Efficacy, acceptability, and tolerability of antipsychotics in children and adolescents with schizophrenia: A network meta-analysis.

PubMed

Krause, Marc; Zhu, Yikang; Huhn, Maximilian; Schneider-Thoma, Johannes; Bighelli, Irene; Chaimani, Anna; Leucht, Stefan

2018-06-01

Children and adolescents with schizophrenia are a particularly vulnerable group. Thus, we integrated all the randomized evidence from the available antipsychotics used for this subgroup by performing a network-meta-analysis and pairwise meta-analysis using a random-effects model. We searched multiple databases up to Nov 17, 2016 (final update search in PubMed: Dec 12, 2017). The primary outcome was efficacy as measured by overall change/endpoint in symptoms of schizophrenia. Secondary outcomes included positive and negative symptoms, response, dropouts, quality of life, social functioning, weight gain, sedation, prolactin, extrapyramidal side effects (EPS) and antiparkinsonian medication. Twenty-eight randomized controlled trials (RCTs) with 3003 unique participants (58% males; mean age 14.41 years) published from 1967 to 2017 were identified. Clozapine was significantly more effective than all other analyzed antipsychotics. Nearly all antipsychotics were more efficacious compared to placebo, but ziprasidone showed no efficacy. In terms of preventing weight gain, molindone, lurasidone and ziprasidone were benign. The highest weight gain was found for clozapine, quetiapine and olanzapine. Most antipsychotics had some sedating effects. Risperidone, haloperidol, paliperidone and olanzapine were associated with prolactin increase. There were evidence gaps for some drugs and many outcomes, especially safety outcomes. Most of the comparisons are based only on one study or just on indirect evidence. Nevertheless, the available direct and indirect evidence showed that the treatment effects were similar compared to findings in adult patients with schizophrenia. Copyright © 2018 Elsevier B.V. and ECNP. All rights reserved.

An update of safety of clinically used atypical antipsychotics.

PubMed

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.

Dose Equivalents for Second-Generation Antipsychotic Drugs: The Classical Mean Dose Method

PubMed Central

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

Lurasidone in the Treatment of Bipolar Depression: Systematic Review of Systematic Reviews

PubMed Central

Perna, Giampaolo; Solmi, Marco; Veronese, Nicola; Buonaguro, Elisabetta Filomena; Köhler, Cristiano André; de Bartolomeis, Andrea

2017-01-01

Introduction A burgeoning number of systematic reviews considering lurasidone in the treatment of bipolar depression have occurred since its Food and Drug Administration extended approval in 2013. While a paucity of available quantitative evidence still precludes preliminary meta-analysis on the matter, the present quality assessment of systematic review of systematic reviews, nonetheless, aims at highlighting current essential information on the topic. Methods Both published and unpublished systematic reviews about lurasidone mono- or adjunctive therapy in the treatment of bipolar depression were searched by two independent authors inquiring PubMed/Cochrane/Embase/Scopus from inception until October 2016. Results Twelve included systematic reviews were of moderate-to-high quality and consistent in covering the handful of RCTs available to date, suggesting the promising efficacy, safety, and tolerability profile of lurasidone. Concordance on the drug profile seems to be corroborated by a steadily increasing number of convergent qualitative reports on the matter. Limitations Publication, sponsorship, language, citation, and measurement biases. Conclusions Despite being preliminary in nature, this overview stipulates the effectiveness of lurasidone in the acute treatment of Type I bipolar depression overall. As outlined by most of the reviewed evidence, recommendations for future research should include further controlled trials of extended duration. PMID:28573138

Effects of lurasidone on ketamine-induced joint visual attention dysfunction as a possible disease model of autism spectrum disorders in common marmosets.

PubMed

Nakako, Tomokazu; Murai, Takeshi; Ikejiri, Masaru; Hashimoto, Takashi; Kotani, Manato; Matsumoto, Kenji; Manabe, Shoji; Ogi, Yuji; Konoike, Naho; Nakamura, Katsuki; Ikeda, Kazuhito

2014-11-01

Infants with autism have difficulties performing joint visual attention (JVA), defined as following another person's pointing gesture and gaze. Some non-human primates (NHPs) can also perform JVA. Most preclinical research on autism spectrum disorders (ASD) has used rodents as animal models of this social interaction disorder. However, models using rodents fail to capture the complexity of social interactions that are disrupted in ASD. Therefore, JVA impairment in NHPs might be a more useful model of ASD. The aim of this study was to develop an appropriate and convenient ASD model with common marmosets. We first tested whether marmosets were capable of performing JVA. Subsequently, we administered ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, to induce JVA impairment and investigated the effects of lurasidone, a newer antipsychotic agent, on the JVA impairments. An apparatus was constructed using 4 white boxes, which were attached to the corners of a frame. All boxes had a hinged door, and marmosets could easily obtain a reward by pushing the door. An experimenter pointed and gazed at the boxes to inform the marmosets which box contained the reward. Their behavior was scored according to the number of incorrect choices. The JVA score was significantly higher in the cued vs. uncued tasks. Ketamine significantly decreased the JVA score, but lurasidone significantly reversed this effect. These findings suggest that this experimental system could be a useful animal model of neuropsychiatric disorders characterized by NMDA-receptor signaling, including ASD, and that lurasidone might be effective for some aspects of ASD. Copyright © 2014 Elsevier B.V. All rights reserved.

A Multicenter, Rater-Blinded, Randomized Controlled Study of Auditory Processing-Focused Cognitive Remediation Combined With Open-Label Lurasidone in Patients With Schizophrenia and Schizoaffective Disorder.

PubMed

Kantrowitz, Joshua T; Sharif, Zafar; Medalia, Alice; Keefe, Richard S E; Harvey, Philip; Bruder, Gerard; Barch, Deanna M; Choo, Tse; Lee, Seonjoo; Lieberman, Jeffrey A

2016-06-01

Small-scale studies of auditory processing cognitive remediation programs have demonstrated efficacy in schizophrenia. We describe a multicenter, rater-blinded, randomized, controlled study of auditory-focused cognitive remediation, conducted from June 24, 2010, to June 14, 2013, and approved by the local institutional review board at all sites. Prior to randomization, participants with schizophrenia (DSM-IV-TR) were stabilized on a standardized antipsychotic regimen (lurasidone [40-160 mg/d]), followed by randomization to adjunctive cognitive remediation: auditory focused (Brain Fitness) versus control (nonspecific video games), administered 1-2 times weekly for 30 sessions. Coprimary outcome measures included MATRICS Consensus Cognitive Battery (MCCB) and the University of California, San Diego, Performance-Based Skills Assessment-Brief scale. 120 participants were randomized and completed at least 1 auditory-focused cognitive remediation (n = 56) or video game control session (n = 64). 74 participants completed ≥ 25 sessions and postrandomization assessments. At study completion, the change from prestabilization was statistically significant for MCCB composite score (d = 0.42, P < .0001) across groups. Participants randomized to auditory-focused cognitive remediation had a trend-level higher mean MCCB composite score compared to participants randomized to control cognitive remediation (P = .08). After controlling for scores at the time of randomization, there were no significant between-treatment group differences at study completion. Auditory processing cognitive remediation combined with lurasidone did not lead to differential improvement over nonspecific video games. Across-group improvement from prestabilization baseline to study completion was observed, but since all participants were receiving lurasidone open label, it is difficult to interpret the source of these effects. Future studies comparing both pharmacologic and behavioral cognitive enhancers should consider a 2 × 2 design, using a control for both the medication and the cognitive remediation. ClinicalTrials.gov identifier: NCT01173874. © Copyright 2016 Physicians Postgraduate Press, Inc.

Neural Basis for the Ability of Atypical Antipsychotic Drugs to Improve Cognition in Schizophrenia

PubMed Central

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

GLYX-13 (rapastinel) ameliorates subchronic phencyclidine- and ketamine-induced declarative memory deficits in mice

PubMed Central

Rajagopal, Lakshmi; Burgdorf, Jeffrey S.; Moskal, Joseph R.; Meltzer, Herbert Y.

2016-01-01

GLYX-13 (rapastinel), a tetrapeptide (Thr-Pro-Pro-Thr-amide), has been reported to have fast acting antidepressant properties in man based upon its N-methyl-d-aspartate receptor (NMDAR) glycine site functional partial agonism. Ketamine, a non-competitive NMDAR antagonist, also reported to have fast acting antidepressant properties, produces cognitive impairment in rodents and man, whereas rapastinel has been reported to have cognitive enhancing properties in rodents, without impairing cognition in man, albeit clinical testing has been limited. The goal of this study was to compare the cognitive impairing effects of rapastinel and ketamine in novel object recognition (NOR), a measure of declarative memory, in male C57BL/6J mice treated with phencyclidine (PCP), another NMDAR noncompetitive antagonist known to severely impair cognition, in both rodents and man. C57BL/6J mice given a single dose or subchronic ketamine (30 mg/kg. i.p.) showed acute or persistent deficits in NOR, respectively. Acute i.v. rapastinel (1.0 mg/kg), did not induce NOR deficit. Pre-treatment with rapastinel significantly prevented acute ketamine-induced NOR deficit. Rapastinel (1.0 mg/kg, but not 0.3 mg/kg, iv) significantly reversed both subchronic ketamine- and subchronic PCP-induced NOR deficits. Rapastinel also potentiated the atypical antipsychotic drug with antidepressant properties, lurasidone, to restore NOR in subchronic ketamine-treated mice. These findings indicate that rapastinel, unlike ketamine, does not induce a declarative memory deficit in mice, and can prevent or reverse the ketamine-induced NOR deficit. Further study is required to determine if these differences translate during clinical use of ketamine and rapastinel as fast acting antidepressant drugs and if rapastinel could have non-ionotropic effects as an add-on therapy with antipsychotic/antidepressant medications. PMID:26632337

Recovery in bipolar depression: Post-hoc analysis of a placebo-controlled lurasidone trial followed by a long-term continuation study.

PubMed

Loebel, Antony; Siu, Cynthia; Rajagopalan, Krithika; Pikalov, Andrei; Cucchiaro, Josephine; Ketter, Terence A

2015-11-01

In this post-hoc analysis, rates of remission and recovery were evaluated in patients with bipolar depression treated with lurasidone. Outpatients meeting DSM-IV-TR criteria for bipolar I depression, were randomized to 6 weeks of once-daily, double-blind treatment with lurasidone 20-60mg, lurasidone 80-120mg or placebo, followed by a 6-month, open-label, flexible-dose, lurasidone continuation study. Recovery was defined as meeting criteria for combined symptomatic remission (Montgomery-Asberg Depression Rating Scale total score ≤12) and functional remission (all Sheehan Disability Scale domain scores ≤3) sustained for at least 3 months in the 6-month continuation study. A significantly higher proportion of lurasidone-treated patients met criteria for combined symptomatic remission and functional remission (33.3%, 91/273) compared to the placebo group (21.0%, 30/143, p<0.05, NNT=9) at the 6-week study endpoint. In the 6-month continuation study, the proportion of lurasidone-treated patients achieving sustained recovery was 60.7% (85/140) and 44.9% (31/69), for patients who continued lurasidone treatment and who switched from placebo to lurasidone, respectively. The definition of recovery used has not been previously validated and the analysis was post hoc. Lack of a control group in the continuation study limits data interpretation. Recovery in patients with bipolar depression was assessed based on rates of combined symptomatic and functional remission sustained over time. A majority of patients initially treated with lurasidone in the acute phase achieved recovery status in the continuation study. Treatment with lurasidone (vs. placebo) earlier in the course of the bipolar depressive episode increased the likelihood of subsequent recovery. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

Efficacy and Safety of Lurasidone in Children and Adolescents With Bipolar I Depression: A Double-Blind, Placebo-Controlled Study.

PubMed

DelBello, Melissa P; Goldman, Robert; Phillips, Debra; Deng, Ling; Cucchiaro, Josephine; Loebel, Antony

2017-12-01

To evaluate the efficacy and safety of lurasidone in children and adolescents with bipolar depression. Patients 10 to 17 years old with a DSM-5 diagnosis of bipolar I depression were randomized to 6 weeks of double-blind treatment with flexible doses of lurasidone 20 to 80 mg/day. The primary endpoint was change from baseline to week 6 in the Children's Depression Rating Scale-Revised (CDRS-R) total score, evaluated by a mixed-model repeated-measures analysis. A total of 347 patients were randomized and received at least 1 dose of lurasidone (n = 175; mean age 14.2 years; mean dose 33.6 mg/day) or placebo (n = 172; mean age 14.3 years). At week 6, treatment with lurasidone was associated with statistically significant improvement compared with placebo in CDRS-R total score (-21.0 versus -15.3; p < .0001; effect size 0.45). Lurasidone also was associated with statistically significant improvement in the Clinical Global Impression-Bipolar Severity depression score (key secondary measure) and in measures of anxiety, quality of life, and global functioning. Study completion rates were 92.0% in the lurasidone group and 89.7% in the placebo group; discontinuation rates due to adverse events were the same for the 2 groups (1.7%). The 2 most common adverse events on lurasidone were nausea and somnolence. Treatment with lurasidone was associated with few effects on weight and metabolic parameters. In this placebo-controlled study, monotherapy with lurasidone, in the dose range of 20 to 80 mg/day, significantly decreased depressive symptoms in children and adolescents with bipolar depression. Lurasidone was well tolerated, with minimal effects on weight and metabolic parameters. Clinical trial registration information-Lurasidone Pediatric Bipolar Study; http://Clinicaltrials.gov; NCT02046369. Copyright © 2017 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

Lurasidone

MedlinePlus

Lurasidone is used to treat the symptoms of schizophrenia (a mental illness that causes disturbed or unusual ... often than prescribed by your doctor.Lurasidone controls schizophrenia and depression in people with bipolar disorder but ...

Weight change during long-term treatment with lurasidone: pooled analysis of studies in patients with schizophrenia.

PubMed

Meyer, Jonathan M; Mao, Yongcai; Pikalov, Andrei; Cucchiaro, Josephine; Loebel, Antony

2015-11-01

The objective of this analysis was to evaluate the effect of 12 months of treatment with lurasidone on weight in patients with schizophrenia. Post-hoc, observed-case analysis included pooled data from six studies on 40-160 mg/day lurasidone; two studies included active comparators (2-6 mg/day risperidone or 200-800 mg/day quetiapine XR). Overall, 593 patients completed 12 months of treatment (N=471 lurasidone, N = 89 risperidone, N = 33 quetiapine XR). The mean baseline weight was 72.8, 80.8, and 72.4 kg in the lurasidone, risperidone, and quetiapine XR groups, respectively. The mean weight change at month 12 was -0.4 kg with lurasidone, +2.6 kg with risperidone, and +1.2 kg with quetiapine XR. Weight gain of at least 7% from study baseline was observed in 16.0, 25.8, and 15.2% of patients, and weight loss of at least 7% was seen in 18.5, 6.7, and 9.1% of patients treated with lurasidone, risperidone, and quetiapine XR, respectively. A shift from normal/underweight baseline BMI status to overweight/obese at month 12 occurred in 10.2, 27.6, and 15.0% of patients in the lurasidone, risperidone, and quetiapine XR groups, respectively. Conversely, 14.3, 1.7, and 7.7% of patients, respectively, shifted from overweight/obese to normal/underweight. In summary, a low potential for clinically significant weight gain was observed in patients with schizophrenia treated continuously with lurasidone for 12 months.

Atypical antipsychotics: recent research findings and applications to clinical practice: Proceedings of a symposium presented at the 29th Annual European College of Neuropsychopharmacology Congress, 19 September 2016, Vienna, Austria.

PubMed

Murray, Robin; Correll, Christoph U; Reynolds, Gavin P; Taylor, David

2017-03-01

Available evidence suggests that second-generation atypical antipsychotics are broadly similar to first-generation agents in terms of their efficacy, but may have a more favourable tolerability profile, primarily by being less likely to cause extrapyramidal symptoms. However, atypical antipsychotics are variably associated with disturbances in the cardiometabolic arena, including increased body weight and the development of metabolic syndrome, which may reflect differences in their receptor binding profiles. Effective management of schizophrenia must ensure that the physical health of patients is addressed together with their mental health. This should therefore involve consideration of the specific tolerability profiles of available agents and individualization of treatment to minimize the likelihood of adverse metabolic sequelae, thereby improving long-term adherence and optimizing overall treatment outcomes. Alongside this, modifiable risk factors (such as exercise, diet, obesity/body weight and smoking status) must be addressed, in order to optimize patients' overall health and quality of life (QoL). In addition to antipsychotic-induced side effects, the clinical management of early nonresponders and psychopharmacological approaches for patients with treatment-resistant schizophrenia remain important unmet needs. Evidence suggests that antipsychotic response starts early in the course of treatment and that early nonresponse accurately predicts nonresponse over the longer term. Early nonresponse therefore represents an important modifiable risk factor for poor efficacy and effectiveness outcomes, since switching or augmenting antipsychotic treatment in patients showing early nonresponse has been shown to improve the likelihood of subsequent treatment outcomes. Recent evidence has also demonstrated that patients showing early nonresponse to treatment with lurasidone at 2 weeks may benefit from an increase in dose at this timepoint without compromising tolerability/safety. However, further research is required to determine whether these findings are generalizable to other antipsychotic agents.

The direct and indirect effects of lurasidone monotherapy on functional improvement among patients with bipolar depression: results from a randomized placebo-controlled trial.

PubMed

Rajagopalan, Krithika; Bacci, Elizabeth Dansie; Wyrwich, Kathleen W; Pikalov, Andrei; Loebel, Antony

2016-12-01

Bipolar depression is characterized by depressive symptoms and impairment in many areas of functioning, including work, family, and social life. The objective of this study was to assess the independent, direct effect of lurasidone treatment on functioning improvement, and examine the indirect effect of lurasidone treatment on functioning improvement, mediated through improvements in depression symptoms. Data from a 6-week placebo-controlled trial assessing the effect of lurasidone monotherapy versus placebo in patients with bipolar depression was used. Patient functioning was measured using the Sheehan disability scale (SDS). Descriptive statistics were used to assess the effect of lurasidone on improvement on the SDS total and domain scores (work/school, social, and family life), as well as number of days lost and unproductive due to symptoms. Path analyses evaluated the total effect (β1), as well as the indirect effect (β2×β3) and direct effect (β4) of lurasidone treatment on SDS total score change, using standardized beta path coefficients and baseline scores as covariates. The direct effect of treatment on SDS total score change and indirect effects accounting for mediation through depression improvement were examined for statistical significance and magnitude using MPlus. In this 6-week trial (N = 485), change scores from baseline to 6-weeks were significantly larger for both lurasidone treatment dosage groups versus placebo on the SDS total and all three SDS domain scores (p < 0.05). Through path analyses, lurasidone treatment predicted improvement in depression (β2 = -0.33, p = 0.009), subsequently predicting improvement in functional impairment (β3 = 0.70, p < 0.001; indirect effect = -0.23). The direct effect was of medium magnitude (β4 = -0.17, p = 0.04), indicating lurasidone had a significant and direct effect on improvement in functional impairment, after accounting for depression improvement. Results demonstrated statistically significant improvement in functioning among patients on lurasidone monotherapy compared to placebo. Improvement in functioning among patients on lurasidone was largely mediated through a reduction in depression symptoms, but lurasidone also had a medium and statistically significant independent direct effect in improving functioning.

Lurasidone for the Treatment of Irritability Associated with Autistic Disorder.

PubMed

Loebel, Antony; Brams, Matthew; Goldman, Robert S; Silva, Robert; Hernandez, David; Deng, Ling; Mankoski, Raymond; Findling, Robert L

2016-04-01

The aim of this study was to evaluate the short-term efficacy and safety of lurasidone in treating irritability associated with autistic disorder. In this multicenter trial, outpatients age 6-17 years who met DSM-IV-TR criteria for autistic disorder, and who demonstrated irritability, agitation, and/or self-injurious behaviors were randomized to 6 weeks of double-blind treatment with lurasidone 20 mg/day (N = 50), 60 mg/day (N = 49), or placebo (N = 51). Efficacy measures included the Aberrant Behavior Checklist Irritability subscale (ABC-I, the primary endpoint) and the Clinical Global Impressions, Improvement (CGI-I) scale, and were analyzed using a likelihood-based mixed model for repeated measures. Least squares (LS) mean (standard error [SE]) improvement from baseline to Week 6 in the ABC-I was not significantly different for lurasidone 20 mg/day (-8.8 [1.5]) and lurasidone 60 mg/day (-9.4 [1.4]) versus placebo (-7.5 [1.5]; p = 0.55 and 0.36, respectively). CGI-I scores showed significantly greater LS mean [SE] improvement at Week 6 for lurasidone 20 mg/day versus placebo (2.8 [0.2] vs. 3.4 [0.2]; p = 0.035) but not for lurasidone 60 mg/day (3.1 [0.2]; p = 0.27). Discontinuation rates due to adverse events were: lurasidone 20 mg/day, 4.1%; 60 mg/day, 3.9%; and placebo, 8.2%. Adverse events with an incidence ≥10% (lurasidone combined, placebo) included vomiting (18.0, 4.1%) and somnolence (12.0, 4.1%). Modest changes were observed in weight and selected metabolic parameters. In this study, once-daily, fixed doses of 20 and 60 mg/day of lurasidone were not demonstrated to be efficacious compared to placebo for the short-term treatment of children and adolescents with moderate-to-severe irritability associated with autistic disorder.

Remission and recovery associated with lurasidone in the treatment of major depressive disorder with subthreshold hypomanic symptoms (mixed features): post-hoc analysis of a randomized, placebo-controlled study with longer-term extension.

PubMed

Goldberg, Joseph F; Ng-Mak, Daisy; Siu, Cynthia; Chuang, Chien-Chia; Rajagopalan, Krithika; Loebel, Antony

2017-04-01

This post-hoc analysis assessed rates of symptomatic and functional remission, as well as recovery (combination of symptomatic and functional remission), in patients treated with lurasidone for major depressive disorder (MDD) associated with subthreshold hypomanic symptoms (mixed features). Patients with MDD plus two or three manic symptoms (defined as per the DSM-5 mixed-features specifier) were randomly assigned to flexible-dose lurasidone 20-60 mg/day (n=109) or placebo (n=100) for 6 weeks, followed by a 3-month open-label, flexible-dose extension study for U.S. sites only (n=48). Cross-sectional recovery was defined as the presence of both symptomatic remission (Montgomery-Åsberg Depression Rating Scale score ≤ 12) and functional remission (all Sheehan Disability Scale [SDS] domain scores ≤3) at week 6, and at both months 1 and 3 of the extension study ("sustained recovery"). A significantly higher proportion of lurasidone-treated patients (31.3%) achieved recovery (assessed cross-sectionally) compared to placebo (12.2%, p=0.002) at week 6. The number of manic symptoms at baseline moderated the effect size for attaining cross-sectional recovery for lurasidone treatment (vs. placebo) (p=0.028). Sustained recovery rates were higher in patients initially treated with lurasidone (20.8%) versus placebo (12.5%). In this post-hoc analysis of a placebo-controlled study with open-label extension that involved patients with MDD and mixed features, lurasidone was found to significantly improve the rate of recovery at 6 weeks (vs. placebo) that was sustained at month 3 of the extension study. The presence of two (as opposed to three) manic symptoms moderated recovery at the acute study endpoint.

Insight and Treatment Outcomes in Schizophrenia: Post-hoc Analysis of a Long-term, Double-blind Study Comparing Lurasidone and Quetiapine XR.

PubMed

Harvey, Philip D; Siu, Cynthia O; Loebel, Antony D

2017-12-01

Objective: The objective of this post-hoc analysis was to evaluate the effect of lurasidone and quetiapine extended-release (XR) on insight and judgment and assess the longitudinal relationships between improvement in insight and cognitive performance, functional capacity, quality of well-being, and depressive symptoms in patients with schizophrenia. Design: Clinically unstable patients with schizophrenia (N=488) were randomized to once-daily, fixed-dose treatment with lurasidone 80mg, lurasidone 160mg, quetiapine XR 600mg, or placebo, followed by a long-term, double-blind, flexible-dose continuation study involving these agents. Results: Significantly greater improvement in insight and judgment (assessed by the Positive and Negative Syndrome Scale G12 item) for the lurasidone and quetiapine XR groups, compared to the placebo group, was observed at Week 6. Over a subsequent six-month continuation period, the flexible dose lurasidone group showed significantly greater improvement in insight from acute phase baseline compared to the flexible-dose quetiapine XR group (QXR-QXR) (p=0.032). Improvement in insight was significantly correlated with improvement in cognition ( p =0.014), functional capacity (p=0.006, UPSA-B), quality of well-being ( p =0.033, QWB), and depressive symptoms ( p =0.05, Montgomery-Åsberg Depression Rating Scale [MADRS] score) across treatment groups and study periods. Conclusion: In this post-hoc analysis, flexibly dosed lurasidone 40 to 160mg/d was found to be associated with significantly greater improvement in insight compared to flexibly dosed quetiapine XR 200 to 800mg/d over long-term treatment in patients with schizophrenia. Across treatment groups, improvement in insight and judgment was significantly associated with improvement in cognition, functional capacity, quality of well-being, and depressive symptoms over time.

Lurasidone for major depressive disorder with mixed features and irritability: a post-hoc analysis.

PubMed

Swann, Alan C; Fava, Maurizio; Tsai, Joyce; Mao, Yongcai; Pikalov, Andrei; Loebel, Antony

2017-04-01

The aim of this post-hoc analysis was to evaluate the efficacy of lurasidone in treating major depressive disorder (MDD) with mixed features including irritability. The data in this analysis were derived from a study of patients meeting DSM-IV-TR criteria for unipolar MDD, with a Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥26, presenting with two or three protocol-defined manic symptoms, and who were randomized to 6 weeks of double-blind treatment with either lurasidone 20-60 mg/d (n=109) or placebo (n=100). We defined "irritability" as a score ≥2 on both the Young Mania Rating Scale (YMRS) irritability item (#5) and the disruptive-aggressive item (#9). Endpoint change in the MADRS and YMRS items 5 and 9 were analyzed using a mixed model for repeated measures for patients with and without irritability. Some 20.7% of patients met the criteria for irritability. Treatment with lurasidone was associated with a significant week 6 change vs. placebo in MADRS score in both patients with (-22.6 vs. -9.5, p<0.0001, effect size [ES]=1.4) and without (-19.9 vs. -13.8, p<0.0001, ES=0.7) irritability. In patients with irritable features, treatment with lurasidone was associated with significant week 6 changes vs. placebo in both the YMRS irritability item (-1.4 vs. -0.3, p=0.0012, ES=1.0) and the YMRS disruptive-aggressive item (-1.0 vs. -0.3, p=0.0002, ES=1.2). In our post-hoc analysis of a randomized, placebo-controlled, 6-week trial, treatment with lurasidone significantly improved depressive symptoms in MDD patients with mixed features including irritability. In addition, irritability symptoms significantly improved in patients treated with lurasidone.

Antipsychotics and associated risk of out-of-hospital cardiac arrest.

PubMed

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).

Understanding Antipsychotic Drug Treatment Effects: A Novel Method to Reduce Pseudospecificity of the Positive and Negative Syndrome Scale (PANSS) Factors.

PubMed

Hopkins, Seth C; Ogirala, Ajay; Loebel, Antony; Koblan, Kenneth S

2017-12-01

The Positive and Negative Syndrome Scale (PANSS) is the most widely used efficacy measure in acute treatment studies of schizophrenia. However, interpretation of the efficacy of antipsychotics in improving specific symptom domains is confounded by moderate-to-high correlations among standard (Marder) PANSS factors. The authors review the results of an uncorrelated PANSS score matrix (UPSM) transform designed to reduce pseudospecificity in assessment of symptom change in patients with schizophrenia. Based on a factor analysis of five pooled, placebo-controlled lurasidone clinical trials (N=1,710 patients), a UPSM transform was identified that generated PANSS factors with high face validity (good correlation with standard Marder PANSS factors), and high specificity/orthogonality (low levels of between-factor correlation measuring change during treatment). Between-factor correlations were low at baseline for both standard (Marder) PANSS factors and transformed PANSS factors. However, when measured change in symptom severity was measured during treatment (in a pooled 5-study analysis), there was a notable difference for standard PANSS factors, where changes across factors were found to be highly correlated (factors exhibited pseudospecificity), compared to transformed PANSS factors, where factor change scores exhibited the same low levels of between-factor correlation observed at baseline. At Week 6-endpoint, correlations among PANSS factor severity scores were moderate-to-high for standard factors (0.34-0.68), but continued to be low for the transformed factors (-0.22-0.20). As an additional validity check, we analyzed data from one of the original five pooled clinical trials that included other well-validated assessment scales (MADRS, Negative Symptom Assessment scale [NSA]). In this baseline analysis, UPSM-transformed PANSS factor severity scores (negative and depression factors) were found to correlate well with the MADRS and NSA. The availability of transformed PANSS factors with a high degree of orthogonality/specificity, but which retain a high degree of concurrent and face validity, can reduce pseudospecificity as a measurement confound, and should facilitate the drug development process, permitting a more accurate characterization of the efficacy of putative new agents in targeting specific symptom domains in patients with psychotic illness.

Lurasidone for major depressive disorder with mixed features and anxiety: a post-hoc analysis of a randomized, placebo-controlled study.

PubMed

Tsai, Joyce; Thase, Michael E; Mao, Yongcai; Ng-Mak, Daisy; Pikalov, Andrei; Loebel, Antony

2017-04-01

The aim of this post-hoc analysis was to evaluate the efficacy of lurasidone in treating patients with major depressive disorder (MDD) with mixed features who present with mild and moderate-to-severe levels of anxiety. The data in this analysis were derived from a study of patients meeting the DSM-IV-TR criteria for unipolar MDD, with a Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥26, presenting with two or three protocol-defined manic symptoms, who were randomized to 6 weeks of double-blind treatment with either lurasidone 20-60 mg/day (n=109) or placebo (n=100). Anxiety severity was evaluated using the Hamilton Anxiety Rating Scale (HAM-A). To evaluate the effect of baseline anxiety on response to lurasidone, the following two anxiety groups were defined: mild anxiety (HAM-A≤14) and moderate-to-severe anxiety (HAM-A≥15). Change from baseline in MADRS total score was analyzed for each group using a mixed model for repeated measures. Treatment with lurasidone was associated with a significant week 6 change versus placebo in MADRS total score for patients with both mild anxiety (-18.4 vs. -12.8, p<0.01, effect size [ES]=0.59) and moderate-to-severe anxiety (-22.0 vs. -13.0, p<0.001, ES=0.95). Treatment with lurasidone was associated with a significant week 6 change versus placebo in HAM-A total score for patients with both mild anxiety (-7.6 vs. -4.0, p<0.01, ES=0.62), and moderate-to-severe anxiety (-11.4 vs. -6.1, p<0.0001, ES=0.91). In this post-hoc analysis of an MDD with mixed features and anxiety population, treatment with lurasidone was associated with significant improvement in both depressive and anxiety symptoms in subgroups with mild and moderate-to-severe levels of anxiety at baseline.

Intraoperative floppy-iris syndrome associated with use of antipsychotic drugs.

PubMed

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.

Psychotic and Bipolar Disorders: Antipsychotic Drugs.

PubMed

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.

The prefrontal cortex: a target for antipsychotic drugs.

PubMed

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.

Histamine H3 receptors and its antagonism as a novel mechanism for antipsychotic effect: a current preclinical & clinical perspective.

PubMed

Mahmood, Danish

2016-10-01

Histamine H 3 receptors are present as autoreceptors on histaminergic neurons and as heteroreceptors on nonhistaminergic neurones. They control the release and synthesis of histamine and several other key neurotransmitters in the brain. H 3 antagonism may be a novel approach to develop a new class of antipsychotic medications given the gathering evidence reporting therapeutic efficacy in several central nervous system disorders. Several medications such as cariprazine, lurasidone, LY214002, bexarotene, rasagiline, raloxifene, BL-1020 and ITI-070 are being developed to treat the negative symptoms and cognitive impairments of schizophrenia. These medications works through diverse mechanisms which include agonism at metabotropic glutamate receptor (mGluR2/3), partial agonism at dopamine D 2 , D 3 and serotonin 5-HT 1A receptors, antagonism at D 2 , 5-HT 2A, 5-HT 2B and 5-HT 7 receptors, combined dopamine antagonism with GABA agonist activity, inhibition of monoamine oxidase-B, modulation of oestrogen receptor, and activation of nuclear retinoid X receptor. However, still specific safe therapy for psychosis remains at large. Schizophrenia is a severe neuropsychiatric disorder result both from hyper- and hypo-dopaminergic transmission causing positive and negative symptoms, respectively. Pharmacological stimulation of dopamine release in the prefrontal cortex has been a viable approach in treating negative symptoms and cognitive deficits of schizophrenia symptoms that are currently not well treated and continue to represent significant unmet medical challenges. Administration of H 3 antagonists/inverse agonists increase extracellular dopamine concentrations in rat prefrontal cortex, but not in the striatum suggesting that antagonism via H 3 receptor may be a potential target for treating negative symptoms and cognitive deficits associated with schizophrenia. Further, insights are emerging into the potential role of histamine H 3 receptors as a target of antiobesity therapeutics which is one of the limiting adverse effects of second generation schizophrenia medications. The recent failures of two promising H 3 compounds in clinical trial dampened the interest in seeking antipsychotic like activities of H 3 receptor antagonists. However, due to the inconclusive nature of many of these studies, the development of H 3 compounds via H 3 antagonism/inverse agonism approach still hold lot of promises and may be developed as a novel class of drugs for schizophrenia and its related complications e.g. weight gain.

Randomized Trial of the Effect of Four Second-Generation Antipsychotics and One First-Generation Antipsychotic on Cigarette Smoking, Alcohol, and Drug Use in Chronic Schizophrenia.

PubMed

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.

Regional variation in physician adoption of antipsychotics: Impact on US Medicare expenditures

PubMed Central

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

A case series on the effectiveness of lurasidone in patients with stuttering.

PubMed

Charoensook, Janet; Maguire, Gerald A

2017-08-01

The prevalence of stuttering is approximately 1% of the population, affecting an estimated 3 million individuals in the United States. The dopamine hypothesis of stuttering explains that abnormally increased cerebral dopamine affects the balanced levels that maintain the basal ganglia circuits, which helps with timing cues in initiating speech. This is especially significant when considering treatment strategies. We report a reduction in stuttering with lurasidone, a potent D2 receptor antagonist with a relatively favorable adverse effects profile. We conducted a non-randomized, open-label study of lurasidone in patients with stuttering (N = 7). Patients self-reported stuttering severity, locus of control, and avoidance using the Subjective Screening of Stuttering (SSS) scale and were assessed with the Clinical Global Impression (CGI) Scale. We observed a notable, statistically significant improvement in all areas of stuttering, as rated by the SSS scale. According to the CGI-Improvement Scale, 2 patients were scored as "very much improved" and 5 were scored as "much improved." This open-label study of lurasidone in patients with stuttering showed improvement in subjective symptoms, in CGI scores, and on the SSS scale.

Lurasidone for the Treatment of Irritability Associated with Autistic Disorder

ERIC Educational Resources Information Center

Loebel, Antony; Brams, Matthew; Goldman, Robert S.; Silva, Robert; Hernandez, David; Deng, Ling; Mankoski, Raymond; Findling, Robert L.

2016-01-01

The aim of this study was to evaluate the short-term efficacy and safety of lurasidone in treating irritability associated with autistic disorder. In this multicenter trial, outpatients age 6-17 years who met DSM-IV-TR criteria for autistic disorder, and who demonstrated irritability, agitation, and/or self-injurious behaviors were randomized to…

Psychotropic Polypharmacy in Patients with Dementia: Prevalence and Predictors.

PubMed

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.

Sudden cardiac death secondary to antidepressant and antipsychotic drugs

PubMed Central

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

Physicians' reasons not to discontinue long-term used off-label antipsychotic drugs in people with intellectual disability.

PubMed

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.

Impact of regulatory measures on antipsychotics drug consumption in Castilla y León, Spain.

PubMed

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.

Use of Antipsychotic Drugs in Individuals with Intellectual Disability (ID) in the Netherlands: Prevalence and Reasons for Prescription

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…

Antipsychotic-Induced Dopamine Supersensitivity Psychosis: Pharmacology, Criteria, and Therapy.

PubMed

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.

White matter tract integrity is associated with antidepressant response to lurasidone in bipolar depression.

PubMed

Lan, Martin J; Rubin-Falcone, Harry; Motiwala, Fatima; Chen, Ying; Stewart, Jonathan W; Hellerstein, David J; Mann, J John; McGrath, Patrick J

2017-09-01

Patients with bipolar disorder spend the most time in the depressed phase, and that phase is associated with the most morbidity and mortality. Treatment of bipolar depression lacks a test to determine who will respond to treatment. White matter disruptions have been found in bipolar disorder. Previous reports suggest that white matter disruptions may be associated with resistance to antidepressant medication, but this has never been investigated in a prospective study using a Food and Drug Administration (FDA)-approved medication. Eighteen subjects with bipolar disorder who were in a major depressive episode and off all medications were recruited. Magnetic resonance imaging was acquired using a 64-direction diffusion tensor imaging sequence on a 3T scanner. Subjects were treated with 8 weeks of open-label lurasidone. The Montgomrey-Asberg Depression Rating Scale (MADRS) was completed weekly. Tract-Based Spatial Statistics were utilized to perform a regression analysis of fractional anisotropy (FA) data with treatment outcome as assessed by percent change in MADRS as a regressor while controlling for age and sex, using a threshold of P (threshold-free cluster enhancement-corrected) <.05. FA was positively correlated with antidepressant treatment response in multiple regions of the mean FA skeleton bilaterally, including tracts in the frontal and parietal lobes. Greater disruptions in the white matter tracts in bipolar disorder were associated with poorer antidepressant response to lurasidone. The disruptions may potentially indicate treatment with a different antidepressant medication class. These results are limited by the open-label study design, sample size and lack of a healthy control group. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Atypical Antipsychotic Drugs and the Risk of Sudden Cardiac Death

PubMed Central

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

Repurposing psychiatric drugs as anti-cancer agents.

