, waist circumference, blood pressure, glucose, lipids, prolactin, electrocardiograms, and extrapyramidal symptoms is recommended. Lifestyle interventions are recommended to mitigate antipsychotic-induced weight gain. Prescribers should follow Canadian guidelines on the treatment of obesity, dyslipidemia, and diabetes. Recommendations on antipsychotic drug choice are made for users particularly concerned about extrapyramidal symptoms. Conclusion: Careful monitoring and attention by prescribers may mitigate adverse effects associated with antipsychotic medications. PMID:28718324
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Silvestre, Jordi S; O'Neill, Michael F; Prous, Josep R
2014-04-01
Blockade of the cardiac hERG channel is recognized as the main mechanism underlying the QT prolongation induced by many classes of drugs, including antipsychotics. However, antipsychotics interact with a variety of other pharmacological targets that could also modulate cardiac function. The present study aims to identify those key factors involved in the QT prolongation induced by antipsychotics. The interactions of 28 antipsychotics were measured on a variety of pharmacological targets. Binding affinity (K(i)), functional channel blockade (IC₅₀), and the corresponding ratios to total and free plasma drug concentration were compared with the corrected QT changes (QTc) associated with the therapeutic use of these drugs by multivariable linear regression analysis to determine the best predictors of QTc. Besides confirming hERG as the primary predictor of QTc, all analyses consistently show the concomitant involvement of Na(V)1.5 channel as modulating factor of the QTc related to hERG blockade. In particular, the hERG/Na(V)1.5 ratio explains the 57% of the overall QTc variability associated with antipsychotics. Since it is known that inhibition of late I Na could offset the dysfunctional effects of hERG blockade, we hypothesize the inhibition of late I(Na) as a crucial compensatory mechanism of the QTc associated with antipsychotics and hence an important factor to consider concomitantly with hERG blockade to appraise the arrhythmogenic risk of these drugs more accurately.
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Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug.
Zuardi, A W; Crippa, J A S; Hallak, J E C; Moreira, F A; Guimarães, F S
2006-04-01
A high dose of delta9-tetrahydrocannabinol, the main Cannabis sativa (cannabis) component, induces anxiety and psychotic-like symptoms in healthy volunteers. These effects of delta9-tetrahydrocannabinol are significantly reduced by cannabidiol (CBD), a cannabis constituent which is devoid of the typical effects of the plant. This observation led us to suspect that CBD could have anxiolytic and/or antipsychotic actions. Studies in animal models and in healthy volunteers clearly suggest an anxiolytic-like effect of CBD. The antipsychotic-like properties of CBD have been investigated in animal models using behavioral and neurochemical techniques which suggested that CBD has a pharmacological profile similar to that of atypical antipsychotic drugs. The results of two studies on healthy volunteers using perception of binocular depth inversion and ketamine-induced psychotic symptoms supported the proposal of the antipsychotic-like properties of CBD. In addition, open case reports of schizophrenic patients treated with CBD and a preliminary report of a controlled clinical trial comparing CBD with an atypical antipsychotic drug have confirmed that this cannabinoid can be a safe and well-tolerated alternative treatment for schizophrenia. Future studies of CBD in other psychotic conditions such as bipolar disorder and comparative studies of its antipsychotic effects with those produced by clozapine in schizophrenic patients are clearly indicated.
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Rizzo, Francesca; Nespoli, Ester; Abaei, Alireza; Bar-Gad, Izhar; Deelchand, Dinesh K.; Fegert, Jörg; Rasche, Volker; Hengerer, Bastian; Boeckers, Tobias M.
2018-01-01
Tourette’s syndrome (TS) is a neurodevelopmental disorder characterized primarily by motor and vocal tics. Comorbidities such as attention deficit and hyperactivity disorder (ADHD) are observed in over 50% of TS patients. We applied aripiprazole in a juvenile rat model that displays motor tics and hyperactivity. We additionally assessed the amount of ultrasonic vocalizations (USVs) as an indicator for the presence of vocal tics and evaluated the changes in the striatal neurometabolism using in vivo proton magnetic resonance spectroscopy (1H-MRS) at 11.7T. Thirty-one juvenile spontaneously hypertensive rats (SHRs) underwent bicuculline striatal microinjection and treatment with either aripiprazole or vehicle. Control groups were sham operated and sham injected. Behavior, USVs, and striatal neurochemical profile were analyzed at early, middle, and late adolescence (postnatal days 35 to 50). Bicuculline microinjections in the dorsolateral striatum induced motor tics in SHR juvenile rats. Acute aripiprazole administration selectively reduced both tic frequency and latency, whereas stereotypies, USVs, and hyperactivity remained unaltered. The striatal neurochemical profile was only moderately altered after tic-induction and was not affected by systemic drug treatment. When applied to a young rat model that provides high degrees of construct, face, and predictive validity for TS and comorbid ADHD, aripiprazole selectively reduces motor tics, revealing that tics and stereotypies are distinct phenomena in line with clinical treatment of patients. Finally, our 1H-MRS results suggest a critical revision of the striatal role in the hypothesized cortico-striatal dysregulation in TS pathophysiology. PMID:29487562
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Sparkman, Nathan L.; Li, Ming
2016-01-01
Patients with schizophrenia often have anxiety and depression, and thus are treated with multiple psychotherapeutic medications. This practice of polypharmacy increases the possibility for drug–drug interactions. However, the pharmacological and behavioral mechanisms underlying drug–drug interactions in schizophrenia remain poorly understood. In the present study, we adopted a preclinical approach and examined a less known behavioral mechanism, drug–drug conditioning (DDC) between haloperidol (a typical antipsychotic) or olanzapine (atypical antipsychotic) and citalopram (a selective serotonin reuptake inhibitor). A rat two-way conditioned avoidance response paradigm was used to measure antipsychotic activity and determine how DDC may alter the antipsychotic efficacy in this model. Following acquisition of the avoidance response, rats were then randomly assigned to receive vehicle, citalopram (10.0 mg/kg, intraperitoneally), haloperidol (0.05 mg/kg, subcutaneously), olanzapine (1.0 mg/kg, subcutaneously), combined haloperidol with citalopram, or combined olanzapine with citalopram treatment for seven avoidance test sessions. In comparison with antipsychotic treatment alone, combined treatment with citalopram potentiated the antiavoidance effect of olanzapine or haloperidol (to a lesser extent) during the seven drug-test sessions. In addition, repeated pairing of citalopram with haloperidol or olanzapine caused citalopram to show a newly acquired avoidance-disruptive effect. This effect was context specific because citalopram paired with haloperidol or olanzapine outside the avoidance testing context (i.e. home cages) did not show such an effect. These findings indicate that concurrent antidepressant and antipsychotic treatments may engender a DDC process that follows the general Pavlovian associative conditioning principles. They also indicate that adjunctive citalopram treatment may enhance the antipsychotic efficacy of haloperidol and olanzapine in the treatment of schizophrenia. PMID:22903071
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Pharmacological interventions for borderline personality disorder
Stoffers, Jutta; Völlm, Birgit A; Rücker, Gerta; Timmer, Antje; Huband, Nick; Lieb, Klaus
2014-01-01
Background Drugs are widely used in borderline personality disorder (BPD) treatment, chosen because of properties known from other psychiatric disorders (“off-label use”), mostly targeting affective or impulsive symptom clusters. Objectives To assess the effects of drug treatment in BPD patients. Search methods We searched bibliographic databases according to the Cochrane Developmental, Psychosocial and Learning Problems Group strategy up to September 2009, reference lists of articles, and contacted researchers in the field. Selection criteria Randomised studies comparing drug versus placebo, or drug versus drug(s) in BPD patients. Outcomes included total BPD severity, distinct BPD symptom facets according to DSM-IV criteria, associated psychopathology not specific to BPD, attrition and adverse effects. Data collection and analysis Two authors selected trials, assessed quality and extracted data, independently. Main results Twenty-eight trials involving a total of 1742 trial participants were included. First-generation antipsychotics (flupenthixol decanoate, haloperidol, thiothixene); second-generation antipsychotics (aripirazole, olanzapine, ziprasidone), mood stabilisers (carbamazepine, valproate semisodium, lamotrigine, topiramate), antidepressants (amitriptyline, fluoxetine, fluvoxamine, phenelzine sulfate, mianserin), and dietary supplementation (omega-3 fatty acid) were tested. First-generation antipsychotics were subject to older trials, whereas recent studies focussed on second-generation antipsychotics and mood stabilisers. Data were sparse for individual comparisons, indicating marginal effects for first-generation antipsychotics and antidepressants. The findings were suggestive in supporting the use of second-generation antipsychotics, mood stabilisers, and omega-3 fatty acids, but require replication, since most effect estimates were based on single studies. The long-term use of these drugs has not been assessed. Adverse event data were scarce, except for olanzapine. There was a possible increase in self-harming behaviour, significant weight gain, sedation and changes in haemogram parameters with olanzapine. A significant decrease in body weight was observed with topiramate treatment. All drugs were well tolerated in terms of attrition. Direct drug comparisons comprised two first-generation antipsychotics (loxapine versus chlorpromazine), first-generation antipsychotic against antidepressant (haloperidol versus amitriptyline; haloperidol versus phenelzine sulfate), and second-generation antipsychotic against antidepressant (olanzapine versus fluoxetine). Data indicated better outcomes for phenelzine sulfate but no significant differences in the other comparisons, except olanzapine which showed more weight gain and sedation than fluoxetine. The only trial testing single versus combined drug treatment (olanzapine versus olanzapine plus fluoxetine; fluoxetine versus fluoxetine plus olanzapine) yielded no significant differences in outcomes. Authors’ conclusions The available evidence indicates some beneficial effects with second-generation antipsychotics, mood stabilisers, and dietary supplementation by omega-3 fatty acids. However, these are mostly based on single study effect estimates. Antidepressants are not widely supported for BPD treatment, but may be helpful in the presence of comorbid conditions. Total BPD severity was not significantly influenced by any drug. No promising results are available for the core BPD symptoms of chronic feelings of emptiness, identity disturbance and abandonment. Conclusions have to be drawn carefully in the light of several limitations of the RCT evidence that constrain applicability to everyday clinical settings (among others, patients’ characteristics and duration of interventions and observation periods). PMID:20556762
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Understanding epigenetics of schizophrenia in the backdrop of its antipsychotic drug therapy.
Swathy, Babu; Banerjee, Moinak
2017-05-01
The diatheses of gene and environment interaction in schizophrenia (SCZ) are becoming increasingly evident. Genetic and epigenetic backgrounds are being considered in stratifying and addressing phenotypic variation and drug response in SCZ. But how much of these epigenetic alterations are the primary contributing factor, toward disease pathogenesis and drug response, needs further clarity. Evidence indicates that antipsychotic drugs can also alter the epigenetic homeostasis thereby inducing pharmacoepigenomic effects. We re-examine the context of epigenetics in disease pathogenesis and antipsychotic drug therapy in SCZ to understand how much of these observations act as real indicators of the disease or therapeutic response. We propose that epigenetic viewpoint in SCZ needs to be critically examined under the genetic, epigenetic and pharmacoepigenetic background.
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Psychedelics and schizophrenia.
González-Maeso, Javier; Sealfon, Stuart C
2009-04-01
Research on psychedelics such as lysergic acid diethylamide (LSD) and dissociative drugs such as phencyclidine (PCP) and the symptoms, neurochemical abnormalities and treatment of schizophrenia have converged. The effects of hallucinogenic drugs resemble some of the core symptoms of schizophrenia. Some atypical antipsychotic drugs were identified by their high affinity for serotonin 5-HT(2A) receptors, which is also the target of LSD-like drugs. Several effects of PCP-like drugs are strongly affected by both 5-HT(2A) and metabotropic glutamate 2/3 receptor modulation. A serotonin-glutamate receptor complex in cortical pyramidal neurons has been identified that might be the target both of psychedelics and the atypical and glutamate classes of antipsychotic drugs. Recent results on the receptor, signalling and circuit mechanisms underlying the response to psychedelic and antipsychotic drugs might lead to unification of the serotonin and glutamate neurochemical hypotheses of schizophrenia.
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Mixed states in bipolar disorder - changes in DSM-5 and current treatment recommendations.
Betzler, Felix; Stöver, Laura Apollonia; Sterzer, Philipp; Köhler, Stephan
2017-11-01
Mixed states in affective disorders represent a particular challenge in clinical routine, characterized by a complicated course of treatment and a worse treatment response. Clinical features of mixed states and the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria are presented and critical discussed. We then performed a systematic review using the terms 'bipolar', 'mixed' and 'randomized' to evaluate current treatment options. For pharmacological treatment of mixed states in total, there is still insufficient data from RCTs. However, there is some evidence for efficacy in mixed states from RCTs for atypical antipsychotics, especially olanzapine, aripiprazole and asenapine as well as mood stabilizers as valproate and carbamazepine. Mixed states are of a high clinical relevance and the DSM-5 criteria substantially reduced the diagnostic threshold. Besides advantages of a better characterization of patients with former DSM-IV-defined mixed episodes, disadvantages arise for example differential diagnoses with a substantial overlap in symptoms such as borderline personality disorders. Atypical antipsychotics, valproate and carbamazepine demonstrated efficacy in a limited sample of RCTs. The number of RCTs in the treatment of mixed states is highly limited. Furthermore, nearly all studies were funded by pharmaceutical companies which may lead to an underestimation of classical mood stabilizers such as lithium.
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Popolo, Raffaele; Vinci, Giancarlo; Balbi, Andrea
2010-03-01
Abstract Objective. The majority of patients with schizophrenia have cognitive deficits early in the disease. We evaluated the relationship between cognitive function, social functioning and quality of life in patients with first-episode psychosis. Methods. This was a longitudinal study in 15 patients aged 18-30 years who had recently experienced a first psychotic episode and were treated with the atypical antipsychotic aripiprazole, cognitive-behavioural therapy, psycho-educational sessions, family supportive sessions and social interventions. Patients were evaluated at baseline and after 1 year. Cognitive assessment included attention, memory, language skills and problem solving. Social functioning, quality of life, and psychopathological evaluation were performed with validated tools. Results. At baseline, patients had a severe impairment of social functioning and a low quality of life, while a specific pattern of cognitive functions was not identified. After 1-year, we observed a significant improvement in social functioning and quality of life, without a significant decrease in cognitive function. Conclusion. Contrary to previous findings, we found that social functioning and quality of life are related, but independent of cognitive impairment. The use of antipsychotic agents that do not interefere with cognitive function plus psychological assistance is a valuable treatment approach in patients with first-episode schizophrenia.
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Antipsychotics and Amotivation
Fervaha, Gagan; Takeuchi, Hiroyoshi; Lee, Jimmy; Foussias, George; Fletcher, Paul J; Agid, Ofer; Remington, Gary
2015-01-01
Antipsychotic drugs are thought to produce secondary negative symptoms, which can also exacerbate primary negative symptoms. In the present study, we examined whether motivational deficits in particular were related to antipsychotic treatment in patients with schizophrenia in a dose-dependent manner. Five hundred and twenty individuals with schizophrenia who were receiving antipsychotic monotherapy for at least 6 months and followed prospectively were included in the present study. Participants were receiving one of five antipsychotic medications (olanzapine, perphenazine, quetiapine, risperidone, or ziprasidone), and analyses were conducted for patients receiving each drug separately. Analysis of covariance models were constructed to examine the effect of antipsychotic dose on level of motivational impairment, controlling for selected demographic and clinical variables (eg, positive symptoms). Level of motivation, or deficits therein, were evaluated using a derived measure from the Quality of Life Scale, and in addition with scores derived from the Positive and Negative Syndrome Scale. Antipsychotic dose was not related to the level of amotivation for any of the medications examined. Moreover, severity of sedation was not significantly related to the degree of amotivation. One hundred and twenty-one individuals were identified as antipsychotic-free at baseline, and after 6 months of antipsychotic treatment, no change in motivation was found. Chronic treatment with antipsychotics does not necessarily impede or enhance goal-directed motivation in patients with schizophrenia. It is possible that the negative impact of antipsychotics in this regard is overstated; conversely, the present results also indicate that we must look beyond antipsychotics in our efforts to improve motivation. PMID:25567425
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Antipsychotics and amotivation.
Fervaha, Gagan; Takeuchi, Hiroyoshi; Lee, Jimmy; Foussias, George; Fletcher, Paul J; Agid, Ofer; Remington, Gary
2015-05-01
Antipsychotic drugs are thought to produce secondary negative symptoms, which can also exacerbate primary negative symptoms. In the present study, we examined whether motivational deficits in particular were related to antipsychotic treatment in patients with schizophrenia in a dose-dependent manner. Five hundred and twenty individuals with schizophrenia who were receiving antipsychotic monotherapy for at least 6 months and followed prospectively were included in the present study. Participants were receiving one of five antipsychotic medications (olanzapine, perphenazine, quetiapine, risperidone, or ziprasidone), and analyses were conducted for patients receiving each drug separately. Analysis of covariance models were constructed to examine the effect of antipsychotic dose on level of motivational impairment, controlling for selected demographic and clinical variables (eg, positive symptoms). Level of motivation, or deficits therein, were evaluated using a derived measure from the Quality of Life Scale, and in addition with scores derived from the Positive and Negative Syndrome Scale. Antipsychotic dose was not related to the level of amotivation for any of the medications examined. Moreover, severity of sedation was not significantly related to the degree of amotivation. One hundred and twenty-one individuals were identified as antipsychotic-free at baseline, and after 6 months of antipsychotic treatment, no change in motivation was found. Chronic treatment with antipsychotics does not necessarily impede or enhance goal-directed motivation in patients with schizophrenia. It is possible that the negative impact of antipsychotics in this regard is overstated; conversely, the present results also indicate that we must look beyond antipsychotics in our efforts to improve motivation.
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Effect of Environmental Cues on Behavioral Efficacy of Haloperidol, Olanzapine and Clozapine in Rats
Sun, Tao; Liu, Xinfeng; Li, Ming
2014-01-01
Previous studies have reported that context can powerfully modulate the inhibitory effect of an antipsychotic drug on phencyclidine (PCP)-induced hyperlocomotion (a behavioral test used to evaluate putative antipsychotic drugs). The present study investigated the experimental conditions under which environmental stimuli exert their influence through associative conditioning processes. Experiment 1 examined the extent to which prior antipsychotic treatment in the home cages affected a drug’s ability to inhibit PCP-induced hyperlocomotion in a novel motor activity test apparatus. Five days of repeated haloperidol (0.05 mg/kg, sc) and olanzapine (2.0 mg/kg, sc) treatment in the home cages still potentiated their inhibition of PCP-induced hyperlocomotion (i.e. sensitization) assessed in a new environment, whereas the clozapine (10.0 mg/kg, sc) treatment enhanced the development of clozapine tolerance, indicating a lack of environmental modulation of antipsychotic efficacy. Experiment 2 assessed the impact of different numbers of antipsychotic administrations in either the home environment or test environment (e.g. 4, 2 or 0) on a drug’s ability to inhibit PCP-induced hyperlocomotion. Repeated administration of clozapine (5.0 mg/kg, sc) or olanzapine (1.0 mg/kg, sc) for 4 consecutive days, regardless of where these treatments occurred, caused a similar level of inhibition on PCP-induced hyperlocomotion. However, 4-day haloperidol (0.03 mg/kg, sc) treatment in the test apparatus caused a significant higher inhibition than 4-day home cage treatment. Thus, more exposures to the test environment under the influence of haloperidol (but not clozapine or olanzapine) cause a stronger inhibition than fewer exposures, indicating a strong environmental modulation. Collectively, these findings suggest that prior antipsychotic treatment in one environment could alter later antipsychotic-like response assessed in a different environment under certain test conditions. Therefore, whether the circumstances surrounding antipsychotic drug administration exert a powerful control of the expression of antipsychotic-like efficacy is dependent on specific experimental and drug treatment factors. PMID:24949569
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Biagiarelli, Mario; Curto, Martina; Di Pomponio, Ileana; Comparelli, Anna; Baldessarini, Ross J; Ferracuti, Stefano
2017-05-01
The Rorschach-based Perceptual Thinking Index (PTI) is used to identify and rate features of psychotic disorders, but effects of antipsychotic treatment on such ratings is not clear. Accordingly, we examined potential effects of antipsychotic drugs on PTI measures in 114 patients with a psychotic or bipolar-I disorder. Use and doses of antipsychotic drugs (as chlorpromazine-equivalent [CPZ-eq] mg/day) were unrelated to PTI total or subscale scores in any diagnostic group. PTI scores were independently and significantly associated with psychotic symptomatic severity (PANSS score) and less with female sex. These findings support the validity and value of the PTI in identifying features of psychosis even in the presence of antipsychotic treatment. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.
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Perez-Iglesias, Rocio; Vazquez-Barquero, Jose Luis; Amado, Jose Antonio; Berja, Ana; Garcia-Unzueta, Maria Teresa; Pelayo-Terán, Jose María; Carrasco-Marín, Eugenio; Mata, Ignacio; Crespo-Facorro, Benedicto
2008-06-01
Weight gain has become one of the most common and concerning side effects of antipsychotic treatment. The mechanisms whereby antipsychotics induce weight gain are not known. It has been suggested that peptides related to food intake and energy balance could play a role in weight gain secondary to antipsychotic therapy. To better understand the pathophysiology of antipsychotic-induced weight gain, we studied the effects of 3 antipsychotic drugs (haloperidol, olanzapine, and risperidone) on peptides involved in energy balance (insulin, ghrelin, leptin, adiponectin, visfatin, and resistin) in a population of drug-naive patients with first episode of psychosis.A significant increase in weight (10.16 kg [SD, 8.30 kg]; P < 0.001), body mass index (3.56 kg/m [SD, 2.89 kg/m]; P < 0.001), and fasting insulin (3.93 muU/mL [SD, 3.93 muU/mL]; P = 0.028), leptin (6.76 ng/mL [SD, 7.21 ng/mL]; P < 0.001), and ghrelin (15.47 fmol/mL [SD, 47.90 fmol/mL]; P = 0.009) plasma levels were observed. The increments in insulin and leptin concentrations were highly correlated with the increment in weight and body mass index and seem to be a consequence of the higher fat stores. The unexpected increase in ghrelin levels might be related with the causal mechanism of weight gain induced by antipsychotics. Finally, the 3 antipsychotics had similar effects in all parameters evaluated.
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Bartoli, Francesco; Clerici, Massimo; Di Brita, Carmen; Riboldi, Ilaria; Crocamo, Cristina; Carrà, Giuseppe
2018-04-01
Randomised placebo-controlled trials investigating treatments for bipolar disorder have been hampered by wide variations of active drugs and placebo clinical response rates. It is important to estimate whether the active drug or placebo response has a greater influence in determining the relative efficacy of drugs for psychosis (antipsychotics) and relapse prevention (mood stabilisers) for bipolar depression and mania. We identified 53 randomised, placebo-controlled trials assessing antipsychotic or mood stabiliser monotherapy ('active drugs') for bipolar depression or mania. We carried out random-effects meta-regressions, estimating the influence of active drugs and placebo response rates on treatment relative efficacy. Meta-regressions showed that treatment relative efficacy for bipolar mania was influenced by the magnitude of clinical response to active drugs ( p=0.002), but not to placebo ( p=0.60). On the other hand, treatment relative efficacy for bipolar depression was influenced by response to placebo ( p=0.047), but not to active drugs ( p=0.98). Despite several limitations, our unexpected findings showed that antipsychotics / mood stabilisers relative efficacy for bipolar depression seems unrelated to active drugs response rates, depending only on clinical response to placebo. Future research should explore strategies to reduce placebo-related issues in randomised, placebo-controlled trials for bipolar depression.
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Antipsychotic prescribing in older people.
Neil, Wendy; Curran, Stephen; Wattis, John
2003-09-01
Antipsychotic medications have made a significant contribution to the care of the mentally ill people over the past 50 years, with good evidence that both typical and atypical agents are effective in the treatment of schizophrenia and related conditions. In addition they are widely used to good effect in other disorders including psychotic depression, dementia and delirium. Both typical and atypical agents may cause severe side-effects and, in the elderly in particular, there is an increased propensity for drug interactions. If used with care, antipsychotics are usually well tolerated, especially the atypical drugs. Although antipsychotics are effective at reducing psychotic symptoms their limitations should be recognised. They do not 'cure' the underlying illness, and the management of psychotic and behavioural symptoms must take into consideration treatment of physical illness as well as psychosocial interventions. In addition, the antipsychotic effect may take one to two weeks to be evident so doses should not be increased too rapidly. Often small doses are effective in the elderly if they are given sufficient time to work. As our understanding of the mechanisms of psychosis improves it is hoped that new drugs will be developed with novel mechanisms of action with improved efficacy and reduced side-effects. There are several drugs in development, some sharing similarities to currently available agents whilst others have novel mechanisms of actions involving glutamate and nicotinic receptors. Pharmacogenetics is also likely to be increasingly important over the next few years. As the genetic basis of many psychiatric disorders becomes more clearly established it is likely that drugs specifically designed for particular sub-groups of receptors will be developed. Finally, although the pharmacological treatment of psychotic disorders in younger people has been given considerable attention, there is a paucity of good quality research on antipsychotic drug use in older people. There is a need to redress this balance to ensure that the prescribing of antipsychotics in older people is evidence based.
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Salzman, C; Jeste, D; Meyer, RE; Cohen-Mansfield, J; Cummings, J; Grossberg, G; Jarvik, L; Kraemer, H; Lebowitz, B; Maslow, K; Pollock, B; Raskind, M; Schultz, S; Wang, P; Zito, JM; Zubenko, GS
2009-01-01
Atypical antipsychotic drugs have been used off-label in clinical practice for treatment of serious dementia-associated agitation and aggression. Following reports of cerebrovascular adverse events associated with the use of atypical antipsychotic in elderly patients with dementia, the FDA issued black box warnings for several atypical antipsychotics, titled “Cerebrovascular Adverse Events, including Stroke, in Elderly Patients with Dementia.” Subsequently, the FDA initiated a meta-analysis of safety data from 17 registration trials across six antipsychotic drugs (five atypical antipsychotics and haloperidol). In 2005, the Agency issued a black box warning regarding increased risk of mortality associated with the use of atypical antipsychotic drugs in this patient population. Geriatric mental health experts participating in a 2006 consensus conference reviewed evidence on the safety and efficacy of antipsychotics, as well as nonpharmacologic approaches, in treating dementia-related symptoms of agitation and aggression. They concluded that, while problems in clinical trials design may have been one of the contributors to the failure to find a signal of drug efficacy, the findings related to drug safety should be taken seriously by clinicians in assessing the potential risks and benefits of treatment in a frail population, and in advising families about treatment. Information provided to patients and family members should be documented in the patient’s chart. Drugs should be used only when non-pharmacologic approaches have failed to adequately control behavioral disruption. Participants also agreed that that there is a need for an FDA-approved medication for the treatment of severe, persistent or recurrent dementia-related symptoms of agitation and aggression (even in the absence of psychosis), that are unresponsive to nonpharmacologic intervention. The authors have outlined methodological enhancements to better evaluate treatment approaches in future registration trials, and they provided an algorithm for improving the treatment of these patients in nursing home and non-nursing home settings. PMID:18494535
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Aripiprazole and Acute Extrapyramidal Symptoms in Children and Adolescents: A Meta-Analysis.