PubMed

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.

Lipid profile in antipsychotic drug users: A comparative study

PubMed Central

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

A critical assessment of antipsychotic drug monitoring.

PubMed

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.

Mental disorder diagnoses among children and adolescents who use antipsychotic drugs.

PubMed

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.

Do Atypical Antipsychotics Have Antisuicidal Effects? A Hypothesis-Generating Overview

PubMed Central

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

[Antipsychotic-drug-induced hyperprolactinemia: physiopathology, clinical features and guidance].

PubMed

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.

Do antipsychotic drugs affect brain structure? A systematic and critical review of MRI findings.

PubMed

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.

Fluvoxamine for blonanserin-associated akathisia in patients with schizophrenia: report of five cases

PubMed Central

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

Fluvoxamine for blonanserin-associated akathisia in patients with schizophrenia: report of five cases.

PubMed

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.

Evaluation of the Expression Profile of Extrapyramidal Symptoms Due to Antipsychotics by Data Mining of Japanese Adverse Drug Event Report (JADER) Database.

PubMed

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.

Thiol Disulfide Homeostasis in Schizophrenic Patients Using Atypical Antipsychotic Drugs

PubMed Central

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

Transformed PANSS Factors Intended to Reduce Pseudospecificity Among Symptom Domains and Enhance Understanding of Symptom Change in Antipsychotic-Treated Patients With Schizophrenia

PubMed Central

Hopkins, Seth C; Ogirala, Ajay; Loebel, Antony; Koblan, Kenneth S

2018-01-01

Abstract Positive and Negative Syndrome Scale (PANSS) total score is the standard primary efficacy measure in acute treatment studies of schizophrenia. However, PANSS factors that have been derived from factor analytic approaches over the past several decades have uncertain clinical and regulatory status as they are, to varying degrees, intercorrelated. As a consequence of cross-factor correlations, the apparent improvement in key clinical domains (eg, negative symptoms, disorganized thinking/behavior) may largely be attributable to improvement in a related clinical domain, such as positive symptoms, a problem often referred to as pseudospecificity. Here, we analyzed correlations among PANSS items, at baseline and change post-baseline, in a pooled sample of 5 placebo-controlled clinical trials (N = 1710 patients), using clustering and factor analysis to identify an uncorrelated PANSS score matrix (UPSM) that minimized the degree of correlation between each resulting transformed PANSS factor. The transformed PANSS factors corresponded well with discrete symptom domains described by prior factor analyses, but between-factor change-scores correlations were markedly lower. We then used the UPSM to transform PANSS in data from 4657 unique schizophrenia patients included in 12 additional lurasidone clinical trials. The results confirmed that transformed PANSS factors retained a high degree of specificity, thus validating that low between-factor correlations are a reliable property of the USPM when transforming PANSS data from a variety of clinical trial data sets. These results provide a more robust understanding of the structure of symptom change in schizophrenia and suggest a means to evaluate the specificity of antipsychotic treatment effects. PMID:28981857

Novel antipsychotics: issues and controversies. Typicality of atypical antipsychotics.

PubMed Central

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

Does mental health staffing level affect antipsychotic prescribing? Analysis of Italian national statistics.

PubMed

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.

Trends in the Outpatient Utilization of Antipsychotic Drugs in the City of Zagreb in the Ten-Year Period as a Tool to Assess Drug Prescribing Rationality.

PubMed

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.

Nature and Quality of Antipsychotic Prescribing Practice in UK Psychiatry of Intellectual Disability Services

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…

Comparison of Unlicensed and Off-Label Use of Antipsychotics Prescribed to Child and Adolescent Psychiatric Outpatients for Treatment of Mental and Behavioral Disorders with Different Guidelines: The China Food and Drug Administration Versus the FDA.

PubMed

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.

Potentiation of latent inhibition by haloperidol and clozapine is attenuated in Dopamine D2 receptor (Drd-2)-deficient mice: Do antipsychotics influence learning to ignore irrelevant stimuli via both Drd-2 and non-Drd-2 mechanisms?

PubMed Central

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

Trends in prescriptions and costs of drugs for mental disorders in England, 1998-2010.

PubMed

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.

Movement side effects of antipsychotic drugs in adults with and without intellectual disability: UK population-based cohort study.

PubMed

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.

Influence of the drug exposure definition on the assessment of the antipsychotic metabolic impact in patients initially treated with mood-stabilizers.

PubMed

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.

[Creativity and antipsychotic drugs].

PubMed

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.

Efficacy and safety of novel antipsychotics: a critical review.

PubMed

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.

Effects of the Antipsychotic Drug, Haloperidol, on Reproduction in the Fathead Minnow

EPA Science Inventory

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...

Impact of Modafinil Add-on with Atypical Anti-psychotics on Excessive Daytime Drowsiness

PubMed Central

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

Impact of antipsychotic medication on transcranial direct current stimulation (tDCS) effects in schizophrenia patients.

PubMed

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.

Metabolic syndrome in drug-naïve and drug-free patients with schizophrenia and in their siblings.

PubMed

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.

Patient-oriented randomisation: A new trial design applied in the Neuroleptic Strategy Study.

PubMed

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.

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…

Effects of controlled-release formulations of atypical antipsychotics on functioning and quality of life of schizophrenic individuals.

PubMed

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.

Use of antipsychotic medication and suicidality--the Northern Finland Birth Cohort 1966.

PubMed

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.

Physical Health and Drug Safety in Individuals with Schizophrenia

PubMed Central

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

Evidence for a crucial modulating role of the sodium channel in the QTc prolongation related to antipsychotics.

PubMed

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.

Long-acting injectable antipsychotics update: lengthening the dosing interval and expanding the diagnostic indications.

PubMed

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.

Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug.

PubMed

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.

Drug–drug conditioning between citalopram and haloperidol or olanzapine in a conditioned avoidance response model: implications for polypharmacy in schizophrenia

PubMed Central

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

Pharmacological interventions for borderline personality disorder

PubMed Central

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

Methadone

MedlinePlus

... asenapine (Saphris), cariprazine (Vraylar), chlorpromazine, clozapine (Versacloz), fluphenazine, haloperidol (Haldol), iloperidone (Fanapt), loxapine, lurasidone (Latuda), molindone, olanzapine ( ...

Understanding epigenetics of schizophrenia in the backdrop of its antipsychotic drug therapy.

PubMed

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.

Psychedelics and schizophrenia.

PubMed

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.

Antipsychotics and Amotivation

PubMed Central

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

Antipsychotics and amotivation.

PubMed

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.

Effectiveness of Antipsychotic Drugs for 24-Month Maintenance Treatment in First-Episode Schizophrenia: Evidence From a Community-Based "Real-World" Study.

PubMed

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.

Effect of Environmental Cues on Behavioral Efficacy of Haloperidol, Olanzapine and Clozapine in Rats

PubMed Central

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

Antipsychotic treatment and the Rorschach Perceptual Thinking Index (PTI) in psychotic disorder patients: Effects of treatment.

PubMed

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.

Effect of antipsychotics on peptides involved in energy balance in drug-naive psychotic patients after 1 year of treatment.

PubMed

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.

Effect of clinical response to active drugs and placebo on antipsychotics and mood stabilizers relative efficacy for bipolar depression and mania: A meta-regression analysis.

PubMed

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.

Antipsychotic prescribing in older people.

PubMed

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.

Elderly Patients with Dementia-Related Symptoms of Severe Agitation and Aggression: Consensus Statement on Treatment Options, Clinical Trials Methodology, and Policy

PubMed Central

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

Antipsychotic drugs prevent the motor hyperactivity induced by psychotomimetic MK-801 in zebrafish (Danio rerio).

PubMed

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.

Effect of second-generation antipsychotics on cognition: current issues and future challenges

PubMed Central

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

Effects of Psychosocial Interventions for Behavioral and Psychological Symptoms in Dementia on the Prescription of Psychotropic Drugs: A Systematic Review and Meta-Analyses.

PubMed

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.

Antipsychotic drug poisoning monitoring of clozapine in urine by using coffee ring effect based surface-enhanced Raman spectroscopy.

PubMed

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.

No alterations of brain GABA after 6 months of treatment with atypical antipsychotic drugs in early-stage first-episode schizophrenia.

PubMed

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.

Allelic variation in ApoC3, ApoA5 and LPL genes and first and second generation antipsychotic effects on serum lipids in patients with schizophrenia.

PubMed

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.

Early-life risperidone enhances locomotor responses to amphetamine during adulthood.

PubMed

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.

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

Buprenorphine Sublingual and Buccal (opioid dependence)

MedlinePlus

... asenapine (Saphris), cariprazine (Vraylar), chlorpromazine, clozapine (Versacloz), fluphenazine, haloperidol (Haldol), iloperidone (Fanapt), loxapine, lurasidone (Latuda), molindone, olanzapine ( ...

Side effect burden of antipsychotic drugs in real life - Impact of gender and polypharmacy.

PubMed

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.

Drug information update. Atypical antipsychotics and neuroleptic malignant syndrome: nuances and pragmatics of the association

PubMed Central

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

Drug information update. Atypical antipsychotics and neuroleptic malignant syndrome: nuances and pragmatics of the association.

PubMed

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.

Pharmacogenetics of leptin in antipsychotic-associated weight gain and obesity-related complications

PubMed Central

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

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…

Overlapping of Serotonin Syndrome with Neuroleptic Malignant Syndrome due to Linezolid-Fluoxetine and Olanzapine-Metoclopramide Interactions: A Case Report of Two Serious Adverse Drug Effects Caused by Medication Reconciliation Failure on Hospital Admission.

PubMed

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.

Formulary decisions and health economics.

PubMed

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.

Experimental treatment of antipsychotic-induced movement disorders

PubMed Central

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

Subjective experience and mental side-effects of antipsychotic treatment.

PubMed

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.

Practical Guidelines for the Use of New Generation Antipsychotic Drugs (except Clozapine) in Adult Individuals with Intellectual Disabilities

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…

Evaluation of human D-amino acid oxidase inhibition by anti-psychotic drugs in vitro.

PubMed

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.

Drug-induced parkinsonism following chronic methamphetamine use by a patient on haloperidol decanoate.

PubMed

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.

Effects of Antipsychotic Drugs Haloperidol and Clozapine on Visual Responses of Retinal Ganglion Cells in a Rat Model of Retinitis Pigmentosa.

PubMed

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.

Virally mediated increased neurotensin 1 receptor in the nucleus accumbens decreases behavioral effects of mesolimbic system activation.

PubMed

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.

[Antipsychotic prescription patterns in patients affiliated to the Social Security Health System in Colombia].

PubMed

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.

Differential Response to Risperidone in Schizophrenia Patients by KCNH2 Genotype and Drug Metabolizer Status.

PubMed

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.

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…

Switching away from pipotiazine palmitate: a naturalistic study.

PubMed

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.

Atypical antipsychotics induce both proinflammatory and adipogenic gene expression in human adipocytes in vitro

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

Association between community pharmacy loyalty and persistence and implementation of antipsychotic treatment among individuals with schizophrenia.

PubMed

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.

Brain site- and transmitter-dependent actions of methamphetamine, morphine and antipsychotics.

PubMed

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.

Cost-effectiveness of antipsychotics for outpatients with chronic schizophrenia.

PubMed

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.

Pharmacoepigenomic responses of antipsychotic drugs on pharmacogenes are likely to be modulated by miRNAs.

PubMed

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.

The Presynaptic Component of the Serotonergic System is Required for Clozapine's Efficacy

PubMed Central

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

Neurodevelopment in Schizophrenia: The Role of the Wnt Pathways

PubMed Central

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

Neuropsychopharmacology of auditory hallucinations: insights from pharmacological functional MRI and perspectives for future research.

PubMed

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.

Effects of antipsychotic drugs on cardiovascular variability in participants with bipolar disorder

PubMed Central

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

The antipsychotic landscape: dopamine and beyond.

PubMed

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.

Amisulpride and symptomatic bradycardia: a case report.

PubMed

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.

Vitamin B12 in Association with Antipsychotic Drugs Can Modulate the Expression of Pro-/Anti-Inflammatory Cytokines in Alzheimer Disease Patients.

PubMed

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.

Oral health impacts of medications used to treat mental illness.

PubMed

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.

In Vitro and In Vivo Characterization of the Alkaloid Nuciferine.

PubMed

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.

Patterns of Antipsychotic Prescribing by Physicians to Young Children.

PubMed

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.

Aripiprazole: the evidence of its therapeutic impact in schizophrenia

PubMed Central

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

Use of atypical antipsychotics in the elderly: a clinical review

PubMed Central

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

Continuous, but not intermittent, antipsychotic drug delivery intensifies the pursuit of reward cues.

PubMed

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.

Antidepressants but not antipsychotics have antiepileptogenic effects with limited effects on comorbid depressive-like behaviour in the WAG/Rij rat model of absence epilepsy

PubMed Central

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

Atypical antipsychotics induce both proinflammatory and adipogenic gene expression in human adipocytes in vitro.

PubMed

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.

The US Food and Drug Administration's Perspective on the New Antipsychotic Pimavanserin.

PubMed

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.

Neuroprotective effect of atypical antipsychotics in cognitive and non-cognitive behavioral impairment in animal models

PubMed Central

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

The atypical antipsychotic quetiapine increases both noradrenaline and dopamine release in the rat prefrontal cortex.

PubMed

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.

What is it like to take antipsychotic medication? A qualitative study of patients with first-episode psychosis.

PubMed

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.

Patient compliance with drug therapy in schizophrenia. Economic and clinical issues.

PubMed

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.

Contextual and behavioral control of antipsychotic sensitization induced by haloperidol and olanzapine.

PubMed

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.

Contextual and behavioral control of antipsychotic sensitization induced by haloperidol and olanzapine

PubMed Central

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

Persistence of Antipsychotic Treatment in Elderly Dementia Patients: A Retrospective, Population-Based Cohort Study.

PubMed

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.

The Potential Risks of Commonly Prescribed Antipsychotics

PubMed Central

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

Antipsychotic polypharmacy prescribing patterns and costs in the Florida adult and child Medicaid populations.

PubMed

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.

Sigma opiates and certain antipsychotic drugs mutually inhibit (+)-[3H] SKF 10,047 and [3H]haloperidol binding in guinea pig brain membranes.

PubMed Central

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

sigma opiates and certain antipsychotic drugs mutually inhibit (+)-(/sup 3/H)SKF 10,047 and (/sup 3/H)haloperidol binding in guinea pig brain membranes

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

Prior Haloperidol, but not Olanzapine, Exposure Augments the Pursuit of Reward Cues: Implications for Substance Abuse in Schizophrenia

PubMed Central

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

K(v) channel interacting protein 3 expression and regulation by haloperidol in midbrain dopaminergic neurons.

PubMed

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.

A Pharmacovigilance Study in First Episode of Psychosis: Psychopharmacological Interventions and Safety Profiles in the PEPs Project

PubMed Central

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

Polygenic overlap between schizophrenia risk and antipsychotic response: a genomic medicine approach

PubMed Central

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

Does changing from a first generation antipsychotic (perphenazin) to a second generation antipsychotic (risperidone) alter brain activation and motor activity? A case report

PubMed Central

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

Does changing from a first generation antipsychotic (perphenazin) to a second generation antipsychotic (risperidone) alter brain activation and motor activity? A case report.

PubMed

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.

Antipsychotics reverse abnormal EEG complexity in drug-naïve schizophrenia: A multiscale entropy analysis

PubMed Central

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

Development of a Web-Based Clinical Decision Support System for Drug Prescription: Non-Interventional Naturalistic Description of the Antipsychotic Prescription Patterns in 4345 Outpatients and Future Applications.

PubMed

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.

Development of a Web-Based Clinical Decision Support System for Drug Prescription: Non-Interventional Naturalistic Description of the Antipsychotic Prescription Patterns in 4345 Outpatients and Future Applications

PubMed Central

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

Extrapyramidal side effects of antipsychotic treatment: scope of problem and impact on outcome.

PubMed

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.

The risk of elevated prolactin levels in pediatric patients exposed to antipsychotics for the treatment of schizophrenia and schizophrenia spectrum disorders: protocol for a systematic review and meta-analysis

PubMed Central

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

Antipsychotic therapeutic drug monitoring: psychiatrists’ attitudes and factors predicting likely future use

PubMed Central

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

Cannabidiol exhibits anxiolytic but not antipsychotic property evaluated in the social interaction test.

PubMed

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.

Secondary pseudomyopia induced by amisulpride.

PubMed

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.

Antibacterial activity of antipsychotic agents, their association with lipid nanocapsules and its impact on the properties of the nanocarriers and on antibacterial activity.

PubMed

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.

[Psychoactive drugs and costs in the Madrid III (Valdemoro) prison].

PubMed

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.

Use of antipsychotics increases the risk of fracture: a systematic review and meta-analysis.

PubMed

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.

Molindone for schizophrenia and severe mental illness.

PubMed

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.

Efficacy of Adenine in the Treatment of Leukopenia and Neutropenia Associated with an Overdose of Antipsychotics or Discontinuation of Lithium Carbonate Administration: Three Case Studies.

PubMed

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.

Antipsychotics promote GABAergic interneuron genesis in the adult rat brain: Role of heat-shock protein production.

PubMed

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.

Dopamine and incentive learning: a framework for considering antipsychotic medication effects.

PubMed

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.

Use of Fixed Dose Combination (FDC) Drugs in India: Central Regulatory Approval and Sales of FDCs Containing Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), Metformin, or Psychotropic Drugs

PubMed Central

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

Risperidone long-acting injection: a review of its long term safety and efficacy

PubMed Central

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

Correlation between plasma homovanillic acid levels and the response to atypical antipsychotics in male patients with schizophrenia.

PubMed

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.

BDNF mRNA expression in rat hippocampus and prefrontal cortex: effects of neonatal ventral hippocampal damage and antipsychotic drugs.

PubMed

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.

Pharmacological causes of hyperprolactinemia

PubMed Central

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

Conventional versus novel antipsychotics: changing concepts and clinical implications.

PubMed Central

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

Dose Equivalents for Antipsychotic Drugs: The DDD Method.

PubMed

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.

Low dose morphine adjuvant therapy for enhanced efficacy of antipsychotic drug action: potential involvement of endogenous morphine in the pathophysiology of schizophrenia.

PubMed

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.

Antipsychotics, mood stabilisers, and risk of violent crime.

PubMed

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.

Antipsychotics, mood stabilisers, and risk of violent crime

PubMed Central

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

Aripiprazole, an Antipsychotic and Partial Dopamine Agonist, Inhibits Cancer Stem Cells and Reverses Chemoresistance.

PubMed

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.

Could cannabidiol be used as an alternative to antipsychotics?

PubMed

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.

Social feeding in Caenorhabditis elegans is modulated by antipsychotic drugs and calmodulin and may serve as a protophenotype for asociality.

PubMed

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.

Comparison of Psychotropic Drug Prescribing Quality between Zagreb, Croatia and Sarajevo, B&H.

PubMed

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.

Cardiovascular and metabolic monitoring of children and adolescents on antipsychotic treatment: A cross-sectional descriptive study.

PubMed

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.

Design of a long-term antipsychotic in situ forming implant and its release control method and mechanism.

PubMed

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.

The Impact of Coverage Restrictions on Antipsychotic Utilization Among Low-Income Medicare Part D Enrollees.

PubMed

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.

Screening of cardiovascular risk factors in patients with schizophrenia and patients treated with antipsychotic drugs: are we equally exhaustive as with the general population?

PubMed

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).

Further Characterization of the Predictive Validity of the Brattleboro Rat Model for Antipsychotic Efficacy

PubMed Central

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

Atypical antipsychotics and glucose homeostasis.

PubMed

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.

Psychotropic drugs in patients with Alzheimer's Disease: a longitudinal study by the Registry of Dementias of Girona (ReDeGi) in Catalonia, Spain.

PubMed

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.

Did FDA Decisionmaking Affect Anti-Psychotic Drug Prescribing in Children?: A Time-Trend Analysis.

PubMed

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.

Differential effects of antipsychotic drugs on insight in first episode schizophrenia: Data from the European First-Episode Schizophrenia Trial (EUFEST).

PubMed

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.

Differences in reporting serious adverse events in industry sponsored clinical trial registries and journal articles on antidepressant and antipsychotic drugs: a cross-sectional study

PubMed Central

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

Jasmine flower extract lowers prolactin.

PubMed

Finny, Philip; Stephen, Charles; Jacob, Rajesh; Tharyan, Prathap; Seshadri, Mandalam S

2015-04-01

Antipsychotic drugs frequently cause amenorrhoea and galactorrhoea. Jasmine flowers used topically were as effective as oral Bromocriptine in suppressing puerperal lactation. This study aims to evaluate the efficacy and safety of intranasal jasmine flower extract (JFE) to reduce prolactin levels of patients on stable doses of antipsychotic drugs. This is a randomized, double blind, crossover clinical trial. An aqueous-ethanol extract of jasmine flowers was prepared and used as nasal drops. A decrease in serum prolactin of ≥25 ng/mL was considered a significant response. Ten out of 35 women had a significant drop in the serum prolactin while on the JFE. The non-responders to JFE were on higher doses of antipsychotic drugs. The main side effect was a transient and mild burning sensation in the nose. A cost analysis favoured JFE over dopamine agonists. JFE contains a prolactin-lowering substance which needs further characterisation. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Improvement of nonsuicidal self-injury following treatment with antipsychotics possessing strong D1 antagonistic activity: evidence from a report of three cases.

PubMed

Wollweber, Bastian; Keck, Martin E; Schmidt, Ulrike

2015-08-01

There is no drug treatment for nonsuicidal self-injury (NSSI), a highly prevalent and burdensome symptom of several psychiatric diseases like posttraumatic stress disorder (PTSD), personality disorders, and major depression (MD). Here, we present a retrospective series of three patients demonstrating a persistent remission in MD-associated NSSI in response to treatment with antipsychotics possessing marked D1 receptor antagonistic activity. To the best of the authors' knowledge, the case series presented is only the second clinical paper suggesting a role for D1 antagonists in NSSI drug therapy. Together with previously published data from rodent models, the findings suggest a role for D1 antagonists in NSSI drug therapy and hence for the D1 receptor in NSSI pathogenesis. This conclusion is limited by the facts that the patients presented here received polypharmacy and that the D1 receptor antagonistic antipsychotics suggested here as effective 'anti-auto-aggressants' do not address D1 receptors only but multiple neurotransmitter receptors/systems.

Antipsychotic drugs and risk of type 2 diabetes: an evidence-based approach.

PubMed

Bellantuono, Cesario; Tentoni, Luigi; Donda, Pietro

2004-12-01

To review studies conducted to evaluate the risk of type 2 diabetes in patients treated with different antipsychotic drugs (AP). a MEDLINE search (January 1985-February 2003) was conducted to establish the potential relationship between the exposure to AP (conventional and second generation) and the development of type 2 diabetes. Studies were classified according to their experimental design as prospective and retrospective (incidence and prevalence based). Twenty-one studies were selected: nine prospective and eleven retrospective. Patients with schizophrenia treated with different AP have an increased risk of developing type 2 diabetes compared with the general population. The data so far available, however, do not establish whether the increasing risk of developing diabetes is a function of the schizophrenia itself or is induced by the antipsychotic treatment. A number of methodological flaws in the study design and data collection do not allow conclusions to be drawn on the risk between patients treated with conventional drugs versus those treated with new ones. 2004 John Wiley & Sons, Ltd.

Prevention of antipsychotic-induced hyperglycaemia by vitamin D: a data mining prediction followed by experimental exploration of the molecular mechanism.

PubMed

Nagashima, Takuya; Shirakawa, Hisashi; Nakagawa, Takayuki; Kaneko, Shuji

2016-05-20

Atypical antipsychotics are associated with an increased risk of hyperglycaemia, thus limiting their clinical use. This study focused on finding the molecular mechanism underlying antipsychotic-induced hyperglycaemia. First, we searched for drug combinations in the FDA Adverse Event Reporting System (FAERS) database wherein a coexisting drug reduced the hyperglycaemia risk of atypical antipsychotics, and found that a combination with vitamin D analogues significantly decreased the occurrence of quetiapine-induced adverse events relating diabetes mellitus in FAERS. Experimental validation using mice revealed that quetiapine acutely caused insulin resistance, which was mitigated by dietary supplementation with cholecalciferol. Further database analysis of the relevant signalling pathway and gene expression predicted quetiapine-induced downregulation of Pik3r1, a critical gene acting downstream of insulin receptor. Focusing on the phosphatidylinositol 3-kinase (PI3K) signalling pathway, we found that the reduced expression of Pik3r1 mRNA was reversed by cholecalciferol supplementation in skeletal muscle, and that insulin-stimulated glucose uptake into C2C12 myotube was inhibited in the presence of quetiapine, which was reversed by concomitant calcitriol in a PI3K-dependent manner. Taken together, these results suggest that vitamin D coadministration prevents antipsychotic-induced hyperglycaemia and insulin resistance by upregulation of PI3K function.

Classics in Chemical Neuroscience: Aripiprazole.

PubMed

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.

Utilization of antihypertensives, antidepressants, antipsychotics, and hormones in Alzheimer disease.

PubMed

Zhu, Carolyn W; Livote, Elayne E; Kahle-Wrobleski, Kristin; Scarmeas, Nikolaos; Albert, Marilyn; Brandt, Jason; Blacker, Deborah; Sano, Mary; Stern, Yaakov

2011-01-01

This study explores the longitudinal relationship between patient characteristics and use of 4 drug classes (antihypertensives, antidepressants, antipsychotics, and hormones) that showed significant changes in use rates over time in patients with Alzheimer disease. Patient/caregiver-reported prescription medication usage was categorized by drug class for 201 patients from the Predictors Study. Patient characteristics included use of cholinesterase inhibitors and/or memantine, function, cognition, living situation, baseline age, and sex. Assessment interval, year of study entry, and site were controlled for. Before adjusting for covariates, useage increased for antihypertensives (47.8% to 62.2%), antipsychotics (3.5% to 27.0%), and antidepressants (32.3% to 40.5%); use of hormones decreased (19.4% to 5.4%). After controlling for patient characteristics, effects of time on the use of antidepressants were no longer significant. Antihypertensive use was associated with poorer functioning, concurrent use of memantine, and older age. Antipsychotic use was associated with poorer functioning and poorer cognition. Antidepressant use was associated with younger age, poorer functioning, and concurrent use of cholinesterase inhibitors and memantine. Hormone use was associated with being female and younger age. Findings suggest accurate modeling of the Alzheimer disease treatment paradigm for certain subgroups of patients should include antihypertensives and antipsychotics in addition to cholinesterase inhibitors and memantine.

Oculomotor and Neuropsychological Effects of Antipsychotic Treatment for Schizophrenia

PubMed Central

Hill, S. Kristian; Reilly, James L.; Harris, Margret S. H.; Khine, Tin; Sweeney, John A.

2008-01-01

Cognitive enhancement has become an important target for drug therapies in schizophrenia. Treatment development in this area requires assessment approaches that are sensitive to procognitive effects of antipsychotic and adjunctive treatments. Ideally, new treatments will have translational characteristics for parallel human and animal research. Previous studies of antipsychotic effects on cognition have relied primarily on paper-and-pencil neuropsychological testing. No study has directly compared neurophysiological biomarkers and neuropsychological testing as strategies for assessing cognitive effects of antipsychotic treatment early in the course of schizophrenia. Antipsychotic-naive patients with schizophrenia were tested before treatment with risperidone and again 6 weeks later. Matched healthy participants were tested over a similar time period. Test-retest reliability, effect sizes of within-subject change, and multivariate/univariate analysis of variance were used to compare 3 neurophysiological tests (visually guided saccade, memory-guided saccade, and antisaccade) with neuropsychological tests covering 4 cognitive domains (executive function, attention, memory, and manual motor function). While both measurement approaches showed robust neurocognitive impairments in patients prior to risperidone treatment, oculomotor biomarkers were more sensitive to treatment-related effects on neurocognitive function than traditional neuropsychological measures. Further, unlike the pattern of modest generalized cognitive improvement suggested by neuropsychological measures, the oculomotor findings revealed a mixed pattern of beneficial and adverse treatment-related effects. These findings warrant further investigation regarding the utility of neurophysiological biomarkers for assessing cognitive outcomes of antipsychotic treatment in clinical trials and in early-phase drug development. PMID:17932088

Sedative effect of Clozapine is a function of 5-HT2A and environmental novelty.

PubMed

Joshi, Radhika S; Quadros, Rolen; Drumm, Michael; Ain, Rupasri; Panicker, Mitradas M

2017-01-01

Antipsychotic drugs are the mainstay in the treatment of schizophrenia and bipolar disorder. However, antipsychotics often exhibit sedation or activity suppression among many other side effects, and the factors that influence them remain poorly understood. We now show, using a 5-HT 2A knockout (Htr2a -/- ) mouse, that environmental circumstances can affect suppression of activity induced by the atypical antipsychotic- Clozapine. We observed that Htr2a -/- mice were more resistant to Clozapine-induced suppression of activity (CISA) and this behaviour was dependent on the environment being 'novel'. In their 'home' environment, at identical doses the mice exhibited CISA. Interestingly, the effect of genotype and environmental novelty on CISA could not be extended to the other antipsychotics that were tested, i.e. Haloperidol and Risperidone. Haloperidol-induced activity suppression was independent of context and genotype. Whereas context affected Risperidone-induced activity suppression only in the Htr2a +/+ mice. Furthermore, we observed that caffeine, a stimulant, elicited resistance to CISA similar to that seen in the 'novel' context. Our study establishes a previously unknown interaction between the environmental context, 5-HT 2A and CISA and emphasises the role of non-pharmacological factors such as environment on the effects of the drug, which seem antipsychotic-specific. Our findings should advance the understanding of the side effects of individual antipsychotics and the role of environment to overcome side effects such as sedation. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

Effect of Metformin on Hypothalamic-Pituitary-Thyroid Axis Activity in Elderly Antipsychotic-Treated Women With Type 2 Diabetes and Subclinical Hypothyroidism: A Preliminary Study.

PubMed

Krysiak, Robert; Szkróbka, Witold; Okopień, Bogusław

2018-05-01

Metformin was found to reduce elevated serum thyrotropin levels, and this effect was partially determined by endogenous dopaminergic tone. The aim of this study was to compare the effect of metformin treatment on hypothalamic-pituitary-thyroid axis activity in elderly women with subclinical hypothyroidism treated with antipsychotic agents and not receiving this drug. The study population consisted of 34 elderly women with subclinical hypothyroidism, 16 of whom received antipsychotic drugs. Because of coexistent type 2 diabetes, these women were treated with metformin (2.55-3 g daily). Glucose homeostasis markers as well as serum levels of thyrotropin, free thyroid hormones and prolactin were measured at the beginning of the study and 6 months later. Thirty women completed the study. With the exception of prolactin, baseline serum levels of the assessed hormones were comparable in both study groups. Although metformin reduced serum thyrotropin levels in both groups, this effect was more pronounced in the antipsychotic-treated than in the antipsychotic-naive patients. The effect on serum prolactin was observed only in antipsychotic-treated patients. The impact on serum thyrotropin levels correlated with improvement in insulin sensitivity and with a reduction in prolactin levels. Free thyroxine and free triiodothyronine remained at a similar level throughout the study. The obtained results indicate that metformin reduces serum thyrotropin levels in elderly women, and this effect is particularly pronounced in women with diminished dopaminergic transmission. © 2017, The American College of Clinical Pharmacology.

Use of Atypical Antipsychotics in Nursing Homes and Pharmaceutical Marketing

PubMed Central

Pimentel, Camilla B.; Donovan, Jennifer L.; Field, Terry S.; Gurwitz, Jerry H.; Harrold, Leslie R.; Kanaan, Abir O.; Lemay, Celeste A.; Mazor, Kathleen M.; Tjia, Jennifer; Briesacher, Becky A.

2014-01-01

BACKGROUND Many nursing home (NH) residents are prescribed atypical antipsychotics despite US Food and Drug Administration warnings of increased risk of death in older adults with dementia. Aggressive pharmaceutical marketing has been cited as a potential cause, although data are scarce. The objectives of this study were to describe the current extent and type of pharmaceutical marketing in NHs in one state, and to provide preliminary evidence for the potential influence of pharmaceutical marketing on the use of atypical antipsychotics in NHs. DESIGN Nested mixed-methods, cross-sectional study of NHs in a cluster randomized trial. SETTING 41 NHs in Connecticut. PARTICIPANTS NH administrators, directors of nursing and medical directors (n = 93, response rate 75.6%). MEASUREMENTS Quantitative data, including prescription drug dispensing data (September 2009–August 2010) linked with Nursing Home Compare data (April 2011), were used to determine facility-level prevalence of atypical antipsychotic use, facility-level characteristics, NH staffing and NH quality. Qualitative data, including semi-structured interviews and surveys of NH leaders conducted in the first quarter of 2011, were used to determine encounters with pharmaceutical marketing. RESULTS Leadership at 46.3% of NHs (19/41) reported pharmaceutical marketing encounters, consisting of educational training, written/Internet-based materials and/or sponsored training. No association was detected between the level of atypical antipsychotic prescribing and reports of any pharmaceutical marketing by at least one NH leader. CONCLUSION NH leaders frequently encounter pharmaceutical marketing through a variety of ways, although the impact on atypical antipsychotic prescribing is unclear. PMID:25688605

Effects of licence change on prescribing and poisons enquiries for antipsychotic agents in England and Scotland

PubMed Central

Bateman, D N; Good, A M; Afshari, R; Kelly, C A

2003-01-01

Aims To examine the effect of licence change for thioridazine at the end of 2000 on the prescription of antipsychotic drugs in England and Scotland, and investigate changes in poisons information inquiries and, for Edinburgh, poisons admissions. Methods Prescription data for antipsychotic drugs were obtained for England and Scotland and quarterly trends examined for 2000 and 2001. Accesses to the UK National Poisons Information Service website TOXBASE for antipsychotic products were examined for the same period. For Scotland telephone enquiry data, and admission data to the Edinburgh Poisons Unit were also evaluated. Trends in poisonings were compared with prescribing change. Results In England prescriptions for thioridazine fell rapidly in 2001 from approximately 35% of market share to less than 5%, and were replaced by risperidone, chlorpromazine and olanzapine. TOXBASE accesses fell from 39.3% of antipsychotics to 4.4%. Accesses for chlorpromazine, olanzapine and risperidone increased. In Scotland prescribing of thioridazine was similar to changes in England, but it was principally replaced by chlorpromazine. These changes were mirrored by TOXBASE accesses, telephone enquiries and in-patient admissions. The ratio of TOXBASE accesses for thioridazine to prescription numbers for the drug increased after the licence change. Conclusions Licence change produced rapid change in prescribing behaviour within 3 months. Prescribing behaviour in England and Scotland was different. Changes in prescribing were mirrored by changes in accesses for poisons information in both England and Scotland, and in Edinburgh by hospital admissions. The increase in the ratio of TOXBASE accesses to prescriptions for thioridazine suggests doctors may have become more aware of its potential toxicity. PMID:12814455

The Novel Antipsychotic Cariprazine (RGH-188): State-of-the-Art in the Treatment of Psychiatric Disorders.

PubMed

De Berardis, Domenico; Orsolini, Laura; Iasevoli, Felice; Prinzivalli, Emiliano; de Bartolomeis, Andrea; Serroni, Nicola; Mazza, Monica; Valchera, Alessandro; Fornaro, Michele; Vecchiotti, Roberta; Carano, Alessandro; Sepede, Gianna; Vellante, Federica; Matarazzo, Ilaria; Pompili, Maurizio; Perna, Giampaolo; Conti, Chiara; Segura-García, Cristina; Martinotti, Giovanni; Di Giannantonio, Massimo

2016-01-01

Cariprazine (RGH-188) is a novel antipsychotic drug that exerts partial agonism of dopamine D2/D3 receptors with preferential binding to D3 receptor, antagonism of 5HT2B receptors and partial agonism of 5HT1A. Currently, cariprazine is in late-stage clinical development (phase III clinical trials) in patients with schizophrenia (S) and in patients with bipolar disorder (BD), as well as an adjunctive treatment in patients with Major Depressive Disorder (MDD) and drug-resistant MDD. Cariprazine has completed phase III trials for the acute treatment of schizophrenia and bipolar mania, phase II trials for the bipolar depression and MDD whilst it is undergoing phase III trials as an adjunct to antidepressants. The present review aims at proving a comprehensive summary of the current evidence on the safety, tolerability and efficacy of cariprazine in the treatment of schizophrenia, BD (manic/mixed/ depressive episode) and MDD. A systematic search was conducted on PubMed/Medline/ Scopus and the database on Clinical Trials from inception until April 2015 by typing a set of specified keywords. Available evidence seems to support cariprazine efficacy in the treatment of cognitive and negative symptoms of schizophrenia. Preliminary findings suggest its antimanic activity whilst it is still under investigation its efficacy in the treatment of bipolar depression and MDD. Furthermore, the available data seems not to allow judgements about its antipsychotic potential in comparison with currently prescribed antipsychotics. Further studies should be carried out to better investigate its pharmacodynamic and clinical potential, particularly as alternative to current antipsychotic drugs.

Primary Care Physician Perspectives about Antipsychotics and Other Medications for Symptoms of Dementia.

PubMed

Kerns, J William; Winter, Jonathan D; Winter, Katherine M; Boyd, Terry; Etz, Rebecca S

2018-01-01

Guidelines, policies, and warnings have been applied to reduce the use of medications for behavioral and psychological symptoms of dementia (BPSD). Because of rare dangerous side effects, antipsychotics have been singled out in these efforts. However, antipsychotics are still prescribed "off label" to hundreds of thousands of seniors residing in nursing homes and communities. Our objective was to evaluate how and why primary-care physicians (PCPs) employ nonpharmacologic strategies and drugs for BPSD. Semi-structured interviews analyzed via template, immersion and crystallization, and thematic development of 26 PCPs (16 family practice, 10 general internal medicine) in full time primary-care practice for at least 3 years in Northwestern Virginia. PCPs described 4 major themes regarding BPSD management: (1) nonpharmacologic methods have substantial barriers; (2) medication use is not constrained by those barriers and is perceived as easy, efficacious, reasonably safe, and appropriate; (3) pharmacologic policies decrease the use of targeted medications, including antipsychotics, but also have unintended consequences such as increased use of alternative risky medications; and (4) PCPs need practical evidence-based guidelines for all aspects of BPSD management. PCPs continue to prescribe medications because they meet patient-oriented goals and because PCPs perceive drugs, including antipsychotics and their alternatives, to be more effective and less dangerous than evidence suggests. To optimally treat BPSD, PCPs need supportive verified prescribing guidelines and access to nonpharmacologic modalities that are as affordable, available, and efficacious as drugs; these require and deserve significant additional research and payer support. Community PCPs should be included in BPSD policy and guideline development. © Copyright 2018 by the American Board of Family Medicine.

Drug discovery based on genetic and metabolic findings in schizophrenia.

PubMed

Dwyer, Donard S; Weeks, Kathrine; Aamodt, Eric J

2008-11-01

Recent progress in the genetics of schizophrenia provides the rationale for re-evaluating causative factors and therapeutic strategies for this disease. Here, we review the major candidate susceptibility genes and relate the aberrant function of these genes to defective regulation of energy metabolism in the schizophrenic brain. Disturbances in energy metabolism potentially lead to neurodevelopmental deficits, impaired function of the mature nervous system and failure to maintain neurites/dendrites and synaptic connections. Current antipsychotic drugs do not specifically address these underlying deficits; therefore, a new generation of more effective medications is urgently needed. Novel targets for future drug discovery are identified in this review. The coordinated application of structure-based drug design, systems biology and research on model organisms may greatly facilitate the search for next-generation antipsychotic drugs.

Forecasting Medicaid Expenditures for Antipsychotic Medications.

PubMed

Slade, Eric P; Simoni-Wastila, Linda

2015-07-01

The ongoing transition from use of mostly branded to mostly generic second-generation antipsychotic medications could bring about a substantial reduction in Medicaid expenditures for antipsychotic medications, a change with critical implications for formulary restrictions on second-generation antipsychotics in Medicaid. This study provided a forecast of the impact of generics on Medicaid expenditures for antipsychotic medications. Quarterly (N=816) state-level aggregate data on outpatient antipsychotic prescriptions in Medicaid between 2008 and 2011 were drawn from the Medicaid state drug utilization database. Annual numbers of prescriptions, expenditures, and cost per prescription were constructed for each antipsychotic medication. Forecasts of antipsychotic expenditures in calendar years 2016 and 2019 were developed on the basis of the estimated percentage reduction in Medicaid expenditures for risperidone, the only second-generation antipsychotic available generically throughout the study period. Two models of savings from generic risperidone use were estimated, one based on constant risperidone prices and the other based on variable risperidone prices. The sensitivity of the expenditure forecast to expected changes in Medicaid enrollment was also examined. In the main model, annual Medicaid expenditures for antipsychotics were forecasted to decrease by $1,794 million (48.8%) by 2016 and by $2,814 million (76.5%) by 2019. Adjustment for variable prices of branded medications and changes in Medicaid enrollment only moderately affected the magnitude of these reductions. Within five years, antipsychotic expenditures in Medicaid may decline to less than half their current levels. Such a spending reduction warrants a reassessment of the continued necessity of formulary restrictions for second-generation antipsychotics in Medicaid.

In vivo occupancy of dopamine D2 receptors by antipsychotic drugs and novel compounds in the mouse striatum and olfactory tubercles.

PubMed

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.

Overcoming the Barriers Experienced in Conducting a Medication Trial in Adults with Aggressive Challenging Behaviour and Intellectual Disabilities

ERIC Educational Resources Information Center

Oliver-Africano, P.; Dickens, S.; Ahmed, Z.; Bouras, N.; Cooray, S.; Deb, S.; Knapp, M.; Hare, M.; Meade, M.; Reece, B.; Bhaumik, S.; Harley, D.; Piachaud, J.; Regan, A.; Ade Thomas, D.; Karatela, S.; Rao, B.; Dzendrowskyj, T.; Lenotre, L.; Watson, J.; Tyrer, P.

2010-01-01

Background: Aggressive challenging behaviour in people with intellectual disability (ID) is frequently treated with antipsychotic drugs, despite a limited evidence base. Method: A multi-centre randomised controlled trial was undertaken to investigate the efficacy, adverse effects and costs of two commonly prescribed antipsychotic drugs…

Impact of Atypical Antipsychotic Therapy on Leptin, Ghrelin, and Adiponectin

PubMed Central

Jin, Hua; Meyer, Jonathan M.; Mudaliar, Sunder; Jeste, Dilip V.

2009-01-01

Background Many adverse effects of atypical antipsychotic treatment are associated with antagonism of monoamine receptors; however, data indicate that important metabolic effects, such as hypertriglyceridemia and impairment in glucose/insulin homeostasis, may not be related to these mechanisms, leading investigators to explore alternative hypotheses. Promising candidates include a possible impact of antipsychotics on peptide hormonal regulators of metabolic control such as leptin, ghrelin, and adiponectin. The purpose of this review is to summarize recent data on changes in these hormones during atypical antipsychotic treatment. Methods A Medline search was performed for papers published from January 1999 to January 2007 using key words antipsychotic, atypical antipsychotic, and individual atypical antipsychotic drug names cross-referenced with leptin, ghrelin, and adiponectin. Results The bulk of the published work focused on changes in body weight and serum leptin, with far less data on ghrelin, and adiponectin, and non-weight metabolic changes. Leptin changes were directly related to a medication’s weight gain liability, with no added antipsychotic effects on leptin signaling. Conflicting results emerged for the other markers, but all three long-term studies on ghrelin showed increased levels in patients on atypical antipsychotics with weight gain liabilities. Conclusions Leptin increases during antipsychotic treatment are a result of weight gain rather than a direct impact of atypical antipsychotics on leptin physiology. Preliminary long-term data show increased ghrelin levels, but this finding must be replicated. The association with antipsychotic effects on glucose and lipid metabolism and these hormones remains virtually unstudied. Future research should indicate whether ghrelin and other peptide hormones may be useful predictors of weight gain or metabolic changes in patients on antipsychotics. PMID:18206351

[Prevention and Treatment of Common Acute Adverse Effects With Antipsychotic Use in Adults With Schizophrenia Diagnosis].

PubMed

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.

Systematic review of early cardiometabolic outcomes of the first treated episode of psychosis.

PubMed

Foley, Debra L; Morley, Katherine I

2011-06-01

The increased mortality associated with schizophrenia is largely due to cardiovascular disease. Treatment with antipsychotics is associated with weight gain and changes in other cardiovascular risk factors. Early identification of modifiable cardiovascular risk factors is a clinical imperative but prospective longitudinal studies of the early cardiometabolic adverse effects of antipsychotic drug treatment other than weight gain have not been previously reviewed. To assess the methods and reporting of cardiometabolic outcome studies of the first treated episode of psychosis, review key findings, and suggest directions for future research. PsycINFO, MEDLINE, and Scopus from January 1990 to June 2010. Subjects were experiencing their first treated episode of psychosis. Subjects were antipsychotic naive or had been exposed to antipsychotics for a short known period at the beginning of the study. Cardiometabolic indices were assessed. Studies used a longitudinal design. Sixty-four articles were identified describing 53 independent studies; 25 studies met inclusion criteria and were retained for detailed review. Consolidated Standards of Reporting Trials and Strengthening the Reporting of Observational Studies in Epidemiology checklists were used to assess the methods and reporting of studies. A qualitative review of findings was conducted. Two key hypotheses were identified based on this review: (1) in general, there is no difference in cardiovascular risk assessed by weight or metabolic indices between individuals with an untreated first episode of psychosis and healthy controls and (2) cardiovascular risk increases after first exposure to any antipsychotic drug. A rank order of drugs can be derived but there is no evidence of significant class differences. Recommended directions for future research include assessing the effect on cardiometabolic outcomes of medication adherence and dosage effects, determining the therapeutic window for antipsychotic use in adults and youth, and testing for moderation of outcomes by demographic factors, including sex and age, and clinical and genetic factors.

Differences in Antipsychotic-Related Adverse Events in Adult, Pediatric, and Geriatric Populations.

PubMed

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.

DISRUPTION OF CONDITIONED REWARD ASSOCIATION BY TYPICAL AND ATYPICAL ANTIPSYCHOTICS

PubMed Central

Danna, C.L.; Elmer, G.I.

2013-01-01

Antipsychotic drugs are broadly classified into typical and atypical compounds; they vary in their pharmacological profile however a common component is their antagonist effects at the D2 dopamine receptors (DRD2). Unfortunately, diminished DRD2 activation is generally thought to be associated with the severity of neuroleptic-induced anhedonia. The purpose of this study was to determine the effect of the atypical antipsychotic olanzapine and typical antipsychotic haloperidol in a paradigm that reflects the learned transfer of incentive motivational properties to previously neutral stimuli, namely autoshaping. In order to provide a dosing comparison to a therapeutically relevant endpoint, both drugs were tested against amphetamine-induced disruption of prepulse inhibition as well. In the autoshaping task, rats were exposed to repeated pairings of stimuli that were differentially predictive of reward delivery. Conditioned approach to the reward predictive cue (sign-tracking) and to the reward (goal-tracking) increased during repeated pairings in the vehicle treated rats. Haloperidol and olanzapine completely abolished this behavior at relatively low doses (100 μg/kg). This same dose was the threshold dose for each drug to antagonize the sensorimotor gating deficits produced by amphetamine. At lower doses (3–30 μg/kg) both drugs produced a dose-dependent decrease in conditioned approach to the reward predictive cue. There was no difference between drugs at this dose range which indicates that olanzapine disrupts autoshaping at a significantly lower proposed DRD2 receptor occupancy. Interestingly, neither drug disrupted conditioned approach to the reward at the same dose range that disrupted conditioned approach to the reward predictive cue. Thus, haloperidol and olanzapine, at doses well below what is considered therapeutically relevant, disrupts the attribution of incentive motivational value to previously neutral cues. Drug effects on this dimension of reward processing are an important consideration in the development of future pharmacological treatments for schizophrenia. PMID:20416333

Aripiprazole.

PubMed

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.

Drug attitude and subjective well-being in antipsychotic treatment monotherapy in real-world settings.

PubMed

Balestrieri, Matteo; Di Sciascio, Guido; Isola, Miriam; Lomonaco, Emanuele; Maso, Elisa; Merli, Roberto; Calò, Salvatore; Bellantuono, Cesario

2009-01-01

To assess using two well-know scales (DAI-30 and SWN) the drug attitude and subjective well-being of patients treated with haloperidol or second-generation antipsychotics (SGA) in four different Italian communities. The sample included 145 patients taking five different antipsychotics (APs) in mono-therapy: haloperidol, clozapine, olanzapine, risperidone, quetiapine. A stepwise multiple regression analysis (SMRA) was used to analyse the contribution of different AP treatments and of other predictors to SWN and DAI-30 scores. Univariate analyses showed no differences in DAI-30 and SWN scores across treatments. The SMRA showed that SWN scores were negatively correlated with the severity of the psychoses (BPRS scores), while the DAI-30 scores were negatively correlated with the severity of the psychoses and positively correlated both with the length of drug treatment and with the use of olanzapine. Our study does not confirm a better drug attitude in patients treated with SGA with respect to haloperidol. The only partial exception is the better performance of olanzapine over haloperidol on DAI-30, which could be due to the lower use of anticholinergic drugs during olanzapine treatment. The differences between the SWN and DAI-30 may give good reason for the use of both instruments during AP treatments.

Diagnoses associated with use of atypical antipsychotics in a commercial health plan: a claims database analysis.

PubMed

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.

Tics and other stereotyped movements as side effects of pharmacological treatment.

PubMed

Madruga-Garrido, Marcos; Mir, Pablo

2013-01-01

Tics and other stereotyped abnormal movements can be seen as adverse effects of some pharmacologic drugs. Among these drugs, antipsychotics may provoke tardive syndromes after a chronic exposure, primarily in the case of typical antipsychotics. These syndromes include tardive tics, tardive dyskinesia, or tardive akathisia, which present with tics or stereotyped movements as a clinical phenomenon. Psychostimulants (mainly methylphenidate) have traditionally been associated with the appearance of tics due to the increased dopamine activity caused by stimulants. Nevertheless, in recent years, several studies have concluded not only that methylphenidate does not exacerbate or reactivate tics but also that tics can improve with its use in patients with associated attention deficit and hyperactivity disorder and tic disorder. Antiepileptic drugs, although infrequently, can also induce tics, with carbamazepine and lamotrigine described as tic inducers. Other antiepileptics, including levetiracetam and topiramate, have been proposed as a potential treatment for tic disorders due to a positive effect on tics, especially in those with associated epileptic disorder. Clinical and therapeutic approaches to tics and stereotyped movements after exposure to antipsychotics, stimulants, and antiepileptic drugs will be reviewed in this chapter. © 2013 Elsevier Inc. All rights reserved.

The modern role of antipsychotics for the treatment of agitation and psychosis in Alzheimer's disease.

PubMed

Creese, Byron; Da Silva, Miguel Vasconcelos; Johar, Iskandar; Ballard, Clive

2018-05-21

Antipsychotics have long been the mainstay of treatment for agitation and psychosis in Alzheimer's disease. Despite their current use successive studies have shown that they only confer a modest benefit which must be balanced against their well-established serious side effects (extrapyramidal symptoms, stroke, accelerated cognitive decline and mortality). Areas covered: This review outlines the current guidance on antipsychotic usage and the evidence of their continued usage against a backdrop of emerging pharmacological treatments and an increasing emphasis on the importance of non-pharmacological interventions. Expert commentary: The current justification for antipsychotic use in the context of the changing landscape of prescribing and provide a view on the most promising alternative candidates to this class of drug are appraised.

Effectiveness and cost of atypical versus typical antipsychotic treatment for schizophrenia in routine care.

PubMed

Stargardt, Tom; Weinbrenner, Susanne; Busse, Reinhard; Juckel, Georg; Gericke, Christian A

2008-06-01

In two recent randomised clinical trials, a meta-analysis and in an effectiveness study analysing routine data from the U.S. Veterans Administration the superiority of the newer atypical drugs over typical antipsychotic drugs, concerning both their efficacy and their side-effect profile, has been questioned. To analyse the effectiveness and cost of atypical versus typical antipsychotic treatment for schizophrenia in routine care. Cohort study using routine care data from a statutory sickness fund with 5.4 million insured in Germany. To be included, patients had to be discharged with a diagnosis of schizophrenia in 2003 and fulfil membership criteria. Main outcome measures were rehospitalisation rates, mean hospital bed days, mean length of stay, cost of inpatient and pharmaceutical care to the sickness fund during follow-up and medication used to treat side-effects. 3121 patients were included into the study. There were no statistically significant differences in the effectiveness of atypical and typical antipsychotics on rehospitalisation during follow-up (rehospitalisation rate ratio 1.07, 95% confidence interval 0.86 to 1.33). However, there were consistent observations of atypical antipsychotics being more effective for severe cases of schizophrenia (14.6% of study population; >61 prior bed days per year in 2000-2002) in the follow-up period, whereas for the other severity strata typical antipsychotics seemed more effective in reducing various rehospitalisation outcomes. Patients treated with atypical antipsychotics received significantly less prescriptions for anticholinergics or tiaprid (relative risk 0.26, 95% confidence interval 0.18 to 0.38). The effectiveness of atypical antipsychotics for schizophrenia on rehospitalisation measures appeared similar to that of typical antipsychotics. With the exception of severe cases, the higher costs for atypical antipsychotics were not offset by savings from reduced inpatient care. Major limitations include the lack of statistical power for subgroup analyses, the lack of clinical severity scale data and of life-course medical history data which both increase the risk of residual confounding by disease severity. This study provides evidence that the effectiveness of atypical and typical antipsychotics measured in terms of hospital readmissions appears to be similar in routine care. From a clinical perspective, this study provides evidence that the effectiveness of atypical and typical antipsychotics measured in terms of hospital readmissions appears to be similar in routine care. Routine data studies can yield valuable information for policy decision-makers on the costs and the effectiveness of pharmaceuticals in routine care, complementing efficacy data from randomised clinical trials currently used for licensing and reimbursement decisions. The non-significant differences in the effectiveness of atypical compared to typical antipsychotics according to severity of disease should be investigated in a prospective observational study or in a randomised clinical trial.

Making the leap from daily oral dosing to long-acting injectables: lessons from the antipsychotics.

PubMed

Remenar, Julius F

2014-06-02

There are now long-acting versions of six antipsychotic drugs on the U.S. market, and with them, five unique combinations of molecular form and delivery strategy long-acting-injectable-antipsychotics (LAIAs) show evidence of reduced relapses of schizophrenia, but their introduction has been slow, taking at least nine years after the approval of each oral drug. Oily solutions of lipophilic prodrugs were the first to enter the LAIA market, but they relied on esterification of a hydroxyl handle that was lost with the emergence of the atypical antipsychotics. A review of the literature and patents shows that companies tested many different approaches before reaching the currently marketed versions, including aqueous suspensions of poorly soluble salts, polymeric microspheres, and new approaches to making prodrugs. Yet, very little has been published to support faster development of safe long-acting injectables (LAIs). This review introduces some of the critical considerations in creating an LAI; then it analyzes the existing products and discusses areas where further research is needed. The available literature suggests that lipophilic prodrugs may be inherently safer than poorly soluble salts as LAIs. Other areas needing additional study include (1) the range of physical properties acceptable for LAIs and the effect of prodrug tail length in achieving them, and (2) the role of physiological responses at the injection site in the release of drug from a depot.

Comparison of the effectiveness of brand-name and generic antipsychotic drugs for treating patients with schizophrenia in Taiwan.

PubMed

Hsu, Chih-Wei; Lee, Sheng-Yu; Wang, Liang-Jen

2018-03-01

The purpose of this nationwide population-based study is to compare the long-term effectiveness of brand-name antipsychotics with generic antipsychotics for treating schizophrenia. We identified patients with schizophrenia who were prescribed antipsychotics from a random sample of one million records from Taiwan's National Health Insurance database, observed between January 1, 2000 and December 31, 2012. Only those with no prior use of antipsychotics for at least 180days were included. We selected patients who were prescribed brand-name risperidone (N=404), generic risperidone (N=145), brand-name sulpiride (N=334), or generic sulpiride (N=991). The effectiveness of the treatments researched in this study consisted of average daily doses, rates of treatment discontinuation, augmentation therapy, and psychiatric hospitalization. We found that compared to patients treated with generic risperidone, those treated with brand-name risperidone required lower daily doses (2.14mg vs. 2.61mg). However, the two groups demonstrated similar rates of treatment discontinuation, augmentation, and psychiatric hospitalization. On the other hand, in comparison with patients prescribed generic sulpiride, those treated with brand-name sulpiride not only required lower daily doses (302.72mg vs. 340.71mg) but also had lower psychiatric admission rates (adjusted hazard ratio: 0.24, 95% confidence interval: 0.10-0.56). In conclusion, for both risperidone and sulpiride, higher daily doses of the respective generic drugs were prescribed than with brand-name drugs in clinical settings. Furthermore, the brand-name sulpiride is more effective at preventing patients from hospitalization than generic sulpiride. These findings can serve as an important reference for clinical practices and healthcare economics for treating schizophrenic patients. Copyright © 2017 Elsevier B.V. All rights reserved.

Nicotine Reduces Antipsychotic-Induced Orofacial Dyskinesia in Rats

PubMed Central

Bordia, Tanuja; McIntosh, J. Michael

2012-01-01

Antipsychotics are an important class of drugs for the management of schizophrenia and other psychotic disorders. They act by blocking dopamine receptors; however, because these receptors are present throughout the brain, prolonged antipsychotic use also leads to serious side effects. These include tardive dyskinesia, repetitive abnormal involuntary movements of the face and limbs for which there is little treatment. In this study, we investigated whether nicotine administration could reduce tardive dyskinesia because nicotine attenuates other drug-induced abnormal movements. We used a well established model of tardive dyskinesia in which rats injected with the commonly used antipsychotic haloperidol develop vacuous chewing movements (VCMs) that resemble human orofacial dyskinesias. Rats were first administered nicotine (minipump; 2 mg/kg per day). Two weeks later, they were given haloperidol (1 mg/kg s.c.) once daily. Nicotine treatment reduced haloperidol-induced VCMs by ∼20% after 5 weeks, with a significant ∼60% decline after 13 weeks. There was no worsening of haloperidol-induced catalepsy. To understand the molecular basis for this improvement, we measured the striatal dopamine transporter and nicotinic acetylcholine receptors (nAChRs). Both haloperidol and nicotine treatment decreased the transporter and α6β2* nAChRs (the asterisk indicates the possible presence of other nicotinic subunits in the receptor complex) when given alone, with no further decline with combined drug treatment. By contrast, nicotine alone increased, while haloperidol reduced α4β2* nAChRs in both vehicle and haloperidol-treated rats. These data suggest that molecular mechanisms other than those directly linked to the transporter and nAChRs underlie the nicotine-mediated improvement in haloperidol-induced VCMs in rats. The present results are the first to suggest that nicotine may be useful for improving the tardive dyskinesia associated with antipsychotic use. PMID:22144565

The optimization of treatment and management of schizophrenia in Europe (OPTiMiSE) trial: rationale for its methodology and a review of the effectiveness of switching antipsychotics.

PubMed

Leucht, Stefan; Winter-van Rossum, Inge; Heres, Stephan; Arango, Celso; Fleischhacker, W Wolfgang; Glenthøj, Birte; Leboyer, Marion; Leweke, F Markus; Lewis, Shôn; McGuire, Phillip; Meyer-Lindenberg, Andreas; Rujescu, Dan; Kapur, Shitij; Kahn, René S; Sommer, Iris E

2015-05-01

Most of the 13 542 trials contained in the Cochrane Schizophrenia Group's register just tested the general efficacy of pharmacological or psychosocial interventions. Studies on the subsequent treatment steps, which are essential to guide clinicians, are largely missing. This knowledge gap leaves important questions unanswered. For example, when a first antipsychotic failed, is switching to another drug effective? And when should we use clozapine? The aim of this article is to review the efficacy of switching antipsychotics in case of nonresponse. We also present the European Commission sponsored "Optimization of Treatment and Management of Schizophrenia in Europe" (OPTiMiSE) trial which aims to provide a treatment algorithm for patients with a first episode of schizophrenia. We searched Pubmed (October 29, 2014) for randomized controlled trials (RCTs) that examined switching the drug in nonresponders to another antipsychotic. We described important methodological choices of the OPTiMiSE trial. We found 10 RCTs on switching antipsychotic drugs. No trial was conclusive and none was concerned with first-episode schizophrenia. In OPTiMiSE, 500 first episode patients are treated with amisulpride for 4 weeks, followed by a 6-week double-blind RCT comparing continuation of amisulpride with switching to olanzapine and ultimately a 12-week clozapine treatment in nonremitters. A subsequent 1-year RCT validates psychosocial interventions to enhance adherence. Current literature fails to provide basic guidance for the pharmacological treatment of schizophrenia. The OPTiMiSE trial is expected to provide a basis for clinical guidelines to treat patients with a first episode of schizophrenia. © The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Manual or automated measuring of antipsychotics' chemical oxygen demand.

PubMed

Pereira, Sarah A P; Costa, Susana P F; Cunha, Edite; Passos, Marieta L C; Araújo, André R S T; Saraiva, M Lúcia M F S

2018-05-15

Antipsychotic (AP) drugs are becoming accumulated in terrestrial and aqueous resources due to their actual consumption. Thus, the search of methods for assessing the contamination load of these drugs is mandatory. The COD is a key parameter used for monitoring water quality upon the assessment of the effect of polluting agents on the oxygen level. Thus, the present work aims to assess the chemical oxygen demand (COD) levels of several typical and atypical antipsychotic drugs in order to obtain structure-activity relationships. It was implemented the titrimetric method with potassium dichromate as oxidant and a digestion step of 2h, followed by the measurement of remained unreduced dichromate by titration. After that, an automated sequential injection analysis (SIA) method was, also, used aiming to overcome some drawbacks of the titrimetric method. The results obtained showed a relationship between the chemical structures of antipsychotic drugs and their COD values, where the presence of aromatic rings and oxidable groups give higher COD values. It was obtained a good compliance between the results of the reference batch procedure and the SIA system, and the APs were clustered in two groups, with the values ratio between the methodologies, of 2 or 4, in the case of lower or higher COD values, respectively. The SIA methodology is capable of operating as a screening method, in any stage of a synthetic process, being also more environmentally friendly, and cost-effective. Besides, the studies presented open promising perspectives for the improvement of the effectiveness of pharmaceutical removal from the waste effluents, by assessing COD values. Copyright © 2018 Elsevier Inc. All rights reserved.

Protocol for a Systematic Review and Meta-Analysis of Lithium, Anticonvulsive or atypical antipsychotic Drugs for Treatment of Refractory Obsessive-Compulsive Disorder.

PubMed

Soleimani, R; Jalali, M M; Keshtkar, A; Jalali, S M

2017-01-01

Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder that causes significant distress to the afflicted individual. About half of OCD patients treated with an adequate trial of serotonin reuptake inhibitors fail to fully respond to treatment and continue to exhibit significant symptoms. Therefore, there is a need for other agents to alleviate the symptoms of these disorders. In spite of considerable research including numerous randomized controlled trials and systematic reviews, there exists uncertainty regarding what treatments are effective. In this systematic review, we evaluated the efficacy of mood stabilizers in treatment-refractory OCD. We conducted a meta-analysis of all randomized clinical trials evaluating lithium, anticonvulsive agents or atypical antipsychotic drugs for OCD to determine which therapies show more effective than a placebo, in reducing obsessive-compulsive symptoms. We acquired eligible studies through a systematic search of Cochrane Central Registry of Controlled Trials, MEDLINE, EMBASE, PsycINFO, Scopus, ProQuest and Google scholar. We conducted meta-analyses to establish the effect of lithium, anticonvulsive agents, or atypical antipsychotic drugs on patient-important outcomes when possible. To assess relative effects of treatments, we constructed a random effect model. Our review was the first to evaluate all treatments for OCD, to provide the relative effectiveness of lithium, anticonvulsive agents, or atypical antipsychotic drugs, and prioritize patient-important outcomes with a focus on functional gains. Our review facilitated the evidence-based management of patients with resistant OCD, and identified the key areas for future research.

Factors influencing acute weight change in patients with schizophrenia treated with olanzapine, haloperidol, or risperidone.

PubMed

Basson, B R; Kinon, B J; Taylor, C C; Szymanski, K A; Gilmore, J A; Tollefson, G D

2001-04-01

Clinical factors predicting weight change in patients with schizophrenia and related disorders during acute treatment with the antipsychotic drugs olanzapine, risperidone, and haloperidol were sought through retrospective analyses. Six-week body-weight data from 2 trials, study 1 comparing olanzapine and haloperidol (N = 1,369) and study 2 olanzapine and risperidone (N = 268), were analyzed. Effects of 8 clinically relevant covariates--therapy, clinical outcome (Brief Psychiatric Rating Scale), baseline body mass index (BBMI), increased appetite, age, gender, race, and dose--on weight were compared. In study 1, olanzapine (vs. haloperidol) therapy, better clinical outcome, lower BBMI, and nonwhite race significantly affected weight gain. Effects of increased appetite and male gender on weight gain were significant for olanzapine but not for haloperidol. In study 2, better clinical outcome, lower BBMI, and younger age significantly affected weight gain. Increased appetite was more frequent during olanzapine treatment than during haloperidol, but not significantly different from risperidone. Significant differences in effect on weight change were found between olanzapine and haloperidol but not between olanzapine and risperidone. No evidence was found that lower antipsychotic drug doses were associated with lower weight gain. This report identifies predictive factors of acute weight change in patients with schizophrenia. Similar factors across antipsychotic drugs in predicting greater weight gain included better clinical outcome, low BBMI, and nonwhite race. Factors differing between conventional (haloperidol) and atypical (olanzapine) agents included increased appetite and gender. Choice of atypical antipsychotic drug (olanzapine vs. risperidone) was of minor importance with regard to influence on acute weight gain.

Use of antipsychotics, benzodiazepine derivatives, and dementia medication among older people with intellectual disability and/or autism spectrum disorder and dementia.

PubMed

Axmon, Anna; Kristensson, Jimmie; Ahlström, Gerd; Midlöv, Patrik

2017-03-01

Although people with intellectual disability (ID) and people with dementia have high drug prescription rates, there is a lack of studies investigating drug use among those with concurrent diagnoses of ID and dementia. To investigate the use of antipsychotics, benzodiazepine derivatives, and drugs recommended for dementia treatment (anticholinesterases [AChEIs] and memantine) among people with ID and dementia. Having received support available for people with ID and/or autism spectrum disorder (ASD) was used as a proxy for ID. The ID cohort consisted of 7936 individuals, aged at least 55 years in 2012, and the referent cohort of age- and sex-matched people from the general population (gPop). People with a specialists' diagnosis of dementia during 2002-2012 were identified (ID, n=180; gPop, n=67), and data on prescription of the investigated drugs during the period 2006-2012 were collected. People with ID/ASD and dementia were more likely than people with ID/ASD but without dementia to be prescribed antipsychotics (50% vs 39% over the study period; odds ratio (OR) 1.85, 95% confidence interval 1.13-30.3) and benzodiazepine derivatives (55% vs 36%; OR 2.42, 1.48-3.98). They were also more likely than people with dementia from the general population to be prescribed antipsychotics (50% vs 25%; OR 3.18, 1.59-6.34), but less likely to be prescribed AChEIs (28% vs 45%; OR 0.32, 0.16-0.64). Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Double activity imaging reveals distinct cellular targets of haloperidol, clozapine and dopamine D(3) receptor selective RGH-1756.

PubMed

Kovács, K J; Csejtei, M; Laszlovszky, I

2001-03-01

Acute administration of typical (haloperidol) and atypical (clozapine) antipsychotics results in distinct and overlapping regions of immediate-early gene expression in the rat brain. RGH-1756 is a recently developed atypical antipsychotic with high affinity to dopamine D(3) receptors that results in a unique pattern of c-Fos induction. A single injection of either antipsychotic results in c-fos mRNA expression that peaks around 30 min after drug administration, while the maximum of c-Fos protein induction is seen 2 h after challenge. The transient and distinct temporal inducibility of c-fos mRNA and c-Fos protein was exploited to reveal and compare cellular targets of different antipsychotic drugs by concomitant localization of c-fos mRNA and c-Fos immunoreactivity in brain sections of rats that were timely challenged with two different antipsychotics. Double activity imaging revealed that haloperidol, clozapine and RGH-1756 share cellular targets in the nucleus accumbens, where 40% of all labeled neurons displayed both c-fos mRNA and c-Fos protein. Haloperidol activates cells in the caudate putamen, while clozapine-responsive, single labeled neurons were dominant in the prefrontal cortex and major island of Calleja. RGH-1756 targets haloperidol-sensitive cells in the caudate putamen, but cells that are activated by clozapine and RGH-1756 in the major island of Calleja are different.

Relation of serum molindone levels to serum prolactin levels and antipsychotic response.

PubMed

Pandurangi, A K; Narasimhachari, N; Blackard, W G; Landa, B S

1989-10-01

The antipsychotic drug molindone is considered to be atypical in its mode of action and to have mild side effects. Currently no data are available on the range of serum levels of this drug during treatment. By means of a high performance liquid chromatographic technique, serum molindone levels were measured in 14 psychotic patients receiving a wide range of doses of this drug. Molindone levels as high as 350 ng/mL were obtained and were not associated with any toxic effects. Significant relations were noted between the serum level of the drug and both serum prolactin level and treatment response. The authors suggest that molindone may have a range of serum levels consistent with therapeutic benefit. Serum molindone and prolactin levels might help assess resistance to molindone treatment.

Side effects as influencers of treatment outcome.

PubMed

Sharif, Zafar

2008-01-01

Research relative to the efficacy of a therapeutic agent commands a clinician's greatest interest, but treatment decisions are made based on optimizing efficacy and tolerability/safety considerations. Second-generation atypical antipsychotic drugs are a study in the importance of taking a careful look at the full benefit-risk profile of each drug. The disorders that atypical antipsychotics are approved to treat--schizophrenia, schizoaffective disorder, and bipolar disorder--are associated with an increased rate of certain medical comorbidities compared to the general population. Between-drug differences in efficacy are relatively modest for the atypicals, or between atypicals and conventionals, while differences in safety and tolerability are larger and more clinically relevant. The current article will provide a brief summary of safety-related issues that influence treatment outcome and choice of drug.

What is the role of sedating antidepressants, antipsychotics, and anticonvulsants in the management of insomnia?

PubMed

McCall, Catherine; McCall, W Vaughn

2012-10-01

Psychiatric medications such as antidepressants, antipsychotics, and anticonvulsants are commonly prescribed by physicians for the off-label use of improving sleep. Reasons for preferential prescription of these medications over FDA-approved insomnia drugs may include a desire to treat concurrent sleep problems and psychiatric illness with a single medication, and/or an attempt to avoid hypnotic drugs due to their publicized side effects. However, there have been few large studies demonstrating the efficacy and safety of most off-label medications prescribed to treat insomnia. In addition, many of these medications have significant known side effect profiles themselves. Here we review the pertinent research studies published in recent years on antidepressant, antipsychotic, and anticonvulsant medications frequently prescribed for sleep difficulties. Although there have been few large-scale studies for most of these medications, some may be appropriate in the treatment of sleep issues in specific well-defined populations.

Pharmacogenetics and outcome with antipsychotic drugs.

PubMed

Pouget, Jennie G; Shams, Tahireh A; Tiwari, Arun K; Müller, Daniel J

2014-12-01

Antipsychotic medications are the gold-standard treatment for schizophrenia, and are often prescribed for other mental conditions. However, the efficacy and side-effect profiles of these drugs are heterogeneous, with large interindividual variability. As a result, treatment selection remains a largely trial-and-error process, with many failed treatment regimens endured before finding a tolerable balance between symptom management and side effects. Much of the interindividual variability in response and side effects is due to genetic factors (heritability, h(2)~ 0.60-0.80). Pharmacogenetics is an emerging field that holds the potential to facilitate the selection of the best medication for a particular patient, based on his or her genetic information. In this review we discuss the most promising genetic markers of antipsychotic treatment outcomes, and present current translational research efforts that aim to bring these pharmacogenetic findings to the clinic in the near future.

Pharmacogenetics and outcome with antipsychotic drugs

PubMed Central

Pouget, Jennie G.; Shams, Tahireh A.; Tiwari, Arun K.; Müller, Daniel J.

2014-01-01

Antipsychotic medications are the gold-standard treatment for schizophrenia, and are often prescribed for other mental conditions. However, the efficacy and side-effect profiles of these drugs are heterogeneous, with large interindividual variability. As a result, treatment selection remains a largely trial-and-error process, with many failed treatment regimens endured before finding a tolerable balance between symptom management and side effects. Much of the interindividual variability in response and side effects is due to genetic factors (heritability, h2~ 0.60-0.80). Pharmacogenetics is an emerging field that holds the potential to facilitate the selection of the best medication for a particular patient, based on his or her genetic information. In this review we discuss the most promising genetic markers of antipsychotic treatment outcomes, and present current translational research efforts that aim to bring these pharmacogenetic findings to the clinic in the near future. PMID:25733959

Switching stable patients with schizophrenia from their oral antipsychotics to aripiprazole lauroxil: a post hoc safety analysis of the initial 12-week crossover period.

PubMed

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.

Sibutramine in the treatment of antipsychotic-induced weight gain: a pilot study in patients with schizophrenia.

PubMed

Biedermann, Falko; Fleischhacker, W Wolfgang; Kemmler, Georg; Ebenbichler, Christoph F; Lechleitner, Monika; Hofer, Alex

2014-05-01

Weight gain represents a frequent side effect of antipsychotic drug treatment. The current trial investigated the effect of add-on treatment with sibutramine in schizophrenia outpatients who had gained more than 7% of weight during the course of treatment. This 24-week placebo-controlled study evaluated the effects of sibutramine added to ongoing antipsychotic treatment. Weight, waist-hip ratio, BMI, blood pressure/pulse and ECG were monitored regularly. In addition, several laboratory tests were performed. Psychopathological symptoms and side effects were assessed frequently. Fifteen patients were assigned randomly to add-on treatment with sibutramine 10 mg or placebo. The two groups did not differ in weight, sociodemographic, or clinical data. Eleven patients were considered for statistical analysis. Significant weight loss was observed in the sibutramine group (mean = -6.1 kg), whereas patients on placebo experienced a mean weight gain of 1.9 kg. A reduction in HbA1c was apparent in the sibutramine but not in the placebo group. No significant between-group differences were found in changes in psychopathology or drug safety. This pilot trial suggests that adjunctive treatment with sibutramine may be safe and effective in schizophrenic patients with antipsychotic-induced weight gain.