Bernagie, Chiara; Danckaerts, Marina; Wampers, Martien; De Hert, Marc
2016-09-01
Both the US FDA and the European Medicines Agency (EMA) have approved aripiprazole for use in adolescents for specific indications. Given the assumed favorable side-effect profile of aripiprazole, its use in children and adolescents has increased for both official and off-label indications (anxiety disorders, eating disorders, personality disorders). However, several cases of children and adolescents with new-onset extrapyramidal symptoms (EPS) after commencing treatment with aripiprazole have been reported, and a more systematic appraisal of this possible risk is lacking. We conducted a systematic review and a meta-analysis to assess the evidence for acute EPS (acute dystonia, akathisia, Parkinsonism) associated with the use of aripiprazole in children and adolescents. We searched the MEDLINE and Embase databases (2003-10 April 2016) for clinical trials in pediatric patients (aged 0-18 years) using the keywords 'aripiprazole' (regardless of the formulation) and 'extrapyramidal symptoms'. We evaluated the abstracts of papers using the following exclusion criteria: (1) study design: case report, letter to the editor, editorial, or poster presentation data; (2) unrelated PICOS (population, intervention, comparators, outcomes, study) structure. We performed a meta-analysis, in which we used effect sizes with 95 % confidence intervals (CIs). To examine the homogeneity of the effect size distribution, we used a Q-statistic. When we observed heterogeneity in effect sizes, we assessed the possible influence of moderator variables (age and sex, mean dose, study duration, and method of measuring EPS incidence) and evaluated the suitability of either a fixed or a random model. Finally, we assessed the incidence of EPS in children and adolescents treated with aripiprazole compared with placebo. An initial search via PubMed and Embase yielded 328 hits. A manual search of the reference lists of review papers revealed seven additional relevant articles. We included 41 studies, with 2114 pediatric patients, in the meta-analysis. For the analysis of the mean incidence of EPS, data were provided by 24 studies, with a total of 1446 pediatric patients. Meta-analysis revealed a mean EPS incidence of 17.1 % (95 % CI 0.128-0.223). In terms of the incidence of various extrapyramidal side effects, overall, no significant effects of age, sex, mean dose, study duration, or measuring method could be demonstrated. The side effects 'EPS', 'parkinsonism', and 'tremor' were significantly more common in children and adolescents treated with aripiprazole than in those treated with placebo. Our meta-analysis provides evidence for a non-negligible incidence of acute EPS in children and adolescents treated with aripiprazole. Although the study has several limitations and further investigation is needed, these findings may help clinicians make more balanced treatment choices and more closely monitor the use of this drug in youth.
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Seibt, Kelly Juliana; Oliveira, Renata da Luz; Zimmermann, Fernanda Francine; Capiotti, Katiúcia Marques; Bogo, Maurício Reis; Ghisleni, Gabriele; Bonan, Carla Denise
2010-12-25
Glutamate N-methyl-d-aspartate (NMDA) receptor antagonists, such as dizocilpine (MK-801), elicit schizophrenia-like symptoms in humans and a behavioral syndrome in rodents, characterized by hyperlocomotion and stereotyped actions, which is antagonized by antipsychotic drugs. Animal models of schizophrenia have been established and used for the development of new antipsychotic drugs. In this work we characterized the behavioral effects of MK-801 and investigated the effect of typical and atypical antipsychotic treatments on locomotor activity as well on the hyperlocomotion induced by MK-801 in zebrafish. MK-801 (20 microM) increased the locomotor behavior as measured by the number of line crossings, distance traveled, and the mean speed in the tank test after 15, 30, and 60 min of exposure. All tested antipsychotics counteracted MK-801-induced hyperactivity on all parameters analyzed and at doses that, given alone, had no effect on spontaneous locomotor activity. The results suggest a similar profile between typical and atypical antipsychotics in the reversal of locomotor disorders induced by MK-801. Moreover, an anxiolytic effect was verified at 30 and 60 min of MK-801 exposure, which was not reversed by antipsychotics tested in this work. In addition, olanzapine, which alone caused an anxiolytic response, when given with MK-801 potentiated the latter's effect on anxiety. In this work we demonstrated the value of the zebrafish, a simple to use animal model, in developing some behavioral features observed in schizophrenia, which may indicate a new approach for drug screening. Copyright (c) 2010 Elsevier B.V. All rights reserved.
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Effect of second-generation antipsychotics on cognition: current issues and future challenges
Hill, S Kristian; Bishop, Jeffrey R; Palumbo, Donna; Sweeney, John A.
2010-01-01
Generalized cognitive impairments are stable deficits linked to schizophrenia and key factors associated with functional disability in the disorder. Preclinical data suggest that second-generation antipsychotics could potentially reduce cognitive impairments; however, recent large clinical trials indicate only modest cognitive benefits relative to first-generation antipsychotics. This might reflect a limited drug effect in humans, a differential drug effect due to brain alterations associated with schizophrenia, or limited sensitivity of the neuropsychological tests for evaluating cognitive outcomes. New adjunctive procognitive drugs may be needed to achieve robust cognitive and functional improvement. Drug discovery may benefit from greater utilization of translational neurocognitive biomarkers to bridge preclinical and clinical proof-of-concept studies, to optimize assay sensitivity, enhance cost efficiency, and speed progress in drug development. PMID:20021320
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Birkenhäger-Gillesse, Elizabeth G; Kollen, Boudewijn J; Achterberg, Wilco P; Boersma, Froukje; Jongman, Lydia; Zuidema, Sytse U
2018-03-01
Dementia is often accompanied by neuropsychiatric symptoms. Psychotropic drugs for the treatment of neuropsychiatric symptoms are frequently used to manage these problems, but they are of limited effectiveness and can have serious side effects. Psychosocial interventions are advocated as first line treatment and may help to reduce psychotropic drug use. To assess the effect of multidisciplinary psychosocial interventions in nursing homes on the psychotropic drug prescription rate. Literature obtained from searches in 9 electronic databases was systematically reviewed. In addition, the pooled effects of specific psychosocial interventions in homogenous subgroups were analyzed (meta-analysis). Eleven randomized controlled studies that investigated multiple psychotropic drugs interventions (psychotropic drugs in 3, antipsychotics in 9, and antidepressants in 5 studies) as well as different types of psychosocial interventions were included. We separately analyzed interventions directed at the care staff level (educational programs in 3, in-reach services or consultation in 1, cultural or process change in 6 studies) and the individual resident level in 1 study. In 7 out of 9 studies reporting on antipsychotic drug use, the physician was actively involved. Nine studies in which antipsychotic drug use was specified reported a significant decrease in prescription rate as a result of psychosocial interventions [relative risk (RR) 0.71, 95% confidence interval (CI) 0.59-0.88], whereas meta-analysis of 5 studies investigating antidepressant drug use failed to show a significant effect (RR 0.82, 95% CI 0.64-1.02). Pooled effect sizes of 6 studies investigating cultural change, showed a significant decrease in antipsychotic drug use (RR 0.65, 95% CI 0.57-0.73). Effect sizes of 2 studies on educational programs on antipsychotic use were nonsignificant (RR 1.50, 95% CI 0.49-4.64). Sensitivity analysis of 7 studies reporting on antipsychotic drug use involving prescribing physicians showed a more robust decrease (RR 0.66, 95% CI 0.54-0.80). The results of this study show that psychosocial interventions may lead to a substantial reduction of antipsychotic drug prescription, especially in studies that reported on cultural change and that involved prescribing physicians. Conspicuously, a profound lack of information was observed in many studies as to what exactly constituted the care-as-usual treatment in the control group. Copyright © 2018 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.
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Zhu, Qingxia; Yu, Xiaoyan; Wu, Zebing; Lu, Feng; Yuan, Yongfang
2018-07-19
Antipsychotics are the drugs most often involved in drug poisoning cases, and therefore, therapeutic drug monitoring (TDM) is necessary for safe and effective medication administration of these drugs. In this study, a coffee ring effect-based surface-enhanced Raman spectroscopy (CRE-SERS) method was developed and successfully used to monitor antipsychotic poisoning by using urine samples for the first time. The established method exhibited excellent SERS performance since more hot spots were obtained in the "coffee ring". Using the optimized CRE-SERS method, the sensitivity was improved one order more than that of the conventional method with reasonable reproducibility. The antipsychotic drug clozapine (CLO) spiked into urine samples at 0.5-50 μg mL -1 was quantitatively detected, at concentrations above the thresholds for toxicity. The CRE-SERS method allowed CLO and its metabolites to be ultimately distinguished from real poisoning urine samples. The coffee-ring effect would provide more opportunities for practical applications of the SERS-based method. The frequent occurrence of drug poisoning may have created a new area for the application of the CRE-SERS method. It is anticipated that the developed method will also have great potential for other drug poisoning monitoring. Copyright © 2018 Elsevier B.V. All rights reserved.
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Smith, R C; Segman, R H; Golcer-Dubner, T; Pavlov, V; Lerer, B
2008-06-01
Schizophrenic patients who are treated with antipsychotics, especially second generation antipsychotics, such as clozapine and olanzapine, manifest an increase in cholesterol and triglycerides as well as other changes associated with diabetes or the metabolic syndrome. Previous studies have shown that polymorphisms in several genes that regulate lipid metabolism can influence the levels of these lipids and response to drug treatment. We have investigated in an exploratory study whether polymorphisms in the apolipoprotein C-III (ApoC3), apolipoprotein A-V gene (ApoA5) and lipoprotein lipase genes influence differential lipid response to treatment with three second generation antipsychotics-olanzapine, clozapine and risperidone-or treatment with a first generation antipsychotic. A total of 189 patients with schizophrenia or schizoaffective disorder who were being treated with a single antipsychotic were studied in a cross-sectional study design in which fasting serum cholesterol and triglycerides and selected single-nucleotide polymorphosms (SNPs) in the three lipid metabolism genes were assessed. The treatment with antipsychotic monotherapy makes drug haplotype ascertainment less complex. Our analyses showed several nominally significant drug x gene and drug x haplotype interactions. The rarer C allele or the ApoA5_1131 (T/C) SNP was associated with higher cholesterol levels in patients treated with first generation antipsychotics and lower cholesterol levels in patients treated with olanzapine or clozapine. The rarer C allele of the ApoA5_SW19 (G/C) SNP was associated with higher cholesterol in risperidone-treated patients. An ApoA5 CG haplotype was associated with decreased cholesterol in olanzapine- or clozapine-treated patients and higher cholesterol in patients treated with first generation antipsychotics. The presence of the rarer T allele of the ApoC3_1100 (C/T) SNP or the presence of the ApoC3 TG haplotype was associated with decreased triglyceride levels in patients treated with olanzapine or clozapine and a nonsignificant trend for increased triglycerides in patients treated with first generation antipsychotics. The presence of the ApoC3 CC haplotype was associated with increased triglycerides in patients treated with olanzapine or clozapine. The overall magnitude of the effects was not large. These results provide a potential initial step toward a pharmacogenetic approach to selection of antipsychotic treatment which may help minimize the side effect of increases in serum lipids.
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Blood Biomarkers Predict the Cognitive Effects of Aripiprazole in Patients with Acute Schizophrenia.
Hori, Hikaru; Yoshimura, Reiji; Katsuki, Asuka; Atake, Kiyokazu; Igata, Ryohei; Konishi, Yuki; Beppu, Hiroki; Tominaga, Hirotaka
2017-03-06
Aripiprazole has been reported to exert variable effects on cognitive function in patients with schizophrenia. Therefore, in the present study, we evaluated biological markers, clinical data, and psychiatric symptoms in order to identify factors that influence cognitive function in patients with schizophrenia undergoing aripiprazole treatment. We evaluated cognitive function in 51 patients with schizophrenia using Brief Assessment of Cognition in Schizophrenia (BACS), as well as background information, psychiatric symptoms, plasma catecholamine metabolites-homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG)-, and serum brain-derived neurotrophic factor (BDNF). Multivariate analyses were performed in order to identify factors independently associated with cognitive function. Brain-derived neurotrophic factor levels, number of hospitalizations, and MHPG levels were associated with verbal memory and learning. Total hospitalization period and MHPG levels were associated with working memory. Age at first hospitalization and education were associated with motor speed. The number of hospital admissions, Positive and Negative Syndrome Scale negative subscale scores (PANSS-N), MHPG levels, BDNF levels, and Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) scores were associated with verbal fluency. Homovanillic acid and MHPG levels, duration of illness, and PANSS-N scores were associated with attention and processing speed. Brain-derived neurotrophic factor and MHPG levels were associated with executive function. These results suggest that treatment of psychiatric symptoms and cognitive dysfunction may be improved in patients treated with aripiprazole by controlling for these contributing factors.
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Early-life risperidone enhances locomotor responses to amphetamine during adulthood.
Lee Stubbeman, Bobbie; Brown, Clifford J; Yates, Justin R; Bardgett, Mark E
2017-10-05
Antipsychotic drug prescriptions for pediatric populations have increased over the past 20 years, particularly the use of atypical antipsychotic drugs such as risperidone. Most antipsychotic drugs target forebrain dopamine systems, and early-life antipsychotic drug exposure could conceivably reset forebrain neurotransmitter function in a permanent manner that persists into adulthood. This study determined whether chronic risperidone administration during development modified locomotor responses to the dopamine/norepinephrine agonist, D-amphetamine, in adult rats. Thirty-five male Long-Evans rats received an injection of one of four doses of risperidone (vehicle, .3, 1.0, 3.0mg/kg) each day from postnatal day 14 through 42. Locomotor activity was measured for 1h on postnatal days 46 and 47, and then for 24h once a week over the next two weeks. Beginning on postnatal day 75, rats received one of four doses of amphetamine (saline, .3, 1.0, 3.0mg/kg) once a week for four weeks. Locomotor activity was measured for 27h after amphetamine injection. Rats administered risperidone early in life demonstrated increased activity during the 1 and 24h test sessions conducted prior to postnatal day 75. Taking into account baseline group differences, these same rats exhibited significantly more locomotor activity in response to the moderate dose of amphetamine relative to controls. These results suggest that early-life treatment with atypical antipsychotic drugs, like risperidone, permanently alters forebrain catecholamine function and increases sensitivity to drugs that target such function. Copyright © 2017 Elsevier B.V. All rights reserved.
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Citrome, Leslie
2016-01-01
Aripiprazole monohydrate (AM) and aripiprazole lauroxil (AL) are two different long-acting injectable formulations of aripiprazole. AM 400 mg administered once monthly demonstrated efficacy in an acute, double-blind, placebo-controlled, randomized clinical trial, as well as in a double-blind, placebo-controlled, randomized-withdrawal maintenance study, and in two non-inferiority maintenance studies. AL is a prodrug of aripiprazole and available in 441 mg, 662 mg or 882 mg strengths. AL 441 mg and 882 mg administered once monthly demonstrated efficacy in an acute, double-blind, placebo-controlled, randomized clinical trial. The pharmacokinetic profile of AL also led to approval of dosing intervals of every 6 weeks for the 882 mg dose. The overall tolerability profiles of both products are consistent with what is known about oral aripiprazole.
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NASA Astrophysics Data System (ADS)
Londhe, Vaishali Y.; Deshmane, Aishwarya B.; Singh, Sarita R.; Kulkarni, Yogesh A.
2018-04-01
Lurasidone hydrochloride (LHD) is an atypical antipsychotic drug has poor aqueous solubility and low bioavailability (9-19%). This study describes effect of different methods of complex formation with β-cyclodextrin (BCD) on enhancement of dissolution and on antidepressant, antipsychotic effects of LHD. Other purpose of this study is to compare pharmacodynamic effects of complexes with that of self microemulsifying drug delivery system of LHD (SMEDDS). Inclusion complexes (IC) of LHD and BCD were prepared by physical mixing (PM), kneading (KN) and spray drying (SD) in a 1:1 M ratio. These complexes were characterized by different techniques. KN and SD showing enhancement in dissolution, were compared with SMEDDS using Forced swim test (FST) and Tail suspension test (TST) for antidepressant action and Paw test for antipsychotic activity. Characterization of complexes confirmed interaction between LHD and BCD. Enhancement in dissolution is seen in following order SD > KN > PM > LHD. In all three animal models, SD, KN and SMEDDS showed statistically significant effect (p < .05) than drug alone showing enhancement in bioavailability. Complexation of LHD with BCD enhances dissolution which reflected in improvement of antidepressant and antipsychotic activity of drug. Solubility enhancement methods like complexation and self microemulsion improves pharmacodynamic activities of drug. Improvement of pharmacodynamic effect is seen in order, SD ≥ SMEDDS ≥ KN > LHD.
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Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs
DOE Office of Scientific and Technical Information (OSTI.GOV)
Farde, L.; Wiesel, F.A.; Halldin, C.
1988-01-01
Using positron emission tomography and the carbon 11-labeled ligand raclopride, central D2-dopamine receptor occupancy in the putamen was determined in psychiatric patients treated with clinical doses of psychoactive drugs. Receptor occupancy in drug-treated patients was defined as the percent reduction of specific carbon 11-raclopride binding in relation to the expected binding in the absence of drug treatment. Clinical treatment of schizophrenic patients with 11 chemically distinct antipsychotic drugs (including both classic and atypical neuroleptics such as clozapine) resulted in a 65% to 85% occupancy of D2-dopamine receptors. In a depressed patient treated with the tricyclic antidepressant nortriptyline, no occupancy wasmore » found. The time course for receptor occupancy and drug levels was followed after withdrawal of sulpiride or haloperidol. D2-dopamine receptor occupancy remained above 65% for many hours despite a substantial reduction of serum drug concentrations. In a sulpiride-treated patient, the dosage was reduced in four steps over a nine-week period and a curvilinear relationship was demonstrated between central D2-dopamine receptor occupancy and serum drug concentrations. The results demonstrate that clinical doses of all the currently used classes of antipsychotic drugs cause a substantial blockade of central D2-dopamine receptors in humans. This effect appears to be selective for the antipsychotics, since it was not induced by the antidepressant nortriptyline.« less
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The effects of antipsychotic switching on diabetes in chronic schizophrenia.
Arnoldy, R; Curtis, J; Samaras, K
2014-03-01
People with severe mental illness have a 20-year life-expectancy shortfall. The majority of antipsychotic medications are associated with obesity and heightened diabetes risk. People with severe mental illness less frequently achieve benchmarked diabetes care, often attributed to poor adherence, lower clinical attendance and documented medical biases in treatment. This case is presented to highlight the profound effect medication change can have on diabetes control. A 56-year-old man with a 42-year history of schizophrenia had required clozapine treatment for the preceding 14 years. Type 2 diabetes and obesity occurred within 4 years of clozapine instigation. Glycaemic control had been continuously poor, despite frequent contact with diabetes services and multiple medications, including insulin at a dose exceeding 200 IU daily. Request for consideration of antipsychotic review and close interaction with the psychiatry team was initiated at the diabetes outpatient clinic. A gradual medication switch from clozapine to aripiprazole was associated with a reduction in HbA(1c) from 80 to 50 mmol/mol (9.5 to 6.7%) over 4 months, associated with a weight loss of 10 kg. Over the ensuing 2 years, the improvement in HbA(1c) has endured, with total weight loss of 13 kg and halving of insulin requirements. This case illustrates the benefits of engagement between endocrinologists and psychiatrists to achieve the shared goal of improved physical health in severe mental illness. Greater interdisciplinary collaboration will help bridge the life-expectancy gap in severe mental illness and may assist in preventing disabling diabetes complications in this vulnerable patient group. © 2013 The Authors. Diabetic Medicine © 2013 Diabetes UK.
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Joshi, Kruti; Lin, Jay; Lingohr-Smith, Melissa; Fu, Dong-Jing; Muser, Erik
2016-01-01
Abstract This study assessed real-world treatment patterns and antipsychotic (AP) medication adherence among commercially insured US patients with schizoaffective disorder (SCA). Continuously insured adults aged 18 years or older with a diagnosis of SCA from January 1, 2009, to December 31, 2012, were identified from the Clinformatics Data Mart database. Patients were categorized into 2 cohorts: incident or prevalent SCA. Demographics and clinical characteristics were evaluated during the baseline period. Use of psychiatric medications and adherence to AP medications were evaluated during a 12-month follow-up period after index diagnosis of SCA. Of the overall study population (N = 2713; mean age, 40.2 y; 52.7% female), 1961 patients (72.3%) (mean age, 38.7 y; 51.3% female) had incident SCA, and 752 patients (27.7%) (mean age, 43.9 y; 56.5% female) had prevalent SCA. Antipsychotics were used by 74.8% of patients in the overall study population during the follow-up period. The most commonly prescribed oral AP was risperidone (23.9%), followed by quetiapine (21.4%) and aripiprazole (20.4%). Use of any long-acting injectable APs in the overall study population during the follow-up period was less than 3%. A total of 49.0% and 38.0% of the overall study population had medication possession ratios and proportion of days covered for APs of 80% or greater, respectively. Overall use of long-acting injectable APs for the treatment of SCA is low, and adherence to AP medications, measured by both medication possession ratio and proportion of days covered, is suboptimal among patients with SCA in the real-world setting. PMID:27525965
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Sochocky, Natalie; Milin, Robert
2013-11-01
Second generation antipsychotics (SGA) have gained increased evidence for the treatment of irritability and aggression in children and adolescents with lower functioning autistic disorder. Individuals with Asperger's Disorder (AD) and High Functioning Autism (HFA) experience significant emotional and behavioral problems and psychiatric comorbidity. There is a need to review the published literature on SGA treatment efficacy in the AD and HFA populations to provide more effective treatment choices for these subgroups. We conducted a systematic review and meta-analysis of the recent English literature on SGA use in children and adolescents (ages 0-24 years) with AD and HFA using the Medline/PubMed and PsychINFO computerized databases. Key search words were 'Asperger', 'high functioning autism', 'autism spectrum disorders (ASD)', and 'pervasive developmental disorder (PDD)' in combination with 'second generation antipsychotics', 'aripiprazole; 'olanzapine', 'quetiapine', 'risperidone', or 'ziprasidone'. Our search yielded 214 citations, however only open-label or randomized-controlled trials (RCT) with ≥25% of their subjects having an IQ≥71 were included in our review. Eleven original studies met our inclusion parameters for review; eight studies for the meta-analysis. These studies, although limited in methodological rigor, and the meta-analytic results suggest that SGAs provide improvement in behavioral symptoms associated with AD and HFA. The majority of the studies reported weight gain as a potentially concerning adverse effect. There is a lack of robustly conducted trials on the use of SGAs in the management of AD and HFA. More research in pharmacological and psychosocial treatments is warranted. Clinicians are cautioned to approach pharmacological treatment prudently balancing benefit with potential cardiometabolic risk.
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Coughlin, Mary; Goldie, Catherine Lindsay; Tranmer, Joan; Khalid-Khan, Sarosh; Tregunno, Deborah
2018-04-01
Children and adolescents with a range of psychiatric disorders are increasingly being prescribed atypical or second-generation antipsychotics (SGAs). While SGAs are effective at treating conduct and behavioural symptoms, they infer significant cardiometabolic risk. This study aims to explore what patient, treatment, and health care utilization variables are associated with adherence to Canadian Alliance for Monitoring Effectiveness and Safety of Antipsychotics in Children (CAMESA) metabolic monitoring guidelines. A retrospective chart review of 294 children and adolescents accessing a large outpatient psychiatry setting within a 2-year study period (2014-2016) was conducted. Baseline and follow-up metabolic monitoring, demographic, treatment, and health care utilization variables were then assessed over a 1-year period of interest. Metabolic monitoring practices did not adhere to CAMESA guidelines and were very poor over the 1-year observation period. There were significant differences between children (ages 4-12 years, n = 99) and adolescents (ages 13-18 years, n = 195). In adolescents, factors associated with any baseline metabolic monitoring were a higher number of psychiatry visits (odds ratio [OR], 1.2; 95% confidence interval [CI], 1.10 to 1.41), longer duration of contact (OR, 14; 95% CI, 2.31 to 82.4), and use of other non-SGA medications (OR, 3.2; 95% CI, 1.17 to 8.94). Among children, having an emergency room visit (OR, 3.4; 95% CI, 1.01 to 11.71) and taking aripiprazole (OR, 7.4; 95% CI, 2.02 to 27.45) increased the odds of receiving baseline metabolic monitoring. Findings from this study highlight the need for better metabolic monitoring for children and adolescents taking SGAs. Enhanced focus on opportunities for multidisciplinary collaboration is needed to improve the quality of care offered to this population.
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Side effect burden of antipsychotic drugs in real life - Impact of gender and polypharmacy.
Iversen, Trude Seselie Jahr; Steen, Nils Eiel; Dieset, Ingrid; Hope, Sigrun; Mørch, Ragni; Gardsjord, Erlend Strand; Jørgensen, Kjetil Nordbø; Melle, Ingrid; Andreassen, Ole A; Molden, Espen; Jönsson, Erik G
2018-03-02
Antipsychotic-associated side effects are well known and represent a significant treatment challenge. Still, few large studies have investigated the overall side effect burden of antipsychotics in real-life settings. To describe the occurrence of side effects and perceived burden of antipsychotics in a large naturalistic sample, taking polypharmacy and patient characteristics into account. Patients (n=1087) with psychotic disorders were assessed for side effects using the Udvalg for Kliniske Undersøgelser (UKU) side effect rating scale in addition to assessment of clinical and pharmacological data. Statistical analyses were performed controlling for possible confounding factors. Use of antipsychotics showed significant associations to neurologic and sexual symptoms, sedation and weight gain, and >75% of antipsychotics-users reported side effects. More side effects were observed in patients using several antipsychotics (p=0.002), with increasing total dose (p=0.021) and with antipsychotics in combinations with other psychotropic drugs. Patients and investigators evaluated the side effect burden differently, particularly related to severity, gender and antipsychotics dose. Twice as many females described side effect burden as severe (p=0.004). Patients with psychotic disorders have a high occurrence of symptoms associated with use of antipsychotics, and polypharmacy and female gender are seemingly risk factors for reporting a severe side effect burden. Due to the cross-sectional design evaluation of causality is tentative, and these findings should be further investigated in prospective studies. Copyright © 2017 Elsevier Inc. All rights reserved.
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Sarkar, Siddharth; Gupta, Nitin
2017-01-01
Neuroleptic malignant syndrome (NMS) is a rare but potentially fatal adverse event associated with the use of antipsychotics. Although atypical antipsychotics were initially considered to carry no risk of NMS, reports have accumulated over time implicating them in NMS causation. Almost all atypical antipsychotics have been reported to be associated with NMS. The clinical profile of NMS caused by certain atypical antipsychotics such as clozapine has been reported to be considerably different from the NMS produced by typical antipsychotics, with diaphoresis encountered more commonly, and rigidity and tremor encountered less frequently. This article briefly discusses the evidence relating to the occurrence, presentation and management of NMS induced by atypical antipsychotics. PMID:28811916
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Sarkar, Siddharth; Gupta, Nitin
2017-08-01
Neuroleptic malignant syndrome (NMS) is a rare but potentially fatal adverse event associated with the use of antipsychotics. Although atypical antipsychotics were initially considered to carry no risk of NMS, reports have accumulated over time implicating them in NMS causation. Almost all atypical antipsychotics have been reported to be associated with NMS. The clinical profile of NMS caused by certain atypical antipsychotics such as clozapine has been reported to be considerably different from the NMS produced by typical antipsychotics, with diaphoresis encountered more commonly, and rigidity and tremor encountered less frequently. This article briefly discusses the evidence relating to the occurrence, presentation and management of NMS induced by atypical antipsychotics.
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Pharmacogenetics of leptin in antipsychotic-associated weight gain and obesity-related complications
Lee, Amy K; Bishop, Jefrey R
2013-01-01
Second-generation antipsychotics can greatly improve symptoms of psychosis-spectrum disorders. Unfortunately, these drugs are associated with weight gain, which increases a patient’s risk for developing chronic diseases including Type 2 diabetes, cardiovascular diseases or other obesity-related complications. There are interindividual differences in weight gain resulting from antipsychotic drug use that may be explained by pharmacodynamic characteristics of these agents as well as clinical factors. In addition, genetic variations in pathways associated with satiety are increasingly recognized as potential contributors to antipsychotic-associated weight gain. Polymorphisms in the leptin gene, as well as the leptin receptor gene, are potential pharmacogenetic markers associated with these outcomes. This article summarizes evidence for the associations of the leptin gene and the leptin receptor gene polymorphisms with antipsychotic-induced weight gain, potential mechanisms underlying these relationships, and discusses areas for future pharmacogenetic investigation. PMID:21787190
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Behavior Disorders in Persons with Mental Retardation Receiving Antipsychotic Medication.
ERIC Educational Resources Information Center
Ono, Yoshiro
1998-01-01
The behavior disorders of 54 Japanese individuals with mental retardation receiving antipsychotic medication were compared to 52 subjects receiving anticonvulsants and 202 subjects without medication. Results found the problem behaviors of subjects receiving antipsychotic drugs were more severe and severity of disability was associated with higher…
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Mazhar, Faizan; Akram, Shahzad; Haider, Nafis; Ahmed, Rafeeque
2016-01-01
Antipsychotic and antidepressant are often used in combination for the treatment of neuropsychiatric disorders. The concomitant use of antipsychotic and/or antidepressant with drugs that may interact can lead to rare, life-threatening conditions such as serotonin syndrome and neuroleptic malignant syndrome. We describe a patient who has a history of taking two offending drugs that interact with drugs given during the course of hospital treatment which leads to the development of serotonin syndrome overlapped with neuroleptic malignant syndrome. The physician should be aware that both NMS and SS can appear as overlapping syndrome especially when patients use a combination of both antidepressants and antipsychotics.
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Formulary decisions and health economics.
Glazer, W M
1998-01-01
Because of increasing concerns about health care costs, physicians must consider the cost-effectiveness of a treatment strategy, as well as its efficacy and safety. The question of whether the greater expense of a newer drug is justified over the cost of a generic drug deserves a comprehensive evaluation. The determination of effectiveness and tolerability of the newer antipsychotics should be expanded to include quality-of-life issues, reintegration of the patient into the community, resource utilization, and medical costs. There are clear indications that patients who take atypical antipsychotics utilize fewer medical resources than patients who take typical antipsychotics; however, the positive outcomes of the newer drugs must be translated into cost benefits if formularies are to be intelligently controlled.
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Muneoka, Katsumasa; Kanahara, Nobuhisa; Kimura, Shou
2017-01-01
The efficacy of a partial agonist for the dopamine D 2 receptor, aripiprazole, for catatonia in schizophrenia has been reported. We report distinct clinical courses in challenging aripiprazole to treat residual mutism after severe catatonic symptoms improved. In the first case, mutism was successfully treated when the patient was switched from olanzapine to aripiprazole. In contract, switching to aripiprazole from risperidone aggravated auditory hallucinations in the second case. We will discuss the benefits and risks of using aripiprazole for the treatment of catatonic schizophrenia and the possibility of dopamine supersensitivity psychosis.
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Experimental treatment of antipsychotic-induced movement disorders
Shireen, Erum
2016-01-01
Antipsychotic drugs are extensively prescribed for the treatment of schizophrenia and other related psychiatric disorders. These drugs produced their action by blocking dopamine (DA) receptors, and these receptors are widely present throughout the brain. Therefore, extended antipsychotic use also leads to severe extrapyramidal side effects. The short-term effects include parkinsonism and the later appearing tardive dyskinesia. Currently available treatments for these disorders are mostly symptomatic and insufficient, and are often linked with a number of detrimental side effects. Antipsychotic-drug-induced tardive dyskinesia prompted researchers to explore novel drugs with fewer undesirable extrapyramidal side effects. Preclinical studies suggest a role of 5-hydroxytryptamine (serotonin)-1A and 2A/2C receptors in the modulation of dopaminergic neurotransmission and motivating a search for better therapeutic strategies for schizophrenia and related disorders. In addition, adjunctive treatment with antioxidants such as vitamin E, red rice bran oil, and curcumin in the early phases of illness may prevent additional oxidative injury, and thus improve and prevent further possible worsening of related neurological and behavioral deficits in schizophrenia. This review explains the role of serotonergic receptors and oxidative stress, with the aim of providing principles for prospect development of compounds to improve therapeutic effects of antischizophrenic drugs. PMID:27540314
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Anand, Ravi; Forrest, Emma C; Hartman, Richard D; Graham, Stephen M; Faravelli, Laura
2018-01-01
Abstract Background Over 70% of schizophrenic patients discontinue treatment with first (F)- or second-generation antipsychotics (SGA) due to dissatisfaction with their therapeutic effects; median time to discontinuation ranges from 3–7 months (1). Switching to another antipsychotic, except clozapine, did not yield better results (2). These results indicate it is essential to modulate mechanisms other than dopaminergic (DA)/serotoninergic (5-HT) systems to improve symptoms of schizophrenia (SCZ). Increasingly, NMDA receptor (NMDAr) hypofunction (3) and hippocampal hyperactivity (4) are implicated in the dysregulation of mesolimbic DA and glutamate (Glu) neurons, leading to increasing synaptic activity of Glu in the PFC (5). Augmenting the effects of current antipsychotics with Glu release inhibitors may improve symptoms of psychosis in patients with SCZ. Evenamide does not interact with monoaminergic (DA, 5-HT, NA, H) pathways affected by current antipsychotics, or with >130 different targets involved in CNS activity, except for sodium channels, leading to modulation of Glu release. Evenamide shows efficacy in animal models of SCZ as monotherapy and as an add-on to FGA or SGA, irrespective of whether impairment was spontaneous, or induced by amphetamine, NMDAr antagonists or stress. Methods In a pilot, proof of mechanism, randomized, double-blind, placebo-controlled, parallel group, 4-week trial, evenamide (n=50; 15–25 mg bid) or placebo (n=39) was added to patients with SCZ worsening on their current antipsychotic doses of risperidone (RIS; ≥2 mg/day) or aripiprazole (ARI; ≥10 mg/day), in 2 sites in the US (n=61) and 3 in India (n=28). Results 89 patients with SCZ (mean baseline PANSS total: 62.9 ± 7.4; CGI-S: 3.5 ± 0.5), experiencing break-through psychotic symptoms on previously effective and stable doses of RIS (mean dose: 4.2 ± 2.0 mg/day; n=70) or ARI (mean dose: 19.7 ± 7.0 mg/day; n=19) were randomized (1.3:1 ratio) to treatment with evenamide or placebo. Analyses demonstrated the addition of evenamide to RIS or ARI was associated with statistically significant efficacy, based on the PANSS Positive Symptoms sub-scale (mean change, responders), and CGI-C responder rates. The study treatments were very well tolerated; 2 patients on evenamide discontinued treatment due to AEs (atrial fibrillation and seizure). The most common AEs (evenamide vs placebo [%]), were somnolence (16 vs 12.8%), insomnia (10 vs 6%) and headache (6 vs 0%). Discussion Addition of evenamide in patients worsening on SGAs modulating DA/5-HT significantly improved positive symptoms and CGI. No AEs such as EPS, endocrine, or sexual side effects, or weight gain were noted. These data indicate that evenamide’s Glu antagonism, demonstrated in preclinical experiments, is of value in patients worsening on current antipsychotics. Evenamide, as monotherapy or add-on, has reversed ketamine- and PCP-induced worsening of PPI. The results in the pilot clinical trial demonstrated an absence of side effects common with DA/5-HT blockers, and a rapid onset of action mediated by evenamide targeting altered Glu transmission in patients in whom SGA treatment had lost its efficacy. Efficacy of evenamide as add-on to antipsychotics would revolutionize development of novel antipsychotics targeting aberrant firing and Glu transmission in SCZ. Potentially pivotal studies with evenamide are in planning to demonstrate that the addition of evenamide, a Glu release inhibitor, augments antipsychotic efficacy in patients worsening on current antipsychotics, and in patients with treatment-resistant SCZ not responding/worsening on clozapine.
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Subjective experience and mental side-effects of antipsychotic treatment.
Gerlach, J; Larsen, E B
1999-01-01
Many schizophrenic patients have a negative attitude towards antipsychotic drugs. This attitude is not only due to lack of insight into the disease, lack of recognition of the beneficial effects of the drugs, and to objective side-effects. The negative attitude is to a high degree due to mental side-effects and a sceptical opinion about antipsychotic medication in general. In a study of 53 chronic schizophrenic out-patients receiving maintenance depot antipsychotic treatment, we found that 60% were positive about the treatment, 32% were ambivalent and 8% had a negative attitude. Only 60% complained of side-effects, even though 94% had objective side-effects. Mental side-effects such as subjective akathisia, dysphoria and emotional indifference were most often observed by the patients, while hypokinesia and hyperkinesia were least noticed by them, but most often observed by the physician. No correlation was found between the patients' subjective assessment of their quality of life and the degree of psychosis and side-effects. With the new atypical antipsychotics this situation seems to be changing. These new drugs are primarily characterized by a lower level of motor extrapyramidal side-effects (EPS), and with fewer motor EPS, fewer mental EPS can be expected. In recent studies comparing the new antipsychotics with haloperidol, better effects have been observed with regard to negative symptoms and depression, and this may at least in part be a reflection of a lower level of mental side-effects of the atypical antipsychotics. This improved clinical profile of new antipsychotics is extremely valuable in the context of an integrated treatment in schizophrenia, consisting of early intervention, psychosocial rehabilitation and family/patient psycho-education.
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Evaluation of human D-amino acid oxidase inhibition by anti-psychotic drugs in vitro.
Shishikura, Miho; Hakariya, Hitomi; Iwasa, Sumiko; Yoshio, Takashi; Ichiba, Hideaki; Yorita, Kazuko; Fukui, Kiyoshi; Fukushima, Takeshi
2014-06-01
It is of importance to determine whether antipsychotic drugs currently prescribed for schizophrenia exert D-amino acid oxidase (DAO)-inhibitory effects. We first investigated whether human (h)DAO can metabolize D-kynurenine (D-KYN) to produce the fluorescent compound kynurenic acid (KYNA) by using high-performance liquid chromatography with mass spectrometry, and fluorescence spectrometry. After confirmation of KYNA production from D-KYN by hDAO, 8 first- and second-generation antipsychotic drugs, and 6 drugs often prescribed concomitantly, were assayed for hDAO-inhibitory effects by using in vitro fluorometric methods with D-KYN as the substrate. DAO inhibitors 3-methylpyrazole-5-carboxylic acid and 4H-thieno[3,2-b]pyrrole-5-carboxylic acid inhibited KYNA production in a dose-dependent manner. Similarly, the second-generation antipsychotics blonanserin and risperidone were found to possess relatively strong hDAO-inhibitory effects in vitro (5.29 ± 0.47 μM and 4.70 ± 0.17 μM, respectively). With regard to blonanserin and risperidone, DAO-inhibitory effects should be taken into consideration in the context of their in vivo pharmacotherapeutic efficacy.
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Matthew, Binoj J; Gedzior, Joanna S
2015-01-01
This report attempts to highlight that use of an antipsychotic and concurrent chronic use of methamphetamine can cause drug-induced parkinsonism. Methamphetamine is usually not encountered in the list of agents that induce drug-induced parkinsonism and so its consideration particularly during chronic use by a patient who is also on an antipsychotic is worthwhile because of its popularity as an illegal narcotic. This case report describes just such a case of drug-induced parkinsonism which is a subacute syndrome that mimics Parkinson's disease. Although less alarming than dystonia, it is more common, more difficult to treat and can be the cause of significant disability during maintenance treatment especially in the elderly. In most cases, symptoms are reversible in days or weeks, but occasionally, especially in the elderly, or if long-acting injectable antipsychotics are used-as in this case-symptoms may last for weeks or months. The report also illustrates the neuronal workings due to chronic methamphetamine-use and the additive effects of dopamine blockade by antipsychotics such as haloperidol. © The Author(s) 2015.
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Jensen, Ralph J
2016-12-01
In the P23H rat model of retinitis pigmentosa, the dopamine D2 receptor antagonists sulpiride and eticlopride appear to improve visual responses of retinal ganglion cells (RGCs) by increasing light sensitivity of RGCs and transforming abnormal, long-latency ON-center RGCs into OFF-center cells. Antipsychotic drugs are believed to mediate their therapeutic benefits by blocking D2 receptors. This investigation was conducted to test whether haloperidol (a typical antipsychotic drug) and clozapine (an atypical antipsychotic drug) could similarly alter the light responses of RGCs in the P23H rat retina. Extracellular recordings were made from RGCs in isolated P23H rat retinas. Responses of RGCs to flashes of light were evaluated before and during bath application of a drug. Both haloperidol and clozapine increased light sensitivity of RGCs on average by ∼0.3 log unit. For those ON-center RGCs that exhibit an abnormally long-latency response to the onset of a small spot of light, both haloperidol and clozapine brought out a short-latency OFF response and markedly reduced the long-latency ON response. The selective serotonin 5-HT2A antagonist MDL 100907 had similar effects on RGCs. The effects of haloperidol on light responses of RGCs can be explained by its D2 receptor antagonism. The effects of clozapine on light responses of RGCs on the other hand may largely be due to its 5-HT2A receptor antagonism. Overall, the results suggest that antipsychotic drugs may be useful in improving vision in patients with retinitis pigmentosa.
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Cáceda, Ricardo; Kinkead, Becky; Owens, Michael J; Nemeroff, Charles B
2005-12-14
Dopamine receptor agonist and NMDA receptor antagonist activation of the mesolimbic dopamine system increases locomotion and disrupts prepulse inhibition of the acoustic startle response (PPI), paradigms frequently used to study both the pharmacology of antipsychotic drugs and drugs of abuse. In rats, virally mediated overexpression of the neurotensin 1 (NT1) receptor in the nucleus accumbens antagonized d-amphetamine- and dizocilpine-induced PPI disruption, hyperlocomotion, and D-amphetamine-induced rearing. The NT receptor antagonist SR 142948A [2-[[5-(2,6-dimethoxyphenyl)-1-(4-N-(3-dimethylaminopropyl)-N-methylcarbamoyl)-2-isopropylphenyl)-1H-pyrazole-3-carbonyl]amino] adamantane-2-carboxylic acid, hydrochloride] blocked inhibition of dizocilpine-induced hyperlocomotion mediated by overexpression of the NT1 receptor. Together, these results suggest that increased nucleus accumbens NT neurotransmission, via the NT1 receptor, can decrease the effects of activation of the mesolimbic dopamine system and disruption of the glutamatergic input from limbic cortices, resembling the action of the atypical antipsychotic drug clozapine. In contrast to clozapine, virally mediated overexpression of the NT1 receptor in the nucleus accumbens had prolonged protective effects (up to 4 weeks after viral injection) without perturbing baseline PPI and locomotor behaviors. These data further confirm the NT1 receptor as the receptor mediating the antistimulant- and antipsychotic-like properties of NT and provide rationale for the development of NT1 receptor agonists as novel antipsychotic drugs. In addition, the NT1 receptor vector might be a valuable tool for understanding the mechanism of action of antipsychotic drugs and drugs of abuse and may have potential therapeutic applications.
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Machado-Alba, Jorge E; Morales-Plaza, Cristhian David
2013-01-01
Schizophrenia alters individual perception, thought, affection and behavior. Drug therapy can improve these manifestations. To determine prescription patterns of antipsychotic drugs in a group of patients affiliated to the Social Security Health System in Colombia. This was a descriptive study with a 6.2 million people database. We selected 3,075 patients medicated with antipsychotics, of both sexes, and all ages, with continuous treatment from March to June, 2012, and residing in 57 Colombian cities. We designed a database on drug consumption, obtained by the company that distributes the drugs to the patients. A total of 3,075 patients were studied, with an age mean of 55.8 ± 21.5 years; 50.3% of the participants were women. Of all patients, 81.9% were receiving monotherapy and 18.1% two or more antipsychotics. Prescription order was 77.1% atypical and 31.9% conventional. The most frequently used drugs were: quetiapine (on 30.3% of the patients), clozapine (23.7%), levomepropamize (18.4%), and risperidone (14.9%). The most common combinations were: haloperidol + levomepromazine (n=67, 12.1%), clozapine + pipotiazine (n=54, 9.7%), clozapine + risperidone (n=45, 8.1%), and quetiapine + levomepromazine (n=40, 7.2%). The most prescribed co-medications were: antidepressants (n=998, 32.5%), anxiolytic (n=799, 26.0%), statins (n=672, 21.9%); antiparkinsonians (n=341, 11.1%), and antidiabetic drugs (n=327, 10.6%). The practice of prescribing drugs with a high therapeutic value predominates mainly in antipsychotic monotherapy. Most agents were used in higher doses than recommended. This raises the need to design educational strategies to address these prescribing habits and research for evaluating the effectiveness of the treatment.
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Heide, Juliane; Zhang, Fengyu; Bigos, Kristin L; Mann, Stefan A; Carr, Vaughan J; Shannon Weickert, Cynthia; Green, Melissa J; Weinberger, Daniel R; Vandenberg, Jamie I
2016-01-01
Antipsychotic drugs target dopamine and serotonin receptors as well as Kv11.1 potassium channels encoded by KCNH2. Variable patient responses and a wide range of side effects, however, limit their efficacy. Slow metabolizer status and gene variants in KCNH2 associated with increased expression of Kv11.1-3.1, an alternatively spliced isoform of Kv11.1, are correlated with improved responses to antipsychotic medications. Here, the authors test the hypothesis that these effects may be influenced by differential drug binding to Kv11.1 channel isoforms. Drug block of Kv11.1 isoforms was tested in cellular electrophysiology assays. The effects of drug metabolism and KCNH2 genotypes on clinical responses were assessed in patients enrolled in the multicenter Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). Risperidone caused greater in vitro block of the alternatively spliced Kv11.1-3.1 isoform than full-length Kv11.1-1A channels, whereas its metabolite paliperidone and other atypical antipsychotics have similar potencies for the two isoforms. In the CATIE study (N=362), patients with genotypes associated with increased Kv11.1-3.1 expression (N=52) showed a better treatment response to risperidone compared with other drugs, but this association was dependent on metabolism status. Patients with KCNH2 risk genotypes and slow metabolizer status (approximately 7% of patients) showed marked improvement in symptoms when treated with risperidone compared with patients with fast metabolizer status or without the KCNH2 risk genotypes. These data support the hypothesis that Kv11.1 channels play a role in the therapeutic action of antipsychotic drugs, particularly risperidone, and further highlight the promise of optimizing response with genotype-guided therapy for schizophrenia patients.
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[Use of aripiprazole in the treatment of catatonia].
Vörös, Viktor; Tényi, Tamás
2010-06-01
Successful aripiprazole treatment of catatonia was reported in some recent case reports. Review of the literature and three case reports. In the presented cases it was demonstrated that aripiprazole was effective in the treatment of catatonia in patients with schizophrenia, major depression or brief psychotic disorder. Besides benzodiazepines and electroconvulsive therapy, aripiprazole might be an alternative treatment for catatonia, however randomized controlled trials are required to prove the effectiveness of aripiprazole in patients with catatonia.
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Trends in Antipsychotic Drug Use by Very Young, Privately Insured Children
ERIC Educational Resources Information Center
Olfson, Mark; Crystal, Stephen; Huang, Cecilia; Gerhard, Tobias
2010-01-01
Objective: This study describes recent trends and patterns in antipsychotic treatment of privately insured children aged 2 through 5 years. Method: A trend analysis is presented of antipsychotic medication use (1999-2001 versus 2007) stratified by patient characteristics. Data are analyzed from a large administrative database of privately insured…
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Switching away from pipotiazine palmitate: a naturalistic study.
Mustafa, Feras Ali
2017-01-01
In March 2015, pipotiazine palmitate depot antipsychotic was globally withdrawn due to the shortage of its active ingredient. Thus, all patients receiving this medication had to be switched to an alternative antipsychotic drug. In this study we set to evaluate the process of switching away from pipotiazine palmitate within our clinical service, and its impact on hospitalization. Demographic and clinical data on patients who were receiving pipotiazine palmitate in Northamptonshire at the time of its withdrawal were anonymously extracted from their electronic records and analyzed using descriptive statistics. A total of 17 patients were switched away from pipotiazine palmitate at the time of its withdrawal, all of whom had a prior history of nonadherence with oral treatment. A total of 14 patients were switched to another depot antipsychotic drug, while three patients chose an oral alternative which they subsequently discontinued resulting in relapse and hospitalization. There was a five-fold increase in mean hospitalization among patients who completed a year after the switch. Switching away from pipotiazine palmitate was associated with significant clinical deterioration in patients who switched to an oral antipsychotic, whereas most patients who switched to another depot treatment maintained stability. Clinicians should exercise caution when switching patients with schizophrenia away from depot antipsychotic drugs, especially in cases of patients with a history of treatment nonadherence who prefer to switch to oral antipsychotics.
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Zongo, Frank E; Moisan, Jocelyne; Grégoire, Jean-Pierre; Lesage, Alain; Dossa, Anara Richi; Lauzier, Sophie
2018-01-01
Non-adherence is a major obstacle to optimal treatment of schizophrenia. Community pharmacists are in a key position to detect non-adherence and put in place interventions. Their role is likely to be more efficient when individuals are loyal to a single pharmacy. To assess the association between the level of community pharmacy loyalty and persistence with and implementation of antipsychotic drug treatment among individuals with schizophrenia. A cohort study using databases from the Quebec health insurance board (Canada) was conducted among new antipsychotic users insured by Quebec's public drug plan. Level of community pharmacy loyalty was assessed as the number of pharmacies visited in the year after antipsychotics initiation. Persistence was defined as having an antipsychotic supply in the user's possession on the 730 th day after its initiation and implementation as having antipsychotics in the user's possession for ≥80% of the days in the second year after antipsychotics initiation (among persistent only). Generalized linear models were used to estimate adjusted prevalence ratios (aPR) and 95% confidence intervals (95%CI). 6,251 individuals were included in the cohort and 54.1% had their drug prescriptions filled in >1 pharmacy. When compared to those who had their prescriptions filled in a single pharmacy, those who had their prescriptions filled in ≥4 different pharmacies were 22% more likely to be non-persistent (aPR = 1.22; 95%CI = 1.10-1.37) and 49% more likely to have an antipsychotic for <80% of the days (aPR = 1.49; 95%IC = 1.28-1.74). This first exploration of community pharmacy loyalty in the context of severe mental illness indicates that this healthcare organisation factor might be associated with antipsychotics persistence and implementation. Identification of individuals with low community pharmacy loyalty and initiatives to optimize community pharmacy loyalty could contribute to enhanced persistence and implementation. Copyright © 2016 Elsevier Inc. All rights reserved.
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Brain site- and transmitter-dependent actions of methamphetamine, morphine and antipsychotics.
Mori, Tomohisa; Iwase, Yoshiyuki; Murata, Asami; Iwata, Noriyuki; Suzuki, Tsutomu
2016-06-01
While several methamphetamine- and morphine-induced psychotic states are ordinarily treated by antipsychotics, the therapeutic mechanisms of antipsychotic drugs have yet been elucidated. The present study was designed to investigate the mechanisms how antipsychotic drugs suppress the behavioral changes induced by psychoactive drugs in mice. Low to medium doses of methamphetamine produced hyperlocomotion, whereas high dose of methamphetamine induced hypolocomotion. Hyperlocomotion induced by methamphetamine was potently suppressed by clozapine and 5-HT2 receptor antagonists, but not by the intra-accumbens injection of haloperidol. On the other hand, microinjection of haloperidol into the ventrolateral striatum increased locomotor activity with high dose of methamphetamine. In contrast, morphine-induced hyperlocomotion was suppressed by systemic as well as intra-accumbens injection of haloperidol, whereas relatively resistant to clozapine, compared to its effects in the case of methamphetamine. It has been widely believed that methamphetamine-induced psychosis is an animal model of schizophrenia, which is mediated by activation of accumbal dopamine receptors. Our findings suggest that methamphetamine differentially regulate monoaminergic systems (e.g., dopaminergic vs. 5-HTnergic), and accumbal dopamine receptors are not involved in methamphetamine-induced hyperlocomotion in mice. Thus, our findings may lead to a better understanding of the therapeutic mechanisms that underlie the effects of antipsychotic drugs and behavioral effects of methamphetamine and morphine. Copyright © 2016 Elsevier B.V. All rights reserved.
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Swathy, Babu; Saradalekshmi, Koramannil R; Nair, Indu V; Nair, Chandrasekharan; Banerjee, Moinak
2017-06-01
It is imperative to differentiate the role of host epigenetics from pharmacoepigenetics in resolving therapeutic response. Therefore, the objective was to identify how antipsychotic drugs influence epigenetic response on pharmacogenes. The study design was based on in vitro evaluation of pharmacoepigenetic response of haloperidol, clozapine and olanzapine. Post antipsychotic treatment, the alterations in expression of ABCB1, CYP1A2 and CYP3A4 were monitored, and followed up by promoter methylation and their target miRNA expression studies. Critical observations were followed up in a restrictive clinical setting. Under in vitro conditions increased expression of ABCB1, CYP1A2 and CYP3A4 was observed which seems to be regulated by miR-27a and miR-128a and not by methylation. A similar pattern was observed in clinical setting with ABCB1, which was reflective of good therapeutic response. The study demonstrates that antipsychotic drugs can influence miRNA-mediated epigenetic response in pharmacogenes resulting in modulating therapeutic response.
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The Presynaptic Component of the Serotonergic System is Required for Clozapine's Efficacy
Yadav, Prem N; Abbas, Atheir I; Farrell, Martilias S; Setola, Vincent; Sciaky, Noah; Huang, Xi-Ping; Kroeze, Wesley K; Crawford, LaTasha K; Piel, David A; Keiser, Michael J; Irwin, John J; Shoichet, Brian K; Deneris, Evan S; Gingrich, Jay; Beck, Sheryl G; Roth, Bryan L
2011-01-01
Clozapine, by virtue of its absence of extrapyramidal side effects and greater efficacy, revolutionized the treatment of schizophrenia, although the mechanisms underlying this exceptional activity remain controversial. Combining an unbiased cheminformatics and physical screening approach, we evaluated clozapine's activity at >2350 distinct molecular targets. Clozapine, and the closely related atypical antipsychotic drug olanzapine, interacted potently with a unique spectrum of molecular targets. This distinct pattern, which was not shared with the typical antipsychotic drug haloperidol, suggested that the serotonergic neuronal system was a key determinant of clozapine's actions. To test this hypothesis, we used pet1−/− mice, which are deficient in serotonergic presynaptic markers. We discovered that the antipsychotic-like properties of the atypical antipsychotic drugs clozapine and olanzapine were abolished in a pharmacological model that mimics NMDA-receptor hypofunction in pet1−/− mice, whereas haloperidol's efficacy was unaffected. These results show that clozapine's ability to normalize NMDA-receptor hypofunction, which is characteristic of schizophrenia, depends on an intact presynaptic serotonergic neuronal system. PMID:21048700
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Neurodevelopment in Schizophrenia: The Role of the Wnt Pathways
Panaccione, Isabella; Napoletano, Flavia; Forte, Alberto Maria; Kotzalidis, Giorgio D.; Del Casale, Antonio; Rapinesi, Chiara; Brugnoli, Chiara; Serata, Daniele; Caccia, Federica; Cuomo, Ilaria; Ambrosi, Elisa; Simonetti, Alessio; Savoja, Valeria; De Chiara, Lavinia; Danese, Emanuela; Manfredi, Giovanni; Janiri, Delfina; Motolese, Marta; Nicoletti, Ferdinando; Girardi, Paolo; Sani, Gabriele
2013-01-01
Objectives. To review the role of Wnt pathways in the neurodevelopment of schizophrenia. Methods: Systematic PubMed search, using as keywords all the terms related to the Wnt pathways and crossing them with each of the following areas: normal neurodevelopment and physiology, neurodevelopmental theory of schizophrenia, schizophrenia, and antipsychotic drug action. Results: Neurodevelopmental, behavioural, genetic, and psychopharmacological data point to the possible involvement of Wnt systems, especially the canonical pathway, in the pathophysiology of schizophrenia and in the mechanism of antipsychotic drug action. The molecules most consistently found to be associated with abnormalities or in antipsychotic drug action are Akt1, glycogen synthase kinase3beta, and beta-catenin. However, the extent to which they contribute to the pathophysiology of schizophrenia or to antipsychotic action remains to be established. Conclusions: The study of the involvement of Wnt pathway abnormalities in schizophrenia may help in understanding this multifaceted clinical entity; the development of Wnt-related pharmacological targets must await the collection of more data. PMID:24403877
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Johnsen, Erik; Hugdahl, Kenneth; Fusar-Poli, Paolo; Kroken, Rune A; Kompus, Kristiina
2013-01-01
Experiencing auditory verbal hallucinations is a prominent symptom in schizophrenia that also occurs in subjects at enhanced risk for psychosis and in the general population. Drug treatment of auditory hallucinations is challenging, because the current understanding is limited with respect to the neural mechanisms involved, as well as how CNS drugs, such as antipsychotics, influence the subjective experience and neurophysiology of hallucinations. In this article, the authors review studies of the effect of antipsychotic medication on brain activation as measured with functional MRI in patients with auditory verbal hallucinations. First, the authors examine the neural correlates of ongoing auditory hallucinations. Then, the authors critically discuss studies addressing the antipsychotic effect on the neural correlates of complex cognitive tasks. Current evidence suggests that blood oxygen level-dependant effects of antipsychotic drugs reflect specific, regional effects but studies on the neuropharmacology of auditory hallucinations are scarce. Future directions for pharmacological neuroimaging of auditory hallucinations are discussed.