Sexual dysfunction with antihypertensive and antipsychotic agents.

PubMed

Smith, P J; Talbert, R L

1986-05-01

The physiology of the normal sexual response, epidemiology of sexual dysfunction, and the pharmacologic mechanisms involved in antihypertensive- and antipsychotic-induced problems with sexual function are discussed, with recommendations for patient management. The physiologic mechanisms involved in the normal sexual response include neurogenic, psychogenic, vascular, and hormonal factors that are coordinated by centers in the hypothalamus, limbic system, and cerebral cortex. Sexual dysfunction is frequently attributed to antihypertensive and antipsychotic agents and is a cause of noncompliance. Drug-induced effects include diminished libido, delayed orgasm, ejaculatory disturbances, gynecomastia, impotence, and priapism. The pharmacologic mechanisms proposed to account for these adverse effects include adrenergic inhibition, adrenergic-receptor blockade, anticholinergic properties, and endocrine and sedative effects. The most frequently reported adverse effect on sexual function with the antihypertensive agents is impotence. It is seen most often with methyldopa, guanethidine, clonidine, and propranolol. In contrast, the most common adverse effect on sexual function with the antipsychotic agents involves ejaculatory disturbances. Thioridazine, with its potent anticholinergic and alpha-blocking properties, is cited most often. Drug-induced sexual dysfunction may be alleviated by switching to agents with dissimilar mechanisms to alter the observed adverse effect while maintaining adequate control of the patient's disease state.

Rising Trend of Use of Antidepressants Induced Non- Puerperal Lactation: A Case Report.

PubMed

Kukreti, Prerna; Ali, Wazid; Jiloha, R C

2016-06-01

Non puerperal lactation or galactorrhea is a well known side effect of antipsychotic drugs but has been infrequently described with the use of antidepressants. In past few decades, there have been emerging trend of isolated case reports of selective serotonin reuptake inhibitors induced non puerperal lactation. We report a case of non puerperal lactation following usage of second generation tricyclic antidepressant, nortriptyline and resolution on withdrawing the drug. Literature review has been done for antidepressant induced galactorrhea to understand the current trends, putative mechanism as different from one implicated for antipsychotics and its clinical utility.

Inflammation and psychotropic drugs: the relationship between C-reactive protein and antipsychotic drug levels.

PubMed

Hefner, Gudrun; Shams, Mohamed E E; Unterecker, Stefan; Falter, Tanja; Hiemke, Christoph

2016-05-01

In psychiatric clinical practice, there is a need to identify psychotropic drugs whose metabolisms are prone to be altered with increased inflammatory activity in an individual patient. The aim of this study was to find out whether elevated serum levels (≥5 mg/l) of C-reactive protein (CRP), an established laboratory marker of infection and inflammation, are associated with increased serum concentrations of the atypical antipsychotic drugs clozapine, quetiapine, and risperidone. Therapeutic drug monitoring request forms of patients whose antipsychotic drug concentrations had been measured under conditions of normal (<5 mg/l) and pathological (>5 mg/l) levels of C-reactive protein were retrospectively screened. The serum concentrations in relation to the daily doses [concentration per dose (C/D) (ng/mL/mg)] and the metabolic ratios [ratio of concentrations (metabolite/drug)] were compared intraindividually by the Wilcoxon signed rank test. To the study effects of the intensity of infections on drug concentrations, C-reactive protein and C/D levels were submitted to Spearman's correlation analysis. Elevated levels of C-reactive protein were found in 105 patients. They were significantly associated with elevated values in C/D for clozapine (n = 33, P < 0.01) and risperidone (n = 40, P < 0.01). A trend for an increase was found for quetiapine (n = 32, P = 0.05). Median increases were 48.0 % (clozapine), 11.9 % (quetiapine), and 24.2 % (active moiety of risperidone), respectively. In patients who exhibit signs of inflammation or infection with increased C-reactive protein values during psychopharmacological treatment, especially under clozapine and risperidone, therapeutic drug monitoring is recommendable in order to minimize the risk of intoxications due to elevated drug concentrations.

Central nervous system drug consumption depending on the time between symptom onset and the diagnosis of Alzheimer's disease: an analysis by the Registry of Dementias of Girona.

PubMed

Calvó-Perxas, Laia; López-Pousa, Secundino; Vilalta-Franch, Joan; Turró-Garriga, Oriol; Blankenburg, Michael; Febrer, Laia; Flaqué, Margarida; Vallmajó, Natàlia; Aguirregomozcorta, Maria; Genís, David; Casas, Isabel; Perkal, Héctor; Coromina, Joan; Garre-Olmo, Josep

2012-01-01

To describe central nervous system (CNS) drug consumption patterns depending on the time to diagnosis of Alzheimer's disease (AD), and to check whether the cases diagnosed later are associated with greater severity and consuming more CNS drugs. Cross-sectional study using 952 cases of the Registry of Dementias of Girona. A binary logistic regression was used to detect variables associated with the use of CNS drugs depending on the time to diagnosis. CNS drugs were consumed by 95.8% of the AD patients. Only antipsychotics presented a statistically significant increase in the frequency of prescription to patients with longer time elapsed from symptom onset to AD diagnosis. Longer time elapsed from the onset of symptoms to the diagnosis resulted in increased probability of antipsychotic consumption. Copyright © 2012 S. Karger AG, Basel.

Switching and augmentation strategies for antipsychotic medications in acute-phase schizophrenia: latest evidence and place in therapy

PubMed Central

Hatta, Kotaro; Sugiyama, Naoya; Ito, Hiroto

2018-01-01

In terms of effectiveness of antipsychotics in schizophrenia, discrepancy often exists between results from double-blind randomized controlled trials and observations in emergency or acute-phase clinical practice. For instance, the antipsychotic switching strategy is not always applicable in emergency or acute-phase situations, and augmentation of another antipsychotic is occasionally done instead. In this review, we discuss strategies for early nonresponse to an antipsychotic drug such as switching and augmentation from the perspective of emergency and acute-phase treatment. We searched PubMed for the latest evidence on switching and augmentation strategies of antipsychotics for an emergency or acute-phase period. For risperidone and olanzapine, there is some evidence on switching and augmentation strategies in the management of acute-phase schizophrenia. There may be responders to olanzapine alone among early nonresponders to risperidone, whereas there may be few responders to risperidone alone among early nonresponders to olanzapine. However, there is still insufficient evidence at this time for application of these findings to routine clinical practice. For other antipsychotics, there is little evidence for their augmentation in acute-phase practice. We should be wary of polypharmacy, as multiple agents are too often prescribed by clinicians when not warranted. Considering current evidence, we propose how to switch antipsychotics in the acute phase of schizophrenia in routine practice. PMID:29854396

Cannabidiol as a Potential New Type of an Antipsychotic. A Critical Review of the Evidence.

PubMed

Rohleder, Cathrin; Müller, Juliane K; Lange, Bettina; Leweke, F M

2016-01-01

There is urgent need for the development of mechanistically different and less side-effect prone antipsychotic compounds. The endocannabinoid system has been suggested to represent a potential new target in this indication. While the chronic use of cannabis itself has been considered a risk factor contributing to the development of schizophrenia, triggered by the phytocannabinoid delta-9-tetrahydrocannabinol (Δ 9 -THC), cannabidiol, the second most important phytocannabinoid, appears to have no psychotomimetic potential. Although, results from animal studies are inconsistent to a certain extent and seem to depend on behavioral paradigms, treatment duration and experimental conditions applied, cannabidiol has shown antipsychotic properties in both rodents and rhesus monkeys. After some individual treatment attempts, the first randomized, double-blind controlled clinical trial demonstrated that in acute schizophrenia cannabidiol exerts antipsychotic properties comparable to the antipsychotic drug amisulpride while being accompanied by a superior, placebo-like side effect profile. As the clinical improvement by cannabidiol was significantly associated with elevated anandamide levels, it appears likely that its antipsychotic action is based on mechanisms associated with increased anandamide concentrations. Although, a plethora of mechanisms of action has been suggested, their potential relevance for the antipsychotic effects of cannabidiol still needs to be investigated. The clarification of these mechanisms as well as the establishment of cannabidiol's antipsychotic efficacy and its hopefully benign side-effect profile remains the subject of a number of previously started clinical trials.

Pharmacogenetics of schizophrenia.

PubMed

Reynolds, Gavin P; Templeman, Lucy A; Godlewska, Beata R

2006-08-01

There is substantial unexplained interindividual variability in the drug treatment of schizophrenia. A substantial proportion of patients respond inadequately to antipsychotic drugs, and many experience limiting side effects. As genetic factors are likely to contribute to this variability, the pharmacogenetics of schizophrenia has attracted substantial effort. The approaches have mainly been limited to association studies of polymorphisms in candidate genes, which have been indicated by the pharmacology of antipsychotic drugs. Although some advances have been made, particularly in understanding the pharmacogenetics of some limiting side effects, genetic prediction of symptom response remains elusive. Nevertheless, with improvements in defining the response phenotype in carefully assessed and homogeneous subject groups, the near future is likely to see the identification of genetic predictors of outcome that may inform the choice of pharmacotherapy.

Antipsychotic-like vs cataleptogenic actions in mice of novel antipsychotics having D2 antagonist and 5-HT1A agonist properties.

PubMed

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.

Review and analysis of hospitalization costs associated with antipsychotic nonadherence in the treatment of schizophrenia in the United States.

PubMed

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.

Opioids, antiepileptic and anticholinergic drugs and the risk of fractures in patients 65 years of age and older: a prospective population-based study.

PubMed

Nurminen, Janne; Puustinen, Juha; Piirtola, Maarit; Vahlberg, Tero; Lyles, Alan; Kivelä, Sirkka-Liisa

2013-05-01

in men, the concomitant use of two or more benzodiazepines or two or more antipsychotics is associated with an increased risk of fracture(s). Potential associations between the concomitant use of drugs with central nervous system effects and fracture risk have not been studied. the purpose was to describe the gender-specific risk of fractures in a population aged 65 years or over associated with the use of an opioid, antiepileptic or anticholinergic drug individually; or, their concomitant use with each other; or the concomitant use of one of these with a psychotropic drug. this study was part of a prospective, population-based study performed in Lieto, Finland. Information about fractures in 1,177 subjects (482 men and 695 women) was confirmed with radiology reports. at 3 years of follow-up, the concomitant use of an opioid with an antipsychotic was associated with an increased risk of fractures in men. During the 6-year follow-up, the concomitant use of an opioid with a benzodiazepine was also related to the risk of fractures for males. No significant associations were found for females. the concomitant use of an opioid with an antipsychotic, or with a benzodiazepine may increase the risk of fractures in men aged 65 years and older.

Antipsychotics and physical attractiveness.

PubMed

Seeman, Mary V

2011-10-01

Antipsychotics are effective in treating the symptoms of schizophrenia, but they may induce adverse effects, some of which-those that impact negatively on physical appearance-have not been sufficiently discussed in the psychiatric literature. Through a narrative review, to catalog antipsychotic side effects that interfere with physical attractiveness and to suggest ways of addressing them. PubMed databases were searched for information on the association between "antipsychotic side effects" and "attractiveness" using those two search phrases plus the following terms: "weight," "teeth," "skin," "hair," "eyes," "gait," "voice," "odor." Data from relevant qualitative and quantitative articles were considered, contextualized, and summarized. Antipsychotics, as a group, increase weight and may lead to dry mouth and bad breath, cataracts, hirsutism, acne, and voice changes; they may disturb symmetry of gait and heighten the risk for tics and spasms and incontinence, potentially undermining a person's attractiveness. Clinicians need to be aware of the impact of therapeutic drugs on appearance and how important this issue is to patients. Early in treatment, they need to plan preventive and therapeutic strategies.

Benefits and limits of anticholinergic use in schizophrenia: focusing on its effect on cognitive function.

PubMed

Ogino, Shin; Miyamoto, Seiya; Miyake, Nobumi; Yamaguchi, Noboru

2014-01-01

All currently available antipsychotic drugs are the dopamine D2 receptor antagonists and are capable of producing extrapyramidal side-effects (EPS). Anticholinergic drugs are primarily used to treat EPS or prevent EPS induced by antipsychotics in the treatment of psychosis and schizophrenia. However, they can cause a variety of distressing peripheral side-effects (e.g. dry mouth, urinary disturbances, and constipation) and central adverse effects (e.g. cognitive impairment, worsening of tardive dyskinesia, and delirium). Disturbances in cognitive abilities are cardinal features of schizophrenia from its earliest phases and account for much of the functional disability associated with the illness. It is likely that long-term concomitant administration of anticholinergics exacerbates the underlying cognitive impairment in patients with schizophrenia and subsequently affects patients' quality of life. Thus, current treatment guidelines for schizophrenia generally do not recommend the prophylactic and long-term use of anticholinergics. However, the high use of long-term anticholinergic drugs with antipsychotics has been identified as an important issue in the treatment of schizophrenia in several countries. To assess the benefits and limits of anticholinergic use in psychosis and schizophrenia, this article will provide a brief review of the pharmacology and clinical profiles of anticholinergic drugs and will focus on their effects on cognitive function in schizophrenia, particularly during the course of the early phase of the illness. In addition, we will address the effects of discontinuation of anticholinergics on cognitive function in patients with schizophrenia and provide a strategy for adjunctive anticholinergic use in patients treated with long-acting injectable antipsychotics. © 2013 The Authors. Psychiatry and Clinical Neurosciences © 2013 Japanese Society of Psychiatry and Neurology.

The natural hallucinogen 5-MeO-DMT, component of Ayahuasca, disrupts cortical function in rats: reversal by antipsychotic drugs.

PubMed

Riga, Maurizio S; Soria, Guadalupe; Tudela, Raúl; Artigas, Francesc; Celada, Pau

2014-08-01

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a natural hallucinogen component of Ayahuasca, an Amazonian beverage traditionally used for ritual, religious and healing purposes that is being increasingly used for recreational purposes in US and Europe. 5MeO-DMT is of potential interest for schizophrenia research owing to its hallucinogenic properties. Two other psychotomimetic agents, phencyclidine and 2,5-dimethoxy-4-iodo-phenylisopropylamine (DOI), markedly disrupt neuronal activity and reduce the power of low frequency cortical oscillations (<4 Hz, LFCO) in rodent medial prefrontal cortex (mPFC). Here we examined the effect of 5-MeO-DMT on cortical function and its potential reversal by antipsychotic drugs. Moreover, regional brain activity was assessed by blood-oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI). 5-MeO-DMT disrupted mPFC activity, increasing and decreasing the discharge of 51 and 35% of the recorded pyramidal neurons, and reducing (-31%) the power of LFCO. The latter effect depended on 5-HT1A and 5-HT2A receptor activation and was reversed by haloperidol, clozapine, risperidone, and the mGlu2/3 agonist LY379268. Likewise, 5-MeO-DMT decreased BOLD responses in visual cortex (V1) and mPFC. The disruption of cortical activity induced by 5-MeO-DMT resembles that produced by phencyclidine and DOI. This, together with the reversal by antipsychotic drugs, suggests that the observed cortical alterations are related to the psychotomimetic action of 5-MeO-DMT. Overall, the present model may help to understand the neurobiological basis of hallucinations and to identify new targets in antipsychotic drug development.

The hallucinogen DOI reduces low-frequency oscillations in rat prefrontal cortex: reversal by antipsychotic drugs.

PubMed

Celada, Pau; Puig, M Victoria; Díaz-Mataix, Llorenç; Artigas, Francesc

2008-09-01

Perceptual and psychic alterations and thought disorder are fundamental elements of schizophrenia symptoms, a pathology associated with an abnormal macro- and microcircuitry of several brain areas including the prefrontal cortex (PFC). Alterations in information processing in PFC may partly underlie schizophrenia symptoms. The 5-HT(2A/2C) agonist DOI and antipsychotic drugs were administered to anesthetized rats. Single unit and local field potential (LFP) extracellular recordings were made in medial PFC (mPFC). Electrolytic lesions were performed in the thalamic nuclei. DOI markedly disrupts cellular and network activity in rat PFC. DOI altered pyramidal discharge in mPFC (39% excited, 27% inhibited, 34% unaffected; n = 51). In all instances, DOI concurrently reduced low-frequency oscillations (.3-4 Hz; power spectrum: .25 +/- .02 and .14 +/- .01 microV(2) in basal conditions and after 50-300 microg/kg intravenous (i.v.) DOI, respectively; n = 51). Moreover, DOI disrupted the temporal association between the active phase of LFP and pyramidal discharge. Both effects were reversed by M100907 (5-HT(2A) receptor antagonist) and were not attenuated by thalamic lesions, supporting an intracortical origin of the effects of DOI. The reduction in low-frequency oscillations induced by DOI was significantly reversed by the antipsychotic drugs haloperidol (.1-.2 mg/kg i.v.) and clozapine (1 mg/kg i.v.). DOI disorganizes network activity in PFC, reducing low-frequency oscillations and desynchronizing pyramidal discharge from active phases of LFP. These effects may underlie DOI's psychotomimetic action. The reversal by clozapine and haloperidol indicates that antipsychotic drugs may reduce psychotic symptoms by normalizing an altered PFC function.

Identification of Candidate Single-Nucleotide Polymorphisms in NRXN1 Related to Antipsychotic Treatment Response in Patients with Schizophrenia

PubMed Central

Jenkins, Aaron; Apud, José A; Zhang, Fengyu; Decot, Heather; Weinberger, Daniel R; Law, Amanda J

2014-01-01

Neurexins are presynaptic neuronal adhesion molecules that interact with postsynaptic neuroligins to form an inter-synaptic complex required for synaptic specification and efficient neurotransmission. Deletions and point mutations in the neurexin 1 (NRXN1) gene are associated with a broad spectrum of neuropsychiatric and neurodevelopmental disorders, including autism, intellectual disability, epilepsy, developmental delay, and schizophrenia. Recently, small nucleotide polymorphisms in NRXN1 have been associated with antipsychotic drug response in patients with schizophrenia. Based on previous suggestive evidence of an impact on clozapine response in patients with schizophrenia, we conducted an association study of NRXN1 polymorphisms (rs12467557 and rs10490162) with antipsychotic treatment response in 54 patients with schizophrenia in a double blind, placebo-controlled NIMH inpatient crossover trial and examined for association with risk for schizophrenia in independent case-control and family-based clinical cohorts. Pharmacogenetic analysis in the placebo controlled trial revealed significant association of rs12467557and rs10490162 with drug response, whereby individuals homozygous for the A allele, at either SNP, showed significant improvement in positive symptoms, general psychopathology, thought disturbance, and negative symptoms, whereas patients carrying the G allele showed no overall response. Although we did not find evidence of the same NRXN1 SNPs being associated with results of the NIMH sponsored CATIE trial, other SNPs showed weakly positive signals. The family and case-control analyses for schizophrenia risk were negative. Our results provide confirmatory evidence of genetically determined differences in drug response in patients with schizophrenia related to NRXN1 variation. Furthermore, these findings potentially implicate NRXN1 in the therapeutic actions of antipsychotic drugs. PMID:24633560

Blonanserin extensively occupies rat dopamine D3 receptors at antipsychotic dose range.

PubMed

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.

Akathisia: prevalence and risk factors in a community-dwelling sample of patients with schizophrenia. Results from the FACE-SZ dataset.

PubMed

Berna, F; Misdrahi, D; Boyer, L; Aouizerate, B; Brunel, L; Capdevielle, D; Chereau, I; Danion, J M; Dorey, J M; Dubertret, C; Dubreucq, J; Faget, C; Gabayet, F; Lancon, C; Mallet, J; Rey, R; Passerieux, C; Schandrin, A; Schurhoff, F; Tronche, A M; Urbach, M; Vidailhet, P; Llorca, P M; Fond, G

2015-12-01

The main objective of this study was to determine the prevalence of akathisia in a community-dwelling sample of patients with schizophrenia, and to determine the effects of treatments and the clinical variables associated with akathisia. 372 patients with schizophrenia or schizoaffective disorder were systematically included in the network of FondaMental Expert Center for Schizophrenia and assessed with validated scales. Akathisia was measured with the Barnes Akathisia Scale (BAS). Ongoing psychotropic treatment was recorded. The global prevalence of akathisia (as defined by a score of 2 or more on the global akathisia subscale of the BAS) in our sample was 18.5%. Patients who received antipsychotic polytherapy were at higher risk of akathisia and this result remained significant (adjusted odd ratio=2.04, p=.025) after controlling the influence of age, gender, level of education, level of psychotic symptoms, substance use comorbidities, current administration of antidepressant, anticholinergic drugs, benzodiazepines, and daily-administered antipsychotic dose. The combination of second-generation antipsychotics was associated with a 3-fold risk of akathisia compared to second-generation antipsychotics used in monotherapy. Our results indicate that antipsychotic polytherapy should be at best avoided and suggest that monotherapy should be recommended in cases of akathisia. Long-term administration of benzodiazepines or anticholinergic drugs does not seem to be advisable in cases of akathisia, given the potential side effects of these medications. Copyright © 2015 Elsevier B.V. All rights reserved.

Long-term efficacy and tolerability of quetiapine in patients with schizophrenia who switched from other antipsychotics because of inadequate therapeutic response-a prospective open-label study.

PubMed

Hashimoto, Naoki; Toyomaki, Atsuhito; Honda, Minoru; Miyano, Satoru; Nitta, Nobuyuki; Sawayama, Hiroyuki; Sugawara, Yasufumi; Uemura, Keiichi; Tsukamoto, Noriko; Koyama, Tsukasa; Kusumi, Ichiro

2015-01-01

While the frequency and importance of antipsychotic switching in patients with schizophrenia, there is insufficient evidence with regard to switching strategy. Quetiapine is one of the drugs of choice for switch because of its unique receptor profile. However, there were no data on the long-term clinical and neurocognitive effect of quetiapine in patients who had responded inadequately to prior antipsychotics. The purpose of this study is to examine the long-term efficacy and tolerability of quetiapine in patients with schizophrenia who switched from other antipsychotics because of inadequate therapeutic response. We hypothesized that quetiapine would show long-term effectiveness in broad symptom dimensions including negative and neurocognitive symptoms while having good tolerability. Twenty-nine subjects with schizophrenia who did not respond to their current monotherapy of antipsychotic or who could not tolerate the treatment were switched to quetiapine and assessed at baseline and at 3, 6, and 12 months. The outcome measures included the brief assessment of cognition in schizophrenia (BACS), the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impressions Scale (CGI), the Schizophrenia Quality of Life Scale Japanese version (JSQLS), the Athens Insomnia Scale (AIS), and the Drug Attitude Inventory with 30 items (DAI-30). The Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS), HbA1c, prolactin (PRL), and body weight were also evaluated. Statistically significant improvements were observed in all subscores of the PANSS, the GAF, and the symptoms and side effects subscale of the JSQLS, the DIEPSS, the AIS, and the PRL level, and nearly significant improvements were observed in the DAI-30. Quetiapine monotherapy was associated with significant improvement in the verbal memory test, even after controlling for the practice effect. Although quetiapine was well tolerated, three subjects dropped out because of the worsening of the psychotic symptoms and two additional subjects dropped out because of somnolence. In this open-label, single-arm study of 29 patients, quetiapine improved both the clinical symptoms and the neurocognitive impairment in chronic schizophrenia patients who failed to respond to prior antipsychotic treatment.

Association of antidepressant and atypical antipsychotic use with cardiovascular events and mortality in a veteran population.

PubMed

Acharya, Tushar; Acharya, Sabeena; Tringali, Steven; Huang, Jian

2013-10-01

To determine the patterns of antidepressant and atypical antipsychotic use in a veteran population with depression, and to determine if an association exists between specific antidepressant classes and atypical antipsychotics and the occurrence of cardiovascular events and all-cause mortality. Retrospective, cross-sectional study. Primary care clinic at a Veterans Affairs hospital. A total of 1136 patients diagnosed with depression who were receiving antidepressant monotherapy (664 patients) or no antidepressant therapy (472 patients [controls]) between June 2009 and December 2010. Data on patient demographics, disease diagnoses, laboratory data, and drug therapy profiles were collected through medical record review. Of the 1136 patients, the mean patient age was 61 years, 90% were men, and 77% were smokers. Mean body mass index was 30.4 kg/m(2) , blood pressure 126/73 mm Hg, hemoglobin A1c 6%, low-density lipoprotein cholesterol level 106.7 mg/dl, and Framingham score 17. Patients receiving antidepressant monotherapy were grouped according to antidepressant class; selective serotonin reuptake inhibitors (SSRIs) were most common. Concomitant use of atypical antipsychotics was more common with the serotonin-norepinephrine reuptake inhibitor (venlafaxine), SSRI, and serotonin receptor antagonist (trazodone) classes (p=0.0067). After adjusting for demographics, concomitant drugs, and comorbidities, SSRI use was significantly associated with lower all-cause mortality (odds ratio [OR] 0.37, 95% confidence interval [CI] 0.19-0.71, p=0.0028). Notably, noradrenergic and specific serotonergic antidepressant (mirtazapine) use was significantly associated with higher prevalence of heart failure (OR 3.26, 95% CI 1.029-10.38, p=0.0445). Use of atypical antipsychotics was significantly associated with a higher prevalence of cerebrovascular events (OR 2.23, 95% CI 1.29-3.83, p=0.0036) and all-cause mortality (OR 2.05, 95% CI 1.03-4.1, p=0.04). Our results favor treatment of depression with SSRIs among patients at increased cardiovascular risk due to the potential mortality benefit of this class of drugs. Atypical antipsychotics should be used with caution in the elderly population. Mirtazapine use in patients with heart failure and depression deserves further investigation. © 2013 Pharmacotherapy Publications, Inc.

Early Exposure to Haloperidol or Olanzapine Induces Long-Term Alterations of Dendritic Form

PubMed Central

Frost, Douglas O.; Page, Stephanie Cerceo; Carroll, Cathy; Kolb, Bryan

2009-01-01

Exposure of the developing brain to a wide variety of drugs of abuse (eg., stimulants, opioids, ethanol, etc.) can induce life-long changes in behavior and neural circuitry. However, the long-term effects of exposure to therapeutic, psychotropic drugs have only recently begun to be appreciated. Antipsychotic drugs are little studied in this regard. Here we quantitatively analyzed dendritic architecture in adult mice treated with paradigmatic typical- (haloperidol) or atypical (olanzapine) antipsychotic drugs at developmental stages corresponding to fetal or fetal plus early childhood stages in humans. In layer 3 pyramidal cells of the medial and orbital prefrontal cortices and the parietal cortex and in spiny neurons of the core of the nucleus accumbens, both drugs induced significant changes (predominantly reductions) in the amount and complexity of dendritic arbor and the density of dendritic spines. The drug-induced plasticity of dendritic architecture suggests changes in patterns of neuronal connectivity in multiple brain regions that are likely to be functionally significant. PMID:19862684

Cerebrovascular accidents in elderly people treated with antipsychotic drugs: a systematic review.

PubMed

Sacchetti, Emilio; Turrina, Cesare; Valsecchi, Paolo

2010-04-01

After 2002, an association between stroke and antipsychotic use was reported in clinical trials and large database studies. This review considers previous quantitative reviews, newly published clinical trials, and recent observational cohort and case-control studies, and focuses on the clinical significance of the risk for stroke, the difference between typical and atypical antipsychotics, the possible at-risk patient profile and the timing of stroke after exposure. A search of MEDLINE covering the period from 1966 to June 2009 was carried out using selected keywords. Inclusion criteria were (i) quantitative reviews on stroke and antipsychotics; (ii) double-blind, placebo-controlled clinical trials involving patients with dementia treated with antipsychotics; and (iii) observational database cohort studies and observational case-control studies investigating the association between stroke and antipsychotics. Clinical trials were excluded if they were single-blind or if patients were affected by dementia and/or other neurological illnesses. Four reviews with aggregate data, 2 meta-analyses, 13 randomized, double-blind, controlled trials, 7 observational cohort studies and 4 observational case-control studies were selected and analysed. The incidence of cerebrovascular accidents (CVAs) was found to be very low in aggregate reviews and meta-analyses (2-4%). When the number collected was sufficiently high, or different drug treatments were grouped together, the higher rate in subjects exposed to antipsychotics was statistically significant. Inspection of other randomized controlled clinical trials, not included in aggregate reviews and meta-analyses, reported similar rates of CVAs. The majority of observational cohort studies compared typical and atypical antipsychotics and no significant class differences were found. A comparison with non-users was carried out in some cohort studies. In case-control studies, the probability of CVAs in users compared with non-users was in the range of 1.3- to 2-fold greater. Preliminary data also indicate that the highest risk of stroke is related to the first weeks of treatment, and a risk profile for stroke is emerging, such as older age, cognitive impairment and vascular illness. Different pathophysiological pathways may be involved, ranging from the facilitation of thrombosis, pre-existing cardiovascular factors, sedation and a common diathesis for stroke of dementia, schizophrenia and affective illness. Before prescribing an antipsychotic, clinicians should weigh all the risk factors for a given patient and consider not only the indications as provided by the regulatory agencies, but also the overall effectiveness of typical and atypical antipsychotics.

Blonanserin treatment in patients with methamphetamine-induced psychosis comorbid with intellectual disabilities

PubMed Central

Okazaki, Kosuke; Makinodan, Manabu; Yamamuro, Kazuhiko; Takata, Tomoyo; Kishimoto, Toshifumi

2016-01-01

Objective Methamphetamine (MA) use has recently been associated with high levels of psychiatric hospitalization and serious social dysfunction. MA use causes frequent psychotic symptoms, which can be treated with antipsychotics. However, people with intellectual disabilities (ID) are vulnerable to adverse effects resulting from treatment with antipsychotic medications. Method We report two cases of MA-induced psychosis (MAP) in patients with ID who were treated with the antipsychotic blonanserin. Results In both the cases presented, symptoms of psychosis were improved by switching medications from other antipsychotic drugs to blonanserin. Despite the presence of ID in these patients, no significant adverse effects, such as sedation, were detected after treatment with blonanserin. Conclusion Blonanserin may be an effective and well-tolerated pharmacotherapeutical treatment for patients with MAP comorbid with ID. However, further work is necessary to validate this claim. PMID:28008256

Blonanserin treatment in patients with methamphetamine-induced psychosis comorbid with intellectual disabilities.

PubMed

Okazaki, Kosuke; Makinodan, Manabu; Yamamuro, Kazuhiko; Takata, Tomoyo; Kishimoto, Toshifumi

2016-01-01

Methamphetamine (MA) use has recently been associated with high levels of psychiatric hospitalization and serious social dysfunction. MA use causes frequent psychotic symptoms, which can be treated with antipsychotics. However, people with intellectual disabilities (ID) are vulnerable to adverse effects resulting from treatment with antipsychotic medications. We report two cases of MA-induced psychosis (MAP) in patients with ID who were treated with the antipsychotic blonanserin. In both the cases presented, symptoms of psychosis were improved by switching medications from other antipsychotic drugs to blonanserin. Despite the presence of ID in these patients, no significant adverse effects, such as sedation, were detected after treatment with blonanserin. Blonanserin may be an effective and well-tolerated pharmacotherapeutical treatment for patients with MAP comorbid with ID. However, further work is necessary to validate this claim.

Determinants of physical health parameters in individuals with intellectual disability who use long-term antipsychotics.

PubMed

de Kuijper, Gerda; Mulder, Hans; Evenhuis, Heleen; Scholte, Frans; Visser, Frank; Hoekstra, Pieter J

2013-09-01

Individuals with intellectual disability frequently use antipsychotics for many years. This may have detrimental health effects, including neurological symptoms and metabolic and hormonal dysregulation, the latter possibly affecting bone metabolism. There is large variability in the degree in which antipsychotic agents lead to these health problems. In the current study we investigated potential determinants of physical symptoms and biological parameters known to be associated with use of antipsychotics in a convenience sample of 99 individuals with intellectual disability who had used antipsychotics for more than one year for behavioural symptoms. We focused on extrapyramidal symptoms; on overweight and presence of components of the metabolic syndrome; and on elevated plasma prolactin and bone turnover parameters. As predictor variables, we used patient (sex, age, genetic polymorphisms, and severity of intellectual disability) and medication use (type and dosage) characteristics. We found extrapyramidal symptoms to be present in 53%, overweight or obesity in 46%, and the metabolic syndrome in 11% of participants. Hyperprolactineaemia and one or more elevated bone turnover markers were present in 17% and 25%, respectively. Higher age and more severe intellectual disability were associated with dyskinesia and a higher dosage of the antipsychotic drug was associated with parkinsonism. Less severe intellectual disability was related to higher Body Mass Index. Use of atypical antipsychotics was associated with higher diastolic blood pressure and elevated fasting glucose. Clinicians who prescribe antipsychotics in individuals with intellectual disability should carefully balance the potential benefits of prolonged treatment against the risk of health hazards associated with the use of antipsychotics. Copyright © 2013 Elsevier Ltd. All rights reserved.

Antipsychotic drug use since the FDA black box warning: survey of nursing home policies.

PubMed

Lester, Paula; Kohen, Izchak; Stefanacci, Richard G; Feuerman, Martin

2011-10-01

To use a nationwide survey to assess changes in antipsychotic utilization patterns and usage policies in nursing homes (NHs) in the United States since the introduction of the black box warning by the FDA. A survey was distributed online and was completed by 250 directors of nursing of NH. The directors of nursing answered questions concerning policies about and use of antipsychotic medications. The most commonly reported intervention to manage symptoms in residents with dementia since the black box warning was to lower doses of antipsychotics. Over half of facilities report obtaining more frequent psychiatry/psychology consults. One-hundred seven facilities have a policy regarding informing family members of residents about the black box warning. Most facilities (63.6%) with a policy require family to sign consent. In the NH setting, the presence or absence of a policy did not correlate with the reported change in use of antipsychotics or types of alternative interventions. Notably, a large number of NH facilities have policies regarding informed consent on the use of antipsychotics. However, in our study, the rate of use of antipsychotics did not change in many facilities since the black box warning. In addition, having a policy did not correlate with decreased antipsychotic use or with use of alternate agents or nonpharmacologic methods to address symptoms. The results of this survey suggest that NH administrators should worry less about the legal exposure of using antipsychotics and focus on actions that result in improved patient care. Copyright © 2011 American Medical Directors Association. Published by Elsevier Inc. All rights reserved.

Morbidity and mortality of women and men with intellectual and developmental disabilities newly initiating antipsychotic drugs.

PubMed

Vigod, Simone N; Lunsky, Yona; Cobigo, Virginie; Wilton, Andrew S; Somerton, Sarah; Seitz, Dallas P

2016-03-01

While up to 45% of individuals with intellectual and developmental disabilities (IDD) have a comorbid psychiatric disorder, and antipsychotics are commonly prescribed, gender differences in the safety of antipsychotics have rarely been studied in this population. To compare men and women with IDD on medical outcomes after antipsychotic initiation. Our population-based study in Ontario, Canada, compared 1457 women and 1951 men with IDD newly initiating antipsychotic medication on risk for diabetes mellitus, hypertension, venous thromboembolism, myocardial infarction, stroke and death, with up to 4 years of follow-up. Women were older and more medically complex at baseline. Women had higher risks for venous thromboembolism (HR 1.72, 95% CI 1.15-2.59) and death (HR 1.46, 95% CI 1.02-2.10) in crude analyses; but only thromboembolism risk was greater for women after covariate adjustment (aHR 1.58, 95% CI 1.05-2.38). Gender should be considered in decision-making around antipsychotic medications for individuals with IDD. None. © The Royal College of Psychiatrists 2016. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) licence.

One-year follow-up study of psychotic patients treated with blonanserin: a case series.

PubMed

Takahashi, Sakae; Suzuki, Masahiro; Uchiyama, Makoto

2013-09-01

Blonanserin is a relatively new atypical antipsychotic drug, and has been used in Korea and Japan for 1 and 3 years, respectively. Therefore, the clinical characteristics of blonanserin remain unclear. In this study, to clarify the features of blonanserin, we performed prospective and long-term comparative investigations of patients treated with blonanserin. We followed 10 psychiatric patients who were switched to blonanserin from other antipsychotics for 1 year (schizophrenia: 8; mental retardation: 2). In the light of quality of life, we focused on adverse effects of patients during the follow-up. In the long-term follow-up, (i) hyperprolactinemia is more frequently in risperidone than in blonanserin; however, it is more often in blonanserin than in olanzapine; and (ii) weight gain is more common in olanzapine than in blonanserin. We switched to blonanserin from other antipsychotic drugs within the same case, and then followed the case for 1 year. We consider that long-term observations within the same case lead to obvious comparisons among drugs. On the basis of our findings, we conclude that blonanserin may be useful for the maintenance treatment of schizophrenia without inducing hyperprolactinemia and weight gain. Copyright © 2012 Wiley Publishing Asia Pty Ltd.