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Effects of antipsychotic drugs on cardiovascular variability in participants with bipolar disorder
Linder, Jonathan R.; Sodhi, Simrit K.; Haynes, William G.; Fiedorowicz, Jess G.
2014-01-01
Objective The risk for cardiovascular diseases is elevated in persons with bipolar disorder. However, it remains unknown how much of this excess risk is secondary to pharmacologic treatment. We tested the hypothesis that current and cumulative antipsychotic drug exposure is associated with increased cardiovascular risk as indicated by lower heart rate variability (HRV) and increased blood pressure variability (BPV). Methods 55 individuals with bipolar disorder (33±7 years; 67% female) underwent non-invasive electrocardiogram assessment of time- and frequency-domain HRV, as well as BPV analysis. Medication histories were obtained through systematic review of pharmacy records for the past five years. Results Current antipsychotic exposure was associated with lower SDNN. Second generation antipsychotics were associated with lower SDNN and RMSSD. There was no significant relationship between five-year antipsychotic exposure and HRV in subjects with bipolar disorder. Exploratory analysis revealed a possible link between SSRI exposure and increased low frequency spectral HRV. Conclusions Current antipsychotic use (particularly second generation antipsychotics with high affinities for the D2S receptor) is associated with reduced autonomic-mediated variability of heart rate. The absence of an association with cumulative exposure suggests that the effects are acute in onset, and may therefore relate more to altered autonomic function than structural cardiovascular abnormalities. Future studies should prospectively examine effects of these antipsychotics on autonomic function. PMID:24590543
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The antipsychotic landscape: dopamine and beyond.
Morrison, Paul D; Murray, Robin M
2018-04-01
Until recently, the actions of antipsychotic and pro-psychotic drugs have largely been evaluated in the framework of neuronal doctrine - namely, that neurons communicate by releasing transmitters, and that psychiatric disorders are caused by neurotransmitter imbalances. Moreover, the majority of studies have focused on single transmitter systems - neglecting the fact that in the nervous system, different transmitter systems work in concert and impact on not only their immediate receptors but also downstream pathways that shape structural plasticity. In this review, we discuss the history of understanding the antipsychotic and pro-psychotic actions of drugs, recent developments and future perspectives.
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Amisulpride and symptomatic bradycardia: a case report.
Huang, Li-Chung; Huang, Li-Yen; Tseng, Shih-Yen; Hou, Yuh-Ming; Hsiao, Cheng-Cheng
2015-01-01
Amisulpride is a second-generation antipsychotic agent indicated for the treatment of schizophrenia and other major psychotic illnesses. Amisulpride-induced bradycardia is a rare condition of unknown etiology and mechanism. Asymptomatic bradycardia has been associated with amisulpride in only two cases. In our case, the association was rated as "probable" on the Naranjo adverse drug reaction probability scale. Case report. A 45-year-old male patient developed symptomatic bradycardia during usage of amisulpride (400-800 mg/day), which dramatically improved after the complete termination of amisulpride usage. The psychiatric condition remained relatively stable without bradycardia after administration of another antipsychotic agent [risperidone (3 mg/day)]. This is the first case report of symptomatic bradycardia associated with the use of amisulpride. Although bradycardia is a rare adverse reaction to antipsychotics, this finding may alert psychiatrists and physicians to this antipsychotic drug side effect. Further study is needed to disclose the role of antipsychotics in bringing about symptomatic bradycardia. Copyright © 2015 Elsevier Inc. All rights reserved.
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Vakilian, Alireza; Razavi-Nasab, Seyed Moein; Ravari, Ali; Mirzaei, Tayebeh; Moghadam-Ahmadi, Amir; Jalali, Nazanin; Bahramabadi, Reza; Rezayati, Mohammadtaghi; Yazdanpanah-Ravari, Amin; Bahmaniar, Farhad; Bagheri, Mohammad Reza; Sheikh Fathollahi, Mahmood; Asadikaram, Gholamreza; Kazemi Arababadi, Mohammad
2017-01-01
Patients with Alzheimer disease (AD) suffer from psychotic symptoms including pain. The current antipsychotic drugs confer limited effectiveness, and hence new strategies are being designed to decrease pain in order to increase antipsychological effectiveness. Vitamin B12 is a safe supplementary drug to decrease pain. Additionally, cytokines participate in the pathogenesis of immune-related diseases such as AD. Thus, the main aim of this clinical trial study was to determine the effects of treatment with risperidone and quetiapine, as antipsychotic drugs, with and without vitamin B12 on the psychotic symptoms of AD patients and the expression of IL-6, IL-8, tumor growth factor (TGF)-β, tumor necrosis factor (TNF)-α, and endothelin (ET)-1). Serum levels of IL-6, IL-8, TGF-β, TNF-α, and ET-1 were evaluated in the following groups: healthy controls, nonpsychotic AD patients, psychotic AD patients, psychotic AD patients under treatment with risperidone, psychotic AD patients under treatment with risperidone plus vitamin B12, psychotic AD patients under treatment with quetiapine, and psychotic AD patients under treatment with quetiapine plus vitamin B12. Treatment with antipsychotic drugs plus vitamin B12 led to a decreased expression of IL-8 and TNF-α and an increased expression of TGF-β. Vitamin B12 in association with quetiapine reduced the pain in psychotic AD patients. Proinflammatory cytokines play important roles in the pathogenesis of psychosis in AD patients. Antipsychotic drugs plus vitamin B12 can reduce and induce the expression of proinflammatory and anti-inflammatory cytokines to improve psychotic symptoms in AD patients. © 2018 S. Karger AG, Basel.
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Chen, Shih-Fen; Shen, Yu-Chih; Chen, Chia-Hsiang
2009-08-01
Aripiprazole acts as a partial agonist at dopamine D2 and D3 and serotonin 1A receptors and as an antagonist at serotonin 2A receptors (HTR2A). Since aripiprazole acts as an antagonist at HTR2A, genetic variants of HTR2A may be important in explaining variability in response to aripiprazole. This study investigated whether the efficacy of aripiprazole can be predicted by functional HTR2A A-1438G/T102C polymorphisms (rs63311/rs6313) as modified by clinical factors in Han Chinese hospitalized patients with acutely exacerbated schizophrenia. After hospitalization, the patients (n = 128) were given a 4-week course of aripiprazole. Patients were genotyped for HTR2A A-1438G/T102C polymorphisms via the restriction fragment length polymorphism method. Clinical factors such as gender, age, duration of illness, education level, diagnostic subtype, and medication dosage were noted as well. The researchers measured psychopathology biweekly, using the Positive and Negative Syndrome Scale (PANSS). A mixed model regression approach (SAS Proc MIXED) was used to analyze the effects of genetic and clinical factors on PANSS performance after aripiprazole treatment. We found that the GG/CC genotype group of HTR2A A-1438G/T102C polymorphisms predicts poor aripiprazole response specifically for negative symptoms. In addition, the clinical factors, including dosage of aripiprazole, age, duration of illness, and diagnostic subtype, were found to influence PANSS performance after aripiprazole treatment. The data suggest HTR2A A-1438G/T102C polymorphisms may predict negative symptoms performance upon aripiprazole treatment in schizophrenic patients as modified by clinical factors.
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Ishigooka, Jun; Nakamura, Jun; Fujii, Yasuo; Iwata, Nakao; Kishimoto, Toshifumi; Iyo, Masaomi; Uchimura, Naohisa; Nishimura, Ryoji; Shimizu, Naoaki
2015-02-01
This study was designed to evaluate efficacy and safety of aripiprazole once-monthly (AOM) by verifying non-inferiority of AOM to oral aripiprazole in Asian patients with schizophrenia. The study consisted of a screening phase and three phases: an oral conversion phase (≤12weeks), an oral stabilization phase (≤12weeks) and a 52-week double-blind phase. Patients meeting stabilization criteria for 4weeks during the oral stabilization phase were randomly assigned (1:1) to AOM (400mg) or oral aripiprazole (6-24mg/day). The primary endpoint was Kaplan-Meier estimated rate of non-exacerbation of psychotic symptoms/non-relapse at Week 26. A total of 724 patients were screened, and 502 patients entered the oral stabilization phase. Of 455 patients randomized in the double-blind phase, 228 received AOM and 227 received oral aripiprazole. The non-exacerbation of psychotic symptoms/non-relapse rates at Week 26 were 95.0% (AOM) and 94.7% (oral aripiprazole) and the difference was 0.3% (95% CI: -3.9,4.5), thus non-inferiority of AOM compared to oral aripiprazole with respect to non-exacerbation of psychotic symptoms/non-relapse rate was shown with a margin of -3.9% which is well above the pre-defined non-inferiority limit (-15%). The proportions of patients meeting exacerbation of psychotic symptoms/relapse criteria and stabilization of psychotic symptoms/maintenance criteria were 6.6% and 92.5% in both groups. Discontinuation rates due to all reasons were 25.9% (AOM) and 33.5% (oral aripiprazole). AOM was well tolerated as well as oral aripiprazole. Non-inferiority of AOM to oral aripiprazole was established. AOM is efficacious in maintenance treatment of stabilized schizophrenia, with comparable efficacy and tolerability to oral aripiprazole. JapicCTI-101175. Copyright © 2014 Elsevier B.V. All rights reserved.
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Cuomo, Ilaria; Kotzalidis, Georgios D; De Filippis, Sergio
2017-08-23
Mood disorders are often complicated by comorbidity with epilepsy. Anxiety and personality disorders may worsen prognosis and treatment outcome. Lacosamide has been recently introduced as adjunctive treatment for partial epilepsy. Its mechanism consists of selective slow inactivation of voltage-gated sodium channels, thus promoting an extended stabilisation of cell membranes. Antiepileptic drugs have been largely used since the 1950s in psychiatry as mood stabilisers due to their membrane stabilising and anti-kindling effects. Like lithium, antiepileptic drugs are first choice treatment for Bipolar and Cyclothymic Disorders. We tested the efficacy of the most recent antiepileptic medication, lacosamide, in a patient with simultaneously occurring cyclothymic disorder, severe post-traumatic stress disorder, and fronto-temporal epilepsy. Lacosamide was titrated up to 200 mg/day, added on ongoing 750 mg/day lithium, 15 mg/day oral aripiprazole then switched to 400 mg/month long-acting aripiprazole, and 2 mg/day N-desmethyldiazepam. We observed EEG normalisation one month later, along with reduced anxiety and an additive effect to lithium-induced stabilisation of mood fluctuations since the second week of lacosamide addition. Further studies with this drug in the bipolar spectrum are warranted.
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Oral health impacts of medications used to treat mental illness.
Cockburn, N; Pradhan, A; Taing, M W; Kisely, S; Ford, P J
2017-12-01
Many psychotropic medications affect oral health. This review identified oral side effects for antidepressant, antipsychotic, anticonvulsant, antianxiety and sedative drugs that are recommended in Australia for the management of common mental illnesses and provides recommendations to manage these side-effects. The Australian Therapeutic Guidelines and the Australian Medicines Handbook were searched for medications used to treat common mental health conditions. For each medication, the generic name, class, and drug company reported side-effects were extracted from the online Monthly Index of Medical Specialties (eMIMs) and UpToDate databases. Meyler's Side Effect of Drugs Encyclopaedia was used to identify additional oral adverse reactions to these medications. Fifty-seven drugs were identified: 23 antidepressants, 22 antipsychotics or mood stabilisers, and 12 anxiolytic or sedative medications. Xerostomia (91%) the most commonly reported side effect among all classes of medications of the 28 identified symptoms. Other commonly reported adverse effects included dysguesia (65%) for antidepressants, and tardive dyskinesia (94%) or increased salivation (78%) for antipsychotic medications. While xerostomia has often been reported as a common adverse effect of psychotropic drugs, this review has identified additional side effects including dysguesia from antidepressants and tardive dyskinesia and increased salivation from antipsychotics. Clinicians should consider oral consequences of psychotropic medication in addition to other side-effects when prescribing. For antidepressants, this would mean choosing duloxetine, agomelatine and any of the serotonin re-uptake inhibitors except sertraline. In the case of antipsychotics and mood stabilisers, atypical agents have less oral side effects than older alternatives. Copyright © 2017 Elsevier B.V. All rights reserved.
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Yorbik, Ozgur; Mutlu, Caner; Ozilhan, Selma; Eryilmaz, Gul; Isiten, Nuket; Alparslan, Serdar; Saglam, Esra
2015-06-01
There are limited studies investigating the relationship between oral release osmotic system-methylphenidate (OROS-MPH) doses and plasma methylphenidate (MPH) concentrations in children and adolescents. The aim of this study was to investigate the relationship between the doses of OROS-MPH and the plasma levels of the drug. We also examined the effects of the other drugs including aripiprazole, risperidone, fluoxetine, and sertraline on the levels of the MPH in the plasma. The files of 100 attention deficit hyperactivity disorder (ADHD) subjects (76 male, 24 female) who were diagnosed as ADHD according to the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition criteria, were screened. The ages of subjects were between 6 and 18 years (mean = 11.5 ± 3.8 years). Plasma MPH levels were determined by high-performance liquid chromatography-tandem mass spectrometry assay. Daily mean OROS-MPH dose used in ADHD children was 0.7 ± 0.2 mg/kg (range: 0.3-1.3 mg/kg). The mean plasma OROS-MPH was 11.6 ± 7.3 ng/mL (range: 0.5-43.4 ng/mL). There was no group difference in the mean plasma MPH and dose-related MPH levels between the groups that used any additional drug including aripiprazole (n = 25), risperidone (n = 10), fluoxetine (n = 16), sertraline (n = 10), and did not use these drugs (P > 0.05). There was a positive correlation between the OROS-MPH doses (mg/kg) and the blood MPH levels (Pearson correlation = 0.40; P < 0.001). The plasma levels of MPH were found to be less than 13 ng/mL in 65% of the subjects. Our findings point to the fact that plasma levels of MPH show a wide range of changes at similar doses, correlate positively with the doses and, as expected, are not affected by using risperidone, sertraline, fluoxetine, and aripiprazole. Therapeutic drug monitoring may help to optimize MPH dose in patients not responding to treatment or in those experiencing serious side effects, but not in routine clinical practice. The presence of intermediate dose formulations such as 45-mg tablets for OROS-MPH may contribute to the optimization.
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Patterns of Antipsychotic Prescribing by Physicians to Young Children.
Huskamp, Haiden A; Horvitz-Lennon, Marcela; Berndt, Ernst R; Normand, Sharon-Lise T; Donohue, Julie M
2016-12-01
Antipsychotic use among young children has grown rapidly despite a lack of approval by the U.S. Food and Drug Administration (FDA) for broad use in this age group. Characteristics of physicians who prescribed antipsychotics to young children were identified, and prescribing patterns involving young children and adults were compared. Physician-level prescribing data from IMS Health's Xponent database were linked with American Medical Association Masterfile data and analyzed. The sample included all U.S. psychiatrists and a random sample of 5% of family medicine physicians who wrote at least ten antipsychotic prescriptions per year from 2008 to 2011 (N=31,713). Logistic and hierarchical binomial regression models were estimated to examine physician prescribing for children ages zero to nine, and the types and numbers of ingredients used for children versus adults ages 20 to 64 were compared. Among antipsychotic prescribers, 42.2% had written at least one antipsychotic prescription for young children. Such prescribing was more likely among physicians age ≤39 versus ≥60 (odds ratio [OR]=1.70) and physicians in rural versus nonrural areas (OR=1.11) and was less likely among males (OR=.93) and graduates of a top-25 versus a lower-ranked U.S. medical school (OR=.87). Among physicians who prescribed antipsychotics to young children and adults, 75.0% of prescriptions for children and 35.7% of those for adults were for drugs with an FDA-approved indication for that age. Fewer antipsychotic agents were prescribed for young children (median=2) versus adults (median=7). Prescribing antipsychotics for young children was relatively common, but prescribing patterns differed between young children and adults.
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Use of atypical antipsychotics in the elderly: a clinical review
Gareri, Pietro; Segura-García, Cristina; Manfredi, Valeria Graziella Laura; Bruni, Antonella; Ciambrone, Paola; Cerminara, Gregorio; De Sarro, Giovambattista; De Fazio, Pasquale
2014-01-01
The use of atypical antipsychotic drugs in the elderly has become wider and wider in recent years; in fact, these agents have novel receptor binding profiles, good efficacy with regard to negative symptoms, and reduced extrapyramidal symptoms. However, in recent years, the use of both conventional and atypical antipsychotics has been widely debated for concerns about their safety in elderly patients affected with dementia and the possible risks for stroke and sudden death. A MEDLINE search was made using the words elderly, atypical antipsychotics, use, schizophrenia, psychosis, mood disorders, dementia, behavioral disorders, and adverse events. Some personal studies were also considered. This paper reports the receptor binding profiles and the main mechanism of action of these drugs, together with their main use in psychiatry and the possible adverse events in elderly people. PMID:25170260
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Bédard, Anne-Marie; Maheux, Jérôme; Lévesque, Daniel; Samaha, Anne-Noël
2011-05-01
Chronic exposure to antipsychotic medications can persistently change brain dopamine systems. Most studies on the functional significance of these neural changes have focused on motor behavior and few have addressed how long-term antipsychotic treatment might influence dopamine-mediated reward function. We asked, therefore, whether a clinically relevant antipsychotic treatment regimen would alter the incentive motivational properties of a reward cue. We assessed the ability of a Pavlovian-conditioned stimulus to function as a conditioned reward, as well as to elicit approach behavior in rats treated with haloperidol, either continuously (achieved via subcutaneous osmotic minipump) or intermittently (achieved via daily subcutaneous injections). Continuous, but not intermittent, treatment enhanced the ability of amphetamine to potentiate the conditioned reinforcing effects of a cue associated with water. This effect was not related to differences in the ability to attribute predictive value to a conditioned stimulus (as measured by conditioned approach behavior), but was potentially linked to the development of behavioral supersensitivity to amphetamine and to augmented amphetamine-induced immediate early-gene expression (c-fos and Nur77) in dorsal striatopallidal and striatonigral cells. By enhancing the ability of reward cues to control behavior and by intensifying dopamine-mediated striatopallidal and striatonigral cell activity, standard (ie, continuous) antipsychotic treatment regimens might exacerbate drug-seeking and drug-taking behavior in schizophrenia. Achieving regular but transiently high antipsychotic levels in the brain (as modeled in the intermittent condition) might be a viable option to prevent these changes. This possibility should be explored in the clinic.
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Citraro, Rita; Leo, Antonio; De Fazio, Pasquale; De Sarro, Giovambattista; Russo, Emilio
2015-01-01
Background and Purpose Two of the most relevant unmet needs in epilepsy are represented by the development of disease-modifying drugs able to affect epileptogenesis and/or the study of related neuropsychiatric comorbidities. No systematic study has investigated the effects of chronic treatment with antipsychotics or antidepressants on epileptogenesis. However, such drugs are known to influence seizure threshold. Experimental Approach We evaluated the effects of an early long-term treatment (ELTT; 17 weeks), started before seizure onset (P45), with fluoxetine (selective 5-HT-reuptake inhibitor), duloxetine (dual-acting 5-HT-noradrenaline reuptake inhibitor), haloperidol (typical antipsychotic drug), risperidone and quetiapine (atypical antipsychotic drugs) on the development of absence seizures and comorbid depressive-like behaviour in the WAG/Rij rat model. Furthermore, we studied the effects of these drugs on established absence seizures in adult (6-month-old) rats after a chronic 7 weeks treatment. Key Results ELTT with all antipsychotics did not affect the development of seizures, whereas, both ELTT haloperidol (1 mg·kg−1 day−1) and risperidone (0.5 mg·kg−1 day−1) increased immobility time in the forced swimming test and increased absence seizures only in adult rats (7 weeks treatment). In contrast, both fluoxetine (30 mg·kg−1 day−1) and duloxetine (10–30 mg·kg−1 day−1) exhibited clear antiepileptogenic effects. Duloxetine decreased and fluoxetine increased absence seizures in adult rats. Duloxetine did not affect immobility time; fluoxetine 30 mg·kg−1 day−1 reduced immobility time while at 10 mg·kg−1 day−1 an increase was observed. Conclusions and Implications In this animal model, antipsychotics had no antiepileptogenic effects and might worsen depressive-like comorbidity, while antidepressants have potential antiepileptogenic effects even though they have limited effects on comorbid depressive-like behaviour. PMID:25754610
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The US Food and Drug Administration's Perspective on the New Antipsychotic Pimavanserin.
Mathis, Mitchell V; Muoio, Brendan M; Andreason, Paul; Avila, Amy M; Farchione, Tiffany; Atrakchi, Aisar; Temple, Robert J
2017-06-01
To summarize the US Food and Drug Administration's (FDA's) review of the safety and effectiveness for pimavanserin, an atypical antipsychotic, for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis. We describe the regulatory and clinical issues important to the FDA's approval of this New Drug Application, with special focus on the risk-benefit balance. We also describe a new labeling feature that presents additional efficacy data to clinicians. Data sets for all relevant clinical trials of pimavanserin and the Applicant's and FDA's analyses of these data were considered in this review. Data were available from 616 patients with Parkinson's disease with hallucinations and delusions who received at least 1 dose of pimavanserin, with a total exposure of 825 patient-years in the Parkinson's disease psychosis population. Pimavanserin 34 mg/d was effective in treating hallucinations and delusions associated with Parkinson's disease. In the Applicant's single pivotal trial, 80.5% of pimavanserin patients experienced at least some improvement in symptoms compared to 58.1% of patients taking placebo. Pimavanserin did not worsen motor function, an adverse effect commonly observed with other antipsychotics, probably because of a lack of consequential dopamine binding. Pimavanserin is the only FDA-approved treatment for the hallucinations and delusions seen in patients with psychosis of Parkinson's disease. Although pimavanserin appears to have a pharmacologic mechanism that is different from other atypical antipsychotics, concern remained that the increased risk of death seen with antipsychotic use in elderly demented patients, and described in all approved antipsychotic labels, would also occur with pimavanserin. Pimavanserin bears the same boxed warning about the risk of death associated with antipsychotic use in elderly patients with dementia. © Copyright 2017 Physicians Postgraduate Press, Inc.
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Aripiprazole in the treatment of irritability in children and adolescents with autistic disorder.
Owen, Randall; Sikich, Linmarie; Marcus, Ronald N; Corey-Lisle, Patricia; Manos, George; McQuade, Robert D; Carson, William H; Findling, Robert L
2009-12-01
The objective of this study was to evaluate short-term efficacy and safety of aripiprazole in the treatment of irritability in children and adolescents with autistic disorder who were manifesting behaviors such as tantrums, aggression, self-injurious behavior, or a combination of these. This 8-week, double-blind, randomized, placebo-controlled, parallel-group study was conducted of children and adolescents (aged 6-17 years) with autistic disorder. Patients were randomly assigned (1:1) to flexibly dosed aripiprazole (target dosage: 5, 10, or 15 mg/day) or placebo. Efficacy outcome measures included the Aberrant Behavior Checklist irritability subscale and the Clinical Global Impression-Improvement score (CGI-I). Safety and tolerability were also assessed. Ninety-eight patients were randomly assigned to receive placebo (n = 51) or aripiprazole (n = 47). Mean improvement in Aberrant Behavior Checklist irritability subscale score was significantly greater with aripiprazole than with placebo from week 1 through week 8. Aripiprazole demonstrated significantly greater global improvements than placebo, as assessed by the mean CGI-I score from week 1 through week 8; however, clinically significant residual symptoms may still persist for some patients. Discontinuation rates as a result of adverse events (AEs) were 10.6% for aripiprazole and 5.9% for placebo. Extrapyramidal symptom-related AE rates were 14.9% for aripiprazole and 8.0% for placebo. No serious AEs were reported. Mean weight gain was 2.0 kg on aripiprazole and 0.8 kg on placebo at week 8. Aripiprazole was efficacious in children and adolescents with irritability associated with autistic disorder and was generally safe and well tolerated.
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Metabolic effects of adjunctive aripiprazole in clozapine-treated patients with schizophrenia
Fan, Xiaoduo; Borba, Christina P.C.; Copeland, Paul; Hayden, Doug; Freudenreich, Oliver; Goff, Donald C.; Henderson, David C.
2015-01-01
Objective This study examined the effects of adjunctive aripiprazole therapy on metabolism in clozapine-treated patients with schizophrenia. Method In an 8-week randomized, double-blind, placebo-controlled study, subjects received either aripiprazole (15mg/day) or placebo. At baseline and week 8, metabolic parameters were assessed by the frequently sampled intravenous glucose tolerance test, nuclear magnetic resonance spectroscopy and whole-body dual-energy X-ray absorptiometry (DXA). Results Thirty subjects completed the study (16 in the aripiprazole group and 14 in the placebo group). Glucose effectiveness measured by the frequently sampled intravenous glucose tolerance test improved significantly in the aripiprazole group (0.003 ± 0.006 versus −0.005 ± 0.007/min, P = 0.010). The aripiprazole group showed significant reductions in both plasma low-density lipoprotein (LDL) levels (−15.1 ± 19.8 vs. 4.4 ± 22.5 mg/dl, P = 0.019) and LDL particle numbers (−376 ± 632 vs. −36 ± 301 nM, P= 0.035). Further, there was a significant reduction in lean mass (−1125 ± 1620 vs. 607 ± 1578 g, P= 0.011) measured by whole-body DXA scan in the aripiprazole group. All values were expressed as mean ± standard deviation, aripiprazole vs. placebo. Conclusion Adjunctive therapy with aripiprazole may have some metabolic benefits in clozapine-treated patients with schizophrenia. PMID:22943577
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He, Jue; Kong, Jiming
2009-01-01
Antipsychotic drugs are divided into two groups: typical and atypical. Recent clinical studies show atypical antipsychotics have advantages over typical antipsychotics in a wide variety of neuropsychiatric conditions, in terms of greater efficacy for positive and negative symptoms, beneficial effects on cognitive functioning, and fewer extra pyramidal side effects in treating schizophrenia. As such, atypical antipsychotics may be effective in the treatment of depressive symptoms associated with psychotic and mood disorders, posttraumatic stress disorder and psychosis in Alzheimer disease. In this paper, we describe the effects and potential neurochemical mechanisms of action of atypical antipsychotics in several animal models showing memory impairments and/or non-cognitive behavioral changes. The data provide new insights into the mechanisms of action of atypical antipsychotics that may broaden their clinical applications. PMID:19372744
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Dose Trends of Aripiprazole from 2004 to 2014 in Psychiatric Inpatients in Korea.
Woo, Young Sup; Shim, In Hee; Lee, Sang-Yeol; Lee, Dae-Bo; Kim, Moon-Doo; Jung, Young-Eun; Lee, Jonghun; Won, Seunghee; Jon, Duk-In; Bahk, Won-Myong
2017-05-31
Although aripiprazole has been widely used to treat various psychiatric disorders, little is known about the adequate dosage for Asian patients in clinical practice. Hence, we evaluated the initial and maximum doses of aripiprazole from 2004 to 2014 to estimate the appropriate dosage for Korean psychiatric inpatients in clinical practice. In this retrospective study, we reviewed the medical records of patients who were hospitalized in five university hospitals in Korea from March 2004 to December 2014. The psychiatric diagnosis according to the text revision of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition during index hospitalization and the initial and maximum doses of aripiprazole were evaluated. There were 74 patients in Wave 1 (2004-2006), 201 patients in Wave 2 (2007-2010), and 353 patients in Wave 3 (2011-2014). The initial doses of aripiprazole in all diagnostic groups were significantly lower in Wave 3 than in Wave 2. The maximum doses of aripiprazole in each diagnostic group were not significantly different among Waves 1, 2, and 3. The relatively low initial doses of aripiprazole documented in our study may reflect a strategy by clinicians to minimize the side effects associated with aripiprazole use, such as akathisia.
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Pira, Luigi; Mongeau, Raymond; Pani, Luca
2004-11-03
Quetiapine is a novel atypical antipsychotic drug with multi-receptorial affinity. Using in vivo microdialysis, we investigated if quetiapine modulates extracellular noradrenaline and dopamine in brain areas generally believed to be involved in the pathophysiology of schizophrenia and in the action of antipsychotic drugs. Quetiapine (5, 10 and 20 mg/kg, i.p.) increased levels of noradrenaline in both the prefrontal cortex and the caudate nucleus, while it increased dopamine levels mainly in the prefrontal cortex. It is argued that the marked increase of dopaminergic transmission in the prefrontal cortex induced by quetiapine might be relevant to its therapeutical action.