NeuN+ Neuronal Nuclei in Non-Human Primate Prefrontal Cortex and Subcortical White Matter After Clozapine Exposure

PubMed Central

Halene, Tobias B.; Kozlenkov, Alexey; Jiang, Yan; Mitchell, Amanda; Javidfar, Behnam; Dincer, Aslihan; Park, Royce; Wiseman, Jennifer; Croxson, Paula; Giannaris, Eustathia Lela; Hof, Patrick R.; Roussos, Panos; Dracheva, Stella; Hemby, Scott E.; Akbarian, Schahram

2016-01-01

Increased neuronal densities in subcortical white matter have been reported for some cases with schizophrenia. The underlying cellular and molecular mechanisms remain unresolved. We exposed 26 young adult macaque monkeys for 6 months to either clozapine, haloperidol or placebo and measured by structural MRI frontal gray and white matter volumes before and after treatment, followed by observer-independent, flow-cytometry-based quantification of neuronal and non-neuronal nuclei and molecular fingerprinting of cell-type specific transcripts. After clozapine exposure, the proportion of nuclei expressing the neuronal marker NeuN increased by approximately 50% in subcortical white matter, in conjunction with a more subtle and non-significant increase in overlying gray matter. Numbers and proportions of nuclei expressing the oligodendrocyte lineage marker, OLIG2, and cell-type specific RNA expression patterns, were maintained after antipsychotic drug exposure. Frontal lobe gray and white matter volumes remained indistinguishable between antipsychotic-drug-exposed and control groups. Chronic clozapine exposure increases the proportion of NeuN+ nuclei in frontal subcortical white matter, without alterations in frontal lobe volumes or cell type-specific gene expression. Further exploration of neurochemical plasticity in non-human primate brain exposed to antipsychotic drugs is warranted. PMID:26776227

Design and in vivo evaluation of solid lipid nanoparticulate systems of Olanzapine for acute phase schizophrenia treatment: Investigations on antipsychotic potential and adverse effects.

PubMed

Joseph, Emil; Reddi, Satish; Rinwa, Vibhu; Balwani, Garima; Saha, Ranendra

2017-06-15

The present paper discusses the design, characterization and in vivo evaluation of glyceryl monostearate nanoparticles of Olanzapine, an atypical antipsychotic drug for acute schizophrenia treatment, during which hospitalization is mandatory and adverse effects are at its peak. The solid lipid nanoparticulate system was obtained by emulsification-ultra sonication technique wherein three factors such as solid lipid content, concentration of surfactant and drug: solid lipid ratio were selected at three different levels in order to study their influence on significant characteristic responses such as particle size, encapsulation efficiency and drug content. A Box Behnken design with 17 runs involving whole factors at three levels was employed for the study. The optimized formulation was further coated with Polysorbate 80 in order to enhance its brain targeting potential through endocytosis transport process via blood brain barrier. The designed formulations were pre-clinically tested successfully in Wistar rat model for in vivo antipsychotic efficacy (apomorphine induced psychosis) and adverse effects (weight gain study for 28days). The results obtained indicated that solid lipid nanoparticles had very narrow size distribution (151.29±3.36nm) with very high encapsulation efficiency (74.51±1.75%). Morphological studies by SEM have shown that solid lipid nanoparticles were spherical in shape with smooth surface. Olanzapine-loaded nanoparticles prepared from solid lipid, extended the release of drug for 48h, as found by the in vitro release studies. The formulations also exhibited high redispersibility after freeze-drying and stability study results demonstrated good stability, with no significant change for a period of 6months. In vivo evaluation and adverse effects studies of Olanzapine-loaded nanoparticulate systems in animal model have demonstrated an improved therapeutic efficacy than pure Olanzapine. The antipsychotic effect of drug loaded nanoparticulate systems was maintained for 48h as compared to 8h antipsychotic action of pure Olanzapine solution. The weight gain studies for 28days demonstrated a significant inhibition in weight gain for Olanzapine-loaded nanoparticulate systems as compared to the pure Olanzapine. The present research findings indicate that OLN-loaded nanoparticulate systems may be highly promising for effective delivery of Olanzapine with better efficacy and minimum adverse effects. Copyright © 2017 Elsevier B.V. All rights reserved.

Psychotropic medicine prescriptions in Italian youths: a multiregional study.

PubMed

Piovani, Daniele; Clavenna, Antonio; Cartabia, Massimo; Bonati, Maurizio

2016-03-01

The aim of the study was to evaluate the trend of paediatric psychotropic drug prescriptions in Italy. Data sources were regional, outpatient prescription databases. Seven Italian regions, covering 50 % of the Italian population, provided data from 2006 to 2011. Prevalence and incidence of prescriptions by age and gender were evaluated for psychotropic, antidepressant, antipsychotic, and attention-deficit/hyperactivity disorders (ADHD) medications. The hospital admission rate for psychiatric conditions was calculated, also at the local health unit (LHU) level. The presence of trends in prescription prevalence and incidence during the 6 year period was assessed. Finally, the correlation between prevalence, prescription, hospital admission rates, latitude, longitude, and average annual income at the LHU level was also investigated. In 2011, 8834 youths received at least one psychotropic drug prescription, with a prevalence of 1.76 ‰ (95 % CI 1.72-1.80). The incidence of new psychotropic drug users was 1.03 ‰ (1.00-1.06). The prevalence of antidepressants was 1.02 ‰ (0.99-1.04), while that of antipsychotics was 0.70 ‰ (0.68-0.72), and that of ADHD medications 0.19 ‰ (0.18-0.21). The psychotropic drug prevalence increased with increasing age. Males were more exposed to psychotropic drugs than females (AUC0-17 male/female = 1.23). Antipsychotics were the most prescribed psychotropic drugs in males, while antidepressants were in females. Between-region prevalence ranged from 1.56 to 2.17 ‰. The overall prevalence of psychotropic drug from 2006 to 2011 was stable (χ(t)2 ≤ 0.001, p = 0.97). No correlation was found between prevalence and the variables investigated. Psychotropic drug prescription was very limited and stable. No geographical patterns were found.

The quetiapine active metabolite N-desalkylquetiapine and the neurotensin NTS₁ receptor agonist PD149163 exhibit antidepressant-like effects on operant responding in male rats.

PubMed

Hillhouse, Todd M; Shankland, Zachary; Matazel, Katelin S; Keiser, Ashley A; Prus, Adam J

2014-12-01

Major depressive disorder is the most common mood disorder in the United States and European Union; however, the limitations of clinically available antidepressant drugs have led researchers to pursue novel pharmacological treatments. Clinical studies have reported that monotherapy with the atypical antipsychotic drug quetiapine produces a rapid reduction in depressive symptoms that is apparent after 1 week of treatment, and it is possible that the active metabolite N-desalkylquetiapine, which structurally resembles an antidepressant drug, produces antidepressant effects. Neuropharmacological evaluations of the neurotensin NTS1 receptor agonist PD149163 suggest antidepressant efficacy, but the effects of a NTS₁ receptor agonist in an antidepressant animal model have yet to be reported. The present study examined the antidepressant-like effects of N-desalkylquetiapine, PD14916, quetiapine, the tricyclic antidepressant drug imipramine, the atypical antipsychotic drug risperidone, and the typical antipsychotic drug raclopride on responding in male Sprague-Dawley rats trained on a differential-reinforcement-of-low-rate 72-s operant schedule, a procedure used for screening antidepressant drugs. Quetiapine, PD149163, risperidone, and imipramine exhibited antidepressant-like effects by increasing the number of reinforcers earned, decreasing the number of responses emitted, and shifting the interresponse time (IRT) distributions to the right. N-Desalkylquetiapine produced a partial antidepressant-like effect by decreasing the number of responses emitted and producing a rightward shift in the IRT distributions, but it did not significantly alter the number of reinforcers earned. Raclopride decreased reinforcers and responses. These data suggest that N-desalkylquetiapine likely contributes to quetiapine's antidepressant efficacy and identify NTS₁ receptor activation as a potential novel pharmacologic strategy for antidepressant drugs. PsycINFO Database Record (c) 2014 APA, all rights reserved.

Dopamine and serotonin interactions in the prefrontal cortex: insights on antipsychotic drugs and their mechanism of action.

PubMed

Di Pietro, N C; Seamans, J K

2007-12-01

Diminished activity within the prefrontal cortex (PFC) has been associated with many of the cognitive deficits that are observed in schizophrenia. It has been hypothesized that antipsychotic drugs (APDs) used to treat schizophrenia restore normal activity by antagonizing the dopamine (DA) D2 receptor, which is also known to modulate key ionic currents in the PFC. However, the hypothesis that an under-active cortical DA system is responsible for schizophrenic symptoms has been challenged by evidence that newer atypical APDs are weak antagonists at the D2 receptor but potent antagonists at the serotonin (5-HT) 2A receptor . This review examines how DA and 5-HT modulate cortical activity and how they may interact in ways that are relevant to schizophrenia. It is concluded that although D2 receptor antagonism remains a critical factor in restoring impaired cortical activity, effects on 5-HT receptors may act in a synergistic manner on NMDA and GABA currents to potentiate antipsychotic actions in the PFC.

[Antipsychotic-induced weight gain--pharmacogenetic studies].

PubMed

Olajossy-Hilkesberger, Luiza; Godlewska, Beata; Marmurowska-Michałowskal, Halina; Olajossy, Marcin; Landowski, Jerzy

2006-01-01

Drug-naive patients with schizophrenia often present metabolic abnormalities and obesity. Weight gain may be the side effect of treatment with many antipsychotic drugs. Genetic effects, besides many other factors, are known to influence obesity in patients with schizophrenia treated with antipsychotics. Numerous studies of several genes' polymorphisms have been performed. -759C/T polymorphism of 5HT2C gene attracted most attention. In 5 independent studies of this polymorphism the association between T allele with the lower AP-induced weight gain was detected. No associations could be detected between weight gain and other polymorphisms of serotonergic system genes as well as histaminergic system genes. Studies of adrenergic and dopaminergic system have neither produced any unambiguous results. Analysis of the newest candidate genes (SAP-25, leptin gene) confirmed the role of genetic factors in AP-induced weight gain. It is worth emphasising, that the studies have been conducted in relatively small and heterogenic groups and that various treatment strategies were used.

Interpreting serum risperidone concentrations.

PubMed

Boerth, Joel M; Caley, Charles F; Goethe, John W

2005-02-01

Risperidone is an atypical antipsychotic commonly used for treatment of schizophrenia and other psychotic disorders. Although therapeutic drug monitoring is not routine for any of the atypical antipsychotics, serum antipsychotic concentrations are measured routinely to assess treatment nonadherence. In humans, risperidone is metabolized by cytochrome P450 2D6 to 9-hydroxyrisperidone; together these constitute the active moiety. Dose-proportional increases in serum concentrations have not been reported for the parent drug, but have been reported for 9-hydroxyrisperidone and the active moiety (i.e., the combined concentrations of risperidone and 9-hydroxyrisperidone). We describe a 34-year-old Caucasian man of Sicilian descent with a history of schizophrenia, disorganized type. He was suspected to be noncompliant with his risperidone therapy. Initially, active moiety risperidone concentrations increased linearly with prescribed dosage increases. However, with continued increases, active moiety concentrations adjusted downward and remained 17-36% below anticipated levels. We propose a method for estimating target active moiety concentrations of risperidone based on dosage-a method that may be used to guide clinicians in assessing nonadherence to risperidone treatment.

Identifying a predictive model for response to atypical antipsychotic monotherapy treatment in south Indian schizophrenia patients.

PubMed

Gupta, Meenal; Moily, Nagaraj S; Kaur, Harpreet; Jajodia, Ajay; Jain, Sanjeev; Kukreti, Ritushree

2013-08-01

Atypical antipsychotic (AAP) drugs are the preferred choice of treatment for schizophrenia patients. Patients who do not show favorable response to AAP monotherapy are subjected to random prolonged therapeutic treatment with AAP multitherapy, typical antipsychotics or a combination of both. Therefore, prior identification of patients' response to drugs can be an important step in providing efficacious and safe therapeutic treatment. We thus attempted to elucidate a genetic signature which could predict patients' response to AAP monotherapy. Our logistic regression analyses indicated the probability that 76% patients carrying combination of four SNPs will not show favorable response to AAP therapy. The robustness of this prediction model was assessed using repeated 10-fold cross validation method, and the results across n-fold cross-validations (mean accuracy=71.91%; 95%CI=71.47-72.35) suggest high accuracy and reliability of the prediction model. Further validations of these results in large sample sets are likely to establish their clinical applicability. Copyright © 2013 Elsevier Inc. All rights reserved.

Reprint of: Clinical management of tardive dyskinesia: Five steps to success.

PubMed

Citrome, Leslie

2018-06-15

Tardive dyskinesia (TD) has long been thought to be a generally irreversible consequence of the use of dopamine receptor blocking agents. There is now an opportunity to successfully manage this condition with agents approved by the US Food and Drug Administration. This is important because TD has not been eliminated with the use of second-generation antipsychotics, and the expansion of antipsychotics to treat conditions other than schizophrenia has resulted in millions of additional individuals at risk for developing TD. Recognition of TD requires careful observation; a structured approach using the Abnormal Involuntary Movement Scale is encouraged. Harm reduction can be achieved by using antipsychotics judiciously when possible and by paying attention to other modifiable risk factors such as drug-induced parkinsonian symptoms and the use of anticholinergic medication. Once TD has emerged and is associated with dysfunction or distress, treatment with a VMAT2 inhibitor such as deutetrabenazine or valbenazine is well supported by several controlled clinical trials. Copyright © 2017 Elsevier B.V. All rights reserved.

Clinical management of tardive dyskinesia: Five steps to success.

PubMed

Citrome, Leslie

2017-12-15

Tardive dyskinesia (TD) has long been thought to be a generally irreversible consequence of the use of dopamine receptor blocking agents. There is now an opportunity to successfully manage this condition with agents approved by the US Food and Drug Administration. This is important because TD has not been eliminated with the use of second-generation antipsychotics, and the expansion of antipsychotics to treat conditions other than schizophrenia has resulted in millions of additional individuals at risk for developing TD. Recognition of TD requires careful observation; a structured approach using the Abnormal Involuntary Movement Scale is encouraged. Harm reduction can be achieved by using antipsychotics judiciously when possible and by paying attention to other modifiable risk factors such as drug-induced parkinsonian symptoms and the use of anticholinergic medication. Once TD has emerged and is associated with dysfunction or distress, treatment with a VMAT2 inhibitor such as deutetrabenazine or valbenazine is well supported by several controlled clinical trials. Copyright © 2017 Elsevier B.V. All rights reserved.

Dopamine antagonists for treatment resistance in autism spectrum disorders: review and focus on BDNF stimulators loxapine and amitriptyline.

PubMed

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.

Add-on clinical effects of selective antagonist of 5HT6 receptors AVN-211 (CD-008-0173) in patients with schizophrenia stabilized on antipsychotic treatment: pilot study.

PubMed

Morozova, Margarita A; Lepilkina, Taisiya A; Rupchev, Georgy E; Beniashvily, Allan G; Burminskiy, Denis S; Potanin, Sergey S; Bondarenko, Evgeny V; Kazey, Vasily I; Lavrovsky, Yan; Ivachtchenko, Alexandre V

2014-08-01

The serotoninergic system as a target for add-on treatment seems to be a promising approach in patients with schizophrenia. To clarify if selective 5HT-6 antagonist AVN-211 (CD-008-0173) adds clinical and cognitive effects to stable antipsychotic treatment. A randomized, double-blind, placebo-controlled, add-on, 4r-week trial in 47 schizophrenia patients (21 patients receiving study drug and 26 receiving placebo) who were stabilized on antipsychotic medication was performed. Seventeen patients from the study drug group and 25 patients from the placebo group completed the trial. Treatment effects were measured using clinical rating scales and attention tests. With no differences at baseline, there was a significant difference between the groups in Positive and Negative Syndrome Scale (PANSS) positive subscale score (p = 0.058) in favor of patients in the treatment group at the endpoint. The PANSS positive subscore (p = 0.0068) and Clinical Global Impression-Severity (CGI-S) (p = 0.048) score significantly changed only in the treatment group. Only in the placebo group were significant changes in Calgary Depression Rating Scale (CDRS) total score registered. The indices of attention tests at endpoint did not show differences between the groups, with the exception of the scope of change in the results of the subtest VIII of the Wechsler Adult Intelligence Scale (WAIS), which showed difference between the groups (p = 0.02) and was significantly larger in the treatment group. Only inside the study drug group, significant changes in selectivity and continuous attention were observed regarding total correct responses (p = 0.0038) and reaction time (p = 0.058) in the Continuous Attention Task (CAT) test. Selective 5HT6 antagonist AVN-211 (CD-008-0173) added antipsychotic and some procognitive (attention) effects to antipsychotic medication.

Medication adherence and subjective weight perception in patients with first-episode psychotic disorder.

PubMed

Wong, Mimi M C; Chen, E Y H; Lui, Simon S Y; Tso, Steve

2011-10-01

Medication adherence is critical to the management of psychotic disorder. Different factors associated with medication adherence have been investigated in previous studies. However, the association with subjective weight perception, which is related to the weight gain side effect of antipsychotics, has not been thoroughly investigated. Subjective weight perception may not equal objective weight status. This study tests the hypothesis that medication adherence is related to subjective weight perception in a group of patients with first-episode psychotic disorder who have taken antipsychotics for one year. This study recruited 160 participants with one-year histories of first-episode psychotic disorder and measured their actual and perceived weights, amount of weight gain in the past year, body size satisfaction and medication adherence levels. The associations between medication adherence and both the actual and perceived weight status were analyzed controlling for other confounding factors including insight, drug attitude, illness severity and other medication side effects. Stepwise multiple regression analysis found that the participants' perceived weight status, negative attitude toward their drugs and insight were the major factors associated with poor medication adherence. Of the participants who perceived themselves as being overweight, 86% believed that antipsychotics were responsible. Among those who had such beliefs, 72% had reduced their antipsychotic dosages on their own. About half of the participants had gained more than 7% of their baseline weight and 43.1% of the participants were found to be overweight after one year of treatment with antipsychotics. The results of this study indicate that medication adherence is associated with perceived weight status. Healthcare professionals should be aware of this relationship and address this issue early in the management of patients. Apart from weight management programs, education on a correct weight perception should be carried out with the promotion of proper drug attitudes and better insight for the improvement of medication adherence in the early course of psychotic disorder.

Preventing Olanzapine-Induced Weight Gain Using Betahistine: A Study in a Rat Model with Chronic Olanzapine Treatment

PubMed Central

Lian, Jiamei; Huang, Xu-Feng; Pai, Nagesh; Deng, Chao

2014-01-01

Olanzapine is the one of first line antipsychotic drug for schizophrenia and other serious mental illness. However, it is associated with troublesome metabolic side-effects, particularly body weight gain and obesity. The antagonistic affinity to histamine H1 receptors (H1R) of antipsychotic drugs has been identified as one of the main contributors to weight gain/obesity side-effects. Our previous study showed that a short term (2 weeks) combination treatment of betahistine (an H1R agonist and H3R antagonist) and olanzapine (O+B) reduced (−45%) body weight gain induced by olanzapine in drug-naïve rats. A key issue is that clinical patients suffering with schizophrenia, bipolar disease and other mental disorders often face chronic, even life-time, antipsychotic treatment, in which they have often had previous antipsychotic exposure. Therefore, we investigated the effects of chronic O+B co-treatment in controlling body weight in female rats with chronic and repeated exposure of olanzapine. The results showed that co-administration of olanzapine (3 mg/kg, t.i.d.) and betahistine (9.6 mg/kg, t.i.d.) significantly reduced (−51.4%) weight gain induced by olanzapine. Co-treatment of O+B also led to a decrease in feeding efficiency, liver and fat mass. Consistently, the olanzapine-only treatment increased hypothalamic H1R protein levels, as well as hypothalamic pAMPKα, AMPKα and NPY protein levels, while reducing the hypothalamic POMC, and UCP1 and PGC-1α protein levels in brown adipose tissue (BAT). The olanzapine induced changes in hypothalamic H1R, pAMPKα, BAT UCP1 and PGC-1α could be reversed by co-treatment of O+B. These results supported further clinical trials to test the effectiveness of co-treatment of O+B for controlling weight gain/obesity side-effects in schizophrenia with chronic antipsychotic treatment. PMID:25084453

Aripiprazole, A Drug that Displays Partial Agonism and Functional Selectivity.

PubMed

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.

Effects of atypical antipsychotic drugs on QT interval in patients with mental disorders

PubMed Central

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

Haloperidol-induced striatal Nur77 expression in a non-human primate model of tardive dyskinesia

PubMed Central

Mahmoudi, Souha; Blanchet, Pierre J.; Lévesque, Daniel

2015-01-01

Tardive dyskinesia (TD) is a delayed and potentially irreversible motor complication arising in patients chronically exposed to antipsychotic drugs. As several modern (so-called atypical) antipsychotic drugs are common offenders, the widening clinical indications for prescription as well as exposure of vulnerable individuals, TD will remain a significant drug-induced unwanted side effect. In addition, the pathophysiology of TD remains elusive and therapeutics difficult. Based on rodent experiments, we have previously shown that the transcriptional factor Nur77 (also known as NGFI-B or Nr4a1) is induced in the striatum following antipsychotic drug exposure as part of a long-term neuroadaptive process. To confirm this, we exposed adult capuchin (Cebus apella) monkeys to prolonged treatments with haloperidol (median 18.5 months, N=11) or clozapine (median 6 months, N=6). Six untreated animals were used as controls. Six haloperidol-treated animals developed mild TD movements similar to those found in humans. No TD was observed in the clozapine group. Postmortem analysis of Nur77 expression measured by in situ hybridization revealed a stark contrast between the two drugs, as Nur77 mRNA levels in the caudate-putamen were strongly upregulated in animals exposed to haloperidol while spared following clozapine treatment. Interestingly, within the haloperidol-treated group, TD-free animals showed higher Nur77 expression in putamen subterritories compared to dyskinetic animals. This suggests that Nur77 expression might be associated with a reduced risk to TD in this experimental model and could provide a novel target for drug intervention. PMID:23551242

Magic Bullets for Mental Disorders: The Emergence of the Concept of an “Antipsychotic” Drug

PubMed Central

2013-01-01

When “antipsychotic” drugs were introduced into psychiatry in the 1950s, they were thought to work by inducing a state of neurological suppression, which reduced behavioral disturbance as well as psychotic symptoms. This view was reflected in the name “neuroleptic.” Within a few years, however, the idea that the drugs were a disease-specific treatment for schizophrenia or psychosis, and that they worked by modifying the underlying pathology of the condition, replaced this earlier view, and they became known as “antipsychotics.” This transformation of views about the drugs’ mode of action occurred with little debate or empirical evaluation in the psychiatric literature and obscured earlier evidence about the nature of these drugs. Drug advertisements in the British Journal of Psychiatry reflect the same changes, although the nondisease-specific view persisted for longer. It is suggested that professional interests rather than scientific merit facilitated the rise of the disease-specific view of drug action. The increasing popularity of atypical antipsychotics makes it important to examine the origins of the assumptions on which modern drug treatment is based. PMID:23323530

The Effect of Chronic Antipsychotic Drug on Hypothalamic Expression of Neural Nitric Oxide Synthase and Dopamine D2 Receptor in the Male Rat

PubMed Central

Zhang, Zhi Jun; Li, Lei; Reynolds, Gavin P.

2012-01-01

Antipsychotic-induced sexual dysfunction is a common and serious clinical side effect. It has been demonstrated that both neuronal nitric oxide (nNOS) and dopamine D2 receptor (DRD2) in the medial preoptic area (MPOA) and the paraventricular nucleus (PVN) of the hypothalamus have important roles in the regulation of sexual behaviour. We investigated the influences of 21 days’ antipsychotic drug administration on expression of nNOS and DRD2 in the rat hypothalamus. Haloperidol (0.5 mg/kg/day i.p.) significantly decreased nNOS integrated optical density in a sub-nucleus of the MPOA, medial preoptic nucleus (MPN), and decreased the nNOS integrated optical density and cell density in another sub-nucleus of the MPOA, anterodorsal preoptic nucleus (ADP). Risperidone (0.25 mg/kg) inhibited the nNOS integrated optical density in the ADP. nNOS mRNA and protein in the MPOA but not the PVN was also significantly decreased by haloperidol. Haloperidol and risperidone increased DRD2 mRNA and protein expression in both the MPOA and the PVN. Quetiapine (20 mg/kg/day i.p.) did not influence the expression of nNOS and DRD2 in either the MPOA or the PVN. These findings indicate that hypothalamic nNOS and DRD2 are affected to different extents by chronic administration of risperidone and haloperidol, but are unaffected by quetiapine. These central effects might play a role in sexual dysfunction induced by certain antipsychotic drugs. PMID:22514604

Hemodynamic Changes by Drug Interaction of Adrenaline With Chlorpromazine

PubMed Central

Higuchi, Hitoshi; Yabuki, Akiko; Ishii-Maruhama, Minako; Tomoyasu, Yumiko; Maeda, Shigeru; Miyawaki, Takuya

2014-01-01

Adrenaline (epinephrine) is included in dental local anesthesia for the purpose of vasoconstriction. In Japan, adrenaline is contraindicated for use in patients receiving antipsychotic therapy, because the combination of adrenaline and an antipsychotic is considered to cause severe hypotension; however, there is insufficient evidence supporting this claim. The purpose of the present study was to clarify the changes in hemodynamics caused by drug interaction between adrenaline and an antipsychotic and to evaluate the safety of the combined use of adrenaline and an antipsychotic in an animal study. Male Sprague-Dawley rats were anesthetized with sodium pentobarbital. A catheter was inserted into the femoral artery to measure blood pressure and pulse rate. Rats were pretreated by intraperitoneal injection of chlorpromazine or chlorpromazine and propranolol, and after 20 minutes, saline or 1 of 3 different doses of adrenaline was administered by intraperitoneal injection. Changes in the ratio of mean arterial blood pressure and pulse rate were measured after the injection of adrenaline. Significant hypotension and tachycardia were observed after the injection of adrenaline in the chlorpromazine-pretreated rats. These effects were in a dose-dependent manner, and 100 μg/kg adrenaline induced significant hemodynamic changes. Furthermore, in the chlorpromazine and propranolol–pretreated rats, modest hypertension was induced by adrenaline, but hypotension and tachycardia were not significantly shown. Hypotension was caused by a drug interaction between adrenaline and chlorpromazine through the activation of the β-adrenergic receptor and showed a dose-dependent effect. Low-dose adrenaline similar to what might be used in human dental treatment did not result in a significant homodynamic change. PMID:25517550

Hemodynamic changes by drug interaction of adrenaline with chlorpromazine.

PubMed

Higuchi, Hitoshi; Yabuki, Akiko; Ishii-Maruhama, Minako; Tomoyasu, Yumiko; Maeda, Shigeru; Miyawaki, Takuya

2014-01-01

Adrenaline (epinephrine) is included in dental local anesthesia for the purpose of vasoconstriction. In Japan, adrenaline is contraindicated for use in patients receiving antipsychotic therapy, because the combination of adrenaline and an antipsychotic is considered to cause severe hypotension; however, there is insufficient evidence supporting this claim. The purpose of the present study was to clarify the changes in hemodynamics caused by drug interaction between adrenaline and an antipsychotic and to evaluate the safety of the combined use of adrenaline and an antipsychotic in an animal study. Male Sprague-Dawley rats were anesthetized with sodium pentobarbital. A catheter was inserted into the femoral artery to measure blood pressure and pulse rate. Rats were pretreated by intraperitoneal injection of chlorpromazine or chlorpromazine and propranolol, and after 20 minutes, saline or 1 of 3 different doses of adrenaline was administered by intraperitoneal injection. Changes in the ratio of mean arterial blood pressure and pulse rate were measured after the injection of adrenaline. Significant hypotension and tachycardia were observed after the injection of adrenaline in the chlorpromazine-pretreated rats. These effects were in a dose-dependent manner, and 100 μg/kg adrenaline induced significant hemodynamic changes. Furthermore, in the chlorpromazine and propranolol-pretreated rats, modest hypertension was induced by adrenaline, but hypotension and tachycardia were not significantly shown. Hypotension was caused by a drug interaction between adrenaline and chlorpromazine through the activation of the β-adrenergic receptor and showed a dose-dependent effect. Low-dose adrenaline similar to what might be used in human dental treatment did not result in a significant homodynamic change.

Adjunctive Treatment with Asenapine Augments the Escitalopram-Induced Effects on Monoaminergic Outflow and Glutamatergic Neurotransmission in the Medial Prefrontal Cortex of the Rat

PubMed Central

Björkholm, Carl; Frånberg, Olivia; Malmerfelt, Anna; Marcus, Monica M.; Konradsson-Geuken, Åsa; Schilström, Björn; Jardemark, Kent

2015-01-01

Background: Substantial clinical data support the addition of low doses of atypical antipsychotic drugs to selective serotonin reuptake inhibitors (SSRIs) to rapidly enhance the antidepressant effect in treatment-resistant depression. Preclinical studies suggest that this effect is at least partly explained by an increased catecholamine outflow in the medial prefrontal cortex (mPFC). Methods: In the present study we used in vivo microdialysis in freely moving rats and in vitro intracellular recordings of pyramidal cells of the rat mPFC to investigate the effects of adding the novel atypical antipsychotic drug asenapine to the SSRI escitalopram with regards to monoamine outflow in the mPFC and dopamine outflow in nucleus accumbens as well as glutamatergic transmission in the mPFC. Results: The present study shows that addition of low doses (0.05 and 0.1 mg/kg) of asenapine to escitalopram (5 mg/kg) markedly enhances dopamine, noradrenaline, and serotonin release in the rat mPFC as well as dopamine release in the nucleus accumbens. Moreover, this drug combination facilitated both N-methyl-d-Aspartate (NMDA)– and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)–induced currents as well as electrically evoked excitatory postsynaptic potentials in pyramidal cells of the rat mPFC. Conclusions: Our results support the notion that the augmentation of SSRIs by atypical antipsychotic drugs in treatment-resistant depression may, at least in part, be related to enhanced catecholamine output in the prefrontal cortex and that asenapine may be clinically used to achieve this end. In particular, the subsequent activation of the D1 receptor may be of importance for the augmented antidepressant effect, as this mechanism facilitated both NMDA and AMPA receptor-mediated transmission in the mPFC. Our novel observation that the drug combination, like ketamine, facilitates glutamatergic transmission in the mPFC may contribute to explain the rapid and potent antidepressant effect obtained when atypical antipsychotic drugs are added to SSRIs. PMID:25522408

Synthesis of Quaternary Ammonium Salts of Tricyclic Cationic Drugs: A One-Pot Synthesis for the Bioorganic Chemistry Laboratory

ERIC Educational Resources Information Center

Brunauer, Linda S.; Mogannam, Abid C.; Hwee, Won B.; Chen, James Y.

2007-01-01

A one-pot conversion of tricyclic cationic drugs to their quaternary ammonium forms is described for a widely used bioactive drug: chlorpromazine, a phenothiazine-based antipsychotic. After conversion to its free base, the parent drug was methylated using substoichiometric amounts of methyl iodide dissolved in ether; the charged quaternary…

Antipsychotic drugs versus cognitive behavioural therapy versus a combination of both in people with psychosis: a randomised controlled pilot and feasibility study.

PubMed

Morrison, Anthony P; Law, Heather; Carter, Lucy; Sellers, Rachel; Emsley, Richard; Pyle, Melissa; French, Paul; Shiers, David; Yung, Alison R; Murphy, Elizabeth K; Holden, Natasha; Steele, Ann; Bowe, Samantha E; Palmier-Claus, Jasper; Brooks, Victoria; Byrne, Rory; Davies, Linda; Haddad, Peter M

2018-05-01

Little evidence is available for head-to-head comparisons of psychosocial interventions and pharmacological interventions in psychosis. We aimed to establish whether a randomised controlled trial of cognitive behavioural therapy (CBT) versus antipsychotic drugs versus a combination of both would be feasible in people with psychosis. We did a single-site, single-blind pilot randomised controlled trial in people with psychosis who used services in National Health Service trusts across Greater Manchester, UK. Eligible participants were aged 16 years or older; met ICD-10 criteria for schizophrenia, schizoaffective disorder, or delusional disorder, or met the entry criteria for an early intervention for psychosis service; were in contact with mental health services, under the care of a consultant psychiatrist; scored at least 4 on delusions or hallucinations items, or at least 5 on suspiciousness, persecution, or grandiosity items on the Positive and Negative Syndrome Scale (PANSS); had capacity to consent; and were help-seeking. Participants were assigned (1:1:1) to antipsychotics, CBT, or antipsychotics plus CBT. Randomisation was done via a secure web-based randomisation system (Sealed Envelope), with randomised permuted blocks of 4 and 6, stratified by gender and first episode status. CBT incorporated up to 26 sessions over 6 months plus up to four booster sessions. Choice and dose of antipsychotic were at the discretion of the treating consultant. Participants were followed up for 1 year. The primary outcome was feasibility (ie, data about recruitment, retention, and acceptability), and the primary efficacy outcome was the PANSS total score (assessed at baseline, 6, 12, 24, and 52 weeks). Non-neurological side-effects were assessed systemically with the Antipsychotic Non-neurological Side Effects Rating Scale. Primary analyses were done by intention to treat; safety analyses were done on an as-treated basis. The study was prospectively registered with ISRCTN, number ISRCTN06022197. Of 138 patients referred to the study, 75 were recruited and randomly assigned-26 to CBT, 24 to antipsychotics, and 25 to antipsychotics plus CBT. Attrition was low, and retention high, with only four withdrawals across all groups. 40 (78%) of 51 participants allocated to CBT attended six or more sessions. Of the 49 participants randomised to antipsychotics, 11 (22%) were not prescribed a regular antipsychotic. Median duration of total antipsychotic treatment was 44·5 weeks (IQR 26-51). PANSS total score was significantly reduced in the combined intervention group compared with the CBT group (-5·65 [95% CI -10·37 to -0·93]; p=0·019). PANSS total scores did not differ significantly between the combined group and the antipsychotics group (-4·52 [95% CI -9·30 to 0·26]; p=0·064) or between the antipsychotics and CBT groups (-1·13 [95% CI -5·81 to 3·55]; p=0·637). Significantly fewer side-effects, as measured with the Antipsychotic Non-neurological Side Effects Rating Scale, were noted in the CBT group than in the antipsychotics (3·22 [95% CI 0·58 to 5·87]; p=0·017) or antipsychotics plus CBT (3·99 [95% CI 1·36 to 6·64]; p=0·003) groups. Only one serious adverse event was thought to be related to the trial (an overdose of three paracetamol tablets in the CBT group). A head-to-head clinical trial of CBT versus antipsychotics versus the combination of the two is feasible and safe in people with first-episode psychosis. National Institute for Health Research. Copyright © 2018 Elsevier Ltd. All rights reserved.

Long-term metabolic effects of aripiprazole, ziprasidone and quetiapine: a pragmatic clinical trial in drug-naïve patients with a first-episode of non-affective psychosis.

PubMed

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.

Antipsychotics, chlorpromazine and haloperidol inhibit voltage-gated proton currents in BV2 microglial cells.

PubMed

Shin, Hyewon; Song, Jin-Ho

2014-09-05

Microglial dysfunction and neuroinflammation are thought to contribute to the pathogenesis of schizophrenia. Some antipsychotic drugs have anti-inflammatory activity and can reduce the secretion of pro-inflammatory cytokines and reactive oxygen species from activated microglial cells. Voltage-gated proton channels on the microglial cells participate in the generation of reactive oxygen species and neuronal toxicity by supporting NADPH oxidase activity. In the present study, we examined the effects of two typical antipsychotics, chlorpromazine and haloperidol, on proton currents in microglial BV2 cells using the whole-cell patch clamp method. Chlorpromazine and haloperidol potently inhibited proton currents with IC50 values of 2.2 μM and 8.4 μM, respectively. Chlorpromazine and haloperidol are weak bases that can increase the intracellular pH, whereby they reduce the proton gradient and affect channel gating. Although the drugs caused a marginal positive shift of the activation voltage, they did not change the reversal potential. This suggested that proton current inhibition was not due to an alteration of the intracellular pH. Chlorpromazine and haloperidol are strong blockers of dopamine receptors. While dopamine itself did not affect proton currents, it also did not alter proton current inhibition by the two antipsychotics, indicating dopamine receptors are not likely to mediate the proton current inhibition. Given that proton channels are important for the production of reactive oxygen species and possibly pro-inflammatory cytokines, the anti-inflammatory and antipsychotic activities of chlorpromazine and haloperidol may be partly derived from their ability to inhibit microglial proton currents. Copyright © 2014 Elsevier B.V. All rights reserved.

Evidence for the hERG Liability of Antihistamines, Antipsychotics, and Anti-Infective Agents: A Systematic Literature Review From the ARITMO Project.

PubMed

Hazell, Lorna; Raschi, Emanuel; De Ponti, Fabrizio; Thomas, Simon H L; Salvo, Francesco; Ahlberg Helgee, Ernst; Boyer, Scott; Sturkenboom, Miriam; Shakir, Saad

2017-05-01

A systematic review was performed to categorize the hERG (human ether-a-go-go-related gene) liability of antihistamines, antipsychotics, and anti-infectives and to compare it with current clinical risk of torsade de pointes (TdP). Eligible studies were hERG assays reporting half-minimal inhibitory concentrations (IC50). A "hERG safety margin" was calculated from the IC50 divided by the peak human plasma concentration (free C max ). A margin below 30 defined hERG liability. Each drug was assigned an "uncertainty score" based on volume, consistency, precision, and internal and external validity of evidence. The hERG liability was compared to existing knowledge on TdP risk (www.credibledrugs.org). Of 1828 studies, 82 were eligible, allowing calculation of safety margins for 61 drugs. Thirty-one drugs (51%) had evidence of hERG liability including 6 with no previous mention of TdP risk (eg, desloratadine, lopinavir). Conversely, 16 drugs (26%) had no evidence of hERG liability including 6 with known, or at least conditional or possible, TdP risk (eg, chlorpromazine, sulpiride). The main sources of uncertainty were the validity of the experimental conditions used (antihistamines and antipsychotics) and nonuse of reference compounds (anti-infectives). In summary, hERG liability was categorized for 3 widely used drug classes, incorporating a qualitative assessment of the strength of available evidence. Some concordance with TdP risk was observed, although several drugs had hERG liability without evidence of clinical risk and vice versa. This may be due to gaps in clinical evidence, limitations of hERG/C max data, or other patient/drug-specific factors that contribute to real-life TdP risk. © 2016, The American College of Clinical Pharmacology.

The Effects of Prior Authorization Policies on Medicaid-Enrolled Children's Use of Antipsychotic Medications: Evidence from Two Mid-Atlantic States

PubMed Central

Leckman-Westin, Emily; Okeke, Edward; Scharf, Deborah M.; Sorbero, Mark; Chen, Qingxian; Chor, Ka Ho Brian; Finnerty, Molly; Wisdom, Jennifer P.

2014-01-01

Abstract Objective: The purpose of this study was to examine the impact of prior authorization policies on the receipt of antipsychotic medication for Medicaid-enrolled children. Methods: Using de-identified administrative Medicaid data from two large, neighboring, mid-Atlantic states from November 2007 through June 2011, we identified subjects <18 years of age using antipsychotics, from the broader group of children and adolescents receiving behavioral health services or any psychotropic medication. Prior authorization for antipsychotics was required for children in State A <6 years of age from September 2008, and for children <13 years of age from August 2009. No such prior authorizations existed in State B during that period. Filled prescriptions were identified in the data using national drug codes. Using a triple-difference strategy (using differences among the states, time periods, and differences in antidepressant prescribing rates among states over the same time periods), we examined the effect of the prior authorization policy on the rate at which antipsychotic prescriptions were filled for Medicaid-enrolled children and adolescents. Results: The impact of prior authorization policies on antipsychotic medication use varied by age: Among 6–12 year old children, the impact of the prior authorization policy on antipsychotic medication prescribing was a modest but statistically significant decrease of 0.47% after adjusting for other factors; there was no effect of the prior authorization among children 0–5 years. Conclusions: Prior authorization policies had a modest but statistically significant effect on antipsychotic use in 6–12 year old children, but had no impact in younger children. Future research is needed to understand the utilization and clinical effects of prior authorization and other policies and interventions designed to influence antipsychotic use in children. PMID:25144909

Blonanserin, a novel antipsychotic, is suitable for treating schizophrenia associated with hyperprolactinemia: a case series.

PubMed

Kawabe, Kentaro; Horiuchi, Fumie; Ueno, Shu-ichi

2013-01-01

Recently, atypical antipsychotic agents have primarily been used in pharmacological treatment of schizophrenia because of the fewer associated adverse effects. Blonanserin is a novel atypical antipsychotic recently introduced to treat patients with schizophrenia in Japan and South Korea. In this study, we examined the efficacy of switching antipsychotic medications to blonanserin monotherapy in patients with chronic schizophrenia with associated hyperprolactinemia. Ten schizophrenic patients (5 males and 5 females) with hyperprolactinemia were recruited. Clinical data before (baseline) and 12 weeks after (end point) switching to blonanserin monotherapy were assessed using the Brief Psychiatric Rating Scale score, Drug-Induced Extrapyramidal Symptoms Scale, and serum prolactin levels. The mean (SD) blonanserin dosage was 14.8 (3.8) mg/d. After switching to blonanserin, there were significant improvements in the Brief Psychiatric Rating Scale in the patients from both sexes. Moreover, serum prolactin levels in the female patients significantly decreased to within reference range. There were no additional adverse effects observed with the blonanserin treatment. Switching to blonanserin can reverse medication-induced prolactin elevations found in female patients- and blonanserin is a suitable antipsychotic for schizophrenic patients.

Antipsychotics side effects' influence on stigma of mental illness: focus group study results.

PubMed

Novak, Lan; Svab, Vesna

2009-03-01

Little research was done on the influence of antipsychotics' side effects on stigma of mental illness. An overview of studies shows that people with mental illness state that because of medication side effects they feel discriminated in the field of employment, observe worsening of family relations and tend to skip or discontinue their regular medication. It is difficult to discriminate between stigmatizing effects of antipsychotics and other stigma related factors such as illness symptoms. A focus group of ten patients with schizophrenia or schizoaffective disorder with severe and remitting mental illness treated with antipsychotic medication was conducted to obtain their personal views on how side effects of antipsychotic drugs affect their everyday lives and contribute to the stigmatization because of mental illness. The patients felt most stigmatized in areas of employment and occupation. They repeatedly skipped or discontinued regular medication due to side effects. Their families supported them throughout treatment and recovery despite problems associated with psychotropic medication. Medication induced stigma affects patients' lives in substantial ways and therefore merits further research, part of which is the patients' personal experience.

Brain structural changes associated with chronicity and antipsychotic treatment in schizophrenia.

PubMed

Tomelleri, Luisa; Jogia, Jigar; Perlini, Cinzia; Bellani, Marcella; Ferro, Adele; Rambaldelli, Gianluca; Tansella, Michele; Frangou, Sophia; Brambilla, Paolo

2009-12-01

Accumulating evidence suggest a life-long impact of disease related mechanisms on brain structure in schizophrenia which may be modified by antipsychotic treatment. The aim of the present study was to investigate in a large sample of patients with schizophrenia the effect of illness duration and antipsychotic treatment on brain structure. Seventy-one schizophrenic patients and 79 age and gender matched healthy participants underwent brain magnetic resonance imaging (MRI). All images were processed with voxel based morphometry, using SPM5. Compared to healthy participants, patients showed decrements in gray matter volume in the left medial and left inferior frontal gyrus. In addition, duration of illness was negatively associated with gray matter volume in prefrontal regions bilaterally, in the temporal pole on the left and the caudal superior temporal gyrus on the right. Cumulative exposure to antipsychotics correlated positively with gray matter volumes in the cingulate gyrus for typical agents and in the thalamus for atypical drugs. These findings (a) indicate that structural abnormalities in prefrontal and temporal cortices in schizophrenia are progressive and, (b) suggest that antipsychotic medication has a significant impact on brain morphology.

Antipsychotics increase vesicular glutamate transporter 2 (VGLUT2) expression in thalamolimbic pathways.

PubMed

Moutsimilli, Larissa; Farley, Severine; El Khoury, Marie-Anne; Chamot, Christophe; Sibarita, Jean-Baptiste; Racine, Victor; El Mestikawy, Salah; Mathieu, Flavie; Dumas, Sylvie; Giros, Bruno; Tzavara, Eleni T

2008-03-01

Recently the two vesicular-glutamate-transporters VGLUT1 and VGLUT2 have been cloned and characterized. VGLUT1 and VGLUT2 together label all glutamatergic neurons, but because of their distinct expression patterns in the brain they facilitate our ability to define between a VGLUT1-positive cortical and a VGLUT2-positive subcortical glutamatergic systems. We have previously demonstrated an increased cortical VGLUT1 expression as marker of antidepressant activity. Here, we assessed the effects of different psychotropic drugs on brain VGLUT2 mRNA and protein expression. The typical antipsychotic haloperidol, and the atypicals clozapine and risperidone increased VGLUT2 mRNA selectively in the central medial/medial parafascicular, paraventricular and intermediodorsal thalamic nuclei; VGLUT2 protein was accordingly amplified in paraventricular and ventral striatum and in prefrontal cortex. The antidepressants fluoxetine and desipramine and the sedative anxiolytic diazepam had no effect. These results highlight the implication of thalamo-limbic glutamatergic pathways in the action of antipsychotics. Increased VGLUT2 expression in these neurons might constitute a marker for antipsychotic activity and subcortical glutamate neurotransmission might be a possible novel target for future generation antipsychotics.

Revisiting Antipsychotic-induced Akathisia: Current Issues and Prospective Challenges

PubMed Central

Salem, Haitham; Nagpal, Caesa; Pigott, Teresa; Teixeira, Antonio Lucio

2017-01-01

Background: Akathisia continues to be a significant challenge in current neurological and psychiatric practice. Prompt and accurate detection is often difficult and there is a lack of consensus concerning the neurobiological basis of akathisia. No definitive treatment has been established for akathisia despite numerous preclinical and clinical studies. Method: We reviewed antipsychotic-induced akathisia including its clinical presentation, proposed underlying pathophysiology, current and under investigation therapeutic strategies. Conclusion: Despite the initial promise that second generation antipsychotics would be devoid of akathisia effects, this has not been confirmed. Currently, there are limited therapeutic options for the clinical practice and the evidence supporting the most widely used treatments (beta blockers, anticholinergic drugs) is still absent or inconsistent. PMID:27928948

Antipsychotic drugs a last resort for these 5 conditions (ADHD, Anxiety, Depression, Insomnia and PTSD)

MedlinePlus

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Terminal illness and the increased mortality risk of conventional antipsychotics in observational studies: a systematic review.

PubMed

Luijendijk, Hendrika J; de Bruin, Niels C; Hulshof, Tessa A; Koolman, Xander

2016-02-01

Numerous large observational studies have shown an increased risk of mortality in elderly users of conventional antipsychotics. Health authorities have warned against use of these drugs. However, terminal illness is a potentially strong confounder of the observational findings. So, the objective of this study was to systematically assess whether terminal illness may have biased the observational association between conventional antipsychotics and risk of mortality in elderly patients. Studies were searched in PubMed, CINAHL, Embase, the references of selected studies and articles referring to selected studies (Web of Science). Inclusion criteria were (i) observational studies that estimated (ii) the risk of all-cause mortality in (iii) new elderly users of (iv) conventional antipsychotics compared with atypical antipsychotics or no use. Two investigators assessed the characteristics of the exposure and reference groups, main results, measured confounders and methods used to adjust for unmeasured confounders. We identified 21 studies. All studies were based on administrative medical and pharmaceutical databases. Sicker and older patients received conventional antipsychotics more often than new antipsychotics. The risk of dying was especially high in the first month of use, and when haloperidol was administered per injection or in high doses. Terminal illness was not measured in any study. Instrumental variables that were used were also confounded by terminal illness. We conclude that terminal illness has not been adjusted for in observational studies that reported an increased risk of mortality risk in elderly users of conventional antipsychotics. As the validity of the evidence is questionable, so is the warning based on it. Copyright © 2015 John Wiley & Sons, Ltd.

Morbidity and mortality of women and men with intellectual and developmental disabilities newly initiating antipsychotic drugs

PubMed Central

Lunsky, Yona; Cobigo, Virginie; Wilton, Andrew S.; Somerton, Sarah; Seitz, Dallas P.

2016-01-01

Background While up to 45% of individuals with intellectual and developmental disabilities (IDD) have a comorbid psychiatric disorder, and antipsychotics are commonly prescribed, gender differences in the safety of antipsychotics have rarely been studied in this population. Aims To compare men and women with IDD on medical outcomes after antipsychotic initiation. Method Our population-based study in Ontario, Canada, compared 1457 women and 1951 men with IDD newly initiating antipsychotic medication on risk for diabetes mellitus, hypertension, venous thromboembolism, myocardial infarction, stroke and death, with up to 4 years of follow-up. Results Women were older and more medically complex at baseline. Women had higher risks for venous thromboembolism (HR 1.72, 95% CI 1.15–2.59) and death (HR 1.46, 95% CI 1.02–2.10) in crude analyses; but only thromboembolism risk was greater for women after covariate adjustment (aHR 1.58, 95% CI 1.05–2.38). Conclusions Gender should be considered in decision-making around antipsychotic medications for individuals with IDD. Declaration of interest None. Copyright and usage © The Royal College of Psychiatrists 2016. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) licence. PMID:27703773

Drug-Refractory Aggression, Self-Injurious Behavior, and Severe Tantrums in Autism Spectrum Disorders: A Chart Review Study

ERIC Educational Resources Information Center

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…

An Outline on Psychotropic Drug Use in the Developmentally Disabled Patient. Monograph #102.

ERIC Educational Resources Information Center

Vander Zanden, Jeanne A.

This introduction to basic principles of psychotropic drug use in developmentally disabled patients is intended to provide personnel working in the field with information on appropriate clinical use as well as potential risks. Presented in outline form, information is provided on five classes of psychotropic drugs: antipsychotics; antidepressants;…

Concomitant medication of psychoses in a lifetime perspective.

PubMed

Vares, Maria; Saetre, Peter; Strålin, Pontus; Levander, Sten; Lindström, Eva; Jönsson, Erik G

2011-01-01

Patients treated with antipsychotic drugs often receive concomitant psychotropic compounds. Few studies address this issue from a lifetime perspective. Here, an analysis is presented of the prescription pattern of such concomitant medication from the first contact with psychiatry until the last written note in the case history documents, in patients with a diagnosis of psychotic illness. A retrospective descriptive analysis of all case history data of 66 patients diagnosed with schizophrenia or schizophrenia-like psychotic disorders. Benzodiazepines and benzodiazepine-related anxiolytic drugs had been prescribed to 95% of the patients, other anxiolytics, sedatives or hypnotic drugs to 61%, anti-parkinsonism drugs to 86%, and antidepressants to 56% of the patients. However, lifetime doses were small and most of the time patients had no concomitant medication. The prescribed lifetime dose of anti-parkinsonism drugs was associated with that of prescribed first-generation but not second-generation antipsychotics. Most psychosis patients are sometimes treated with concomitant drugs but mainly over short periods. Lifetime concomitant add-on medication at the individual patient level is variable and complex but not extensive. Copyright © 2011 John Wiley & Sons, Ltd.

Results of a pilot cluster randomised trial of the use of a Medication Review Tool for people taking antipsychotic medication.

PubMed

Moncrieff, Joanna; Azam, Kiran; Johnson, Sonia; Marston, Louise; Morant, Nicola; Darton, Katherine; Wood, Neil

2016-07-04

Government policy encourages increasing involvement of patients in their long-term care. This paper describes the development and pilot evaluation of a 'Medication Review Tool' designed to assist people to participate more effectively in discussions about antipsychotic drug treatment. The Medication Review Tool developed consisted of a form to help patients identify pros and cons of their current antipsychotic treatment and any desired changes. It was associated with a website containing information and links about antipsychotics. For the trial, participants diagnosed with psychotic disorders were recruited from community mental health services. Cluster randomisation was used to allocate health professionals (care co-ordinators) and their associated patients to use of the Medication Review Tool or usual care. All participants had a medical consultation scheduled, and those in the intervention group completed the Medication Review Tool, with the help of their health professional prior to this, and took the completed Form into the consultation. Two follow-up interviews were conducted up to three months after the consultation. The principal outcome was the Decision Self Efficacy Scale (DSES). Qualitative feedback was collected from patients in the intervention group. One hundred and thirty patients were screened, sixty patients were randomised, 51 completed the first follow-up assessment and 49 completed the second. Many patients were not randomised due to the timing of their consultation, and involvement of health professionals was inconsistent. There was no difference between the groups on the DSES (-4.16 95 % CI -9.81, 1.49), symptoms, side effects, antipsychotic doses or patient satisfaction. Scores on the Medication Adherence Questionnaire indicated an increase in participants' reported inclination to adherence in the intervention group (coefficient adjusted for baseline values -0.44; 95 % CI -0.76, -0.11), and there was a small increase in positive attitudes to antipsychotic medication (Drug Attitude Inventory, adjusted coefficient 1.65; 95 % CI -0.09, 3.40). Qualitative feedback indicated patients valued the Tool for identifying both positive and negative aspects of drug treatment. The trial demonstrated the design was feasible, although challenges included service re-configurations and maintaining health professional involvement. Results may indicate a more intensive and sustained intervention is required to facilitate participation in decision-making for this group of patients. Current controlled trials ISRCTN12055530 , Retrospectively registered 9/12/2013.

Subjective response to antipsychotic treatment and compliance in schizophrenia. A naturalistic study comparing olanzapine, risperidone and haloperidol (EFESO Study)

PubMed Central

García-Cabeza, Ignacio; Gómez, Juan-Carlos; Sacristán, Jose A; Edgell, Eric; González de Chavez, Manuel

2001-01-01

Background In order to compare the effectiveness of different antipsychotic drugs in the treatment of schizophrenia it is very important to evaluate subjective response and compliance in patient cohorts treated according to routine clinical practice. Method Outpatients with schizophrenia entered this prospective, naturalistic study when they received a new prescription for an antipsychotic drug. Treatment assignment was based on purely clinical criteria, as the study did not include any experimental intervention. Patients treated with olanzapine, risperidone or haloperidol were included in the analysis. Subjective response was measured using the 10-item version of the Drug Attitude Inventory (DAI-10), and treatment compliance was measured using a physician-rated 4 point categorical scale. Results A total of 2128 patients initiated treatment (as monotherapy) with olanzapine, 417 with risperidone, and 112 with haloperidol. Olanzapine-treated patients had significantly higher DAI-10 scores and significantly better treatment compliance compared to both risperidone- and haloperidol-treated patients. Risperidone-treated patients had a significantly higher DAI-10 score compared to haloperidol-treated patients. Conclusion Subjective response and compliance were superior in olanzapine-treated patients, compared to patients treated with risperidone and haloperidol, in routine clinical practice. Differences in subjective response were explained largely, but not completely, by differences in incidence of EPS. PMID:11835695

Adjunctive Atypical Antipsychotic Treatment for Major Depressive Disorder: A Meta-Analysis of Depression, Quality of Life, and Safety Outcomes

PubMed Central

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

Antipsychotics Activate mTORC1-Dependent Translation to Enhance Neuronal Morphological Complexity

PubMed Central

Bowling, Heather; Zhang, Guoan; Bhattacharya, Aditi; Pérez-Cuesta, Luis M.; Deinhardt, Katrin; Hoeffer, Charles A.; Neubert, Thomas A.; Gan, Wen-biao; Klann, Eric; Chao, Moses V.

2014-01-01

Although antipsychotic drugs can reduce psychotic behavior within a few hours, full efficacy is not achieved for several weeks, implying that there may be rapid, short-term changes in neuronal function, which are consolidated into long-lasting changes. Here, we showed that the antipsychotic drug haloperidol, a dopamine receptor type 2 (D2R) antagonist, stimulated the kinase Akt to activate the mRNA translation pathway mediated by the mammalian target of rapamycin complex 1 (mTORC1). In primary striatal D2R-positive neurons, haloperidol-mediated activation of mTORC1 resulted in increased phosphorylation of ribosomal protein S6 (S6) and eukaryotic translation initiation factor 4E-binding protein (4E-BP). Proteomic mass spectrometry revealed marked changes in the pattern of protein synthesis after acute exposure of cultured striatal neurons to haloperidol, including increased abundance of cytoskeletal proteins and proteins associated with translation machinery. These proteomic changes coincided with increased morphological complexity of neurons that was diminished by inhibition of downstream effectors of mTORC1, suggesting that mTORC1-dependent translation enhances neuronal complexity in response to haloperidol. In vivo, we observed rapid morphological changes with a concomitant increase in the abundance of cytoskeletal proteins in cortical neurons of haloperidol-injected mice. These results suggest a mechanism for both the acute and long-term actions of antipsychotics. PMID:24425786

Antipsychotic Use Among Nursing Home Residents Admitted with Hip Fracture

PubMed Central

Jung, Hye–Young; Meucci, Marissa; Unruh, Mark Aaron; Mor, Vincent; Dosa, David

2012-01-01

Background/Objectives Widespread use of antipsychotic medications among skilled nursing home (NH) residents for off-label indications has become a concern of clinicians and policy makers. The objective of this study was to evaluate the association between receiving antipsychotics and the outcomes of a cohort of NH patients with and without presumed delirium after hip fracture. Design Population based cohort study. Setting 11,119 nursing homes nationwide, from 01 January 2000 to 31 December 2007. Participants First-time NH admits with hip fracture (N=77,759). Measurements The Nursing Home Confusion Assessment Method was utilized to identify residents with no delirium, subsyndromal delirium, and full delirium. Propensity score reweighting was used with analyses stratified by delirium level. Results Among patients with no delirium symptoms, about 5 percent (n = 3,250) received antipsychotic drugs. These individuals were less likely to be discharged home (OR 0.68; P < 0.001), had a higher likelihood of death prior to nursing home discharge (OR 1.28; P = 0.03), stayed in nursing homes longer (β 2.83; P = 0.05), and had less functional improvement at discharge (β -0.47; P = 0.03). Receipt of antipsychotics among participants with mild delirium was associated with a lower likelihood of discharge home (OR 0.74; P = 0.03). Conclusion Among NH residents with hip fracture and no delirium symptoms, use of antipsychotics was associated with worse outcomes, with the exception of rehospitalization. No clear benefits were associated with antipsychotic use for those with presumed delirium. PMID:23252409

Metabotropic glutamate receptor 5, and its trafficking molecules Norbin and Tamalin, are increased in the CA1 hippocampal region of subjects with schizophrenia.

PubMed

Matosin, Natalie; Fernandez-Enright, Francesca; Lum, Jeremy S; Andrews, Jessica L; Engel, Martin; Huang, Xu-Feng; Newell, Kelly A

2015-08-01

Metabotropic glutamate receptor 5 (mGluR5) is involved in hippocampal-dependent learning and memory, which are processes disrupted in schizophrenia. Recent evidence from human genetic and animal studies suggests that the regulation of mGluR5, including its interaction with trafficking molecules, may be altered in the disorder. However there have been no investigations of hippocampal mGluR5 or mGluR5 trafficking molecules in the postmortem schizophrenia brain to confirm this. In the present study, we investigated whether protein expression of mGluR5, as well as Norbin and Tamalin (modulators of mGluR5 signalling and trafficking), might be altered in the schizophrenia brain, using postmortem samples from the hippocampal CA1 region of schizophrenia subjects and matched controls (n=20/group). Protein levels of mGluR5 (total: 42%, p<0.001; monomer: 25%, p=0.011; dimer: 52%, p<0.001) and mGluR5 trafficking molecules (Norbin: 47%, p<0.001; Tamalin: 34%, p=0.009) were significantly higher in schizophrenia subjects compared to controls. To determine any influence of antipsychotic drug treatment, all proteins were also correlated with lifetime chlorpromazine equivalents in patients, and separately measured in the hippocampus of rats exposed to haloperidol or olanzapine treatment. mGluR5 was negatively correlated with lifetime antipsychotic drug exposure in schizophrenia patients, suggesting antipsychotic drugs could reduce mGluR5 protein in schizophrenia subjects. In contrast, mGluR5 and mGluR5 trafficking molecules were not altered in the hippocampus of antipsychotic drug treated rats. This investigation provides strong support for the hypothesis that mGluR5 is involved in the pathology of schizophrenia, and that alterations to mGluR5 trafficking might contribute to the hippocampal-dependent cognitive dysfunctions associated with this disorder. Copyright © 2015 Elsevier B.V. All rights reserved.

A review of evidence for GABergic predominance/glutamatergic deficit as a common etiological factor in both schizophrenia and affective psychoses: more support for a continuum hypothesis of "functional" psychosis.

PubMed

Squires, R F; Saederup, E

1991-10-01

Virtually all antidepressant and antipsychotic drugs, including clozapine, rimcazole and lithium ion, are proconvulsants, and convulsive therapy, using metrazol, a known GABA-A antagonist, as well as electro-convulsive therapy, can be effective in treating both schizophrenia and affective psychoses. Many antidepressant and antipsychotic drugs, including clozapine, as well as some of their metabolites, reverse the inhibitory effect of GABA on 35S-TBPS binding, a reliable predictor of GABA-A receptor blockade. A review of relevant literature suggests that 1) "functional" psychoses constitute a continuum of disorders ranging from schizophrenia to affective psychoses with overlap of symptoms, heredity and treatments, 2) a weakening of GABergic inhibitory activity, or potentiation of counterbalancing glutamatergic neurotransmission, in the brain, may be involved in the therapeutic activities of both antidepressant and antipsychotic drugs, and 3) schizophrenia and the affective psychoses may be different expressions of the same underlying defect: GABergic preponderance/glutamatergic deficit. Schizophrenia and affective psychoses share the following: 1) several treatments are effective in both, 2) similar modes of inheritance, 3) congruent seasonal birth excesses, 4) enlarged cerebral ventricles and cerebellar vermian atrophy, 5) dexamethasone non-suppression. Both genetic and environmental factors are involved in both schizophrenia and affective psychoses, and several lines of evidence suggest that important environmental factors are neurotropic pathogens that selectively destroy glutamatergic neurons. One group of genes associated with psychoses may increase vulnerability to attack and destruction, by neurotropic pathogens, of excitatory glutamatergic neurons that counterbalance inhibitory GABergic neurons. A second group of genes may encode subunits of overactive GABA-A receptors, while a third group of genes may encode subunits of hypo-active glutamate receptors. Improved antipsychotic drugs may be found among selective blockers of GABA-A receptor subtypes and/or enhancers of glutamatergic neurotransmission. A mechanism similar to kindling, leading to long-lasting reduction of GABergic inhibition in the brain, may be involved in several treatments of psychoses.

Long-acting injectable antipsychotics for prevention and management of violent behaviour in psychotic patients.

PubMed

Mohr, Pavel; Knytl, Pavel; Voráčková, Veronika; Bravermanová, Anna; Melicher, Tomáš

2017-09-01

It has been well established that long-term antipsychotic treatment prevents relapse, lowers number of rehospitalisations, and also effectively reduces violent behaviour. Although violent behaviour is not a typical manifestation of schizophrenia or other psychotic disorders, the diagnosis of psychosis increases the overall risk of violence. One of the few modifiable factors of violence risk is adherence with medication. In contrast, non-adherence with drug treatment and subsequent relapse increases risk of violent acts. Non-adherence can be addressed partially by long-acting injectable antipsychotics (LAI). The aim of our review was to examine the role of antipsychotic drugs, especially LAI, in prevention and management of violent behaviour in psychosis. This is a non-systematic, narrative review of the data from open, naturalistic, retrospective, and population studies, case series, and post hoc analyses of randomised controlled trials. Search of electronic databases (PubMed, Embase) was performed to identify relevant papers. Nine published papers (3 cross-sectional chart reviews, 4 retrospective studies, 2 prospective, randomised trials) were found. The results indicated positive clinical and antiaggressive effects of LAI in psychotic patients with high risk of violent behaviour. Reviewed evidence suggests that secured drug treatment with LAI may have clinical benefit in schizophrenia patients with high risk of violent behaviour. LAI significantly reduced the severity of hostility, aggressivity, number of violent incidents, and criminal offences. These findings are supported further by the empirical evidence from clinical practice, high rates of prescribed LAI to schizophrenia patients in high-security and forensic psychiatric facilities. Available data encourage the use of LAI in forensic psychiatry, especially during court-ordered commitment treatment. © 2017 John Wiley & Sons Ltd.

Persistent effects of chronic clozapine on the cellular and behavioral responses to LSD in mice

PubMed Central

Moreno, José L.; Holloway, Terrell; Umali, Adrienne; Rayannavar, Vinayak; Sealfon, Stuart C.

2013-01-01

Rationale In schizophrenia patients, optimal treatment with antipsychotics requires weeks to months of sustained drug therapy. However, single administration of antipsychotic drugs can reverse schizophrenia-like behavioral alterations in rodent models of psychosis. This raises questions about the physiological relevance of such antipsychotic-like activity. Objective This study evaluates the effects of chronic treatment with clozapine on the cellular and behavioral responses induced by the hallucinogenic serotonin 5-HT2A receptor agonist lysergic acid diethylamide (LSD) as a mouse model of psychosis. Method Mice were treated chronically (21 days) with 25 mg/kg/day clozapine. Experiments were conducted 1, 7, 14, and 21 days after the last clozapine administration. [3H]Ketanserin binding and 5-HT2A mRNA expression were determined in mouse somatosensory cortex. Head-twitch behavior, expression of c-fos, which is induced by all 5-HT2A agonists, and expression of egr-1 and egr-2, which are LSD-like specific, were assayed. Results Head-twitch response was decreased and [3H]ketanserin binding was downregulated in 1, 7, and 14 days after chronic clozapine. 5-HT2A mRNA was reduced 1 day after chronic clozapine. Induction of c-fos, but not egr-1 and egr-2, was rescued 7 days after chronic clozapine. These effects were not observed after short treatment (2 days) with clozapine or chronic haloperidol (1 mg/kg/day). Conclusion Our findings provide a murine model of chronic atypical antipsychotic drug action and suggest downregulation of the 5-HT2A receptor as a potential mechanism involved in these persistent therapeutic-like effects. PMID:22842765

A bibliometric study of scientific research conducted on second-generation antipsychotic drugs in Singapore

PubMed Central

López-Muñoz, Francisco; Sim, Kang; Shen, Winston Wu; Huelves, Lorena; Moreno, Raquel; Molina, Juan de Dios; Rubio, Gabriel; Noriega, Concha; Ángel Miguel, Pérez-Nieto; Álamo, Cecilio

2014-01-01

INTRODUCTION 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. METHODS 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. RESULTS 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. CONCLUSION Publications on SGAs in Singapore are still too few to confirm an exponential growth of scientific literature. PMID:24452974

Time to Discontinuation of Second-Generation Antipsychotics Versus Haloperidol and Sulpiride in People With Schizophrenia: A Naturalistic, Comparative Study.

PubMed

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.

Differential effects of antipsychotic and propsychotic drugs on prepulse inhibition and locomotor activity in Roman high- (RHA) and low-avoidance (RLA) rats

PubMed Central

Oliveras, Ignasi; Sánchez-González, Ana; Sampedro-Viana, Daniel; Piludu, Maria Antonietta; Río-Alamos, Cristóbal; Giorgi, Osvaldo; Corda, Maria G.; Aznar, Susana; González-Maeso, Javier; Gerbolés, Cristina; Blázquez, Gloria; Cañete, Toni; Tobeña, Adolf

2017-01-01

Rationale Animal models with predictive and construct validity are necessary for developing novel and efficient therapeutics for psychiatric disorders. Objectives We have carried out a pharmacological characterization of the Roman high-(RHA-I) and low-avoidance (RLA-I) rat strains with different acutely administered propsychotic (DOI, MK-801) and antipsychotic drugs (haloperidol, clozapine), as well as apomorphine, on prepulse inhibition (PPI) of startle and locomotor activity (activity cages). Results RHA-I rats display a consistent deficit of PPI compared with RLA-I rats. The typical antipsychotic haloperidol (dopamine D2 receptor antagonist) reversed the PPI deficit characteristic of RHA-I rats (in particular at 65 and 70 dB prepulse intensities) and reduced locomotion in both strains. The atypical antipsychotic clozapine (serotonin/dopamine receptor antagonist) did not affect PPI in either strain, but decreased locomotion in a dose-dependent manner in both rat strains. The mixed dopamine D1/D2 agonist, apomorphine, at the dose of 0.05 mg/kg, decreased PPI in RHA-I, but not RLA-I rats. The hallucinogen drug DOI (5-HT2A agonist; 0.1–1.0 mg/kg) disrupted PPI in RLA-I rats in a dose-dependent manner at the 70 dB prepulse intensity, while in RHA-Irats, only the 0.5 mg/kg dose impaired PPI at the 80 dB prepulse intensity. DOI slightly decreased locomotion in both strains. Finally, clozapine attenuated the PPI impairment induced by the NMDA receptor antagonist MK-801 only in RLA-I rats. Conclusions These results add experimental evidence to the view that RHA-I rats represent a model with predictive and construct validity of some dopamine and 5-HT2A receptor-related features of schizophrenia. PMID:28154892

ADN-1184 a monoaminergic ligand with 5-HT(6/7) receptor antagonist activity: pharmacological profile and potential therapeutic utility.

PubMed

Kołaczkowski, M; Mierzejewski, P; Bieńkowski, P; Wesołowska, A; Newman-Tancredi, A

2014-02-01

Many dementia patients exhibit behavioural and psychological symptoms (BPSD) that include psychosis, aggressivity, depression and anxiety. Antipsychotic drugs are frequently prescribed but fail to significantly attenuate mood deficits, may interfere with cognitive function and are associated with motor and cardiac side effects, which are problematic in elderly patients. A need therefore exists for drugs that are better suited for the treatment of BPSD. We used in vitro cellular and in vivo behavioural tests to characterize ADN-1184, a novel arylsulfonamide ligand with potential utility for treatment of BPSD. ADN-1184 exhibits substantial 5-HT6 /5-HT7 /5-HT2A /D2 receptor affinity and antagonist properties in vitro. In tests of antipsychotic-like activity, it reversed MK-801-induced hyperactivity and stereotypies and inhibited conditioned avoidance response (MED = 3 mg·kg(-1) i.p.). Remarkably, ADN-1184 also reduced immobility time in the forced swim test at low doses (0.3 and 1 mg·kg(-1) i.p.; higher doses were not significantly active). Notably, up to 30 mg·kg(-1) ADN-1184 did not impair memory performance in the passive avoidance test or elicit significant catalepsy and only modestly inhibited spontaneous locomotor activity (MED = 30 mg·kg(-1) i.p.). ADN-1184 combines antipsychotic-like with antidepressant-like properties without interfering with memory function or locomotion. This profile is better than that of commonly used atypical antipsychotics tested under the same conditions and suggests that it is feasible to identify drugs that improve BPSD, without exacerbating cognitive deficit or movement impairment, which are of particular concern in patients with dementia. © 2013 The British Pharmacological Society.

Trends in psychotropic polypharmacy among youths enrolled in Ohio Medicaid, 2002-2008.

PubMed

Fontanella, Cynthia A; Warner, Lynn A; Phillips, Gary S; Bridge, Jeffrey A; Campo, John V

2014-11-01

This study examined polypharmacy patterns and rates over time among Medicaid-enrolled youths by comparing three enrollment groups (youths in foster care, with a disability, or from a family with low income). Serial cross-sectional trend analyses of Medicaid claims data were conducted for youths age 17 and younger who were continuously enrolled in Ohio Medicaid for a one-year period and prescribed one or more psychotropic medications during fiscal years 2002 (N=26,252) through 2008 (N=50,311). Outcome measures were any polypharmacy (three or more psychotropic medications from any drug class) and multiclass polypharmacy (three or more psychotropic medications from different drug classes). Both types of polypharmacy increased across all three eligibility groups. Any polypharmacy increased from 8.8% to 11.5% for low-income youths (adjusted odds ratio [AOR]=1.12, 99% confidence interval [CI]=1.10-1.13), from 18.0% to 24.9% for youths with a disability (AOR=1.11, CI=1.09-1.13), and from 19.8% to 27.3% for youths in foster care (AOR=1.09, CI=1.07-1.11). Combinations associated with positive increases were two or more antipsychotics, two or more stimulants, and antipsychotics with stimulants. Polypharmacy increased across all enrollment groups, with the highest absolute rates for youths in foster care. Both the overall prevalence and increases in prescriptions for drug combinations with limited evidence of safety and efficacy, such as the prescription of two or more antipsychotics, underscore the need for targeted quality improvement efforts. System oversight and monitoring of psychotropic medication use appears to be warranted, especially for higher-risk groups, such as youths in foster care and those from low-income households who were prescribed multiple antipsychotics.

[Augmented antipsychotic therapy with pantogam active in patients with schizophrenia].

PubMed

Medvedev, V E; Frolova, V I; Gushanskaya, E V; Ter-Israelyan, A U

2015-01-01

to study the efficacy of the GABA-ergic drug pantogam active (D-, L-gopantenic acid) in patients with schizophrenia treated with typical neuroleptics and to assess the rate of treatment response and tolerability of the drug. A sample consisted of 70 patients with schizophrenia stratified into main (n=35) and control (n=35) groups. All patients received one of typical antipsychotics (haloperidol, zuclopenthixol, promazine or perphenazine). Patients of the main group received in addition pantogam active in dose of 1200-1800 mg daily. The maximum allowed dose of 1800 mg daily was used in 62.9% of the patients. The long-term combined therapy with the addition of D-, L-gopantenic acid (pantogam activ) allowed to achieve clinical improvement earlier (on 8th week in the main group versus 16th week in the control group). The frequency and severity of secondary negative symptoms associated with antipsychotic therapy were decreased as well. The high efficacy and tolerability of the combined therapy allow to improve quality of life in patients with schizophrenia and their compliance to treatment as well as to reduce costs of medical care.

Japan useful medication program for schizophrenia (JUMPs)-long-term study on discontinuation rate, resolution and remission, and improvement in social functioning rate associated with atypical antipsychotic medications in patients with schizophrenia

PubMed Central

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

Sensorimotor dysfunction of grasping in schizophrenia: a side effect of antipsychotic treatment?

PubMed Central

Nowak, D A; Connemann, B J; Alan, M; Spitzer, M

2006-01-01

Background Antipsychotic treatment in schizophrenia is frequently associated with extrapyramidal side effects. Objective behavioural measures to evaluate the severity of extrapyramidal side effects in the clinical setting do not exist. Objectives This study was designed to investigate grasping movements in five drug naive and 13 medicated subjects with schizophrenia and to compare their performance with that of 18 healthy control subjects. Deficits of grip force performance were correlated with clinical scores of both parkinson‐like motor disability and psychiatric symptom severity Methods Participants performed vertical arm movements with a handheld instrumented object and caught a weight that was dropped into a handheld cup either expectedly from the opposite hand or unexpectedly from the experimenter's hand. The scaling of grip force and the temporospatial coupling between grip and load force profiles was analysed. The psychiatric symptom severity was assessed by the positive and negative symptom score of schizophrenia and the brief psychiatric rating scale. Extrapyramidal symptoms were assessed by the unified Parkinson's disease rating scale. Results Drug naive subjects with schizophrenia performed similar to healthy controls. In contrast, medicated subjects with schizophrenia exhibited excessive grip force scaling and impaired coupling between grip and load force profiles. These performance deficits were strongly correlated with the severity of both extrapyramidal side effects related to antipsychotic therapy and negative symptoms related to the underlying pathology. Conclusions These data provide preliminary evidence that deficits of sensorimotor performance in schizophrenia are, at least in part, related to the side effects of antipsychotic treatment. The investigation of grasping movements may provide a sensitive measure to objectively evaluate extrapyramidal side effects related to antipsychotic therapy. PMID:16614027

Female schizophrenia patients and risk of breast cancer: A population-based cohort study.