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... a mental illness that causes disturbed or unusual thinking, loss of interest in life, and strong or ... aripiprazole injection and aripiprazole extended-release injection developed gambling problems or other intense urges or behaviors that ...
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Low-dose aripiprazole for refractory burning mouth syndrome.
Umezaki, Yojiro; Takenoshita, Miho; Toyofuku, Akira
2016-01-01
We report a case of refractory burning mouth syndrome (BMS) ameliorated with low dose of aripiprazole. The patient was a 66-year-old female who had suffered from chronic burning pain in her tongue for 13 months. No abnormality associated with the burning sensation was detected in the laboratory tests and the oral findings. Considering the clinical feature and the history together, we diagnosed the burning sensation as BMS. The BMS pain was decreased by aripiprazole (powder) 1.0 mg/d, though no other antidepressants had satisfying pain relief. It could be supposed that the efficacy of aripiprazole is caused by dopamine stabilization in this case, and BMS might have a subtype that is reactive to aripiprazole. Further studies are needed to confirm the efficacy of aripiprazole for BMS.
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Gray, R; Deane, K
2016-03-01
What is known on the subject? Antipsychotic drugs are an important part of treatment for most patients with first episode psychosis. We do not know much about what it is like to take these drugs from the patient's point of view. What this paper adds to existing knowledge? We talked to 20 young people with psychosis about their experiences of taking antipsychotic drugs. Patients relationship with medication was complex, young people found medication often to be both good and bad at the same time. We were interested in how seemingly trivial issues--colour, taste, size, name--could be very important to young people and could result in them stopping. What are the implications for practice? We think our study highlights the complicated internal struggles that people with first episode psychosis have with medication. Our study highlights how Nurses and Doctors need to try and better understand what it is like to take these drugs and work collaboratively with patients to support them to make informed choices about treatment. Low-dose antipsychotic medication is an important part of treatment for people experiencing a first episode of psychosis. Little is known about this group of patients' experiences of taking medication. A qualitative study of purposively sampled young people experiencing a first episode of psychosis was carried out. A mental health nurse working in the early psychosis team interviewed participants using a structured topic guide. Interviews were subjected to thematic analysis. Interviews were completed with 20 young people. Thematic analysis generated six themes: (1) the drugs do work, (2) the drugs don't work (as well as I'd like), (3) side effects, (4) the indirect effects of medication, (5) rage against the machine and (6) the not trivial issues about medication. Our overarching meta-theme was that young people's experience of taking antipsychotics was complex; medication was often considered good and bad at the same time. Our observations underpin the importance of helping patients think through the use of antipsychotic medication in supporting their personal recovery. © 2016 John Wiley & Sons Ltd.
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Patient compliance with drug therapy in schizophrenia. Economic and clinical issues.
Lindström, E; Bingefors, K
2000-08-01
The effectiveness of drug treatment in clinical practice is considerably lower than the efficacy shown in controlled studies. The lower effectiveness in practice presumably leads to lower cost effectiveness of drug treatment in real-life situations compared with that demonstrated by studies based on results from controlled trials. Improved cost effectiveness in routine clinical practice would be a significant advantage in the treatment of schizophrenia, one of the most costly diseases in society. The aetiology of schizophrenia is unknown, and there is no cure. The main aims of therapy with antipsychotic medication include the effective relief of symptoms without the introduction of adverse effects or serious adverse events, improved quality of life, cost effectiveness and a positive long term outcome. The older classical antipsychotic drugs do not always meet these requirements because of their well-known limitations, such as a lack of response in a subgroup of individuals with schizophrenia and intolerable adverse effects. There has long been a need for new antipsychotics that can ameliorate more symptoms and have no or few adverse effects. Some of the recently introduced antipsychotics have been shown to be more effective in certain clinical situations and to have a more favourable adverse effect profile than the classical antipsychotics. A major factor contributing to the lower effectiveness of drug treatment is noncompliance, which may be very high in schizophrenia. There are several factors influencing compliance, including drug type and formulation, patient, disease status, physician, health care system, community care and family. There have been very few studies of compliance improvement strategies in schizophrenia or, indeed, in medicine in general. Current methods are relatively complex and there are differing opinions on their effectiveness. There are several ways to increase compliance in schizophrenia--the evidence is strongest for psychoeducative methods, changing to a new drug or using a depot formulation. However, considerably more research is needed in the field of compliance strategies.
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Zhang, Chen; Li, Ming
2012-02-01
Repeated administration of haloperidol (HAL) and olanzapine (OLZ) causes a progressively enhanced disruption of the conditioned avoidance response (CAR) and a progressively enhanced inhibition of phencyclidine (PCP)-induced hyperlocomotion in rats (termed antipsychotic sensitization). Both actions are thought to reflect intrinsic antipsychotic activity. The present study examined the extent to which antipsychotic-induced sensitization in one model (e.g. CAR) can be transferred or maintained in another (e.g. PCP hyperlocomotion) as a means of investigating the contextual and behavioral controls of antipsychotic sensitization. Well-trained male Sprague-Dawley rats were first repeatedly tested in the CAR or the PCP (3.2 mg/kg, subcutaneously) hyperlocomotion model under HAL or OLZ for 5 consecutive days. Then they were switched to the other model and tested for the expression of sensitization. Finally, all rats were switched back to the original model and retested for the expression of sensitization. Repeated HAL or OLZ treatment progressively disrupted avoidance responding and decreased PCP-induced hyperlocomotion, indicating a robust sensitization. When tested in a different model, rats previously treated with HAL or OLZ did not show a stronger inhibition of CAR-induced or PCP-induced hyperlocomotion than those treated with these drugs for the first time; however, they did show such an effect when tested in the original model in which they received repeated antipsychotic treatment. These findings suggest that the expression of antipsychotic sensitization is strongly influenced by the testing environment and/or selected behavioral response under certain experimental conditions. Distinct contextual cues and behavioral responses may develop an association with unconditional drug effects through a Pavlovian conditioning process. They may also serve as occasion setters to modulate the expression of sensitized responses. As antipsychotic sensitization mimics the clinical effects of antipsychotic treatment, understanding the neurobiological mechanisms of antipsychotic sensitization and its contextual control would greatly enhance our understanding of the psychological and neurochemical nature of antipsychotic treatment in the clinic.
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Zhang, Chen; Li, Ming
2011-01-01
Repeated administration of haloperidol and olanzapine causes a progressively enhanced disruption of conditioned avoidance response (CAR) and a progressively enhanced inhibition of phencyclidine (PCP)-induced hyperlocomotion in rats (termed antipsychotic sensitization). Both actions are thought to reflect intrinsic antipsychotic activity. The present study examined to the extent to which antipsychotic-induced sensitization in one model (e.g. CAR) can be transferred or maintained in another (e.g. PCP hyperlocomotion) as a means of investigating the contextual and behavioral controls of antipsychotic sensitization. Well-trained male Sprague-Dawley rats were first repeatedly tested in the CAR or PCP (3.2 mg/kg, sc) hyperlocomotion model under haloperidol or olanzapine for five consecutive days. Then they were switched to the other model and tested for the expression of sensitization. Finally, all rats were switched back to the original model and retested for the expression of sensitization. Repeated haloperidol or olanzapine treatment progressively disrupted avoidance responding and decreased PCP-induced hyperlocomotion, indicating a robust sensitization. When tested in a different model, rats previously treated with haloperidol or olanzapine did not show a stronger inhibition of CAR or PCP-induced hyperlocomotion than those treated with these drugs for the first time; however, they did show such an effect when tested in the original model in which they received repeated antipsychotic treatment. These findings suggest that the expression of antipsychotic sensitization is strongly influenced by the testing environment and/or selected behavioral response under certain experimental conditions. Distinct contextual cues and behavioral responses may enter an association with unconditional drug effects via a Pavlovian conditioning process. They may also serve as occasion-setters to modulate the expression of sensitized responses. Because antipsychotic sensitization mimics clinical effects of antipsychotic treatment, understanding the neurobiological mechanisms of antipsychotic sensitization and its contextual control would greatly enhance our understanding of the psychological and neurochemical nature of antipsychotic treatment in the clinic. PMID:22157143
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Mast, Gavin; Fernandes, Kimberly; Tadrous, Mina; Martins, Diana; Herrmann, Nathan; Gomes, Tara
2016-06-01
Antipsychotics are commonly used to manage behavioral and psychological symptoms of dementia. Concerns over their safety and efficacy in this role have resulted in antipsychotics typically being recommended for short-term usage only when used among dementia patients. However, there is little work examining the duration of antipsychotic treatment in the elderly dementia patient population. To determine the persistence of use of antipsychotics in elderly dementia patients and the role of dose on therapy duration. A retrospective, population-based cohort study using administrative data, including dispensing records from a provincial public drug program, from Ontario, Canada between 2009 and 2012. Elderly dementia patients newly initiated onto antipsychotics were followed until drug discontinuation, death, 2-year follow-up, or end of study. Competing risk analysis was performed to determine time to discontinuation, stratified by categories of initial dose. After 2 years 49.1 % of the cohort ( N = 22,927 of 46,695) had discontinued treatment. When stratified by dose, the high-dose group (51.1 % discontinued) discontinued more frequently than the medium- (48.7 % discontinued) and low- (47.5 % discontinued) dose groups ( p < 0.0001). Approximately half of elderly dementia patients treated with antipsychotics discontinue within 2 years, with those on higher doses more likely to discontinue. However, the number of patients remaining on therapy represents a serious public health concern.
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Becker, Edmund R; Constantine, Robert J; McPherson, Marie A; Jones, Mary Elizabeth
2013-01-01
The rapid growth in the use of antipsychotic medications and their related costs have resulted in states developing programs to measure, monitor, and insure their beneficial relevance to public program populations. One such program developed in the state of Florida has adopted an evidence-based approach to identify prescribers with unusual psychotherapeutic prescription patterns and track their utilization and costs among Florida Medicaid patients. This study reports on the prescriber prescription and cost patterns for adults and children using three measures of unusual antipsychotic prescribing patterns: (1) two antipsychotics for 60 days (2AP60), (2) three antipsychotics for 60 days (3AP60), and (2) two antipsychotics for 90 or more days (2AP90). We find that over the four-year study period there were substantial increases in several aspects of the Florida Medicaid behavioral drug program. Overall, for adults and children, patient participation increased by 29 percent, the number of prescriptions grew by 30 percent, and the number of prescribers that wrote at least one prescription grew 48.5 percent, while Medicaid costs for behavioral drugs increased by 32 percent. But the results are highly skewed. We find that a relatively small number of prescribers account for a disproportionately large share of prescriptions and costs of the unusual antipsychotic prescriptions. In general, the top 350 Medicaid prescribers accounted for more than 70 percent of the unusual antipsychotic prescriptions, and we find that this disparity in unusual prescribing patterns appears to be substantially more pronounced in adults than in children prescribers. For just the top 13 adult and children prescribers, their practice patterns accounted for 11 percent to 21 percent of the unusual prescribing activity and, overall, these 13 top prescribers accounted for 13 percent of the total spent on antipsychotics by the Florida Medicaid program and 9.3 percent of the total expenditure by the state for all drugs. Our findings suggest that a strategy to monitor and ensure patient safety and prescribing patterns that targets a relatively small number of Medicaid providers could have a substantial benefit and prove to be cost effective.
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Tam, S W; Cook, L
1984-01-01
The relationship between binding of antipsychotic drugs and sigma psychotomimetic opiates to binding sites for the sigma agonist (+)-[3H]SKF 10,047 (N-allylnormetazocine) and to dopamine D2 sites was investigated. In guinea pig brain membranes, (+)-[3H]SKF 10,047 bound to a single class of sites with a Kd of 4 X 10(-8) M and a Bmax of 333 fmol/mg of protein. This binding was different from mu, kappa, or delta opiate receptor binding. It was inhibited by opiates that produce psychotomimetic activities but not by opiates that lack such activities. Some antipsychotic drugs inhibited (+)-[3H]SKF 10,047 binding with high to moderate affinities in the following order of potency: haloperidol greater than perphenazine greater than fluphenazine greater than acetophenazine greater than trifluoperazine greater than molindone greater than or equal to pimozide greater than or equal to thioridazine greater than or equal to chlorpromazine greater than or equal to triflupromazine. However, there were other antipsychotic drugs such as spiperone and clozapine that showed low affinity for the (+)-[3H]SKF 10,047 binding sites. Affinities of antipsychotic drugs for (+)-[3H]SKF 10,047 binding sites did not correlate with those for [3H]spiperone (dopamine D2) sites. [3H]-Haloperidol binding in whole brain membranes was also inhibited by the sigma opiates pentazocine, cyclazocine, and (+)-SKF 10,047. In the striatum, about half of the saturable [3H]haloperidol binding was to [3H]spiperone (D2) sites and the other half was to sites similar to (+)-[3H]SKF 10,047 binding sites. PMID:6147851
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Tam, S.W.; Cook, L.
1984-09-01
The relationship between binding of antipsychotic drugs and sigma psychotomimetic opiates to binding sites for the sigma agonist (+)-(/sup 3/H)SKF 10,047 (N-allylnormetazocine) and to dopamine D/sub 2/ sites was investigated. In guinea pig brain membranes, (+)-(/sup 3/H)SKF 10,047 bound to single class of sites with a K/sub d/ of 4 x 10/sup -8/ M and a B/sub max/ of 333 fmol/mg of protein. This binding was different from ..mu.., kappa, or delta opiate receptor binding. It was inhibited by opiates that produce psychotomimetic activities but not by opiates that lack such activities. Some antipsychotic drugs inhibited (+)-(/sup 3/H)SKF 10,047 bindingmore » with high to moderate affinities in the following order of potency: haloperidol > perphenazine > fluphenazine > acetophenazine > trifluoperazine > molindone greater than or equal to pimozide greater than or equal to thioridazine greater than or equal to chlorpromazine greater than or equal to triflupromazine. However, there were other antipsychotic drugs such as spiperone and clozapine that showed low affinity for the (+)-(/sup 3/H)SKF 10,047 binding sites. Affinities of antipsychotic drugs for (+)-(/sup 3/H)SKF 10,047 binding sites did not correlate with those for (/sup 3/H)spiperone (dopamine D/sub 2/) sites. (/sup 3/H)-Haloperidol binding in whole brain membranes was also inhibited by the sigma opiates pentazocine, cyclazocine, and (+)-(/sup 3/H)SKF 10,047. In the striatum, about half of the saturable (/sup 3/H)haloperidol binding was to (/sup 3/H)spiperone (D/sub 2/) sites and the other half was to sites similar to (+)-(/sup 3/H)SKF 10,047 binding sites. 15 references, 4 figures, 1 table.« less
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Samaha, Anne-Noël
2013-01-01
Drug abuse and addiction are excessively common in schizophrenia. Chronic antipsychotic treatment might contribute to this comorbidity by inducing supersensitivity within the brain’s dopamine system. Dopamine supersensitivity can enhance the incentive motivational properties of reward cues, and reward cues contribute to the maintenance and severity of drug addiction. We have shown previously that rats withdrawn from continuous haloperidol (HAL) treatment (via subcutaneous minipump) develop dopamine supersensitivity and pursue reward cues more vigorously than HAL-naive rats following an amphetamine (AMPH) challenge. Atypical antipsychotic drugs are thought to be less likely than typicals to produce dopamine supersensitivity. Thus, we compared the effects of HAL and the atypical antipsychotic olanzapine (OLZ) on the pursuit of reward cues. Rats were trained to associate a light-tone cue with water then treated with HAL or OLZ. Following antipsychotic withdrawal, we assessed AMPH-induced enhancement of lever pressing for the cue. Withdrawal from HAL, but not from OLZ, enhanced this effect. HAL, but not OLZ, also enhanced AMPH-induced psychomotor activation and c-fos mRNA expression in the caudate-putamen. Thus, prior HAL, but not OLZ, enhanced conditioned reward following an AMPH challenge, and this was potentially linked to enhanced behavioral sensitivity to AMPH and AMPH-induced engagement of the caudate-putamen. These findings suggest that HAL, but not an atypical like OLZ, modifies reward circuitry in ways that increase responsiveness to reward cues. Because enhanced responsiveness to reward cues can promote drug-seeking behavior, it should be investigated whether atypical antipsychotics might be a preferential option in schizophrenic patients at risk for drug abuse or addiction. PMID:22927669
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Duncan, Carlotta E; Schofield, Peter R; Weickert, Cynthia Shannon
2009-12-22
Antipsychotic drugs are the main treatment for schizophrenia, despite their adverse side effects and uncertain mode of action. Gene expression studies in the brains of rodents treated with antipsychotic drugs aim to uncover this mechanism and elucidate more specific targets for schizophrenia treatment. Previous expression profiling analyses showed that K(v) channel interacting protein 3 (KChIP3) was down-regulated in the mouse brain following treatment with multiple antipsychotic drugs. In this study, we used in situ hybridization to anatomically define the expression of KChIP3 mRNA in the mouse brain and to quantify its regulation by 7-day haloperidol treatment. We used immunohistochemistry to localize KChIP3 protein expression in the midbrain, dorsal and ventral striatum and the prefrontal cortex. We found KChIP3 mRNA throughout the grey matter of the brain, with high expression in the hippocampus, specific thalamic nuclei, deeper cortical layers and in the midbrain. KChIP3 mRNA was significantly down-regulated in the dorsal striatum and the ventral tegmental area following haloperidol treatment. KChIP3 protein is expressed in the neuropil in the cortex and striatum, as well as in the soma of deeper layer cortical and striatal neurons. This study, for the first time, also localized KChIP3 protein in the cell bodies and processes of dopaminergic neurons in the midbrain. These findings indicate that regulation of KChIP3, particularly in mesocortical dopamine neurons, may be part of the action of antipsychotic drugs and that prolonged and more specific targeting of ion channel subunits may enhance the therapeutic effects of antipsychotic drugs.
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Bioque, Miquel; Llerena, Adrián; Cabrera, Bibiana; Mezquida, Gisela; Lobo, Antonio; González-Pinto, Ana; Díaz-Caneja, Covadonga M.; Corripio, Iluminada; Aguilar, Eduardo J.; Bulbena, Antoni; Castro-Fornieles, Josefina; Vieta, Eduard; Lafuente, Amàlia; Mas, Sergi; Parellada, Mara; Saiz-Ruiz, Jerónimo; Cuesta, Manuel J.
2016-01-01
Background: The characterization of the first episode of psychosis and how it should be treated are principal issues in actual research. Realistic, naturalistic studies are necessary to represent the entire population of first episode of psychosis attended in daily practice. Methods: Sixteen participating centers from the PEPs project recruited 335 first episode of psychosis patients, aged 7 to 35 years. This article describes and discusses the psychopharmacological interventions and safety profiles at baseline and during a 60-day pharmacovigilance period. Results: The majority of first episode of psychosis patients received a second-generation antipsychotic (96.3%), orally (95%), and in adjusted doses according to the product specifications (87.2%). A total of 24% were receiving an antipsychotic polytherapy pattern at baseline, frequently associated with lower or higher doses of antipsychotics than the recommended ones. Eight patients were taking clozapine, all in monotherapy. Males received higher doses of antipsychotic (P=.043). A total of 5.2% of the patients were being treated with long-acting injectable antipsychotics; 12.2% of the patients received anticholinergic drugs, 12.2% antidepressants, and 13.7% mood stabilizers, while almost 40% received benzodiazepines; and 35.52% reported at least one adverse drug reaction during the pharmacovigilance period, more frequently associated with higher antipsychotic doses and antipsychotic polytherapy (85.2% vs 45.5%, P<.001). Conclusions: These data indicate that the overall pharmacologic prescription for treating a first episode of psychosis in Spain follows the clinical practice guideline recommendations, and, together with security issues, support future research of determinate pharmacological strategies for the treatment of early phases of psychosis, such as the role of clozapine, long-acting injectable antipsychotics, antipsychotic combination, and the use of benzodiazepines. PMID:26506856
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Polygenic overlap between schizophrenia risk and antipsychotic response: a genomic medicine approach
Ruderfer, Douglas M; Charney, Alexander W; Readhead, Ben; Kidd, Brian A; Kähler, Anna K; Kenny, Paul J; Keiser, Michael J; Moran, Jennifer L; Hultman, Christina M; Scott, Stuart A; Sullivan, Patrick F; Purcell, Shaun M; Dudley, Joel T; Sklar, Pamela
2016-01-01
Summary Background Therapeutic treatments for schizophrenia do not alleviate symptoms for all patients and efficacy is limited by common, often severe, side-effects. Genetic studies of disease can identify novel drug targets, and drugs for which the mechanism has direct genetic support have increased likelihood of clinical success. Large-scale genetic studies of schizophrenia have increased the number of genes and gene sets associated with risk. We aimed to examine the overlap between schizophrenia risk loci and gene targets of a comprehensive set of medications to potentially inform and improve treatment of schizophrenia. Methods We defined schizophrenia risk loci as genomic regions reaching genome-wide significance in the latest Psychiatric Genomics Consortium schizophrenia genome-wide association study (GWAS) of 36 989 cases and 113 075 controls and loss of function variants observed only once among 5079 individuals in an exome-sequencing study of 2536 schizophrenia cases and 2543 controls (Swedish Schizophrenia Study). Using two large and orthogonally created databases, we collated drug targets into 167 gene sets targeted by pharmacologically similar drugs and examined enrichment of schizophrenia risk loci in these sets. We further linked the exome-sequenced data with a national drug registry (the Swedish Prescribed Drug Register) to assess the contribution of rare variants to treatment response, using clozapine prescription as a proxy for treatment resistance. Findings We combined results from testing rare and common variation and, after correction for multiple testing, two gene sets were associated with schizophrenia risk: agents against amoebiasis and other protozoal diseases (106 genes, p=0·00046, pcorrected =0·024) and antipsychotics (347 genes, p=0·00078, pcorrected=0·046). Further analysis pointed to antipsychotics as having independent enrichment after removing genes that overlapped these two target sets. We noted significant enrichment both in known targets of antipsychotics (70 genes, p=0·0078) and novel predicted targets (277 genes, p=0·019). Patients with treatment-resistant schizophrenia had an excess of rare disruptive variants in gene targets of antipsychotics (347 genes, p=0·0067) and in genes with evidence for a role in antipsychotic efficacy (91 genes, p=0·0029). Interpretation Our results support genetic overlap between schizophrenia pathogenesis and antipsychotic mechanism of action. This finding is consistent with treatment efficacy being polygenic and suggests that single-target therapeutics might be insufficient. We provide evidence of a role for rare functional variants in antipsychotic treatment response, pointing to a subset of patients where their genetic information could inform treatment. Finally, we present a novel framework for identifying treatments from genetic data and improving our understanding of therapeutic mechanism. PMID:26915512
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Moran, Landhing M.; Phillips, Karran A.; Kowalczyk, William J.; Ghitza, Udi E.; Agage, Daniel A.; Epstein, David H.; Preston, Kenzie L.
2016-01-01
Objectives. Aripiprazole blocks psychostimulant seeking in a rat model of relapse. However, in humans, it may increase ongoing use. We tested aripiprazole specifically for relapse prevention. Methadone-maintained outpatients who were abstinent from cocaine in weeks 11-12 were randomized to double-blind aripiprazole (15/mg daily) or placebo in weeks 13-27, after 12 weeks of contingency management. Participants reported craving via ecological momentary We stopped the trial because too few (18 of 41) participants met the abstinence criterion. The results were suggestive that aripiprazole delayed lapse (HR = 0.45, CI95 = 0.14 – 1.42, p = 0.17) and relapse (HR = 0.31. CI95 = 0.07 – 1.27, p = 0.10), but the effects did not reach statistical significance. Unexpectedly, the proportion of participants reporting cocaine craving was higher in the aripiprazole group (Fisher exact p = .026), though frequency of craving was similar in the aripiprazole and placebo groups (1.89% vs. 1.16%, reffect = .43, CI95 = −.08 - .76). The results suggest that in recently abstinent cocaine users, aripiprazole might delay relapse, but might also slightly increase craving. Difficulty in trial implementation underscores the fact that initial abstinence from cocaine is not a trivial hurdle. PMID:27755017
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Moran, Landhing M; Phillips, Karran A; Kowalczyk, William J; Ghitza, Udi E; Agage, Daniel A; Epstein, David H; Preston, Kenzie L
2017-02-01
Aripiprazole blocks psychostimulant seeking in a rat model of relapse. However, in humans, it may increase ongoing use. We tested aripiprazole specifically for relapse prevention. Methadone-maintained outpatients who were abstinent from cocaine in weeks 11-12 were randomized to double-blind aripiprazole (15 mg daily) or placebo in weeks 13-27 after 12 weeks of contingency management. Participants reported craving through ecological momentary assessment. We stopped the trial because very few (18/41) participants fulfilled the abstinence criterion. The results suggested that aripiprazole delayed lapse [hazard ratio (HR)=0.45, 95% confidence interval (CI)=0.14-1.42, P=0.17] and relapse (HR=0.31, 95% CI=0.07-1.27, P=0.10), but the effects did not reach statistical significance. Unexpectedly, the proportion of participants reporting cocaine craving was higher in the aripiprazole group (Fisher's exact P=0.026), although the frequency of craving was similar in the aripiprazole and placebo groups (1.89 vs. 1.16%, reffect=0.43, 95% CI=-0.08-0.76). The results suggest that in recently abstinent cocaine users, aripiprazole might delay relapse, but might also slightly increase craving. Difficulty in trial implementation underscores the fact that initial abstinence from cocaine is not a trivial hurdle.
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2013-01-01
Background In patients with schizophrenia, altered brain activation and motor activity levels are central features, reflecting cognitive impairments and negative symptoms, respectively. Newer studies using nonlinear methods have addressed the severe disturbances in neurocognitive functioning that is regarded as one of the core features of schizophrenia. Our aim was to compare brain activation and motor activity in a patient during pharmacological treatment that was switched from a first- to a second-generation antipsychotic drug. We hypothesised that this change of medication would increase level of responding in both measures. Case presentation We present the case of a 53-year-old male with onset of severe mental illness in adolescence, ICD-10 diagnosed as schizophrenia of paranoid type, chronic form. We compared brain activation and motor activity in this patient during pharmacological treatment with a first-generation (perphenazin), and later switched to a second-generation (risperidone) antipsychotic drug. We used functional magnetic resonance imaging (fMRI) to measure brain activation and wrist worn actigraphy to measure motor activity. Conclusion Our study showed that brain activation decreased in areas critical for cognitive functioning in this patient, when changing from a first to a second generation antipsychotic drug. However the mean motor activity level was unchanged, although risperidone reduced variability, particularly short-term variability from minute to minute. Compared to the results from previous studies, the present findings indicate that changing to a second-generation antipsychotic alters variability measures towards that seen in a control group, but with reduced brain activation, which was an unexpected finding. PMID:23648137
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Berle, Jan Øystein; Løberg, Else-Marie; Fasmer, Ole Bernt
2013-05-06
In patients with schizophrenia, altered brain activation and motor activity levels are central features, reflecting cognitive impairments and negative symptoms, respectively. Newer studies using nonlinear methods have addressed the severe disturbances in neurocognitive functioning that is regarded as one of the core features of schizophrenia. Our aim was to compare brain activation and motor activity in a patient during pharmacological treatment that was switched from a first- to a second-generation antipsychotic drug. We hypothesised that this change of medication would increase level of responding in both measures. We present the case of a 53-year-old male with onset of severe mental illness in adolescence, ICD-10 diagnosed as schizophrenia of paranoid type, chronic form. We compared brain activation and motor activity in this patient during pharmacological treatment with a first-generation (perphenazin), and later switched to a second-generation (risperidone) antipsychotic drug. We used functional magnetic resonance imaging (fMRI) to measure brain activation and wrist worn actigraphy to measure motor activity. Our study showed that brain activation decreased in areas critical for cognitive functioning in this patient, when changing from a first to a second generation antipsychotic drug. However the mean motor activity level was unchanged, although risperidone reduced variability, particularly short-term variability from minute to minute. Compared to the results from previous studies, the present findings indicate that changing to a second-generation antipsychotic alters variability measures towards that seen in a control group, but with reduced brain activation, which was an unexpected finding.