PubMed

Wu Chou, Ana Isabel; Wang, Yu-Chiao; Lin, Cheng-Li; Kao, Chia-Hung

2017-10-01

Breast cancer is the most common type of cancer in women. This population-based cohort study aimed to examine the association between breast cancer in female schizophrenia patients and its association with the use of antipsychotics drugs. All study subjects were selected from the Taiwan Insurance Claims Data (1998-2008). We compared the risk for breast cancer between female schizophrenia patients receiving antipsychotics (n=29,641) with female patients without any serious mental illnesses nor receiving antipsychotic drugs (n=59,282). We also compared between patients on 1) first-generation antipsychotics (FGAs) alone; 2) combination of first and second generation antipsychotics (SGAs); and 3) SGAs alone. We then stratified those on SGAs into two subgroups according to their prolactin-elevating properties: risperidone (RIS), paliperidone (PAL) or amisulpride (AMI) and all other SGAs. After adjusting for confounding factors, the risk of breast cancer in female schizophrenia patients was 1.94 higher than the non-schizophrenia cohort (aHR: 1.94, 95% CI: 1.43-2.63). Schizophrenia patients receiving a combination of FGAs and SGAs had a slightly higher risk of breast cancer than non-schizophrenic patients (aHR: 2.17, 95% CI: 1.56-3.01). Patients on RIS, PAL, and AMI had a 1.96-fold risk of breast cancer compared to the non-schizophrenic cohort (95% CI: 1.36-2.82). This study raises awareness among both clinicians and patients about the importance of breast cancer screening and the promotion of healthy lifestyle choices. Due to the nature of our database, confounding factors - such as parity, obesity, hormone therapy, and smoking - could not be controlled for. Copyright © 2017 Elsevier B.V. All rights reserved.

The availability of essential medicines for mental healthcare in Sofala, Mozambique

PubMed Central

Wagenaar, Bradley H.; Stergachis, Andy; Rao, Deepa; Hoek, Roxanne; Cumbe, Vasco; Napúa, Manuel; Sherr, Kenneth

2015-01-01

Objective We assessed the availability of essential medicines for mental healthcare (MH) across levels of the public healthcare system to aid in future systems planning. Design Non-expired MH medications were assessed in 24 public health facilities and 13 district warehouses across Sofala Province, Mozambique, from July to August 2014. Medication categories included: antipsychotics, antidepressants, benzodiazepines, antiepileptics and mood stabilizers, and anticholinergics and antihistamines. Results Only 7 of 12 (58.3%) district warehouses, 11 of 24 (45.8%) of all health facilities, and 10 of 12 (83.3%) of facilities with trained MH staff had availability of at least one medication of each category. Thioridazine was the most commonly available antipsychotic across all facilities (9 of 24, 37.5%), while chlorpromazine and thioridazine were most common at facilities providing MH care (8 of 12, 66.7%). The atypical antipsychotic risperidone was not available at any facility or district warehouse. Amitriptyline was the most commonly available antidepressant (10 of 12 districts; 12 of 24 overall facilities; 9 or 12 MH facilities). Despite being on the national essential drug list, fluoxetine was only available at one quaternary-level facility and no district warehouses. Conclusions Essential psychotropic medicines are routinely unavailable at public health facilities. Current essential drug lists include six typical but no atypical antipsychotics, which is concerning given the side-effect profiles of typical antipsychotics. Ensuring consistent availability of at least one selective serotonin reuptake inhibitor should also be a priority, as they are essential for the treatment of individuals with underlying cardiovascular disease and/or suicidal ideation. Similar to successful task-sharing approaches used for HIV/AIDS, mid-level providers could be retrained and certified to prescribe and monitor first-line psychotropic regimens. PMID:26081970

Antipsychotic interventions in prodromal psychosis: safety issues.

PubMed

Liu, Chen-Chung; Demjaha, Arsime

2013-03-01

In recent years, psychopharmacological intervention in prodromal psychosis, also known as the ultra-high risk (UHR) mental state for psychosis, has attracted much attention. Whilst it has been shown that antipsychotic use in UHR individuals may be effective in potentially delaying or even averting progression to frank psychosis, their use in subjects that do not necessarily convert to psychosis has raised considerable ethical concerns because of their adverse effects. Recent treatment guidelines for patients at UHR for psychosis recommend the use of antipsychotics only in exceptional conditions and with great precautions. To date only a few studies have investigated the use of antipsychotic medications in UHR patients and the potential benefits and risks related to their use in prodromal psychosis remain unclear. We review here all published studies that included UHR patients treated with antipsychotics, regardless of study design. These studies were all of second-generation antipsychotics, given that first-generation antipsychotics cannot be recommended because of their adverse drug reactions. We specifically examine the available descriptions of adverse reactions of the individual antipsychotic medication in each study and discuss the potential effects of various demographic and clinical factors that may impact on safety issues of pharmacological interventions in UHR patients. Clinical trials to date investigating potential benefits of antipsychotic treatments in preventing transition to psychosis were of relatively short duration and have involved a small number of patients. Whilst it appears that pharmacological intervention at this stage may be effective in both reducing the psychopathology and decreasing transition rates, and is potentially safe, in the absence of sufficient evidence-based knowledge to guide treatment, definitive clinical recommendations and guidelines cannot be derived. Certain adverse events take time to develop, such as metabolic syndrome and endocrine-related effects, thus longer term clinical trials with a larger number of patients are needed to determine the effectiveness of antipsychotic intervention and the relationship of its duration to emergence of adverse events. This can inform the development of timely strategies to prevent serious negative impacts and thus maximize the benefits of antipsychotic intervention in UHR patients that outweigh the risks associated with their use.

Adherence to depot versus oral antipsychotic medication in schizophrenic patients during the long-term therapy.

PubMed

Stanković, Zana; Ille, Tatjana

2013-03-01

There is a high rate of schizophrenic patients who do not adhere to their prescribed therapy, despite the implementation of antipsychotic long-acting injections and the introduction of atypical antipsychotics. The aim of this study was to investigate the differences in sociodemographic, clinical and medication adherence variables between the two groups of schizophrenic patients on maintenance therapy with depot antipsychotic fluphenazine decanoate and oral antipsychotics only as well as a correlation between the medication adherence and other examined variables. A total of 56 patients of both genders, aged < 60 years, with the diagnosis of schizophrenia (F20) (ICD-10, 1992) clinically stable for at least 6 months were introduced in this cross-sectional study. The patients from the depot group (n = 19) were on classical depot antipsychotic fluphenazine decanoate administering intramuscularly every 4 weeks (with or without oral antipsychotic augmentation) and the patients from the oral group (n = 37) were on oral therapy alone with classical or atypical antipsychotics, either as monotherapy or combined. The Positive and Negative Syndrome Scale (PANSS) was used to assess symptom severity. Item G12 of the PANSS was used to assess insight into the illness. The patients completed the Medical Adherence Rating Scale (MARS) was used to assess adherence to the therapy. A higher MARS score indicates behavior [Medical Adherence Questionnaire (MAQ subscale)] and attitudes toward medication [Drug Attitude Inventory (DAI subscale)] that are more consistent with treatment adherence. The exclusion criteria were determined. The Pearson's chi2 test was used to compare categorical variables, Student's t-test to compare continuous variables and Pearson's correlation to test the correlation significance; p = 0.05. Significant between-group differences in age, illness duration, chlorpromazine equivalents, PANSS score and DAI subscore were found. Item G12 of the PANSS subscore and MARS score correlated significantly negatively. A significant positive correlation between receiving depot antipsychotic and DAI subscore as well as between illness duration and both DAI subscore and MARS score were also found. Schizophrenic patients on classical depot antipsychotic maintenance therapy might present subpopulation of patients with significantly longer illness duration, more favorable medication attitude and outcome in relation to those on oral antipsychotics alone.

Raloxifene Plus Antipsychotics Versus Placebo Plus Antipsychotics in Severely Ill Decompensated Postmenopausal Women With Schizophrenia or Schizoaffective Disorder: A Randomized Controlled Trial.

PubMed

Weiser, Mark; Levi, Linda; Burshtein, Shimon; Hagin, Michal; Matei, Valentin P; Podea, Delia; Micluția, Ioana; Tiugan, Alexandru; Păcală, Bogdan; Grecu, Iosif Gabos; Noy, Adam; Zamora, Daisy; Davis, John M

2017-07-01

Several single-center studies have found raloxifene, an estrogen agonist, to be effective in ameliorating symptoms of schizophrenia in stable patients as augmentation of antipsychotics. This multicenter study assessed whether raloxifene plus antipsychotic treatment, in comparison to placebo plus antipsychotics, improves symptoms or cognition in severely ill decompensated schizophrenia patients. In this 16-week, double-blind, randomized, placebo-controlled study, 200 severely ill, decompensated postmenopausal women who met DSM-IV-TR criteria for schizophrenia or schizoaffective disorder were recruited from January 2011 to December 2012 and were randomized to receive either raloxifene 120 mg/d plus antipsychotics or placebo plus antipsychotics. The primary outcome measure was Positive and Negative Syndrome Scale (PANSS) total score at the end of the trial. The placebo plus antipsychotics group experienced statistically significant improvement in PANSS total score (P < .001) compared to the raloxifene plus antipsychotics group, using mixed models for repeated measures, with results favoring placebo by 4.5 points (95% CI, 2.3-6.7). These results were clearly outside the 95% confidence interval. This negative effect was more pronounced in patients who had more frequent relapses and in those with baseline PANSS scores of 100 or higher. There were no differences between groups in Clinical Global Impression Scale-Severity scores or Composite Brief Assessment of Cognition in Schizophrenia scores at 16 weeks (P > .3). Baseline follicle-stimulating hormone and estradiol levels did not alter the drug-placebo differences. Individuals in the active treatment arm showed worse outcome than those in the placebo arm, most likely as a result of chance variation, but the results unequivocally show no benefit of antipsychotics plus raloxifene versus antipsychotics plus placebo in this large randomized, double-blind, placebo-controlled trial in postmenopausal women. These data do not support the use of raloxifene in severely decompensated schizophrenia patients until reliable research identifies what subgroup of patients or domain of outcome is benefited. ClinicalTrials.gov identifier: NCT01280305. © Copyright 2017 Physicians Postgraduate Press, Inc.

[Antipsychotics for schizophrenia: the paradigm of psychiatric drugs].

PubMed

Pol Yanguas, Emilio

2015-03-01

Antipsychotic drugs do not appear to reverse the causes of schizophrenia, and although they can relieve symptoms in the short to medium term, in the long term they may not be beneficial and could even be counterproductive. Their use should be limited to acute situations in which agitation and tension is disabling. The drugs have significant adverse effects, and given the refusal of a person to continue taking them, a harm reduction strategy to support and monitor the withdrawal may be preferable to coercion. There are alternatives to neuroleptics. Prescribers should be more vigilant and consider the assessments of users regarding the drugs' effects. Adherence to treatment guidelines is low, probably because the guidelines are based on clinical trials of deficient quality which consequently should be improved and extended over a greater period of time. The root of the problem is likely the tautology on the etiology and biological nature of what is known as schizophrenia, which in fact does not seem to be more than a commercial and ideological construct.

Neuromotor Adverse Effects in 342 Youth During 12 Weeks of Naturalistic Treatment With 5 Second-Generation Antipsychotics.

PubMed

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.

Interventions for tic disorders: An overview of systematic reviews and meta analyses.

PubMed

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.

Weight loss in overweight patients maintained on atypical antipsychotic agents.

PubMed

Centorrino, F; Wurtman, J J; Duca, K A; Fellman, V H; Fogarty, K V; Berry, J M; Guay, D M; Romeling, M; Kidwell, J; Cincotta, S L; Baldessarini, R J

2006-06-01

Weight gain and associated medical morbidity offset the reduction of extrapyramidal side effects associated with atypical antipsychotics. Efforts to control weight in antipsychotic-treated patients have yielded limited success. We studied the impact of an intensive 24-week program of diet, exercise, and counseling in 17 chronically psychotic patients (10 women, seven men) who entered at high average body weight (105.0+/-18.4 kg) and body mass index (BMI) (36.6+/-4.6 kg/m(2)). A total of 12 subjects who completed the initial 24 weeks elected to participate in an additional 24-week, less intensive extension phase. By 24 weeks, weight-loss/patient averaged 6.0 kg (5.7%) and BMI decreased to 34.5 (by 5.7%). Blood pressure decreased from 130/83 to 116/74 (11% improvement), pulse fell slightly, and serum cholesterol and triglyceride concentrations changed nonsignificantly. With less intensive management for another 24 weeks, subjects regained minimal weight (0.43 kg). These findings add to the emerging view that weight gain is a major health problem associated with modern antipsychotic drugs and that labor-intensive weight-control efforts in patients requiring antipsychotic treatment yield clinically promising benefits. Improved treatments without weight-gain risk are needed.

Use of aripiprazole for delirium in the elderly: a short review.

PubMed

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.

[A difficult stabilisation. Chlorpromazine in the fifties in Belgium].

PubMed

Majerus, Benoît

2010-01-01

Through a Belgian case study the article tries to trace the gradual stabilisation of chlorpromazine as an antipsychotic in the 1950s. By varying ranges and angles of approach it shows the heterogeneity of actors involved and the semantic bricolage that accompany the marketing of the first antipsychotic. Far from being a revolution, the presence of Largactil in psychiatric practice is rather characterised by integration into a wider range of medicines and sinuous searching to give sense to this new drug.

Deinstitutionalization of American public hospitals for the mentally ill before and after the introduction of antipsychotic medications.

PubMed

Pow, Joni Lee; Baumeister, Alan A; Hawkins, Mike F; Cohen, Alex S; Garand, James C

2015-01-01

Deinstitutionalization following the introduction of antipsychotic medications in 1954 has received much attention as a major narrative in psychiatry. Little attention has been given, however, to deinstitutionalization before 1954. Using United States census data on discharge and readmission rates of US mental hospitals from 1935 to 1964, this article analyzes deinstitutionalization using an interrupted time-series model, with particular attention to the statistical significance of trends before and after the advent of antipsychotics. Discharge rates significantly increased in the period before antipsychotics, indicating that deinstitutionalization began before 1954, although readmissions during that same period increased at the same rate as discharges. A reasonable inference is that patients discharged in the pre-antipsychotic period were unable to live independently outside the hospital. After 1954, both discharges and readmissions increased significantly, but due to a continuing increase in admissions, no significant decrease in mental hospital populations occurred during the seven-year period after 1954. The decline began in 1961 and coincided with changes in federal policy. The fate of mental patients discharged from hospitals during this second period of deinstitutionalization is examined. The central conclusions are (1) the overall reduction in the population of mental hospitals did not coincide with the 1954 introduction of antipsychotic medications, and (2) deinstitutionalization before and after drugs has been met with inadequate community-based care.

A critical review of the antipsychotic effects of cannabidiol: 30 years of a translational investigation.

PubMed

Zuardi, Antonio Waldo; Crippa, Jose Alexandre S; Hallak, Jaime E C; Bhattacharyya, Sagnik; Atakan, Zerrin; Martin-Santos, Rocio; McGuire, Philip K; Guimarães, Francisco Silveira

2012-01-01

Δ(9)-tetrahydrocannabinol (Δ(9)-THC) is the main compound of the Cannabis Sativa responsible for most of the effects of the plant. Another major constituent is cannabidiol (CBD), formerly regarded to be devoid of pharmacological activity. However, laboratory rodents and human studies have shown that this cannabinoid is able to prevent psychotic-like symptoms induced by high doses of Δ(9)- THC. Subsequent studies have demonstrated that CBD has antipsychotic effects as observed using animal models and in healthy volunteers. Thus, this article provides a critical review of the research evaluating antipsychotic potential of this cannabinoid. CBD appears to have pharmacological profile similar to that of atypical antipsychotic drugs as seem using behavioral and neurochemical techniques in animal models. Additionally, CBD prevented human experimental psychosis and was effective in open case reports and clinical trials in patients with schizophrenia with a remarkable safety profile. Moreover, fMRI results strongly suggest that the antipsychotic effects of CBD in relation to the psychotomimetic effects of Δ(9)-THC involve the striatum and temporal cortex that have been traditionally associated with psychosis. Although the mechanisms of the antipsychotic properties are still not fully understood, we propose a hypothesis that could have a heuristic value to inspire new studies. These results support the idea that CBD may be a future therapeutic option in psychosis, in general and in schizophrenia, in particular.

Patient, Physician and Organizational Influences on Variation in Antipsychotic Prescribing Behavior.

PubMed

Tang, Yan; Chang, Chung-Chou H; Lave, Judith R; Gellad, Walid F; Huskamp, Haiden A; Donohue, Julie M

2016-03-01

Physicians face the choice of multiple ingredients when prescribing drugs in many therapeutic categories. For conditions with considerable patient heterogeneity in treatment response, customizing treatment to individual patient needs and preferences may improve outcomes. To assess variation in the diversity of antipsychotic prescribing for mental health conditions, a necessary although not sufficient condition for personalizing treatment. To identify patient caseload, physician, and organizational factors associated with the diversity of antipsychotic prescribing. Using 2011 data from Pennsylvania's Medicaid program, IMS Health's HCOSTM database, and the AMA Masterfile, we identified 764 psychiatrists who prescribed antipsychotics to 10 patients. We constructed three physician-level measures of diversity/concentration of antipsychotic prescribing: number of ingredients prescribed, share of prescriptions for most preferred ingredient, and Herfindahl-Hirschman index (HHI). We used multiple membership linear mixed models to examine patient caseload, physician, and healthcare organizational predictors of physician concentration of antipsychotic prescribing. There was substantial variability in antipsychotic prescribing concentration among psychiatrists, with number of ingredients ranging from 2-17, share for most preferred ingredient from 16%-85%, and HHI from 1,088-7,270. On average, psychiatrist prescribing behavior was relatively diversified; however, 11% of psychiatrists wrote an average of 55% of their prescriptions for their most preferred ingredient. Female prescribers and those with smaller shares of disabled or serious mental illness patients had more concentrated prescribing behavior on average. Antipsychotic prescribing by individual psychiatrists in a large state Medicaid program varied substantially across psychiatrists. Our findings illustrate the importance of understanding physicians' prescribing behavior and indicate that even among specialties regularly prescribing a therapeutic category, some physicians rely heavily on a small number of agents. Health systems may need to offer educational interventions to clinicians in order to improve their ability to tailor treatment decisions to the needs of individual patients. Future studies should examine the impact of the diversity of antipsychotic prescribing to determine whether more diversified prescribing improves patient adherence and outcomes.

Antipsychotics differ in their ability to internalise human dopamine D2S and human serotonin 5-HT1A receptors in HEK293 cells.

PubMed

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.

Concurrent Oral Antipsychotic Drug Use Among Schizophrenia Patients Initiated on Long-Acting Injectable Antipsychotics Post-Hospital Discharge.

PubMed

Doshi, Jalpa A; Pettit, Amy R; Stoddard, Jeffrey J; Zummo, Jacqueline; Marcus, Steven C

2015-08-01

Pharmacological treatment is central to effective management of schizophrenia. Prescribing clinicians have an increasing array of options from which to choose, and oral antipsychotic polypharmacy is common in routine clinical practice. Practice guidelines recommend long-acting injectable (LAI) formulations, typically viewed as monotherapeutic alternatives, for patients with established nonadherence. Yet there are limited data on the prevalence and nature of concurrent oral antipsychotic prescriptions in patients receiving LAIs. Our observational, claims-based study examined the frequency and duration of concurrent oral prescriptions in 340 Medicaid patients receiving LAI therapy. Specifically, we examined patients with a recent history of nonadherence and hospitalization for schizophrenia and included both first-generation antipsychotic depot medications (fluphenazine decanoate, haloperidol decanoate) and more recently available second-generation injectables (LAI risperidone, paliperidone palmitate). Of all patients initiated on LAIs, 75.9% had a concurrent oral antipsychotic prescription in the 6 months post-hospital discharge. Patients receiving concurrent prescriptions were frequently prescribed an oral formulation of their LAI agent, but many first-generation LAI users received a concurrent second-generation oral medication. The lowest rate of concurrent prescribing (58.8%) was found with paliperidone palmitate, whereas the highest rate was with LAI risperidone (88.9%). Overlap in oral and LAI prescriptions typically occurred for a substantial period of time (ie, >30 days) and for a notable percentage of the days covered by LAIs (often 50% or more). Our findings highlight the need to further examine such prescribing patterns, to probe the reasons for them, and to clarify the optimal roles of different antipsychotic treatments in clinical practice.

Changes in Psychotropic Drug Use in Long-Term Residents of an ICF/MR Facility.

ERIC Educational Resources Information Center

Hancock, Robert D.; And Others

1991-01-01

Psychotropic drug use was monitored for 139 persons residing continuously over a 10-year period in an Intermediate Care Facility for mentally retarded persons. Results indicated an ongoing decrease in psychotropic drug use, with usage decreasing from 30-12 percent. Antipsychotic medication was discontinued for 73 percent of the clients over the 10…

Medications Used by Students with Visual and Hearing Impairments: Implications for Teachers.

ERIC Educational Resources Information Center

Kelley, Pat; And Others

This document presents summary information in chart form on medications used by students with visual and hearing impairments. First, a checklist identifies educational considerations for students who are medicated. Next, common antipsychotic, anticonvulsant, antiasthmatic and other drugs are listed in chart form with drug name, indications, peak…

A retrospective, longitudinal study of factors associated with new antipsychotic medication use among recently admitted long-term care residents.

PubMed

Foebel, Andrea; Ballokova, Anna; Wellens, Nathalie I H; Fialova, Daniela; Milisen, Koen; Liperoti, Rosa; Hirdes, John P

2015-10-19

Use of antipsychotic (AP) medications is high and often inappropriate among institutionalized populations. Little is known about the correlates of new AP drug use following admission to long-term care (LTC) settings. This study investigated the frequency and correlates of new AP drug use among newly admitted LTC residents. This longitudinal, retrospective study used data from the interRAI - Nursing Home Minimum Data Set version 2.0 (MDS 2.0) instrument. Data about demographic, clinical and social characteristics, and medication use, were collected in Ontario, Canada, from 2003-2011 by trained nurses. Residents with complete admission and 3-6 month follow-up data were included (N = 47,768). Multivariate logistic regression analyses, stratified by gender, explored correlates of new AP drug use upon admission to LTC. New AP drug users comprised 7 % of the final cohort. Severe cognitive impairment, dementia, and motor agitation were significantly associated with new AP drug use among both sexes. Additionally, behavioural problems, conflicts with staff and reduced social engagement were strong correlates of new AP drug use. Social factors were as strongly associated with new AP drug use after LTC admission as clinical factors. Strategies to prevent the potential misuse of AP drugs upon LTC admission should consider the social determinants of such prescribing.

Self-reported motivation to smoke in schizophrenia is related to antipsychotic drug treatment.

PubMed

Barr, Alasdair M; Procyshyn, Ric M; Hui, Philip; Johnson, Joy L; Honer, William G

2008-03-01

The prevalence of smoking in schizophrenia has reliably been reported as being higher than for any other psychiatric disorder. While a number of theories have been proposed to account for such high rates of smoking, little is known about the subjective motivation for why schizophrenia patients smoke in comparison with those without the disease. The aim of the present study was to evaluate and compare smoking motivation in control subjects and schizophrenia patients, and determine if factors such as type of medication or access to cigarettes could contribute to self-reported motivation for smoking. We assessed motivation to smoke in 61 schizophrenia inpatients and 33 non-psychiatric health worker controls at a tertiary care psychiatric facility in a cross-sectional study. Nicotine dependency and smoking behavior were evaluated using the Fagerstrom Test for Nicotine Dependence and a validated questionnaire that assesses motivation for smoking along seven different dimensions. Schizophrenia patients reported a stronger motivation to smoke than controls for reasons related to pleasure from the act of smoking, as well as a need for psychomotor stimulation. Scores on both these factors were significantly associated with daily antipsychotic drug dose. The sedative and anxiolytic effects of smoking were related to anticholinergic load of psychiatric medications. The findings highlight important differences in self-reported motivation to smoke between schizophrenia patients and normals. Antipsychotic drugs may also influence aspects of motivation to smoke.

Pharmacogenetic study of second-generation antipsychotic long-term treatment metabolic side effects (the SLiM Study): rationale, objectives, design and sample description.

PubMed

Pina-Camacho, Laura; Díaz-Caneja, Covadonga M; Saiz, Pilar A; Bobes, Julio; Corripio, Iluminada; Grasa, Eva; Rodriguez-Jimenez, Roberto; Fernández, Miryam; Sanjuán, Julio; García-López, Aurelio; Tapia-Casellas, Cecilia; Álvarez-Blázquez, María; Fraguas, David; Mitjans, Marina; Arias, Bárbara; Arango, Celso

2014-01-01

Weight gain is an important and common side effect of second generation antipsychotics (SGAs). Furthermore, these drugs can induce other side effects associated with higher cardiovascular morbidity and mortality, such as insulin resistance, diabetes or metabolic syndrome. Preliminary studies show that inter-individual genetic differences produce varying degrees of vulnerability to the different SGA-induced side effects. The Second-generation antipsychotic Long-term treatment Metabolic side effects (SLiM) study aims to identify clinical, environmental and genetic factors that explain inter-individual differences in weight gain and metabolic changes in drug-naïve patients after six months of treatment with SGAs. The SLIM study is a multicenter, observational, six-month pharmacogenetic study where a cohort of 307 drug-naïve paediatric and adult patients (age range 8.8-90.1 years) and a cohort of 150 age- and sex- matched healthy controls (7.8-73.2 years) were recruited. This paper describes the rationale, objectives and design of the study and provides a description of the sample at baseline. Results from the SLiM study will provide a better understanding of the clinical, environmental, and genetic factors involved in weight gain and metabolic disturbances associated with SGA treatment. Copyright © 2014 SEP y SEPB. Published by Elsevier España. All rights reserved.

Influence of antipsychotic agents on heart rate variability in male WKY rats: implications for cardiovascular safety.

PubMed

Wang, Ying-Chieh; Chen, Chun-Yu; Kuo, Terry B J; Lai, Ching-Jung; Yang, Cheryl C H

2012-06-01

Sudden cardiac death is higher among schizophrenic patients and is associated with parasympathetic hypoactivity. Antipsychotic agents are highly suspected to be a precipitating factor. Thus, we aimed to test if the antipsychotics haloperidol, risperidone and clozapine affect cardiac autonomic function, excluding the confounding effect of altered sleep structure by the drugs. In this study, haloperidol, risperidone and clozapine were given separately by intraperitoneal injection to male Wistar-Kyoto rats for 5 days. Electroencephalogram (EEG), electromyogram (EMG) and electrocardiographic signals were recorded at baseline and 5 days after drug treatments. Sleep scoring was based on EEG and EMG signals. Cardiac autonomic function was assessed using heart rate variability analysis. Clozapine increased heart rate and suppressed cardiac sympathetic and parasympathetic activity. Cardiac acceleration was more severe during sleep. Haloperidol tended to decrease heart rate while risperidone mildly increased heart rate; however, their effects were less obvious than those of clozapine. There was a significant drug-by-stage interaction on several heart rate variability measures. Taking this evidence as a whole, we conclude that haloperidol has a better level of cardiovascular safety than either risperidone or clozapine. Application of this approach to other psychotropic agents in the future will be a useful and helpful way to evaluate the cardiovascular safety of the various psychotropic medications that are in clinical use. Copyright © 2012 S. Karger AG, Basel.

A Kappa Opioid Model of Atypical Altered Consciousness and Psychosis: U50488, DOI, AC90179 Effects on Prepulse Inhibition and Locomotion in Mice.

PubMed

Ruderman, Michael A; Powell, Susan B; Geyer, Mark A

2009-07-01

Sensorimortor gating and locomotion are behaviors that reflect pre-attentive sensory filtering and higher order, top-down, sensory processing, respectively. These processes are thought to affect either the perception of novelty in an environment (filtering) or cognition (higher order processing), salient features of models of altered states of consciousness (ASC). Drugs with highly selective receptor affinities that produce ASC can help to establish neural correlates, pathways, and mechanisms underlying ASC. Furthermore, screening for substances that selectively reverse drug-induced sensory processing departures is valuable for development of experimental antipsychotics. This study investigated the anomalous opioid sub-type, the kappa opioid (KA) system, within the two ASC models. Significant interaction and reversal effects between KA and the serotonin/2A (5-HT2A) system - the serotonin sub-type associated with classical psychedelics - were observed in three BPM measures. These measures showed that KA activation-induced effects could be reversed by 5-HT2A deactivation. These results suggest that KA could function as an atypical antipsychotic medications and/or as a screening tool for new antipsychotic medicines. The experimental work for this study comprised dose-response and reversal experiments with drugs that activate and deactivate kappa opioid and serotonin systems in the two behavioral models for the first time in mice.

Determination of myocardium to plasma concentration ratios of five antipsychotic drugs: comparison with their ability to induce arrhythmia and sudden death in clinical practice.

PubMed

Titier, Karine; Canal, Mireille; Déridet, Evelyne; Abouelfath, Abdelilah; Gromb, Sophie; Molimard, Mathieu; Moore, Nicholas

2004-08-15

Reviewing available data shows that most of antipsychotic drugs are associated with arrhythmia and sudden death. Experimental studies have shown a HERG channel blockade, a dose-dependent increase in duration of action potential or of QT interval, with various degrees of indicators of serious arrhythmogenicity. However, it seems difficult to relate these in vitro and in vivo preclinical models to clinical findings, in part, because the relationship between concentrations used and in vivo tissue concentrations during treatment in man is not known. Consequently, we established the myocardium to plasma concentration ratios for a series of antipsychotic drugs by intraperitoneal administration of different level doses to the guinea pig. Then, we compared these values to their ability to induce arrhythmia or torsade de pointes in clinical practice. The myocardium to plasma concentration ratios were 2.2 for clozapine, 2.7 for olanzapine, 3.1 for sertindole, 4.5 for risperidone, and 6.4 for haloperidol. These data suggest that when the ratio is higher than 4, arrhythmia and sudden death may be expected. On the contrary, when the ratio is less than 3, little effect may be predicted. These results underscore the importance of interpreting HERG channel data and electrophysiological data in the context of other pharmacokinetic parameters such as myocardium to plasma distribution.

Inhibition of recombinant Ca(v)3.1 (alpha(1G)) T-type calcium channels by the antipsychotic drug clozapine.

PubMed

Choi, Kee-Hyun; Rhim, Hyewhon

2010-01-25

Low voltage-activated T-type calcium channels are involved in the regulation of the neuronal excitability, and could be subject to many antipsychotic drugs. The effects of clozapine, an atypical antipsychotic drug, on recombinant Ca(v)3.1 T-type calcium channels heterologously expressed in human embryonic kidney 293 cells were examined using whole-cell patch-clamp recordings. At a standard holding potential of -100 mV, clozapine inhibited Ca(v)3.1 currents with an IC(50) value of 23.7+/-1.3 microM in a use-dependent manner. However, 10 microM clozapine inhibited more than 50% of the Ca(v)3.1 currents in recordings at a more physiologically relevant holding potential of -75 mV. Clozapine caused a significant hyperpolarizing shift in the steady-state inactivation curve of the Ca(v)3.1 channels, which is presumably the main mechanism accounting for the inhibition of the Ca(v)3.1 currents. In addition, clozapine slowed Ca(v)3.1 deactivation and inactivation kinetics but not activation kinetics. Clozapine-induced changes in deactivation and inactivation rates of the Ca(v)3.1 channel gating would likely facilitate calcium influx via Ca(v)3.1 T-type calcium channels. Thus, clozapine may exert its therapeutic and/or side effects by altering cell's excitability and firing properties through actions on T-type calcium channels.

Biological substantiation of antipsychotic-associated pneumonia: Systematic literature review and computational analyses

PubMed Central

2017-01-01

Introduction Antipsychotic (AP) safety has been widely investigated. However, mechanisms underlying AP-associated pneumonia are not well-defined. Aim The aim of this study was to investigate the known mechanisms of AP-associated pneumonia through a systematic literature review, confirm these mechanisms using an independent data source on drug targets and attempt to identify novel AP drug targets potentially linked to pneumonia. Methods A search was conducted in Medline and Web of Science to identify studies exploring the association between pneumonia and antipsychotic use, from which information on hypothesized mechanism of action was extracted. All studies had to be in English and had to concern AP use as an intervention in persons of any age and for any indication, provided that the outcome was pneumonia. Information on the study design, population, exposure, outcome, risk estimate and mechanism of action was tabulated. Public repositories of pharmacology and drug safety data were used to identify the receptor binding profile and AP safety events. Cytoscape was then used to map biological pathways that could link AP targets and off-targets to pneumonia. Results The literature search yielded 200 articles; 41 were included in the review. Thirty studies reported a hypothesized mechanism of action, most commonly activation/inhibition of cholinergic, histaminergic and dopaminergic receptors. In vitro pharmacology data confirmed receptor affinities identified in the literature review. Two targets, thromboxane A2 receptor (TBXA2R) and platelet activating factor receptor (PTAFR) were found to be novel AP target receptors potentially associated with pneumonia. Biological pathways constructed using Cytoscape identified plausible biological links potentially leading to pneumonia downstream of TBXA2R and PTAFR. Conclusion Innovative approaches for biological substantiation of drug-adverse event associations may strengthen evidence on drug safety profiles and help to tailor pharmacological therapies to patient risk factors. PMID:29077727

Biological substantiation of antipsychotic-associated pneumonia: Systematic literature review and computational analyses.

PubMed

Sultana, Janet; Calabró, Marco; Garcia-Serna, Ricard; Ferrajolo, Carmen; Crisafulli, Concetta; Mestres, Jordi; Trifirò', Gianluca

2017-01-01

Antipsychotic (AP) safety has been widely investigated. However, mechanisms underlying AP-associated pneumonia are not well-defined. The aim of this study was to investigate the known mechanisms of AP-associated pneumonia through a systematic literature review, confirm these mechanisms using an independent data source on drug targets and attempt to identify novel AP drug targets potentially linked to pneumonia. A search was conducted in Medline and Web of Science to identify studies exploring the association between pneumonia and antipsychotic use, from which information on hypothesized mechanism of action was extracted. All studies had to be in English and had to concern AP use as an intervention in persons of any age and for any indication, provided that the outcome was pneumonia. Information on the study design, population, exposure, outcome, risk estimate and mechanism of action was tabulated. Public repositories of pharmacology and drug safety data were used to identify the receptor binding profile and AP safety events. Cytoscape was then used to map biological pathways that could link AP targets and off-targets to pneumonia. The literature search yielded 200 articles; 41 were included in the review. Thirty studies reported a hypothesized mechanism of action, most commonly activation/inhibition of cholinergic, histaminergic and dopaminergic receptors. In vitro pharmacology data confirmed receptor affinities identified in the literature review. Two targets, thromboxane A2 receptor (TBXA2R) and platelet activating factor receptor (PTAFR) were found to be novel AP target receptors potentially associated with pneumonia. Biological pathways constructed using Cytoscape identified plausible biological links potentially leading to pneumonia downstream of TBXA2R and PTAFR. Innovative approaches for biological substantiation of drug-adverse event associations may strengthen evidence on drug safety profiles and help to tailor pharmacological therapies to patient risk factors.

Handwriting Movement Analyses for Monitoring Drug-Induced Motor Side Effects in Schizophrenia Patients Treated with Risperidone

PubMed Central

Caligiuri, Michael P.; Teulings, Hans-Leo; Dean, Charles E.; Niculescu, Alexander B.; Lohr, James

2009-01-01

Epidemiologic studies indicate that nearly 60% of schizophrenia (SZ) patients treated with conventional antipsychotic drugs develop extrapyramidal side effects (EPS) such as parkinsonism and tardive dyskinesia. Although the prevalence of EPS has decreased due to the newer antipsychotics, EPS continue to limit the effectiveness of these medicines. Ongoing monitoring of EPS is likely to improve treatment outcome or compliance and reduce the frequency of re-hospitalization. A quantitative analysis of handwriting kinematics was used to evaluate effects of antipsychotic medication type and dose in schizophrenia patients. Twenty-seven schizophrenia patients treated with risperidone, six schizophrenia patients who received no antipsychotic medication and 46 healthy comparison participants were enrolled. Participants performed a 20-minute handwriting task consisting of loops of various sizes and a sentence. Data were captured and analyzed using MovAlyzeR software. Results indicated that risperidone-treated participants exhibited significantly more dysfluent handwriting movements than either healthy or untreated SZ participants. Risperidone-treated participants exhibited lower movement velocities during production of simple loops compared to unmedicated patients. Handwriting dysfluency during sentence writing increased with dose. A 3-factor model consisting of kinematic variables derived from sentence writing accounted for 83% (r = .91) of the variability in medication dose. In contrast, we found no association between observer-based EPS severity ratings and medication dose. These findings support the importance of handwriting-based measures to monitor EPS in medicated schizophrenia patients. PMID:19692133

Group II Metabotropic Glutamate Receptors as Targets for Novel Antipsychotic Drugs

PubMed Central

Muguruza, Carolina; Meana, J. Javier; Callado, Luis F.