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Takahashi, Tetsuya; Cho, Raymond Y.; Mizuno, Tomoyuki; Kikuchi, Mitsuru; Murata, Tetsuhito; Takahashi, Koichi; Wada, Yuji
2010-01-01
Multiscale entropy (MSE) analysis is a novel entropy-based approach for measuring dynamical complexity in physiological systems over a range of temporal scales. To evaluate this analytic approach as an aid to elucidating the pathophysiologic mechanisms in schizophrenia, we examined MSE in EEG activity in drug-naïve schizophrenia subjects pre- and post-treatment with antipsychotics in comparison with traditional EEG analysis. We recorded eyes-closed resting state EEG from frontal, temporal, parietal and occipital regions in drug-naïve 22 schizophrenia and 24 age-matched healthy control subjects. Fifteen patients were re-evaluated within 2–8 weeks after the initiation of antipsychotic treatment. For each participant, MSE was calculated on one continuous 60 second epoch for each experimental session. Schizophrenia subjects showed significantly higher complexity at higher time scales (lower frequencies), than that of healthy controls in fronto-centro-temporal, but not in parieto-occipital regions. Post-treatment, this higher complexity decreased to healthy control subject levels selectively in fronto-central regions, while the increased complexity in temporal sites remained higher. Comparative power analysis identified spectral slowing in frontal regions in pre-treatment schizophrenia subjects, consistent with previous findings, whereas no antipsychotic treatment effect was observed. In summary, multiscale entropy measures identified abnormal dynamical EEG signal complexity in anterior brain areas in schizophrenia that normalized selectively in fronto-central areas with antipsychotic treatment. These findings show that entropy-based analytic methods may serve as a novel approach for characterizing and understanding abnormal cortical dynamics in schizophrenia, and elucidating the therapeutic mechanisms of antipsychotics. PMID:20149880
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Hsu, Jonathan H; Mulsant, Benoit H; Lenze, Eric J; Karp, Jordan F; Lavretsky, Helen; Roose, Steven P; Reynolds, Charles F; Blumberger, Daniel M
2016-10-01
Treatment history can inform clinical decisions about subsequent treatment choices. The authors examined the impact of prior antidepressant treatment on treatment outcomes with venlafaxine only and then with augmentation with aripiprazole or placebo in depressed older adults. The authors analyzed outcome data from a randomized, placebo-controlled clinical trial of aripiprazole augmentation in depressed older adults. The study consisted of an open-label lead-in phase with venlafaxine XR, followed by a placebo-controlled phase of aripiprazole augmentation. Treatment history was assessed with the Antidepressant Treatment History Form. Documented prior treatment failure predicted a reduced remission rate with venlafaxine. However, aripiprazole augmentation was efficacious in those with prior treatment failure (42.6% remission with aripiprazole versus 25.8% with placebo; χ(2) = 3.87 df = 1, p = 0.049). Aripiprazole augmentation is an efficacious strategy in older depressed adults who fail to remit with two or more adequate antidepressant trials, including a course of venlafaxine. Copyright © 2016 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.
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Extrapyramidal side effects of antipsychotic treatment: scope of problem and impact on outcome.
Tandon, Rajiv; Jibson, Michael D
2002-06-01
Previously, clinicians worked with antipsychotic drugs (conventional or typical) that almost invariably caused extrapyramidal symptoms (EPS) at clinically effective doses. This led to the false impression that all antipsychotics were the same, and that EPS were an unavoidable consequence of effective antipsychotic therapy. EPS adversely impact several aspects of antipsychotic efficacy and tolerability, thereby worsening outcome of afflicted individuals. EPS reduce beneficial effects of antipsychotic treatment on the negative, cognitive, and mood symptom domains, while increasing the risk of tardive dyskinesia and reducing compliance. By definition, the newer generation of "atypical" antipsychotic agents are significantly better than conventional agents with regard to EPS (i.e., they are clinically effective at doses at which they do not cause EPS). Pharmacologically, this difference is expressed in the greater degree of separation between respective dose response curves for antipsychotic and EPS effects observed for "atypical" in contrast to conventional agents. Clinically, this EPS advantage of atypical antipsychotics translates into several important benefits, including better negative symptom efficacy, less dysphoria, less impaired cognition, a lower risk of TD, and better overall outcome.
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2014-01-01
Background Antipsychotic medications, particularly second-generation antipsychotics, are increasingly being used to alleviate the symptoms of schizophrenia and other severe mental disorders in the pediatric population. While evidence-based approaches examining efficacy and safety outcomes have been reported, no review has evaluated prolactin-based adverse events for antipsychotic treatments in schizophrenia and schizophrenia spectrum disorders. Methods/design Searches involving MEDLINE, EMBASE, CENTRAL, PsycINFO, and clinical trial registries (ClinicalTrials.gov, Drug Industry Document Archive [DIDA], International Clinical Trials Registry Platform [ICTRP]) will be used to identify relevant studies. Two reviewers will independently screen abstracts and relevant full-text articles of the papers identified by the initial search according to the prospectively defined eligibility criteria. Data extraction will be conducted in duplicate independently. Pairwise random effects meta-analyses and network meta-analyses will be conducted on individual drug and class effects where appropriate. Discussion This systematic review will evaluate prolactin-based adverse events of first- and second-generation antipsychotics in the pediatric population with schizophrenia and schizophrenia spectrum disorders. It will also seek to strengthen the evidence base of the safety of antipsychotics by incorporating both randomized controlled trials and observational studies. Systematic review registration PROSPERO CRD42014009506 PMID:25312992
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Law, Suzanne; Haddad, Peter M.; Chaudhry, Imran B.; Husain, Nusrat; Drake, Richard J.; Flanagan, Robert J.; David, Anthony S.
2015-01-01
Background: This study aimed to explore predictive factors for future use of therapeutic drug monitoring (TDM) and to further examine psychiatrists’ current prescribing practices and perspectives regarding antipsychotic TDM using plasma concentrations. Method: A cross-sectional study for consultant psychiatrists using a postal questionnaire was conducted in north-west England. Data were combined with those of a previous London-based study and principal axis factor analysis was conducted to identify predictors of future use of TDM. Results: Most of the 181 participants (82.9%, 95% confidence interval 76.7–87.7%) agreed that ‘if TDM for antipsychotics were readily available, I would use it’. Factor analysis identified five factors from the original 35 items regarding TDM. Four of the factors significantly predicted likely future use of antipsychotic TDM and together explained 40% of the variance in a multivariate linear regression model. Likely future use increased with positive attitudes and expectations, and decreased with potential barriers, negative attitudes and negative expectations. Scientific perspectives of TDM and psychiatrist characteristics were not significant predictors. Conclusion: Most senior psychiatrists indicated that they would use antipsychotic TDM if available. However, psychiatrists’ attitudes and expectations and the potential barriers need to be addressed, in addition to the scientific evidence, before widespread use of antipsychotic TDM is likely in clinical practice. PMID:26301077
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Almeida, Valéria; Levin, Raquel; Peres, Fernanda Fiel; Niigaki, Suzy T; Calzavara, Mariana B; Zuardi, Antônio W; Hallak, Jaime E; Crippa, José A; Abílio, Vanessa C
2013-03-05
Cannabidiol (CBD), a non-psychotomimetic compound of the Cannabis sativa, has been reported to have central therapeutic actions, such as antipsychotic and anxiolytic effects. We have recently reported that Spontaneously Hypertensive Rats (SHRs) present a deficit in social interaction that is ameliorated by atypical antipsychotics. In addition, SHRs present a hyperlocomotion that is reverted by typical and atypical antipsychotics, suggesting that this strain could be useful to study negative symptoms (modeled by a decrease in social interaction) and positive symptoms (modeled by hyperlocomotion) of schizophrenia as well as the effects of potential antipsychotics drugs. At the same time, an increase in social interaction in control animals similar to that induced by benzodiazepines is used to screen potential anxiolytic drugs. The aim of this study was to investigate the effects of CBD on social interaction presented by control animals (Wistar) and SHRs. The lowest dose of CBD (1mg/kg) increased passive and total social interaction of Wistar rats. However, the hyperlocomotion and the deficit in social interaction displayed by SHRs were not altered by any dose of CBD. Our results do not support an antipsychotic property of cannabidiol on symptoms-like behaviors in SHRs but reinforce the anxiolytic profile of this compound in control rats. Copyright © 2012 Elsevier Inc. All rights reserved.
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[Lithium and anticonvulsants in the treatment of mania and in the prophylaxis of recurrences].
Salvi, Virginio; Cat Berro, Alberto; Bechon, Elisa; Bogetto, Filippo; Maina, Giuseppe
2011-01-01
A mood stabilizer is an agent effective in treating both poles of the illness and at the same time being able to prevent both manic and depressive episodes in bipolar disorder. According to a broader definition, a mood stabilizer should be effective in decreasing the frequency or severity of any type of episode in bipolar disorder, without worsening the frequency or severity of episodes of opposite polarity. According to this, anticonvulsants and atypical antipsychotics can be considered as mood stabilizers. In this paper we review the use of lithium and other anticonvulsants that have proved effective in randomized controlled trials of the treatment of manic episodes and prevention of recurrences of bipolar disorder. Lithium and valproate are considered as first-line treatment options for acute mania while evidence regarding carbamazepine is insufficient to consider it as a first-line agent. Patients who fail to respond to first-line treatments may benefit from the adjunct of an atypical antipsychotic such as olanzapine, quetiapine, risperidone or aripiprazole. Lithium retains the strongest evidence of efficacy in the prophylaxis of manic episodes, lamotrigine in the prevention of depressive episodes. Valproate and carbamazepine have no indication for long-term treatment of bipolar disorder. Lithium can still be considered a gold standard in the treatment of manic episodes as well as in the prophylaxis of recurrences. Other anticonvulsants should be employed in particular situations, such as valproic acid in the treatment of mania and lamotrigine in the prevention of depressive recurrences.
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Lindström, Leif; Lindström, Eva; Nilsson, Mikael; Höistad, Malin
2017-04-15
Second generations antipsychotics (SGA) are frequently used for maintenance treatment in bipolar disorder. We systematically reviewed the efficacy and long-term effects of treatment with SGA, regardless of treatment strategy (SGA administered either as monotherapy or as adjunctive therapy), in comparison to placebo, lithium or valproate. Primary outcomes were relapses (mood episode recurrence) and discontinuation. Clinical studies were identified through database searching in PubMed, Embase, PsychInfo and Cochrane Library and critically appraised based on the Cochrane Handbook. Full data extraction of raw data was performed and analyzed with meta-analyses, and level of evidence graded using GRADE. Only randomized controlled studies (RCT) and observational studies were included, with a minimum follow-up of 6 months. Comparators used were restricted to placebo, lithium, valproate or other anti-epileptic drugs. We identified 15 RCTs on SGA in bipolar disorder with follow-up-time of 6 months up to 2 years, and one observational study reporting long-term effects of up to 4 years. A total of 6142 patients were included in the randomized trials. No long-term RCTs beyond 2 years follow-up was identified. All RCTs except for one included patients with bipolar disorder type I only. All RCTs except for two included patients pre-stabilized on the drug under investigation prior to randomization (enrichment design). For SGA as adjunctive therapy to lithium or valproate, meta-analyses showed that treatment with either aripiprazole (RR: 0.65, 95% CI 0.50-0.85), quetiapine (RR: 0.38, 95% CI 0.32-0.46) or ziprasidone (RR: 0.62, 95% CI 0.40-0.96) reduced the overall risk of relapses in patients that had responded during the stabilization phase. Adjunctive therapy with quetiapine was the only drug that reduced both manic and depressive episodes. For SGA as monotherapy, only quetiapine was shown to be better than lithium/ valproate for both manic and depressive relapses, but only for patients stabilized on quetiapine during the acute phase. As monotherapy, olanzapine, quetiapine and risperidone were shown to be superior to placebo in reducing the overall risk of relapses. There were considerable limitations to the evidence base of maintenance treatment with SGA in bipolar disorder. Most studies used stabilized patients, i.e. enrichment design (selection bias), had considerable dropout levels (attrition bias), and variable degree of reporting bias. No long-term RCT data on efficacy is available beyond 2 years, and almost all studies are on bipolar disorder type I patients only. Despite these limitations, we elucidate quantitative findings from meta-analyses conducted on the randomized trials published on the topic. Copyright © 2017 Elsevier B.V. All rights reserved.
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Secondary pseudomyopia induced by amisulpride.
Stratos, Aimilianos A; Peponis, Vasileios G; Portaliou, Dimitra M; Stroubini, Theodora E; Skouriotis, Sotirios; Kymionis, George D
2011-11-01
To report a case of pseudomyopia induced by antipsychotic drug administration. A 30-year-old woman was referred to our ophthalmology department complaining of blurred vision, especially at distance, in both eyes. The patient had been prescribed antipsychotic drugs (haloperidol and biperiden) as treatment for her schizophrenic symptoms and had recently undergone a change of treatment to amisulpride. She had a manifest refraction of -4.00/-1.00 × 180 in the OD and -3.75/-1.25 × 175 in the OS whereas her cycloplegic refraction was -1.75/-1.00 × 180 in the OD and -1.00/-1.25 × 175 in the OS, respectively. A diagnosis of likely drug-induced pseudomyopia was made. Therefore, the patient was advised to visit her psychiatrist, who added an extra 2 mg of biperiden, an anticholinergic agent, to the pre-existing amisulpride treatment, achieving a cessation of the visual symptoms a few days later. Pseudomyopia can be induced by the antipsychotic drug amisulpride. Additional treatment with anticholinergic agents can be used to eliminate this side effect.
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Nehme, Hassan; Saulnier, Patrick; Ramadan, Alyaa A; Cassisa, Viviane; Guillet, Catherine; Eveillard, Matthieu; Umerska, Anita
2018-01-01
Bacterial antibiotic resistance is an emerging public health problem worldwide; therefore, new therapeutic strategies are needed. Many studies have described antipsychotic compounds that present antibacterial activity. Hence, the aims of this study were to evaluate the in vitro antibacterial activity of antipsychotics belonging to different chemical families, to assess the influence of their association with lipid nanocapsules (LNCs) on their antimicrobial activity as well as drug release and to study the uptake of LNCs by bacterial cells. Antibacterial activity was evaluated against Gram-positive Staphylococcus aureus and Gram negative Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii by minimum inhibitory concentration (MIC) assay, and the capability of killing tested microorganisms was evaluated by time kill assay. LNCs were prepared by phase inversion method, and the antipsychotic agents were incorporated using pre-loading and post-loading strategies. Only phenothiazines and thioxanthenes showed antibacterial activity, which was independent of antibiotic-resistance patterns. Loading the nanocarriers with the drugs affected the properties of the former, particularly their zeta potential. The release rate depended on the drug and its concentration-a maximum of released drug of less than 40% over 24 hours was observed for promazine. The influence of the drug associations on the antibacterial properties was concentration-dependent since, at low concentrations (high nanocarrier/drug ratio), the activity was lost, probably due to the high affinity of the drug to nanocarriers and slow release rate, whereas at higher concentrations, the activity was well maintained for the majority of the drugs. Chlorpromazine and thioridazine increased the uptake of the LNCs by bacteria compared with blank LNCs, even below the minimum inhibitory concentration.
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[Psychoactive drugs and costs in the Madrid III (Valdemoro) prison].
Algora-Donoso, I; Varela-González, O
2008-01-01
Annual pharmaceutical expenditures in prisons increases dramatically and the rising costs of psychoactive drugs have especially contributed to this. These drugs are often prescribed in order to find therapeutic uses in the field of personality disorders, addictions, and dysfunctional behaviours that are not included in the authorized indications (compassionate use). This study has enabled a detailed description of the use of psychoactive drugs at the Madrid III prison, a centre with one of the lowest levels of pharmaceutical expenditure in this autonomous community. During a two-week period, all prescriptions of psychoactive drugs were collected and registered along with data of several possible conditioning factors. 20.5% of the population was receiving some kind of psychoactive drug; 76% of those inmates undergoing treatment were receiving one or two substances; 65% were taking anxiolytics, 38% antidepressants and 27% antipsychotics. The total amount of psychoactive drugs consumed was 9,840 defined daily doses, 46% of which were anxiolytics, 17% antidepressants and 14% antipsychotics. The total cost of the fortnight's treatment was euros 5,379 with a saving of euro 611 due to requesting and selecting offers carried out by the pharmacist. 72% of the costs were spent on anti-psychotics and the newer psychoactive drugs, representing 66% of the prescriptions, accounted for 98% of expenditure. The prescriber was one of the key influential factors over the amount, type and cost of the treatments. There are signs that compassionate use of current antipsychotics and antiepileptics, and newer antidepressants are a main cause of the dramatic increase in the costs, with cost-efficiency not always clearly demonstrated. These results are not an isolated fact restricted only to prisons, as demonstrated by consumption data published by the National Health System in the same year.
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Use of antipsychotics increases the risk of fracture: a systematic review and meta-analysis.
Lee, S-H; Hsu, W-T; Lai, C-C; Esmaily-Fard, A; Tsai, Y-W; Chiu, C-C; Wang, J; Chang, S-S; Lee, C C
2017-04-01
Our systematic review and meta-analysis of observational studies indicated that the use of antipsychotics was associated with a nearly 1.5-fold increase in the risk of fracture. First-generation antipsychotics (FGAs) appeared to carry a higher risk of fracture than second-generation antipsychotics (SGAs). The risk of fractures associated with the use of antipsychotic medications has inconsistent evidence between different drug classes. A systematic review and meta-analysis was conducted to evaluate whether there is an association between the use of antipsychotic drugs and fractures. Searches were conducted through the PubMed and EMBASE databases to identify observational studies that had reported a quantitative estimate of the association between use of antipsychotics and fractures. The summary risk was derived from random effects meta-analysis. The search yielded 19 observational studies (n = 544,811 participants) with 80,835 fracture cases. Compared with nonuse, use of FGAs was associated with a significantly higher risk for hip fractures (OR 1.67, 95% CI, 1.45-1.93), and use of second generation antipsychotics (SGAs) was associated with an attenuated but still significant risk for hip fractures (OR 1.33, 95% CI, 1.11-1.58). The risk of fractures associated with individual classes of antipsychotic users was heterogeneous, and odds ratios ranged from 1.24 to 2.01. Chlorpromazine was associated with the highest risk (OR 2.01, 95% CI 1.43-2.83), while Risperidone was associated with the lowest risk of fracture (OR 1.24, 95% CI 0.95-1.83). FGA users were at a higher risk of hip fracture than SGA users. Both FGAs and SGAs were associated with an increased risk of fractures, especially among the older population. Therefore, the benefit of the off-label use of antipsychotics in elderly patients should be weighed against any risks for fracture.
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Molindone for schizophrenia and severe mental illness.
Bagnall, A; Fenton, M; Lewis, R; Leitner, M L; Kleijnen, J
2000-01-01
Typical antipsychotic drugs are widely used as the first line treatment for people with schizophrenia. However, the atypical class of antipsychotic drugs is making important inroads into this approach. 'Atypical' is a term widely used to describe some antipsychotics which have a low propensity to produce movement disorders, sedation and raised serum prolactin. There is some suggestion that the different adverse effect profiles of the atypical antipsychotic group make them more acceptable to people with schizophrenia. Molindone has a similar profile to quetiapine (a novel atypical antipsychotic), with very low binding to all receptors. Some authors have suggested that molindone is safer than other 'typical' antipsychotics in that extrapyramidal adverse effects are not usually seen at clinically effective antipsychotic doses and that it should therefore be classed as an atypical antipsychotic. To determine the effects of molindone compared with placebo, typical and other atypical antipsychotic drugs for schizophrenia and related psychoses. Electronic searches of Biological Abstracts (1980-1999), The Cochrane Library CENTRAL (Issue 1, 1999), The Cochrane Schizophrenia Group's Register (January 1999), CINAHL (1982-1999), EMBASE (1980-1999), MEDLINE (1966-1999), LILACS (1982-1999), PSYNDEX (1977-1999), and PsycLIT (1974-1999) were undertaken. In addition, pharmaceutical databases on the Dialog Corporation Datastar and Dialog services were searched. References of all identified studies were searched for further trials. The manufacturer of molindone and authors of trials were contacted. All randomised controlled trials that compared molindone to other treatments for schizophrenia and schizophrenia-like psychoses were included by independent assessment. Citations and, where possible, abstracts were independently inspected by reviewers, papers ordered, re-inspected and quality assessed. Data were independently extracted. Data were excluded if loss to follow up was greater than 50%. For homogeneous dichotomous data the risk ratio (RR), 95% confidence interval (CI) and, where appropriate, the number needed to treat (NNT) were calculated on an intention-to-treat basis. For continuous data, weighted mean differences (WMD) were calculated. All data were inspected for heterogeneity. Thirteen studies were included in the review. Data for this compound range from very short (10 day) studies of the intramuscular preparation to trials lasting over three months. For measures of global state available data do not justify any conclusions on the comparative efficacy of molindone and placebo. When compared to other typical antipsychotics no difference in effectiveness was evidenced (doctors' RR 1.13, CI 0.69 to 1.86; nurses' RR 1.23, CI 0.82 to 1.86). It is no more or less likely than typical drugs to cause movement disorders, but causes significantly more weight loss (RR 2.78, CI 1.10 to 6.99). The strength of the evidence relating to this compound is limited, owing to small sample size, poor study design, limited outcomes and incomplete reporting. Molindone may be an effective antipsychotic; however, its adverse effect profile does not differ significantly from that of typical antipsychotics, apart from the event of weight loss. At present there is no evidence to suggest that it may have an atypical profile.
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Gierisch, Jennifer M; Nieuwsma, Jason A; Bradford, Daniel W; Wilder, Christine M; Mann-Wrobel, Monica C; McBroom, Amanda J; Hasselblad, Vic; Williams, John W
2014-05-01
Individuals with serious mental illness have high rates of cardiovascular disease (CVD) risk factors and mortality. This systematic review was conducted to evaluate pharmacologic and behavioral interventions to reduce CVD risk in adults with serious mental illness. MEDLINE, EMBASE, PsycINFO, ClinicalTrials.gov, and Cochrane Database of Systematic Reviews were searched from January 1980 to July 2012 for English language studies. Examples of search terms used include schizophrenia, bipolar disorder, antipsychotics, weight, glucose, lipid, and cardiovascular disease. Two reviewers independently screened citations and identified 33 randomized controlled trials of at least 2 months' duration that enrolled adults with serious mental illness and evaluated pharmacologic or behavioral interventions targeting weight, glucose, or lipid control. Reviewers extracted data, assessed applicability, and evaluated study quality; the team jointly graded overall strength of evidence. We included 33 studies. Most studies targeted weight control (28 studies). Compared with control groups, weight control was improved with behavioral interventions (mean difference = -3.13 kg; 95% CI, -4.21 to -2.05), metformin (mean difference = -4.13 kg; 95% CI, -6.58 to -1.68), anticonvulsive medications topiramate and zonisamide (mean difference = -5.11 kg; 95% CI, -9.48 to -0.74), and adjunctive or antipsychotic switching to aripiprazole (meta-analysis not possible). Evidence was insufficient for all other interventions and for effects on glucose and lipid control. The small number of studies precluded analyses of variability in treatment effects by patient characteristics. Few studies have evaluated interventions addressing 1 or more CVD risk factors in people with serious mental illness. Glucose- and lipid-related results were mainly reported as secondary outcome assessments in studies of weight-management interventions. Comparative effectiveness studies are needed to test multimodal strategies, agents known to be effective in nonserious mental illness populations, and antipsychotic-management strategies. © Copyright 2014 Physicians Postgraduate Press, Inc.
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Tomita, Takashi; Goto, Hidekazu; Sumiya, Kenji; Yoshida, Tadashi; Tanaka, Katsuya; Kohda, Yukinao
2016-11-30
Because adenine is effective for managing cases of radiation-induced and drug-induced leukopenia, it may be effective in cases of antipsychotic-induced leukopenia and neutropenia. Here, we report our experience with patients with leukopenia and neutropenia caused by an antipsychotic overdose or discontinuation of lithium carbonate, in whom adenine administration ameliorated the white blood cell and neutrophil counts. The progress of patients suggests that adenine is effective in cases of leukopenia and neutropenia associated with lithium carbonate discontinuation and an antipsychotic overdose.
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Dopamine and incentive learning: a framework for considering antipsychotic medication effects.
Beninger, Richard J
2006-12-01
Hyperfunction of brain dopamine (DA) systems is associated with psychosis in schizophrenia and the medications used to treat schizophrenia are DA receptor blockers. DA also plays a critical role in incentive learning produced by rewarding stimuli. Using DA as the link, these results suggest that psychosis in schizophrenia can be understood from the point of view of excessive incentive learning. Incentive learning is mediated through the non-declarative memory system and may rely on the striatum or medial prefrontal cortex depending on the task. Typical and atypical antipsychotics differentially affect expression of the immediate early gene c-fos, producing greater activity in the striatum and medial prefrontal cortex, respectively. This led to the hypothesis that performance of schizophrenic patients on tasks that depend on the striatum or medial prefrontal cortex will be differentially affected by their antipsychotic medication. Results from a number of published papers supported this dissociation. Furthermore, the effects of two atypical drugs, clozapine and olanzapine, on c-fos expression were different from another atypical, risperidone that resembles the typical antipsychotics. Similarly, in tests of incentive learning, risperidone acted like the typical antipsychotics. Thus, typical and atypical antipsychotic drugs differed in the types of cognitive performance they affected and, furthermore, members of the atypical class differed in their effects on cognition. It remains the task of researchers and clinicians to sort out the symptoms associated with the endogenous illness from possible iatrogenic symptoms resulting from the antipsychotic medications used to treat schizophrenia.
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Conway, Charles R.; Chibnall, John T.; Cumming, Paul; Mintun, Mark A.; Gebara, Marie Anne I.; Perantie, Dana C.; Price, Joseph L.; Cornell, Martha E.; McConathy, Jonathan E.; Gangwani, Sunil; Sheline, Yvette I.
2014-01-01
Several double blind, prospective trials have demonstrated an antidepressant augmentation efficacy of aripiprazole in depressed patients unresponsive to standard antidepressant therapy. Although aripiprazole is now widely used for this indication, and much is known about its receptor-binding properties, the mechanism of its antidepressant augmentation remains ill-defined. In vivo animal studies and in vitro human studies using cloned dopamine dopamine D2 receptors suggest aripiprazole is a partial dopamine agonist; in this preliminary neuroimaging trial, we hypothesized that aripiprazole’s antidepressant augmentation efficacy arises from dopamine partial agonist activity. To test this, we assessed the effects of aripiprazole augmentation on the cerebral utilization of 6-[18F]-fluoro-3,4-dihydroxy-L-phenylalanine (FDOPA) using positron emission tomography (PET). Fourteen depressed patients, who had failed 8 weeks of antidepressant therapy with selective serotonin reuptake inhibitors, underwent FDOPA PET scans before and after aripiprazole augmentation; eleven responded to augmentation. Whole brain, voxel-wise comparisons of pre- and post-aripiprazole scans revealed increased FDOPA trapping in the right medial caudate of augmentation responders. An exploratory analysis of depressive symptoms revealed that responders experienced large improvements only in putatively dopaminergic symptoms of lassitude and inability to feel. These preliminary findings suggest that augmentation of antidepressant response by aripiprazole may be associated with potentiation of dopaminergic activity. PMID:24468015
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Citrome, Leslie; Ota, Ai; Nagamizu, Kazuhiro; Perry, Pamela; Weiller, Emmanuelle; Baker, Ross A
2016-07-01
The aim of this study was to explore the effects of brexpiprazole and aripiprazole on efficacy, cognitive functioning, and safety in patients with acute schizophrenia. Patients who would benefit from hospitalization/continued hospitalization for acute relapse of schizophrenia were enrolled and randomized (2 : 1) to target doses of open-label brexpiprazole 3 mg/day or aripiprazole 15 mg/day for 6 weeks. Outcomes included change from baseline to week 6 in the Positive and Negative Syndrome Scale total score, Barratt Impulsiveness Scale 11-item score, and Cogstate computerized cognitive test battery scores. Patients treated with brexpiprazole (n=64) or aripiprazole (n=33) showed reductions in symptoms of schizophrenia as assessed by Positive and Negative Syndrome Scale total score (-22.9 and -19.4, respectively). A modest reduction in impulsivity was observed with brexpiprazole, but not aripiprazole (mean change in the Barratt Impulsiveness Scale 11-item total score: -2.7 and 0.1, respectively). No change in Cogstate scores was observed for either treatment. Brexpiprazole was well tolerated and the incidence of akathisia was lower in patients treated with brexpiprazole (9.4%) than aripiprazole (21.2%). Clinically relevant improvements in psychopathology were observed in patients with acute schizophrenia treated with brexpiprazole or aripiprazole. Brexpiprazole was well tolerated, with a lower incidence of akathisia than aripiprazole.
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Watanabe, Ken
2009-01-01
The syndrome of paroxysmal perceptual alteration (PPA) was first described by Yamaguchi in 1985. Since then, many PPA cases have been reported, and its pathophysiological mechanism has been proposed: a suppressed (blocked) mesolimbic and mesocortical dopaminergic system and sequential compensatory increase of noradrenergic neuronal activity are crucial for the occurrence of PPA. PPA is characterized by hypersensitivity of perception, psychedelic experience (brightening of colors, sharpening of contrast, visual distortion, etc.), and somatic schema disorder (one feels that one is floating, one's extremities are being pulled and elongated, etc.). PPA in chronic schizophrenic patients occurs abruptly like an attack mainly in the evening, often precipitated by fatigue. During the attack, patients also suffer from mood and thought alteration (anxiety, agitation, depressive mood, and inability to distract their thoughts from one thing), but they are aware that symptoms of PPA are not real and apprehensive about them. The attack ceases gradually and spontaneously while the patient rests or sleeps. These clinical features are clearly different from those of schizophrenic hallucinations. It is believed that PPA is closely related to neuroleptic treatment by conventional antipsychotics. I reported the prevalence of PPA as 4.0% in 1991 when high potential D2 blocking agents were prevailing. The occurrence of PPA has been significantly reduced to the present, when second generation (atypical) antipsychotics are prevailing. However, in my inquiry in 2004, the prevalence of PPA was 3.6% in cases treated with risperidone (RIS), while the rates were 0 in cases treated with olanzapine (OLZ), quetiapine (QTP), and perospirone (PRS). Several cases of PPA have been reported in patients who were treated with OLZ and PRS. Until now, no cases of PPA have been reported who were treated with QTP and aripiprazole (APZ). The prevalence of PPA among cases treated with these second generation antipsychotics might be related to the differences in these agents regarding their affinity for the D2 receptor: RIS has a sustained and close binding affinity, which might be similar to those of conventional antipsychotics, OLZ shows a sustained and loose binding affinity, PRS exhibits a transient and close binding affinity, whereas QTP has a transient and loose binding affinity. APZ is a partial agonist of the D2 receptor; APZ acts as an agonist under the condition of intrinsic dopaminergic dysfunction, which might prevent the occurrence of PPA.
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McGettigan, Patricia; Roderick, Peter; Mahajan, Rushikesh; Kadam, Abhay; Pollock, Allyson M.
2015-01-01
Background In 2012, an Indian parliamentary committee reported that manufacturing licenses for large numbers of fixed dose combination (FDC) drugs had been issued by state authorities without prior approval of the Central Drugs Standard Control Organization (CDSCO) in violation of rules, and considered that some ambiguity until 1 May 2002 about states’ powers might have contributed. To our knowledge, no systematic enquiry has been undertaken to determine if evidence existed to support these findings. We investigated CDSCO approvals for and availability of oral FDC drugs in four therapeutic areas: analgesia (non-steroidal anti-inflammatory drugs [NSAIDs]), diabetes (metformin), depression/anxiety (anti-depressants/benzodiazepines), and psychosis (anti-psychotics). Methods and Findings This was an ecologic study with a time-trend analysis of FDC sales volumes (2007–2012) and a cross-sectional examination of 2011–2012 data to establish the numbers of formulations on the market with and without a record of CDSCO approval (“approved” and “unapproved”), their branded products, and sales volumes. Data from the CDSCO on approved FDC formulations were compared with sales data from PharmaTrac, a database of national drug sales. We determined the proportions of FDC sales volumes (2011–2012) arising from centrally approved and unapproved formulations and from formulations including drugs banned/restricted internationally. We also determined the proportions of centrally approved and unapproved formulations marketed before and after 1 May 2002, when amendments were made to the drug rules. FDC approvals in India, the United Kingdom (UK), and United States of America (US) were compared. For NSAID FDCs, 124 formulations were marketed, of which 34 (27%) were centrally approved and 90 (73%) were unapproved; metformin: 25 formulations, 20 (80%) approved, five (20%) unapproved; anti-depressants/benzodiazepines: 16 formulations, three (19%) approved, 13 (81%) unapproved; anti-psychotics: ten formulations, three (30%) approved, seven (70%) unapproved. After 1 May 2002, the proportions of approved FDC formulations increased for NSAIDs (26%/28%) and anti-psychotics (0%/38%) and decreased for metformin (100%/75%) and anti-depressants/benzodiazepines (20%/18%), and the overall proportion approved remained similar before and after that date. FDC formulations gave rise to multiple branded products, ranging from 211 anti-psychotic FDC products from ten formulations to 2,739 NSAID FDC products from 124 formulations. The proportions of FDC sales volumes arising from unapproved formulations were as follows: anti-depressants/benzodiazepines, 69%; anti-psychotics, 43%; NSAIDs, 28%; and metformin, 0.4%. Formulations including drugs banned/restricted internationally comprised over 12% of NSAID FDC sales and 53% of anti-psychotic FDC sales. Across the four therapeutic areas, 14 FDC formulations were approved in the UK and 22 in the US. Conclusions There was evidence supporting concerns about FDCs. Metformin excepted, substantial numbers of centrally unapproved formulations for NSAID, anti-depressant/benzodiazepine, and anti-psychotic FDCs were marketed; sales volumes were high. The legal need for central approval of new drugs before manufacture has been in place continuously since 1961, including for FDCs meeting the applicable legal test. Proportions of centrally unapproved formulations after 1 May 2002 did not decrease overall, and no ambiguity was found about states’ licensing powers. Unapproved formulations should be banned immediately, prioritising those withdrawn/banned internationally and undertaking a review of benefits and risks for patients in ceasing or switching to other medicines. Drug laws need to be amended to ensure the safety and effectiveness of medicines marketed in India. PMID:25965416
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Etminan, Mahyar; Sodhi, Mohit; Samii, Ali; Procyshyn, Ric M; Guo, Michael; Carleton, Bruce C
2017-02-01
Recently, the US Food and Drug Administration issued a warning regarding the potential risk of gambling disorder, but large epidemiologic studies are lacking. We used a large health claims database from the United States and conducted a nested case-control study. Cases were defined as subjects newly diagnosed with gambling disorder or impulse control disorder. For each case, 10 controls were selected and matched to cases by age and follow-up time and calendar time. Adjusted rate ratios were computed with conditional logistic regression. There are 355 cases of gambling disorder and 3550 controls along with 4341 cases of impulse control disorder and 43,410 corresponding controls. After adjusting for confounders, users of aripiprazole demonstrated an increased risk of pathologic gambling (rate ratio [RR], 5.23; 95% confidence interval [CI], 1.78-15.38) and impulse control disorder (RR, 7.71; 95% CI, 5.81-10.34). The risk was also elevated for pramipexole or ropinirole for both gambling disorder and impulse control disorder (RR, 7.61; 95% CI, 2.75-21.07; RR, 3.28; 95% CI, 2.31-4.66, respectively). Our study confirms an association between aripiprazole, pramipexole, or ropinirole and impulse control disorder and gambling disorder.
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Risperidone long-acting injection: a review of its long term safety and efficacy
Rainer, Michael K
2008-01-01
A long-acting form of the second-generation antipsychotic drug risperidone is now broadly available for the treatment of schizophrenia and closely related psychiatric conditions. It combines the advantage of previously available depot formulations for first-generation drugs with the favorable characteristics of the modern “atypical” antipsychotics, namely higher efficacy in the treatment of the negative symptoms of schizophrenia and reduced motor disturbances. Published clinical studies show an objective clinical efficacy (as per psychiatric symptom scores and relapse data) that exceeds that of oral atypical antipsychotics when patients are switched to the long-acting injectable form, a low incidence of treatment-emergent extrapyramidal side effects, and very good acceptance by patients. Available data for maintenance treatment of bipolar disorder show equivalence with the oral form instead of superiority, but are still limited. As it seems likely that efficacy benefits are mostly due to the fact that the injectable form reduces the demand for patient compliance to one physician visit every 2 weeks instead of self-administration on a daily or twice-daily basis, additional potential could exist in other psychiatric disorders where atypical antipsychotic drugs are of benefit but where patient adherence to treatment schedules is typically low. PMID:19183782
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Kaneda, Yasuhiro; Kawamura, Ichiro; Ohmori, Tetsuro
2005-01-01
The authors investigated the effects of atypical antipsychotic drugs-olanzapine, perospirone, and quetiapine-on plasma homovanillic acid (pHVA) in male patients with chronic schizophrenia. In this prospective, open-label study, the subjects were 30 inpatients who were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, criteria for schizophrenia. The authors switched patients from typical antipsychotic drugs to olanzapine, perospirone, or quetiapine. Each patient gave informed consent for the research. pHVA was assessed before and after switching medications. After the switch, the authors found a significant improvement in psychotic symptoms, nonsignificant improvement in extrapyramidal symptoms, and a nonsignificant reduction in pHVA. In addition, the baseline pHVA correlated positively with the score changes from baseline in the Brief Psychiatric Rating Scale (BPRS) total, positive, and negative symptoms in the group with a whole sample and in the olanzapine-treated group, and with the score changes in the BPRS total and positive symptoms in the quetiapine-treated group. Our findings indicated that the preswitching pHVA levels could be used to predict changes in the psychotic symptoms of male patients with chronic schizophrenia when switching to atypical antipsychotic drugs.
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Lipska, B K; Khaing, Z Z; Weickert, C S; Weinberger, D R
2001-07-01
Brain-derived neurotrophic factor (BDNF) plays an important role in development, synapse remodelling and responses to stress and injury. Its abnormal expression has been implicated in schizophrenia, a neuropsychiatric disorder in which abnormal neural development of the hippocampus and prefrontal cortex has been postulated. To clarify the effects of antipsychotic drugs used in the therapy of schizophrenia on BDNF mRNA, we studied its expression in rats treated with clozapine and haloperidol and in rats with neonatal lesions of the ventral hippocampus, used as an animal model of schizophrenia. Both antipsychotic drugs reduced BDNF expression in the hippocampus of control rats, but did not significantly lower its expression in the prefrontal cortex. The neonatal hippocampal lesion itself suppressed BDNF mRNA expression in the dentate gyrus and tended to reduce its expression in the prefrontal cortex. These results indicate that, unlike antidepressants, antipsychotics down-regulate BDNF mRNA, and suggest that their therapeutic properties are not mediated by stimulation of this neurotrophin. To the extent that the lesioned rat models some pathophysiological aspects of schizophrenia, our data suggest that a neurodevelopmental insult might suppress expression of the neurotrophin in certain brain regions.
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Pharmacological causes of hyperprolactinemia
Torre, Daria La; Falorni, Alberto
2007-01-01
Hyperprolactinemia is a common endocrinological disorder that may be caused by several physiological and pathological conditions. Several drugs may determine a significant increase in prolactin serum concentration that is frequently associated with symptoms. The so-called typical antipsychotics are frequently responsible for drug-related hyperprolactinemia. Risperidone is one of the atypical neuroleptics most likely to induce hyperprolactinemia, while other atypical drugs are unfrequenlty and only transiently associated with increase of prolactin levels. Women are more sensitive than men to the hyperprolactinemic effect of antipsychotics. Classical and risperidone-induced hyperprolactinemia may be revert when a gradual antipsychotic drug discontinuation is combined with olanzapine or clozapine initiation. Antidepressant drugs with serotoninergic activity, including selective serotonin reuptake inhibitors (SSRI), monoamine oxidase inhibitors (MAO-I) and some tricyclics, can cause hyperprolactinemia. A long list of other compounds may determine an increase in prolactin levels, including prokinetics, opiates, estrogens, anti-androgens, anti-hypertensive drugs, H2-receptor antagonists, anti-convulsivants and cholinomimetics. Finally, hyperprolactinemia has also been documented during conditioning and after autologous blood stem-cell transplantation and during chemotherapy, even though disturbances of prolactin seem to occur less frequently than impairments of the hypothalamus-pituitary-gonad/thyroid axis after intensive treatment and blood marrow transplantation. PMID:18473017
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Ozaki, Norio; Otsubo, Tempei; Kato, Masaki; Higuchi, Teruhiko; Ono, Hiroaki; Kamijima, Kunitoshi
2015-01-01
Results from this randomized, placebo-controlled study of aripiprazole augmentation to antidepressant therapy (ADT) in Japanese patients with major depressive disorder (MDD) (the Aripiprazole Depression Multicenter Efficacy [ADMIRE] study) revealed that aripiprazole augmentation was superior to ADT alone and was well tolerated. In subgroup analyses, we investigated the influence of demographic- and disease-related factors on the observed responses. We also examined how individual symptom improvement was related to overall improvement in MDD. Data from the ADMIRE study were analyzed. Subgroup analyses were performed on the primary outcome measures: the mean change in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score from the end of selective serotonin reuptake inhibitor (SSRI)/serotonin norepinephrine reuptake inhibitor (SNRI) treatment to the end of the randomized treatment. Changes in the MADRS total scores were consistently greater with aripiprazole than placebo in each of the subgroups. Efficacy was not related to sex, age, number of adequate ADT trials in the current episode, MDD diagnosis, number of depressive episodes, duration of the current episode, age at first depressive episode, time since the first depressive episode, type of SSRI/SNRI, or severity at the end of SSRI/SNRI treatment phase. Compared to placebo, aripiprazole resulted in significant and rapid improvement on seven of the 10 MADRS items, including sadness. These post-hoc analyses indicated that aripiprazole was effective for a variety of Japanese patients with MDD who had exhibited inadequate responses to ADT. Additionally, we suggest that aripiprazole significantly and rapidly improved the core depressive symptoms. © 2014 The Authors. Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology.
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Conventional versus novel antipsychotics: changing concepts and clinical implications.
Remington, G; Chong, S A
1999-01-01
Novel antipsychotics represent a significant advance in the treatment of schizophrenia after many years of few developments. The conventional antipsychotics are potent D2 antagonists, but fail to achieve a response in about 30% of cases. They are also associated with a high rate of extrapyramidal side effects. The greater and broader spectrum of efficacy combined with the reduced short- and long-term side effects of the new drugs such as quetiapine, risperidone, olanzapine and ziprasidone, contribute to a fresh optimism for the pharmacotherapy of schizophrenia. These novel agents are now driving further advances in schizophrenia research through a growing understanding of their pharmacological and clinical profiles. Clozapine, the first novel antipsychotic, has relatively low activity at D2 receptors, a high affinity for D4 receptors and a greater 5-HT2 (serotonin) than D2 antagonism. Hence, clozapine and other novel antipsychotics can be classified as such by this latter characteristic. However, some of these drugs have D2 occupancy greater than 60% (the clinical response threshold), while others have a lower D2 occupancy. The novel antipsychotics according have also been classified according to their activity on different neurotransmitter systems. While more effective, novel antipsychotics are not a panacea; they have limitations and side effects. In clinical practice, the American Psychiatric Association recommends either a conventional or novel antipsychotic for initial treatment of schizophrenia, whereas Canadian guidelines recommend novel agents. These agents should also be considered for treatment of refractory schizophrenia. Patients whose schizophrenia does not respond to one of these agents may respond to another. Future research should involve longer clinical trials, given the long periods needed to establish efficacy, and should address many remaining questions about the novel agents. PMID:10586534
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Dose Equivalents for Antipsychotic Drugs: The DDD Method.
Leucht, Stefan; Samara, Myrto; Heres, Stephan; Davis, John M
2016-07-01
Dose equivalents of antipsychotics are an important but difficult to define concept, because all methods have weaknesses and strongholds. We calculated dose equivalents based on defined daily doses (DDDs) presented by the World Health Organisation's Collaborative Center for Drug Statistics Methodology. Doses equivalent to 1mg olanzapine, 1mg risperidone, 1mg haloperidol, and 100mg chlorpromazine were presented and compared with the results of 3 other methods to define dose equivalence (the "minimum effective dose method," the "classical mean dose method," and an international consensus statement). We presented dose equivalents for 57 first-generation and second-generation antipsychotic drugs, available as oral, parenteral, or depot formulations. Overall, the identified equivalent doses were comparable with those of the other methods, but there were also outliers. The major strength of this method to define dose response is that DDDs are available for most drugs, including old antipsychotics, that they are based on a variety of sources, and that DDDs are an internationally accepted measure. The major limitations are that the information used to estimate DDDS is likely to differ between the drugs. Moreover, this information is not publicly available, so that it cannot be reviewed. The WHO stresses that DDDs are mainly a standardized measure of drug consumption, and their use as a measure of dose equivalence can therefore be misleading. We, therefore, recommend that if alternative, more "scientific" dose equivalence methods are available for a drug they should be preferred to DDDs. Moreover, our summary can be a useful resource for pharmacovigilance studies. © The Author 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.
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Stefano, George B; Králíčková, Milena; Ptacek, Radek; Kuzelova, Hana; Esch, Tobias; Kream, Richard M
2012-07-01
Major thematic threads linking extensive preclinical and clinical efforts have established a working mechanistic scheme whereby atypical antipsychotic drugs ameliorate negative DSM IV diagnostic criteria by effecting relatively potent blockade of serotonin (5-HT)(2A) receptors coupled with weaker antagonism of dopamine D(2) receptors in frontal cortical areas. These contentions are more or less supported by in vitro binding experiments employing cloned receptors on cultured cells, although significant functional involvement of 5-HT(2C) receptors has also been proposed. It is interesting that a key statistical analysis indicates a major shift in usage back to typical antipsychotic agents for management of schizophrenia from 1995-2008, whereas off-label usage of atypical antipsychotic agents was markedly increased or expanded for bipolar affective disorder. Importantly, meta-analyses generally did not support efficacy differences between the other atypical antipsychotics compared with the older typical agents. A critical examination of putative functional linkages of morphine and its type-selective mu opioid receptor to higher order cortical regulation of cognitive processes may provide novel insights into human behavioral processes that are severely impaired in schizophrenia spectrum disorders.
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Douglas-Hall, Petrina; Curran, Sarah; Bird, Victoria; Taylor, David
2011-01-01
A systematic review and meta-analysis were performed examining the efficacy of aripiprazole for the treatment of irritability associated with autistic disorder in children and adolescents. Aripiprazole was found to be more effective in reducing irritability compared with placebo at 8 weeks, SMD −0.64 [−0.90 to −0.39, P < 0.00001] as determined by the Aberrant Behaviour Checklist irritability subscale (ABC-I). Pooled data from two eight week trials show that sedation is the most commonly reported adverse event. Statistically significant weight gain was also associated with aripiprazole, but there was a decrease in serum prolactin. Most adverse effects were deemed to be mild to moderate in severity. Four open trials and three case series all show support for aripiprazole in reducing the behavioural symptoms of autism. Long-term studies are required to determine the efficacy and safety of aripiprazole in autistic disorder in children. PMID:23861644
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Antipsychotics, mood stabilisers, and risk of violent crime.
Fazel, Seena; Zetterqvist, Johan; Larsson, Henrik; Långström, Niklas; Lichtenstein, Paul
2014-09-27
Antipsychotics and mood stabilisers are prescribed widely to patients with psychiatric disorders worldwide. Despite clear evidence for their efficacy in relapse prevention and symptom relief, their effect on some adverse outcomes, including the perpetration of violent crime, is unclear. We aimed to establish the effect of antipsychotics and mood stabilisers on the rate of violent crime committed by patients with psychiatric disorders in Sweden. We used linked Swedish national registers to study 82,647 patients who were prescribed antipsychotics or mood stabilisers, their psychiatric diagnoses, and subsequent criminal convictions in 2006-09. We did within-individual analyses to compare the rate of violent criminality during the time that patients were prescribed these medications versus the rate for the same patients while they were not receiving the drugs to adjust for all confounders that remained constant within each participant during follow-up. The primary outcome was the occurrence of violent crime, according to Sweden's national crime register. In 2006-09, 40,937 men in Sweden were prescribed antipsychotics or mood stabilisers, of whom 2657 (6·5%) were convicted of a violent crime during the study period. In the same period, 41,710 women were prescribed these drugs, of whom 604 (1·4 %) had convictions for violent crime. Compared with periods when participants were not on medication, violent crime fell by 45% in patients receiving antipsychotics (hazard ratio [HR] 0·55, 95% CI 0·47-0·64) and by 24% in patients prescribed mood stabilisers (0·76, 0·62-0·93). However, we identified potentially important differences by diagnosis-mood stabilisers were associated with a reduced rate of violent crime only in patients with bipolar disorder. The rate of violence reduction for antipsychotics remained between 22% and 29% in sensitivity analyses that used different outcomes (any crime, drug-related crime, less severe crime, and violent arrest), and was stronger in patients who were prescribed higher drug doses than in those prescribed low doses. Notable reductions in violent crime were also recorded for depot medication (HR adjusted for concomitant oral medications 0·60, 95% CI 0·39-0·92). In addition to relapse prevention and psychiatric symptom relief, the benefits of antipsychotics and mood stabilisers might also include reductions in the rates of violent crime. The potential effects of these drugs on violence and crime should be taken into account when treatment options for patients with psychiatric disorders are being considered. The Wellcome Trust, the Swedish Prison and Probation Service, the Swedish Research Council, and the Swedish Research Council for Health, Working Life and Welfare. Copyright © 2014 Fazel et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd. All rights reserved.
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Antipsychotics, mood stabilisers, and risk of violent crime
Fazel, Seena; Zetterqvist, Johan; Larsson, Henrik; Långström, Niklas; Lichtenstein, Paul
2014-01-01
Summary Background Antipsychotics and mood stabilisers are prescribed widely to patients with psychiatric disorders worldwide. Despite clear evidence for their efficacy in relapse prevention and symptom relief, their effect on some adverse outcomes, including the perpetration of violent crime, is unclear. We aimed to establish the effect of antipsychotics and mood stabilisers on the rate of violent crime committed by patients with psychiatric disorders in Sweden. Methods We used linked Swedish national registers to study 82 647 patients who were prescribed antipsychotics or mood stabilisers, their psychiatric diagnoses, and subsequent criminal convictions in 2006–09. We did within-individual analyses to compare the rate of violent criminality during the time that patients were prescribed these medications versus the rate for the same patients while they were not receiving the drugs to adjust for all confounders that remained constant within each participant during follow-up. The primary outcome was the occurrence of violent crime, according to Sweden's national crime register. Findings In 2006–09, 40 937 men in Sweden were prescribed antipsychotics or mood stabilisers, of whom 2657 (6·5%) were convicted of a violent crime during the study period. In the same period, 41 710 women were prescribed these drugs, of whom 604 (1·4 %) had convictions for violent crime. Compared with periods when participants were not on medication, violent crime fell by 45% in patients receiving antipsychotics (hazard ratio [HR] 0·55, 95% CI 0·47–0·64) and by 24% in patients prescribed mood stabilisers (0·76, 0·62–0·93). However, we identified potentially important differences by diagnosis—mood stabilisers were associated with a reduced rate of violent crime only in patients with bipolar disorder. The rate of violence reduction for antipsychotics remained between 22% and 29% in sensitivity analyses that used different outcomes (any crime, drug-related crime, less severe crime, and violent arrest), and was stronger in patients who were prescribed higher drug doses than in those prescribed low doses. Notable reductions in violent crime were also recorded for depot medication (HR adjusted for concomitant oral medications 0·60, 95% CI 0·39–0·92). Interpretation In addition to relapse prevention and psychiatric symptom relief, the benefits of antipsychotics and mood stabilisers might also include reductions in the rates of violent crime. The potential effects of these drugs on violence and crime should be taken into account when treatment options for patients with psychiatric disorders are being considered. Funding The Wellcome Trust, the Swedish Prison and Probation Service, the Swedish Research Council, and the Swedish Research Council for Health, Working Life and Welfare. PMID:24816046
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Could cannabidiol be used as an alternative to antipsychotics?
Fakhoury, Marc
2016-09-01
Schizophrenia is a mental disorder that affects close to 1% of the population. Individuals with this disorder often present signs such as hallucination, anxiety, reduced attention, and social withdrawal. Although antipsychotic drugs remain the cornerstone of schizophrenia treatment, they are associated with severe side effects. Recently, the endocannabinoid system (ECS) has emerged as a potential therapeutic target for pharmacotherapy that is involved in a wide range of disorders, including schizophrenia. Since its discovery, a lot of effort has been devoted to the study of compounds that can modulate its activity for therapeutic purposes. Among them, cannabidiol (CBD), a non-psychoactive component of cannabis, shows great promise for the treatment of psychosis, and is associated with fewer extrapyramidal side effects than conventional antipsychotic drugs. The overarching goal of this review is to provide current available knowledge on the role of the dopamine system and the ECS in schizophrenia, and to discuss key findings from animal studies and clinical trials investigating the antipsychotic potential of CBD. Copyright © 2016 Elsevier Ltd. All rights reserved.
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Newer antipsychotics and upcoming molecules for schizophrenia.
George, Melvin; Amrutheshwar, Radhika; Rajkumar, Ravi Philip; Kattimani, Shivanand; Dkhar, Steven Aibor
2013-08-01
The management of schizophrenia has seen significant strides over the last few decades, due to the increasing availability of a number of antipsychotics. Yet, the diminished efficacy in relation to the negative and cognitive symptoms of schizophrenia, and the disturbing adverse reactions associated with the current antipsychotics, reflect the need for better molecules targeting unexplored pathways. To review the salient features of the recently approved antipsychotics; namely, iloperidone, asenapine, lurasidone and blonanserin. We discuss the advantages, limitations and place in modern pharmacotherapy of each of these drugs. In addition, we briefly highlight the new targets that are being explored. Promising strategies include modulation of the glutamatergic and GABAergic pathways, as well as cholinergic systems. Although regulatory bodies have approved only a handful of antipsychotics in recent years, the wide spectrum of targets that are being explored could eventually bring out antipsychotics with improved efficacy and acceptability, as well as the potential to revolutionize psychiatric practice.
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Dwyer, Donard S; Awatramani, Poonam; Thakur, Rashmi; Seeni, Ramya; Aamodt, Eric J
2015-05-01
Here, we define a protophenotype as an endophenotype that has been conserved during evolution. Social feeding in Caenorhabditis elegans may be an example of a protophenotype related to asociality in schizophrenia. It is regulated by the highly conserved neuropeptide Y receptor, NPR-1, and we speculated that social feeding should be affected by antipsychotic drugs. The social feeding strain, npr-1(g320), was exposed to antipsychotic drugs, dopamine or calmodulin antagonists on plates with bacterial lawns, and the number of aggregates on the plates was counted as a measure of social feeding. First-generation antipsychotics, chlorpromazine, trifluoperazine, fluphenazine, and haloperidol, and the second-generation drug, olanzapine, inhibited social feeding. Dopamine accelerated aggregation, whereas selective D2 dopamine receptor antagonists, sulpiride and raclopride, were inhibitory. Calmodulin antagonists effectively inhibited social feeding, as did RNAi knockdown of calmodulin (cmd-1) expression. In addition, gap junction inhibitors prevented aggregation, which is consistent with the hub-and-spoke arrangement of neurons that regulate social feeding via functional gap junctions. The studies described here revealed novel connections between dopaminergic signaling, the NPY receptor, calmodulin, and gap junctions in the regulation of social behavior in C. elegans. These pathways are evolutionarily-conserved, and have also been implicated in the pathogenesis of schizophrenia. Copyright © 2015 Elsevier Ltd. All rights reserved.
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Comparison of Psychotropic Drug Prescribing Quality between Zagreb, Croatia and Sarajevo, B&H.
Polić-Vižintin, Marina; Štimac, Danijela; Čatić, Tarik; Šostar, Zvonimir; Zelić, Ana; Živković, Krešimir; Draganić, Pero
2014-12-01
The purpose of this paper was to compare outpatient consumption and quality of psychotropic drug prescribing between Croatia and Bosnia & Herzegovina 2006-2010. Data on drug utilization from Zagreb Municipal Pharmacy and Sarajevo Public Pharmacy were used to calculate the number of defined daily doses (DDD) and DDD per 1000 inhabitants per day (DDD/TID) using the WHO Anatomical-Therapeutic-Chemical methodology. Total utilization of psychopharmaceuticals increased in both cities; however, it was higher in Zagreb than in Sarajevo throughout the study period. The utilization of psycholeptics increased in Zagreb by 2.4% (from 74.5 to 76.3 DDD/TID) and in Sarajevo by 3.8% (from 62.4 to 64.8 DDD/TID). The utilization of anxiolytics decreased in Zagreb by 2.1% and in Sarajevo by even 18.7%. The utilization of antidepressants increased in both cities with predominance of SSRI over TCA utilization, greater in Sarajevo (96.6%) than in Zagreb (10.2%). The anxiolytic/antidepressant ratio decreased by 11.1% in Zagreb (from 2.87 to 2.55) and by 58.7% in Sarajevo (from 5.66 to 2.34). Outpatient utilization of antipsychotics increased significantly in Sarajevo, predominated by typical ones, whereas in Zagreb the utilization of antipsychotics was stable, predominated by atypical ones. In Croatia and Bosnia & Herzegovina, there was an obvious tendency to follow western trends in drug prescribing, as demonstrated by the increased use of antidepressants and reduced use of anxiolytics. Despite some improvement observed in the prescribing quality, high use of antipsychotics with dominance of typical antipsychotics in Sarajevo points to the need of prescribing guidelines for antipsychotics.
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de la Torre Villalobos, Miquel; Martin-López, Luis Miguel; Fernández Sanmartín, María Isabel; Pujals Altes, Elena; Gasque Llopis, Silvia; Batlle Vila, Santiago; Pérez-Solá, Victor; Novo Navarro, Patricia; Gómez Simón, Isabel; Fresno González, Cristina; Camprodon Rosanas, Ester; Bulbena Vilarrasa, Antonio
Cardiovascular and metabolic monitoring of patients on antipsychotic medication is essential. This becomes more important in those of paediatric age, as they are more vulnerable, and also because prescriptions of this kind of drugs are still increasing. To evaluate the monitoring of cardiovascular and metabolic risk factors in a group of children and young people on antipsychotic medication. A descriptive cross-sectional study was conducted in which a group of 220 patients aged 8-17 years, diagnosed with a mental disorder and on antipsychotic treatment. They were compared to a control group of 199 asthmatic patients not exposed to antipsychotic drugs. Data was extracted from the computerised clinical history ECAP in 2013. The mean age of the children was 12 years (8-17). Risperidone (67%) was the most frequent treatment. The recording of Body Mass Index (BMI) and blood pressure (AP) was 50% in Mental Disorder (MD) patients. A higher number of cardiovascular monitoring physical parameters (weight, height, BMI and BP) were observed in the MD group compared to the control Asthma control group. Altogether, more physical parameters than biochemistry parameters were recorded. This study shows that the recording of cardiovascular parameters and metabolic studies needs to be improved in children and adolescents on treatment with antipsychotics. Copyright © 2016 SEP y SEPB. Publicado por Elsevier España, S.L.U. All rights reserved.
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Wang, Lexi; Wang, Aiping; Zhao, Xiaolei; Liu, Ximing; Wang, Dan; Sun, Fengying; Li, Youxin
2012-05-10
Two kinds of in situ forming implants (ISFIs) of atypical antipsychotics, risperidone and its 9-hydroxy active metabolite, paliperidone, using poly(lactide-co-glycolide)(PLGA) as carrier, were investigated. Significant difference was observed in the solution-gel transition mechanism of the two systems: homogeneous system of N-methyl-2-pyrrolidone (NMP) ISFI, in which drug was dissolved, and heterogeneous system of dimethyl sulfoxide (DMSO) ISFI, in which drug was dispersed. Fast solvent extractions were found in both systems, but in comparison with the high drug release rate from homogeneous system of drug/polymer/NMP, a fast solvent extraction from the heterogeneous system of drug/polymer/DMSO was not accompanied by a high drug release rate but a rapid solidification of the implant, which resulted in a high drug retention, well-controlled initial burst and slow release of the drug. In vivo study on beagle dogs showed a more than 3-week sustained release with limited initial burst. Pharmacologic evaluation on optimized paliperidone ISFIs presented a sustained-suppressing effect from 1 day to 38 day on the MK-801 induced schizophrenic behavior mice model. A long sustained-release antipsychotic ISFI of 50% drug loading and controlled burst release was achieved, which indicated a good potential in clinic application. Copyright © 2012 Elsevier B.V. All rights reserved.
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Roberto, Pamela N; Brandt, Nicole; Onukwugha, Eberechukwu; Perfetto, Eleanor; Powers, Christopher; Stuart, Bruce
2017-11-01
Prior research demonstrates substantial access problems associated with utilization management and formulary exclusions for antipsychotics in Medicaid, but the use and impact of coverage restrictions for these medications in Medicare Part D remains unknown. We assess the effect of coverage restrictions on antipsychotic utilization in Part D by exploiting a unique natural experiment in which low-income beneficiaries are randomly assigned to prescription drug plans with varying levels of formulary generosity. Despite considerable variation in use of coverage restrictions across Part D plans, we find no evidence that these restrictions significantly deter utilization or reduce access to antipsychotics for low-income beneficiaries.
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29 Year Old Man with Multiple Sclerosis and Schizophrenia: A Case Report.
Noorani, Nahid; Hadi, Fateme; Ahmadkhaniha, Hamid Reza
2016-12-01
Multiple sclerosis (MS) is the most common debilitating neurological disease that affects adults, whether young adults or middle-aged. Although, most attention is toward the neurological signs of the disease, the neuropsychiatric signs are not uncommon. This case report presents a 29 year old male with a record of obsessive-compulsive disorder (OCD) without psychotic disorder, which coincides with the diagnosis MS, has been stricken to auditory hallucinations and reference delusion. The patient received some antipsychotic drugs such as Haloperidol and Perphenazine irregularly, but any psychotic signs of the patient were never in control. During this period he had several active episodes of MS disease, wherein the symptoms had subsided due to hospitalization and received corticosteroids pulse. The first time the patient was submitted to the emergency unit of Rasoul Akram Hospital, there was the possibility of schizophrenia which was confirmed in subsequent visits. The signs of the patient were not controllable for a long time and finally fully controlled by a combination of Aripiprazole (abilizol), Risperidone and Sertraline, and currently, for almost 3 years, both psychotic symptoms and MS disease have been under control. Our patient seems to catch the MS disease and schizophrenia simultaneously. There was no relation between MS and psychosis episodes and the MS attacks. Since the onset the patient had several acute MS attacks of MS, and hospitalization several times. These findings and characteristics regarding our patient made him completely different from other reported cases of MS along with neuropsychiatric signs which may help doctors in diagnosis and managment of similar cases.
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Aripiprazole long-acting injection: promising but more evidence needed.
Keks, Nicholas A; Hope, Judy; Culhane, Christine
2016-08-01
Aripiprazole long acting injection (ALAI) is now available, and this paper aims to assist clinicians in deciding when to use ALAI. Aripiprazole is a partial dopamine agonist with low sedation, relatively favourable metabolic profile and a tendency to lower, rather than raise, prolactin. Available for over a decade, aripiprazole has been increasingly recognised by many clinicians as a useful option in the treatment of psychoses. ALAI is a suspension of crystalline aripiprazole in water which takes 5-7 days to reach steady state after an initial intramuscular injection. Monthly injections achieve steady state in four months. Studies have demonstrated that ALAI is effective in aripiprazole-responsive patients. ALAI was generally well tolerated, but more prone to cause extrapyramidal side-effects than the oral form. ALAI has not been compared with other depots. Although the recommended starting dose is 400 mg, it is likely that there will be significant inter-individual dose variation. Dose optimisation in each patient will be necessary for best effectiveness and tolerability. ALAI is currently appropriate for aripiprazole-responsive patients who need a depot, but clinicians are likely to try ALAI in patients who have been on other depots, particularly in whom weight gain and hyperprolactinaemia have been problematic. © The Royal Australian and New Zealand College of Psychiatrists 2016.
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Kaneriya, Shriya H.; Robbins-Welty, Gregg A.; Smagula, Stephen F.; Karp, Jordan F.; Butters, Meryl A.; Lenze, Eric J.; Mulsant, Benoit H.; Blumberger, Daniel; Anderson, Stewart J; Dew, Mary Amanda; Lotrich, Francis; Aizenstein, Howard J.; Diniz, Breno S.; Reynolds, Charles F.
2016-01-01
Importance Safe, efficacious second-line pharmacological treatment options exist for the large portion of older adults with major depressive disorder that does not respond to first-line pharmacotherapy. However, limited evidence exists to aid clinical decision-making regarding which patients will benefit from which second-line treatments. Objective To test the moderating role of pretreatment executive function, anxiety severity, and medical comorbidity on remission to aripiprazole augmentation for treatment-resistant late-life depression. Design We conducted a National Institute of Mental Health sponsored 12-week, multi-site, randomized, placebo-controlled, double-blind trial of aripiprazole augmentation for first-line resistant late-life major depressive disorder. Using logistic regression, we evaluated the main effects of the following potential moderators and their interactions with treatment: baseline assessments of executive function (set shifting measured by a Trail Making test) and response inhibition control (measured by a color-word interference task), anxiety symptoms, and medical comorbidity. Setting Specialty care. Participants We included 181 participants aged 60 and older whose major depression had failed to remit with venlafaxine monotherapy. Intervention Aripiprazole or placebo tablets were started at 2 mg daily and titrated as tolerated, to a maximal dose of 15 mg daily. Main outcome measure The outcome was remission defined as a MADRS score ≤10 at both of the last two consecutive visits. Results Baseline set-shifting moderated aripiprazole efficacy (p for interaction with treatment = 0.03): among participants with Trail-Making test Scaled Scores ≥7, the odds of remitting were significantly higher with aripiprazole than with placebo (53% versus 28%; NNT = 4; OR = 4.11, 95% CI: 1.83-9.20); among participants with Trail-Making test Scaled Scores <7, aripiprazole and placebo were equally efficacious (aripiprazole vs. placebo remission OR=0.64, 95% CI: 0.15-2.80). Greater severity of anxiety at baseline predicted a lower remission rate but did not moderate aripiprazole efficacy: each standard deviation greater anxiety severity was associated with 50% reduced odds of remission in both aripiprazole and placebo arms. Medical comorbidity and Color-Word interference test performance were neither general predictors nor treatment moderating factors. Conclusion and relevance Set-shifting performance indicates which older adults with treatment-resistant depression may respond favorably to augmentation with aripiprazole and thus may help to personalize treatment. PMID:26963689
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Castillo-Sánchez, Miguel; Fàbregas-Escurriola, Mireia; Bergè-Baquero, Daniel; Fernández-SanMartín, MªIsabel; Goday-Arno, Albert
2017-01-01
Many studies have previously shown increased cardiovascular risk factors related to schizophrenia independently from the use of antipsychotic drugs. However, a poorer effort in clinical detection and management of cardiovascular risk in patients with severe mental illness could also explain these results. To test this hypothesis, we analyzed the differences in screening and incidence of cardiovascular risk factors between schizophrenia, non-schizophrenic patients on treatment with antipsychotic drugs (NS-TAD) and the general population. Data from adult subjects assessed by high-quality register general practitioners from 2006 to 2011 were extracted from the Catalonian SIDIAP database. The schizophrenia, NS-TAD, and control groups were compared in terms of measurements and incidence of diabetes, dyslipidemia, obesity, hypertension, and smoking. A total of 4911 patients in the schizophrenia group, 4157 in NS-TAD group, and 98644 in the control group were included. Schizophrenia patients were screened for dyslipidemia and diabetes more frequently than the control group, while for obesity or hypertension, they were screened equal to controls. Also, as compared to the control group, the NS-TAD group was more frequently screened for obesity with no differences in dyslipidemia and diabetes and less frequently for hypertension. Smoking was less frequently screened in both study groups. The incidence of all risk factors studied in both study groups was higher than or equal to the control group, except for hypertension, which had lower incidence. The lack of screening of risk factors does not appear decisive in the increased cardiovascular risk of patients diagnosed with schizophrenia seen in primary care. Studies evaluating the possible under diagnosis of the risk factors are required. Schizophrenia (SZ); Treatment with antipsychotic drugs (TAD); Cardiovascular risk factor/s (CVRF); Without schizophrenia but on therapy with antipsychotic drugs (NS-TAD); Defined Daily Dose (DDD).
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Feifel, D.; Shilling, P. D.; Melendez, G.
2014-01-01
Our laboratory and others have reported that Brattleboro (BRAT) rats, a Long Evans (LE) strain with a single gene mutation, have inherent deficits in prepulse inhibition (PPI) homologous to those observed in schizophrenia patients and that these deficits are reversed by antipsychotic drugs (APDs). To further evaluate the potential predictive validity of BRAT rat PPI for APDs, we compared the effects of acute subcutaneous administration of the typical APD chlorpromazine to that of three psychotropic drugs without antipsychotic efficacy, the antidepressant imipramine, the anxiolytic diazepam and the anticonvulsant mood stabilizer valproic acid on male and female BRAT rat PPI. Male and female BRAT rats exhibited baseline (saline treatment) PPI that was not different from each other (21.1 % and 21.3 %, respectively) and low compared to those historically exhibited by LE rats (approximately 59 %). Chlorpromazine facilitated PPI in male and female BRAT rats, whereas imipramine, diazepam, and valproic acid had no significant effect on PPI. These results suggest that PPI in the BRAT rat responds specifically to drugs with APD efficacy but not psychotropic drugs of different therapeutic families. PMID:21106605
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Atypical antipsychotics and glucose homeostasis.
Bergman, Richard N; Ader, Marilyn
2005-04-01
Persistent reports have linked atypical antipsychotics with diabetes, yet causative mechanisms responsible for this linkage are unclear. Goals of this review are to outline the pathogenesis of nonimmune diabetes and to survey the available literature related to why antipsychotics may lead to this disease. We accessed the literature regarding atypical antipsychotics and glucose homeostasis using PubMed. The search included English-language publications from 1990 through October 2004. Keywords used included atypical antipsychotics plus one of the following: glucose, insulin, glucose tolerance, obesity, or diabetes. In addition, we culled information from published abstracts from several national and international scientific meetings for the years 2001 through 2004, including the American Diabetes Association, the International Congress on Schizophrenia Research, and the American College of Neuropsychopharmacology. The latter search was necessary because of the paucity of well-controlled prospective studies. We examined publications with significant new data or publications that contributed to the overall comprehension of the impact of atypical antipsychotics on glucose metabolism. We favored original peer-reviewed articles and were less likely to cite single case studies and/or anecdotal information. Approximately 75% of the fewer than 150 identified articles were examined and included in this review. Validity of data was evaluated using the existence of peer-review status as well as our own experience with methodology described in the specific articles. The metabolic profile caused by atypical antipsychotic treatment resembles type 2 diabetes. These agents cause weight gain in treated subjects and may induce obesity in both visceral and subcutaneous depots, as occurs in diabetes. Insulin resistance, usually associated with obesity, occurs to varying degrees with different antipsychotics, although more comparative studies with direct assessment of resistance are needed. A major problem in assessing drug effects is that psychiatric disease itself can cause many of the manifestations leading to diabetes, including weight gain and sedentary lifestyle. While studies in healthy subjects are limited and inconclusive, studies in animal models are more revealing. In the conscious canine model, some atypical antipsychotics cause adiposity, including visceral obesity, a strong risk factor for the metabolic syndrome. Furthermore, while few studies have examined effects of antipsychotics on pancreatic beta-cell function, canine studies demonstrate that expected beta-cell compensation for insulin resistance may be reduced or even eliminated with these agents. Atypical antipsychotics have been shown to contribute to weight gain, which may well reflect increased body fat deposition. Such increased fat is known to cause resistance to insulin action, although more information regarding effect on insulin action is needed. The effect of these drugs on fat distribution has been clearly shown in animal models. It is known that the normal response to insulin resistance is compensatory hyperinsulinemia, which may prevent diabetes. In animals, there is evidence that the hyperinsulinemic compensation is inadequate in the face of atypical antipsychotic agents. It remains to be examined whether failure of adequate pancreatic beta-cell compensation for insulin resistance plays a central role in the pathogenesis of diabetes associated with this class of drugs.
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Rubin, David M; Kreider, Amanda R; Matone, Meredith; Huang, Yuan-Shung; Feudtner, Chris; Ross, Michelle E; Localio, A Russell
2015-04-01
Second-generation antipsychotics (SGAs) have increasingly been prescribed to Medicaid-enrolled children, either singly or in a medication combination. Although metabolic adverse effects have been linked to SGA use in youths, estimating the risk for type 2 diabetes mellitus, a rarer outcome, has been challenging. To determine whether SGA initiation was associated with an increased risk for incident type 2 diabetes mellitus. Secondary analyses examined the risk associated with multiple-drug regimens, including stimulants and antidepressants, as well as individual SGAs. Retrospective national cohort study of Medicaid-enrolled youths between January 2003 and December 2007. In this observational study using national Medicaid Analytic eXtract data files, initiators and noninitiators of SGAs were identified in each month. Included in this study were US youths aged 10 to 18 years with a mental health diagnosis and enrolled in a Medicaid fee-for-service arrangement during the study. Those with chronic steroid exposure, a diagnosis of diabetes mellitus, or SGA use during a 1-year look-back period were ineligible. The mean follow-up time for all participants was 17.2 months. Youths were followed up until diagnosis of diabetes mellitus or end of follow-up owing to censoring caused by the transition into a Medicaid managed care arrangement or Medicaid ineligibility (the end of available data). Propensity weights were developed to balance observed demographic and clinical characteristics between exposure groups. Discrete failure time models were fitted using weighted logistic regression to estimate the risk for incident diabetes mellitus between initiators and noninitiators. A filled SGA prescription. Incident type 2 diabetes mellitus identified through visit and pharmacy claims during the observation period. Among 107,551 SGA initiators and 1,221,434 noninitiators, the risk for incident diabetes mellitus was increased among initiators (odds ratio [OR], 1.51; 95% CI, 1.35-1.69; P < .001). Compared with youths initiating only SGAs, the risk was higher among SGA initiators who used antidepressants concomitantly at the time of SGA initiation (OR, 1.54; 95% CI, 1.17-2.03; P = .002) but was not significantly different for SGA initiators who were concomitantly using stimulants. As compared with a reference group of risperidone initiators, the risk was higher among those initiating ziprasidone (OR, 1.61; 95% CI, 0.99-2.64; P = .06) and aripiprazole (OR, 1.58; 95% CI, 1.21-2.07; P = .001) but not quetiapine fumarate or olanzapine. The risk for incident type 2 diabetes mellitus was increased among youths initiating SGAs and was highest in those concomitantly using antidepressants. Compared with risperidone, newer antipsychotics were not associated with decreased risk.
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Calvó-Perxas, Laia; Turró-Garriga, Oriol; Aguirregomozcorta, Maria; Bisbe, Josep; Hernández, Erélido; López-Pousa, Secundino; Manzano, Anna; Palacios, Mónica; Pericot-Nierga, Imma; Perkal, Héctor; Ramió, Lluís; Vilalta-Franch, Joan; Garre-Olmo, Josep
2014-07-01
Psychotropic drugs are usually prescribed to deal with behavioral and psychological symptoms of dementia, especially when nonpharmacologic approaches are not available or have limited efficacy. Poor outcomes and serious adverse events of the drugs used must be addressed, and risk-benefit ratios need to be considered. The aim of this longitudinal study was to describe the evolution of dispensation of psychotropic drugs in patients with Alzheimer's disease (AD) and to identify the associated demographic and clinical variables. Longitudinal study using 698 cases with AD included in the Registry of Dementias of Girona in 2007 and 2008 and followed up during 3 years. Drugs were categorized according to the Anatomical Therapeutic Chemical classification. Binary logistic regression analyses were used to detect the variables associated with the use of antipsychotics, selective serotonin reuptake inhibitors (SSRIs), anxiolytics, and hypnotics. Of the patients, 51.2% consumed antipsychotics at least once during the three years of the study, whereas 73.3% and 58.2% consumed SSRIs and anxiolytics, respectively; 32.8% used hypnotics. Antipsychotic use was associated with a diagnosis of AD with delusions) [odds ratio (OR) = 5.7] and with increased behavior disorders (OR = 1.2). Patients with AD with depressed mood were more likely to be treated with SSRIs (OR = 3.1), while being a woman was associated with increased dispensation of anxiolytics (OR = 1.9) and SSRIs (OR = 2.2). Consumption of psychotropic drugs by the patients with AD registered in the Registry of Dementias of Girona is very high. Despite all the described adverse effects and recommendations of caution in their use, antipsychotics still are extensively used. Copyright © 2014 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.
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Did FDA Decisionmaking Affect Anti-Psychotic Drug Prescribing in Children?: A Time-Trend Analysis.
Wang, Bo; Franklin, Jessica M; Eddings, Wesley; Landon, Joan; Kesselheim, Aaron S
2016-01-01
Following Food and Drug Administration (FDA) approval, many drugs are prescribed for non-FDA-approved ("off-label") uses. If substantial evidence supports the efficacy and safety of off-label indications, manufacturers can pursue formal FDA approval through supplemental new drug applications (sNDAs). We evaluated the effect of FDA determinations on pediatric sNDAs for antipsychotic drugs on prescribing of these products in children. Retrospective, segmented time-series analysis using new prescription claims during 2003-2012 for three atypical antipsychotics (olanzapine, quetiapine, ziprasidone). FDA approved the sNDAs for pediatric use of olanzapine and quetiapine in December 2009, but did not approve the sNDA for pediatric use of ziprasidone. During the months before FDA approval of its pediatric sNDA, new prescriptions of olanzapine decreased for both children and adults. After FDA approval, the increase in prescribing trends was similar for both age groups (P = 0.47 for schizophrenia and bipolar disorder; P = 0.37 for other indications). Comparable decreases in use of quetiapine were observed between pediatrics and adults following FDA approval of its pediatric sNDA (P = 0.88; P = 0.63). Prescribing of ziprasidone decreased similarly for pediatric and adult patients after FDA non-approval of its pediatric sNDA (P = 0.61; P = 0.79). The FDA's sNDA determinations relating to use of antipsychotics in children did not result in changes in use that favored the approved sNDAs and disfavored the unapproved sNDA. Improved communication may help translate the agency's expert judgments to clinical practice.
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Bruno, Antonio; Romeo, Vincenzo M; Pandolfo, Gianluca; Scimeca, Giuseppe; Zoccali, Rocco A; Muscatello, Maria Rosaria A
2014-01-01
The aims of this study were to evaluate a combination of aripiprazole and topiramate in the treatment of opioid-dependent patients with schizoaffective disorder undergoing methadone maintenance therapy (MMT) and, further, to taper off patients from methadone treatment. Twenty patients who met DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) criteria for opioid dependence and schizoaffective disorder receiving MMT (80 mg/day) were given aripiprazole (10 mg/day) plus topiramate (up to 200 mg/day) for 8 weeks. A methadone dose reduction of 3 mg/day until suspension at week 4 was established. Aripiprazole plus topiramate was effective in reducing clinical symptoms, and a rapid tapering off of MMT was achieved. Combining aripiprazole and topiramate may be effective in patients with a dual diagnosis of opioid dependency and schizoaffective disorder.
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Pijnenborg, G H M; Timmerman, M E; Derks, E M; Fleischhacker, W W; Kahn, R S; Aleman, A
2015-06-01
Although antipsychotics are widely prescribed, their effect of on improving poor illness insight in schizophrenia has seldom been investigated and therefore remains uncertain. This paper examines the effects of low dose haloperidol, amisulpride, olanzapine, quetiapine, and ziprasidone on insight in first-episode schizophrenia, schizoaffective disorder, or schizophreniform disorder. The effects of five antipsychotic drugs in first episode psychosis on insight were compared in a large scale open randomized controlled trial conducted in 14 European countries: the European First-Episode Schizophrenia Trial (EUFEST). Patients with at least minimal impairments in insight were included in the present study (n=455). Insight was assessed with item G12 of the Positive and Negative Syndrome Scale (PANSS), administered at baseline and at 1, 3, 6, 9, and 12 months after randomization. The use of antipsychotics was associated with clear improvements in insight over and above improvements in other symptoms. This effect was most pronounced in the first three months of treatment, with quetiapine being significantly less effective than other drugs. Effects of spontaneous improvement cannot be ruled out due to the lack of a placebo control group, although such a large spontaneous improvement of insight would seem unlikely. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.
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Zhao, Jingyuan; Song, Xueqin; Ai, Xiaoqing; Gu, Xiaojing; Huang, Guangbiao; Li, Xue; Pang, Lijuan; Ding, Minli; Ding, Shuang; Lv, Luxian
2015-01-01
Objective The present study aimed to evaluate the efficacy and safety of adjunctive aripiprazole treatment in schizophrenia patients with risperidone-induced hyperprolactinemia. Methods One hundred and thirteen patients who were receiving a stable dose of risperidone were randomly assigned to either adjunctive aripiprazole treatment (10 mg/day) (aripiprazole group) or no additional treatment (control group) at a 1:1 ratio for 8 weeks. Schizophrenia symptoms were measured using the Positive and Negative Syndrome Scale (PANSS). Rating scales and safety assessments (RSESE, BARS, UKU) were performed at baseline and at weeks 4 and 8. Serum levels of prolactin were determined at baseline and at weeks 2, 4, 6 and 8. Metabolic parameters were determined at baseline and again at weeks 4 and 8. Results One hundred and thirteen patients were enrolled in this study, and 107 patients completed the study (54 in the aripiprazole group, and 53 in the control group). PANSS-total scores in the aripiprazole group decreased significantly at week 4 (P = 0.003) and week 8 (P = 0.007) compared with the control group. PANSS-negative scores in the aripiprazole group also decreased significantly at week 4 (P = 0.005) and week 8 (P< 0.001) compared with the control group. Serum levels of prolactin in the aripiprazole group decreased significantly at week 2 (P< 0.001), week 4 (P< 0.001), week 6 (P< 0.001) and week 8 (P< 0.001) compared with the control group. There were no significant differences in changes of Fasting Plasma Glucose, Total cholesterol, Triglycerides and High Density Lipoprotein within each group at week 4 and 8 execpt low density lipoproteins. There was no significant difference in the incidence of adverse reactions between the two groups. Conclusions Adjunctive aripiprazole treatment may be beneficial in reducing serum levels of prolactin and improving negative symptoms in schizophrenia patients with risperidone-induced hyperprolactinemia. Trial Registration chictr.org ChiCTR-IOR-15006278 PMID:26448615
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Hughes, Shannon; Cohen, David; Jaggi, Rachel
2014-01-01
Objective To examine the degree of concordance in reporting serious adverse events (SAEs) from antidepressant and antipsychotic drug trials among journal articles and clinical trial summaries, and to categorise types of discrepancies. Design Cross-sectional study of summaries of all antidepressant and antipsychotic trials included in an online trial registry and their first associated stand-alone journal articles. Setting Clinicalstudyresults.org, sponsored by Pharmaceutical Research and Manufacturers of America; clinicaltrials.gov, administered by the US National Institutes of Health. Main outcome measure 3 coders extracted data on the numbers and types of SAEs. Results 244 trial summaries for six antidepressant and antipsychotic drugs were retrieved, 142 (58.2%) listing an associated article. Of 1608 SAEs in drug-treated participants according to trial summaries, 694 (43.2%) did not appear in associated articles. Nearly 60% of SAEs counted in articles and 41% in trial summaries had no description. Most cases of death (62.3%) and suicide (53.3%) were not reported in articles. Half or more of the 142 pairs were discordant in reporting the number (49.3%) or description (67.6%) of SAEs. These discrepancies resulted from journal articles’ (1) omission of complete SAE data, (2) reporting acute phase study results only and (3) more restrictive reporting criteria. Trial summaries with zero SAE were 2.35 (95% CI, 1.58 to 3.49; p<0.001) times more likely to be published with no discrepancy in their associated journal article. Since clinicalstudyresults.org was removed from the Internet in 2011, only 7.8% of retrieved trial summaries appear with results on clinicaltrials.gov. Conclusions Substantial discrepancies exist in SAE data found in journal articles and registered summaries of antidepressant and antipsychotic drug trials. Two main scientific sources accessible to clinicians and researchers are limited by incomplete, ambiguous and inconsistent reporting. Access to complete and accurate data from clinical trials of drugs currently in use remains a pressing concern. PMID:25009136