2016-01-01

Schizophrenia is a chronic psychiatric disorder which substantially impairs patients’ quality of life. Despite the extensive research in this field, the pathophysiology and etiology of schizophrenia remain unknown. Different neurotransmitter systems and functional networks have been found to be affected in the brain of patients with schizophrenia. In this context, postmortem brain studies as well as genetic assays have suggested alterations in Group II metabotropic glutamate receptors (mGluRs) in schizophrenia. Despite many years of drug research, several needs in the treatment of schizophrenia have not been addressed sufficiently. In fact, only 5–10% of patients with schizophrenia successfully achieve a full recovery after treatment. In recent years mGluRs have turned up as novel targets for the design of new antipsychotic medications for schizophrenia. Concretely, Group II mGluRs are of particular interest due to their regulatory role in neurotransmission modulating glutamatergic activity in brain synapses. Preclinical studies have demonstrated that orthosteric Group II mGluR agonists exhibit antipsychotic-like properties in animal models of schizophrenia. However, when these compounds have been tested in human clinical studies with schizophrenic patients results have been inconclusive. Nevertheless, it has been recently suggested that this apparent lack of efficacy in schizophrenic patients may be related to previous exposure to atypical antipsychotics. Moreover, the role of the functional heterocomplex formed by 5-HT2A and mGlu2 receptors in the clinical response to Group II mGluR agonists is currently under study. PMID:27242534

Safety and tolerability of olanzapine compared with other antipsychotics in the treatment of elderly patients with schizophrenia: a naturalistic study.

PubMed

Ciudad, Antonio; Montes, José-Manuel; Olivares, José-Manuel; Gómez, Juan-Carlos

2004-09-01

To evaluate the safety and tolerability of olanzapine in the treatment of elderly patients with schizophrenia. A total of 135 outpatients with schizophrenia > or =60 years of age were treated with olanzapine (n = 105) or another antipsychotic (n = 30) and followed up for 6 months. Safety measures included the recording of spontaneous adverse events and extrapyramidal symptoms (EPS). Clinical status and effectiveness of the medications were measured using the Clinical Global Impressions-Severity of Illness and the Global Assessment of Function (GAF) scales. Quality of life was assessed by means of the Spanish version of the EuroQol. The Awad scale was applied to evaluate patients' subjective attitude towards medication. The incidence of overall adverse events and EPS was non-significantly lower in patients treated with olanzapine than in patients treated with other antipsychotics. The use of anticholinergic drugs was significantly lower (P = 0.04) in patients treated with olanzapine. Both groups of patients experienced similar improvements in Clinical Global Impressions-Severity and GAF scores. Non-significantly greater improvement in the acceptance of medication occurred at endpoint in olanzapine-treated patients than in control patients as measured by the Awad scale. The improvement in the EuroQol quality of life scale achieved at the end of study did not differ between both treatment groups. Results from this naturalistic study showed that olanzapine was as safe and effective as other antipsychotic drugs in the treatment of elderly patients with schizophrenia.

Summary of the comparative effectiveness review on off-label use of atypical antipsychotics.

PubMed

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.

Psychosis

MedlinePlus

... may also be found in: Most people with schizophrenia Some people with bipolar disorder (manic-depressive) or ... may be brief. Some chronic conditions, such as schizophrenia , may need lifelong treatment with antipsychotic drugs to ...

Use of antipsychotic and antidepressant within the Psychiatric Disease Centre, Regional Health Service of Ferrara.

PubMed

Bianchi, Stefano; Bianchini, Erica; Scanavacca, Paola

2011-12-20

This study aimed at describing the type and dosage of psychopharmaceuticals dispensed to patients with psychiatric disorders and to assess the percentage of patients treated with antipsychotics and antidepressants, the associated therapies, treatment adherence, and dosages used in individuals registered at the Psychiatric Disease Center (PDC), Regional Health Service of Ferrara. The analysis focused on therapeutic programmes presented to the Department of Pharmacy of the University Hospital of Ferrara of 892 patients treated by the PDC (catchment area of 134605 inhabitants). All diagnoses were made according to International Classification of Diseases (ICD-9). The analysis focused on prescriptions from September 2007 to June 2009. Data on adherence to prescribed therapy have were processed by analysis of variance. Among the patients 63% were treated with antipsychotics and 40% with antidepressants. Among patients receiving antipsychotics 92% used second-generation antipsychotics (SGAs) whereas the remaining 8% used first generation antipsychotics (FGAs). Antipsychotic doses were lower than Daily Defined Dose (DDDs), and SGAs were often given with anticholinergics to decrease side effects. Mean adherence to antipsychotic therapy was 64%. Among antidepressants, selective serotonin reuptake inhibitors (SSRIs) were the most often prescribed, 55%. Dosages of these were within the limits indicated by the technical datasheet but higher than DDDs. Only 26% of patients underwent monotherapy. In antidepressants polytherapy, medication was associated with another antidepressant, 6% or with an antipsychotic, 51%. Mean adherence to the antidepressant therapy was 64%. Patients treated with antipsychotics tend to use doses lower than DDDs. The opposite tendency was noted in patients treated with antidepressants. Only a small percentage of patients (14%) modified their neuroleptic therapy by increasing the dosage. On the contrary, patients treated with antidepressants mainly tended to reduce the doses of their drugs. This study highlights the tendency to follow combination therapies, prescribing SGAs together with anticholinergics in order to minimize extrapyramidal side effects or by combining two antidepressants. The study showed low adherence for both pharmaceutical therapies, which is typical in the setting of the analyzed diseases.

Antipsychotic Use and Risk of Hospitalization or Death Due to Pneumonia in Persons With and Those Without Alzheimer Disease.

PubMed

Tolppanen, Anna-Maija; Koponen, Marjaana; Tanskanen, Antti; Lavikainen, Piia; Sund, Reijo; Tiihonen, Jari; Hartikainen, Sirpa; Taipale, Heidi

2016-12-01

The use of antipsychotic agents has been associated with increased pneumonia risk, but although people with dementia are particularly susceptible to pneumonia, only one small study has assessed the risk of pneumonia in relation to the use of antipsychotic agents among people with Alzheimer disease (AD). We investigated whether the incident use of antipsychotic agents, or specific antipsychotic agents, are related to a higher risk of hospitalization or death due to pneumonia in the Medication and Alzheimer Disease (MEDALZ) cohort. The cohort includes all individuals with AD who received a clinically verified AD diagnosis in Finland in 2005 to 2011 (N = 60,584; incident pneumonia, n = 12,225). A matched comparison cohort without AD (N = 60,584; incident pneumonia, n = 6,195) was used to compare the magnitude of risk. Results were adjusted for a propensity score derived from comorbidities, concomitant medications, and sociodemographic characteristics. Sensitivity analyses with case-crossover design were conducted. The use of antipsychotic agents was associated with a higher risk of pneumonia (adjusted hazard ratio [HR], 2.01; 95% CI, 1.90-2.13) in the AD cohort and a somewhat higher risk in the non-AD cohort (adjusted HR, 3.43; 95% CI, 2.99-3.93). Similar results were observed with case-crossover analyses (OR, 2.02; 95% CI, 1.75-2.34 in the AD cohort and OR, 2.59; 95% CI, 1.77-3.79 in the non-AD cohort). The three most commonly used antipsychotic agents (quetiapine, risperidone, haloperidol) had similar associations with pneumonia risk. Regardless of applied study design, treatment duration, or the choice of drug, the use of antipsychotic agents was associated with a higher risk of pneumonia. With observational data, we cannot fully rule out a shared causality between pneumonia and the use of antipsychotic agents, but the risk to benefit balance should be considered when antipsychotic agents are prescribed. Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

Medications Used for Cognitive Enhancement in Patients With Schizophrenia, Bipolar Disorder, Alzheimer's Disease, and Parkinson's Disease.

PubMed

Hsu, Wen-Yu; Lane, Hsien-Yuan; Lin, Chieh-Hsin

2018-01-01

Cognitive impairment, which frequently occurs in patients with schizophrenia, bipolar disorder, Alzheimer's disease, and Parkinson's disease, has a significant impact on the daily lives of both patients and their family. Furthermore, since the medications used for cognitive enhancement have limited efficacy, the issue of cognitive enhancement still remains a clinically unsolved challenge. We reviewed the clinical studies (published between 2007 and 2017) that focused on the efficacy of medications used for enhancing cognition in patients with schizophrenia, bipolar disorder, Alzheimer's disease, and Parkinson's disease. Acetylcholinesterase inhibitors and memantine are the standard treatments for Alzheimer's disease and Parkinson's disease. Some studies have reported selective cognitive improvement in patients with schizophrenia following galantamine treatment. Newer antipsychotics, including paliperidone, lurasidone, aripiprazole, ziprasidone, and BL-1020, have also been reported to exert cognitive benefits in patients with schizophrenia. Dopaminergic medications were found to improve language function in patients with Parkinson's disease. However, no beneficial effects on cognitive function were observed with dopamine agonists in patients with schizophrenia. The efficacies of nicotine and its receptor modulators in cognitive improvement remain controversial, with the majority of studies showing that varenicline significantly improved the cognitive function in schizophrenic patients. Several studies have reported that N -methyl-d-aspartate glutamate receptor (NMDAR) enhancers improved the cognitive function in patients with chronic schizophrenia. NMDAR enhancers might also have cognitive benefits in patients with Alzheimer's disease or Parkinson's disease. Raloxifene, a selective estrogen receptor modulator, has also been demonstrated to have beneficial effects on attention, processing speed, and memory in female patients with schizophrenia. Clinical trials with larger sample sizes evaluating comprehensive cognitive domains are warranted to examine the efficacy of medications in cognitive enhancement in patients with schizophrenia, bipolar disorder, Alzheimer's disease, and Parkinson's disease.

Treatment recommendations for DSM-5-defined mixed features.

PubMed

Rosenblat, Joshua D; McIntyre, Roger S

2017-04-01

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) mixed features specifier provides a less restrictive definition of mixed mood states, compared to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR), including mood episodes that manifest with subthreshold symptoms of the opposite mood state. A limited number of studies have assessed the efficacy of treatments specifically for DSM-5-defined mixed features in mood disorders. As such, there is currently an inadequate amount of data to appropriately inform evidence-based treatment guidelines of DSM-5 defined mixed features. However, given the high prevalence and morbidity of mixed features, treatment recommendations based on the currently available evidence along with expert opinion may be of benefit. This article serves to provide these interim treatment recommendations while humbly acknowledging the limited amount of evidence currently available. Second-generation antipsychotics (SGAs) appear to have the greatest promise in the treatment of bipolar disorder (BD) with mixed features. Conventional mood stabilizing agents (ie, lithium and divalproex) may also be of benefit; however, they have been inadequately studied. In the treatment of major depressive disorder (MDD) with mixed features, the comparable efficacy of antidepressants versus other treatments, such as SGAs, remains unknown. As such, antidepressants remain first-line treatment of MDD with or without mixed features; however, there are significant safety concerns associated with antidepressant monotherapy when mixed features are present, which merits increased monitoring. Lurasidone is the only SGA monotherapy that has been shown to be efficacious specifically in the treatment of MDD with mixed features. Further research is needed to accurately determine the efficacy, safety, and tolerability of treatments specifically for mood episodes with mixed features to adequately inform future treatment guidelines.

RISPERIDONE VERSUS HALOPERIDOL IN ACUTE AND TRANSIENT PSYCHOTIC DISORDER

PubMed Central

Chaudhuri, Bijoy Pratim; Bhagabati, Dipesh; Medhi, Dipanjali

2000-01-01

The mechanism of action of a relatively new antipsychotic drug-Risperidone differs from conventional antipsychotics like Haloperidol. We compared low dosages of Risperidone with near equivalent dosages of Haloperidol in first episode drug naive Acute and Transient Psychotic disorder. A single blind randomised four-week study protocol was employed. Highly significant and comparable efficacy as assessed by Brief Psychiatric Rating Scale and Global Assessment of Functioning Scale was seen at the end of the Study protocol in both the groups. Risperidone had significantly, an early onset of action on some of the positive as well as negative symptoms with less incidence of Extrapyramidal Symptoms in comparison to Haloperidol. We conclude that Risperidone may represent a potential useful first line agent in the treatment of Acute and Transient Psychotic Disorder. PMID:21407958

Development of near zero-order release PLGA-based microspheres of a novel antipsychotic.

PubMed

Zhao, Jinlong; Wang, Lexi; Fan, Chunyu; Yu, Kongtong; Liu, Ximing; Zhao, Xiaolei; Wang, Dan; Liu, Wenhua; Su, Zhengxing; Sun, Fengying; Li, Youxin

2017-01-10

The novel antipsychotic isoperidone, a prodrug of paliperidone, was designed to improve liposolubility for the development of poly(D,L-lactide-co-glycolide) (PLGA)-based microspheres to achieve near zero-order release behaviour in vivo. Microspheres with a smooth surface were obtained using the oil-in-water emulsion solvent evaporation method and yielded a high encapsulation efficiency of 92%. Pharmacokinetic studies in beagle dogs showed a one-week plateau phase followed by a two-week quasi-zero-order release with no burst release. The in vitro release method with a good in vitro-in vivo correlation was also established. Pharmacodynamic evaluation was performed using the MK-801-induced schizophrenic behavioural mouse model, and the sustained suppressive effect lasted two weeks. The pharmacokinetic-pharmacodynamic (PK-PD) relationship of isoperidone microspheres was compared to that of oral administration of free drug. The results revealed a strong correlation between the plasma drug level and the antipsychotic effect. A stable drug plasma concentration was detected in mice both intraday and interday from 8 to 22 d after a single injection of isoperidone microspheres, and a sustained suppressive effect on the schizophrenic model was also observed. In comparison, the mouse group receiving oral daily administration exhibited more dose-dependent effects, and the pharmacological effect diminished rapidly in conjunction with a reduction of the plasma drug levels 8h after the last administration of isoperidone on day 3. The above results confirm the superiority of long-acting release over oral administration and indicate a valuable alternative for the clinical treatment of schizophrenia. Copyright © 2016 Elsevier B.V. All rights reserved.

[Evaluation of therapeutical appropriateness in psychiatric treatment of schizophrenia, by integrating computer data records with clinical audit results].

PubMed

Farina, Giuseppina; Menditto, Enrica; Corea, Gabriella; Manna, Sonia; Pagliaro, Claudia; Troncone, Chiara; Linguiti, Claudio; Orlando, Valentina; Putignano, Daria; Tari, Daniele Ugo; Buffardi, Gianfranco

2015-01-01

The aim is to evaluate prescriptive patterns of atypical antipsychotic drugs for the treatment of schizophrenia in the LHU Caserta in 2011-2013, and to indicate potentially inappropriate therapy; to plan or schedule corrective/preventive activities to support the continuous improvement of health services. Retrospective cohort study, based on integration of health records and clinical audit. The study was performed in the following steps: data retrieval and analysis; comparison of data with international literature; editing of the Diagnostic-Therapeutic Path. The analysis was performed by using the administrative database of drug prescriptions and treatment plans in the SANIARP portal, a web platform available to specialist facilities and private and public pharmacies of LHU Caserta. The subject of our analysis was to gain information about the diagnosis and treatment of users of atypical antipsychotics in the LHU of Caserta in the years 2011-2013. We identified 2,768 patients with at least one prescription of atypical antipsychotics and diagnosis coded in the study period. Schizophrenia is the most frequent diagnosis (31.1%) and the most common drug in use is olanzapine (29.1%). About 70% of schizophrenics were on monotherapy with no change in drug, 23.6% were under polytherapy and 7.9% made a switch. Our findings were a starting point for editing Diagnostic and Therapeutic Paths aimed at raising the awareness of the scientific community about the appropriateness of diagnosis and treatment in schizophrenia. Pharmacological treatment of schizophrenia should be focused on improving the overall quality of life aimed at remission and possible recovery, although difficult.

New functional activity of aripiprazole revealed: robust antagonism of D2 dopamine receptor-stimulated Gβγ signaling

PubMed Central

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

A high throughput screening for TLR3-IRF3 signaling pathway modulators identifies several antipsychotic drugs as TLR inhibitors1

PubMed Central

Zhu, Jianzhong; Smith, Kevin; Hsieh, Paishiun N.; Mburu, Yvonne K.; Chattopadhyay, Saurabh; Sen, Ganes C.; Sarkar, Saumendra N.

2010-01-01

Toll-like Receptor 3 (TLR3) is one of the major innate immune sensors of double stranded RNA (dsRNA). The signal transduction pathway activated by TLR3, upon binding to dsRNA, leads to the activation of two major transcription factors: NF-κB and IRF3. In an effort to identify specific chemical modulators of TLR3-IRF3 signal transduction pathway we developed a cell-based read out system. Using the interferon stimulated gene 56 (ISG56) promoter driven firefly luciferase gene stably integrated in a TLR3 expressing HEK293 cell line, we were able to generate a cell line where treatment with dsRNA resulted in a dose dependent induction of luciferase activity. A screen of two pharmacologically active compound libraries using this system, identified a number of TLR3-IRF3 signaling pathway modulators. Among them we focused on a subset of inhibitors and characterized their mode of action. Several antipsychotic drugs, such as Sertraline, Trifluoperazine and Fluphenazine were found to be direct inhibitors of the innate immune signaling pathway. These inhibitors also showed the ability to inhibit ISG56 induction mediated by TLR4 and TLR7/8 pathways. Interestingly, they did not show significant effect on TLR3, TLR7 and TLR8 mediated NF-κB activation. Detailed analysis of the signaling pathway indicated that these drugs may be exerting their inhibitory effects on IRF3 via PI3K signaling pathway. The data presented here provides mechanistic explanation of possible anti-inflammatory roles of some antipsychotic drugs. PMID:20382888

Effects of antipsychotic drugs on insight in schizophrenia.

PubMed

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.

Weight change by baseline BMI from three-year observational data: findings from the Worldwide Schizophrenia Outpatient Health Outcomes Database.

PubMed

Bushe, Chris J; Slooff, Cees J; Haddad, Peter M; Karagianis, Jamie L

2013-04-01

The aim was to explore weight and body mass index (BMI) changes by baseline BMI in patients completing three years of monotherapy with various first- and second-generation antipsychotics in a large cohort in a post hoc analysis of three-year observational data. Data were analyzed by antipsychotic and three baseline BMI bands: underweight/normal weight (BMI <25 kg/m²), overweight (25-30 kg/m²) and obese (>30 kg/m²). Baseline BMI was associated with subsequent weight change irrespective of the antipsychotic given. Specifically, a smaller proportion of patients gained ≥7% baseline bodyweight, and a greater proportion of patients lost ≥7% baseline bodyweight with increasing baseline BMI. For olanzapine (the antipsychotic associated with highest mean weight gain in the total drug cohort), the percentage of patients gaining ≥7% baseline weight was 45% (95% CI: 43-48) in the underweight/normal weight BMI cohort and 20% (95% CI: 15-27) in the obese BMI cohort; 7% (95% CI: 6-8) of the underweight/normal cohort and 19% (95% CI: 13-27) of the obese cohort lost ≥7% baseline weight. BMI has an association with the likelihood of weight gain or loss and should be considered in analyses of antipsychotic weight change.

Principles of Antipsychotic Prescribing for Policy Makers, Circa 2008. Translating Knowledge to Promote Individualized Treatment

PubMed Central

Parks, Joseph; Radke, Alan; Parker, George; Foti, May-Ellen; Eilers, Robert; Diamond, Mary; Svendsen, Dale; Tandon, Rajiv

2009-01-01

Findings from 2 pivotal government-funded studies of comparative antipsychotic effectiveness undermine assumptions about the marked superiority of the more expensive second-generation “atypical” medications in comparison to the less expensive first-generation “typical” drugs. Because this assumption was the basis for the almost universal recommendation that these newer antipsychotics be used preferentially resulting in a 10-fold increase in state governmental expenditures on this class of medications over the past decade, a reassessment of policy is called for. To address the issue, the Medical Directors Council of the National Association of State Mental Health Program Directors critically reviewed findings of these studies in the context of other data and considered policy implications in the light of the obligations of state government to make available best possible and individually optimized treatment that is cost-effective. The Medical Directors Council unanimously adopted a set of recommendations to promote appropriate access, efficient utilization, and best practice use. We present our policy statement, in which we provide a succinct background, articulate general principles, and describe a set of 4 broad recommendations. We then summarize our understanding of the current state of knowledge about comparative antipsychotic effectiveness, best antipsychotic practice, and considerations for state policy that represent the basis of our position statement. PMID:18385207

Association Study of 60 Candidate Genes with Antipsychotic-induced Weight Gain in Schizophrenia Patients.

PubMed

Ryu, S; Huh, I-S; Cho, E-Y; Cho, Y; Park, T; Yoon, S C; Joo, Y H; Hong, K S

2016-03-01

This study aimed to investigate the association of multiple candidate genes with weight gain and appetite change during antipsychotic treatment. A total of 233 single nucleotide polymorphisms (SNPs) within 60 candidate genes were genotyped. BMI changes for up to 8 weeks in 84 schizophrenia patients receiving antipsychotic medication were analyzed using a linear mixed model. In addition, we assessed appetite change during antipsychotic treatment in a different group of 46 schizophrenia patients using the Drug-Related Eating Behavior Questionnaire. No SNP showed a statistically significant association with BMI or appetite change after correction for multiple testing. We observed trends of association (P<0.05) between 19 SNPs of 11 genes and weight gain, and between 7 SNPs of 5 genes and appetite change. In particular, rs696217 in GHRL showed suggestive evidence of association with not only weight gain (P=0.001) but also appetite change (P=0.042). Patients carrying the GG genotype of rs696217 exhibited higher increase in both BMI and appetite compared to patients carrying the GT/TT genotype. Our findings suggested the involvement of a GHRL polymorphism in weight gain, which was specifically mediated by appetite change, during antipsychotic treatment in schizophrenia patients. © Georg Thieme Verlag KG Stuttgart · New York.

Use of atypical antipsychotics in nursing homes and pharmaceutical marketing.

PubMed

Pimentel, Camilla B; Donovan, Jennifer L; Field, Terry S; Gurwitz, Jerry H; Harrold, Leslie R; Kanaan, Abir O; Lemay, Celeste A; Mazor, Kathleen M; Tjia, Jennifer; Briesacher, Becky A

2015-02-01

To describe the current extent and type of pharmaceutical marketing in nursing homes (NHs) in one state and to provide preliminary evidence for the potential influence of pharmaceutical marketing on the use of atypical antipsychotics in NHs. Nested mixed-methods, cross-sectional study of NHs in a cluster randomized trial. Forty-one NHs in Connecticut. NH administrators, directors of nursing, and medical directors (n = 93, response rate 75.6%). Quantitative data, including prescription drug dispensing data (September 2009-August 2010) linked with Nursing Home Compare data (April 2011), were used to determine facility-level prevalence of atypical antipsychotic use, facility-level characteristics, NH staffing, and NH quality. Qualitative data, including semistructured interviews and surveys of NH leaders conducted in the first quarter of 2011, were used to determine encounters with pharmaceutical marketing. Leadership at 46.3% of NHs (n = 19) reported pharmaceutical marketing encounters, consisting of educational training, written and Internet-based materials, and sponsored training. No association was detected between level of atypical antipsychotic prescribing and reports of any pharmaceutical marketing by at least one NH leader. NH leaders frequently encounter pharmaceutical marketing through a variety of ways, although the impact on atypical antipsychotic prescribing is unclear. © 2015, Copyright the Authors Journal compilation © 2015, The American Geriatrics Society.

Effect of Vitamin B6 Versus Propranolol on Antipsychotic-Induced Akathisia: A pilot Comparative Double-blind Study.

PubMed

Shams-Alizadeh, Narges; Bakhshayesh, Hamid; Rezaei, Farzin; Ghaderi, Ebrahim; Shams-Alizadeh, Nasim; Hassanzadeh, Kambiz

2018-01-01

Akathisia is a common adverse effect of antipsychotic drugs and is characterized by subjective feelings of restlessness. First-line treatment usually consists of propranolol, a beta adrenergic antagonist. However, propranolol does not seem to be efficacious in up to 70% of patients. This study was aimed to evaluate the effect of vitamin B6 versus propranolol on antipsychotic-induced akathisia (AIA). This study was a comparative, double-blind, randomized trial. In the present study, 66 adult patients with antipsychotic-induced akathisia were enrolled and randomized into three groups, and received vitamin B6 300 mg/12 h or 600 mg/12 h or propranolol 20 mg/12 h. The diagnosis of AIA was made by clinical examination and its severity was assessed by the Barnes Akathisia Rating Scale. Fifty one patients completed 5 days of the trial. The results showed that there was no significant difference in BARS score among the different groups which means that vitamin B6 attenuated the AIA similar to propranolol. However, there wasn't any significant difference between high or low dose of vitamin B6. In conclusion, the results of this trial suggest that vitamin B6 may be beneficial for ameliorating of antipsychotic-induced akathisia.

Bioactivity guided isolation of antipsychotic constituents from the leaves of Rauwolfia tetraphylla L.

PubMed

Gupta, Shikha; Khanna, Vinay Kumar; Maurya, Anupam; Bawankule, Dnyaneshwar Umrao; Shukla, Rajendra Kumar; Pal, Anirban; Srivastava, Santosh Kumar

2012-09-01

This study was undertaken to ascertain the antipsychotic properties of Rauwolfia tetraphylla L. leaves and to isolate and characterize the antipsychotic constituents. Among the MeOH extract and some alkaloidal fractions at different pHs, the alkaloidal CHCl(3) fraction at pH-9 (2C) showed the highest antipsychotic activity against dopaminergic (DA-D(2)) and serotonergic (5-HT(2A)) receptors in-vitro and amphetamine induced hyperactive mouse model in-vivo. The activity guided isolation of CHCl(3) fraction (2C) afforded six indole alkaloids: 10-methoxytetrahydroalstonine (1), isoreserpiline (2), an isomeric mixture of 11-demethoxyreserpiline (3) and 10-demethoxyreserpiline (4), α-yohimbine (5) and reserpiline (6). Given orally, alkaloids 3-6 showed significant antipsychotic activity in a dose dependent manner. None of the extract, alkaloidal fractions or alkaloids showed any extra pyramidal symptoms at the tested doses. It was also observed that MeOH extract was behaving similar to other clinically used novel atypical antipsychotics in having 5-HT(2A) occupancy greater than the DA-D(2) receptor at the tested doses. Further toxicity and safety evaluation studies of MeOH extracts of R. tetraphylla leaves at different doses (10, 100, 300 and 2000 mg/kg) on female Swiss albino mice showed that MeOH extract is non toxic. The isolated alkaloids, 3-6 could serve as a promising lead structure for drug development of treating psychotic conditions in human. Copyright © 2012 Elsevier B.V. All rights reserved.

Psychotropic drugs and bruxism.

PubMed

Falisi, Giovanni; Rastelli, Claudio; Panti, Fabrizio; Maglione, Horacio; Quezada Arcega, Raul

2014-10-01

Sleep and awake bruxism is defined as 'a parafunctional activity including clenching, bracing, gnashing, and grinding of the teeth'. Some evidence suggests that bruxism may be caused by, or associated with, alterations in the CNS neurotransmission. Several classes of psychotropic drugs interfering with CNS activity may potentially contribute to bruxism. Thus, the purpose of this study was to examine relevant peer-reviewed papers to identify and describe the various classes of psychotropic substances that may cause, exacerbate or reduce bruxism as the result of their pharmacological action in CNS neurons. A literature search from 1980 to the present was performed using PubMed database. The term 'bruxism' was used in association with 'psychotropic', 'dopamine (DA)', 'serotonin', 'histamine', 'antipsychotics', 'antidepressants', 'antihistaminergics' and 'stimulants'. Studies on the effects of DA agonists (Levo-DOPA, psychostimulants) and antagonists (antipsychotics) identified a central role of DA in the pathogenesis of pharmacologically induced bruxism. Important information from studies on drugs acting on serotonin neurotransmission (antidepressants) was recognized. Other mechanisms involving different neurotransmitters are emerging. This is the case of antihistaminergic drugs which may induce bruxism as a consequence of their disinhibitory effect on the serotonergic system.

Differential agonist and inverse agonist profile of antipsychotics at D2L receptors coupled to GIRK potassium channels.

PubMed

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.

An explorative study of school performance and antipsychotic medication.

PubMed

van der Schans, J; Vardar, S; Çiçek, R; Bos, H J; Hoekstra, P J; de Vries, T W; Hak, E

2016-09-21

Antipsychotic therapy can reduce severe symptoms of psychiatric disorders, however, data on school performance among children on such treatment are lacking. The objective was to explore school performance among children using antipsychotic drugs at the end of primary education. A cross-sectional study was conducted using the University Groningen pharmacy database linked to academic achievement scores at the end of primary school (Dutch Cito-test) obtained from Statistics Netherlands. Mean Cito-test scores and standard deviations were obtained for children on antipsychotic therapy and reference children, and statistically compared using analyses of covariance. In addition, differences in subgroups as boys versus girls, ethnicity, household income, and late starters (start date within 12 months of the Cito-test) versus early starters (start date > 12 months before the Cito-test) were tested. In all, data from 7994 children could be linked to Cito-test scores. At the time of the Cito-test, 45 (0.6 %) were on treatment with antipsychotics. Children using antipsychotics scored on average 3.6 points lower than the reference peer group (534.5 ± 9.5). Scores were different across gender and levels of household income (p < 0.05). Scores of early starters were significantly higher than starters within 12 months (533.7 ± 1.7 vs. 524.1 ± 2.6). This first exploration showed that children on antipsychotic treatment have lower school performance compared to the reference peer group at the end of primary school. This was most noticeable for girls, but early starters were less affected than later starters. Due to the observational cross-sectional nature of this study, no causality can be inferred, but the results indicate that school performance should be closely monitored and causes of underperformance despite treatment warrants more research.

Ethanolic extracts of Alstonia Scholaris and Bacopa Monniera possess neuroleptic activity due to anti-dopaminergic effect

PubMed Central

Jash, Rajiv; Chowdary, K. Appana

2014-01-01

Background: An increased inclination has been observed for the use of herbal drugs in chronic and incurable diseases. Treatment of psychiatric diseases like schizophrenia is largely palliative and more importantly, a prominent adverse effect prevails with the majority of anti-psychotic drugs, which are the extrapyramidal motor disorders. Existing anti-psychotic drug therapy is not so promising, and their adverse effect is a matter of concern for continuing the therapy for long duration. Objective: This experimental study was done to evaluate the neuroleptic activity of the ethanolic extracts of two plants Alstonia Scholaris and Bacopa Monnieri with different anti-psychotic animal models with a view that these plant extracts shall have no or at least reduced adverse effect so that it can be used for long duration. Materials and Methods: Two doses of both the extracts (100 and 200 mg/kg) and also standard drug haloperidol (0.2 mg/kg) were administered to their respective groups once daily with 5 different animal models. After that, the concentration of the dopamine neurotransmitter was estimated in two different regions of the brain viz. frontal cortex and striatum. Results: The result of the study indicated a significant reduction of amphetamine-induced stereotype and conditioned avoidance response for both the extracts compared with the control group, but both did not have any significant effect in phencyclidine-induced locomotor activity and social interaction activity. However, both the extracts showed minor signs of catalepsy compared to the control group. The study also revealed that the neuroleptic effect was due to the reduction of the dopamine concentration in the frontal cortex region of the rat brain. The results largely pointed out the fact that both the extract may be having the property to alleviate the positive symptoms of schizophrenia by reducing the dopamine levels of dopaminergic neurons of the brain. Conclusion: The estimation of dopamine in the two major regions of brain indicated the alteration of dopamine levels was the reason for the anti-psychotic activity as demonstrated by the different animal models. PMID:24497742

Buspirone Counteracts MK-801-Induced Schizophrenia-Like Phenotypes through Dopamine D3 Receptor Blockade

PubMed Central

Torrisi, Sebastiano Alfio; Salomone, Salvatore; Geraci, Federica; Caraci, Filippo; Bucolo, Claudio; Drago, Filippo; Leggio, Gian Marco

2017-01-01

Background: Several efforts have been made to develop effective antipsychotic drugs. Currently, available antipsychotics are effective on positive symptoms, less on negative symptoms, but not on cognitive impairment, a clinically relevant dimension of schizophrenia. Drug repurposing offers great advantages over the long-lasting, risky and expensive, de novo drug discovery strategy. To our knowledge, the possible antipsychotic properties of buspirone, an azapirone anxiolytic drug marketed in 1986 as serotonin 5-HT1A receptor (5-HT1AR) partial agonist, have not been extensively investigated despite its intriguing pharmacodynamic profile, which includes dopamine D3 (D3R) and D4 receptor (D4R) antagonist activity. Multiple lines of evidence point to D3R as a valid therapeutic target for the treatment of several neuropsychiatric disorders including schizophrenia. In the present study, we tested the hypothesis that buspirone, behaving as dopamine D3R antagonist, may have antipsychotic-like activity. Materials and Methods: Effects of acute administration of buspirone was assessed on a wide-range of schizophrenia-relevant abnormalities induced by a single administration of the non-competitive NMDAR antagonist MK-801, in both wild-type mice (WT) and D3R-null mutant mice (D3R-/-). Results: Buspirone (3 mg⋅kg-1, i.p.) was devoid of cataleptogenic activity in itself, but resulted effective in counteracting disruption of prepulse inhibition (PPI), hyperlocomotion and deficit of temporal order recognition memory (TOR) induced by MK-801 (0.1 mg⋅kg-1, i.p.) in WT mice. Conversely, in D3R-/- mice, buspirone was ineffective in preventing MK-801-induced TOR deficit and it was only partially effective in blocking MK-801-stimulated hyperlocomotion. Conclusion: Taken together, these results indicate, for the first time, that buspirone, might be a potential therapeutic medication for the treatment of schizophrenia. In particular, buspirone, through its D3R antagonist activity, may be a useful tool for improving the treatment of cognitive deficits in schizophrenia that still represents an unmet need of this disease. PMID:29046641

Crosstalk between insulin and dopamine signaling: A basis for the metabolic effects of antipsychotic drugs.

PubMed

Nash, Abigail I

2017-10-01

In the setting of rising rates of obesity and metabolic syndrome, characterized in part by hyperinsulinemia, it is increasingly important to understand the mechanisms that contribute to insulin dysregulation. The higher risk for metabolic syndrome imparted by antipsychotic medication use highlights one such mechanism. Though there is great variation in the number and types of signaling pathways targeted by these medications, the one common mechanism of action is through dopamine. Dopamine's effects on insulin signaling begin at the level of insulin secretion from the pancreas and continue through the central nervous system. In a reciprocal fashion, insulin also affects dopamine signaling, with specific effects on dopamine reuptake from the synapse. This review probes the dopamine-insulin connection to provide a comprehensive examination of how antipsychotics may contribute towards insulin resistance. Published by Elsevier B.V.

The effects of antiepileptic inducers in neuropsychopharmacology, a neglected issue. Part I: A summary of the current state for clinicians.

PubMed

de Leon, Jose

2015-01-01

The literature on inducers in epilepsy and bipolar disorder is seriously contaminated by false negative findings. This is part i of a comprehensive review on antiepileptic drug (AED) inducers using both mechanistic pharmacological and evidence-based medicine to provide practical recommendations to neurologists and psychiatrists concerning how to control for them. Carbamazepine, phenobarbital and phenytoin, are clinically relevant AED inducers; correction factors were calculated for studied induced drugs. These correction factors are rough simplifications for orienting clinicians, since there is great variability in the population regarding inductive effects. As new information is published, the correction factors may need to be modified. Some of the correction factors are so high that the drugs (e.g., bupropion, quetiapine or lurasidone) should not co-prescribed with potent inducers. Clobazam, eslicarbazepine, felbamate, lamotrigine, oxcarbazepine, rufinamide, topiramate, vigabatrin and valproic acid are grouped as mild inducers which may (i)be inducers only in high doses; (ii)frequently combine with inhibitory properties; and (iii)take months to reach maximum effects or de-induction, definitively longer than the potent inducers. Potent inducers, definitively, and mild inducers, possibly, have relevant effects in the endogenous metabolism of (i)sexual hormones, (ii) vitamin D, (iii)thyroid hormones, (iv)lipid metabolism, and (v)folic acid. Copyright © 2014 SEP y SEPB. Published by Elsevier España. All rights reserved.

Therapeutic window of dopamine D2/3 receptor occupancy to treat psychosis in Alzheimer's disease.

PubMed

Reeves, Suzanne; McLachlan, Emma; Bertrand, Julie; Antonio, Fabrizia D; Brownings, Stuart; Nair, Akshay; Greaves, Suki; Smith, Alan; Taylor, David; Dunn, Joel; Marsden, Paul; Kessler, Robert; Howard, Robert

2017-04-01

See Caravaggio and Graff-Guerrero (doi:10.1093/awx023) for a scientific commentary on this article.Antipsychotic drugs, originally developed to treat schizophrenia, are used to treat psychosis, agitation and aggression in Alzheimer's disease. In the absence of dopamine D2/3 receptor occupancy data to inform antipsychotic prescribing for psychosis in Alzheimer's disease, the mechanisms underpinning antipsychotic efficacy and side effects are poorly understood. This study used a population approach to investigate the relationship between amisulpride blood concentration and central D2/3 occupancy in older people with Alzheimer's disease by combining: (i) pharmacokinetic data (280 venous samples) from a phase I single (50 mg) dose study in healthy older people (n = 20, 65-79 years); (ii) pharmacokinetic, 18F-fallypride D2/3 receptor imaging and clinical outcome data on patients with Alzheimer's disease who were prescribed amisulpride (25-75 mg daily) to treat psychosis as part of an open study (n = 28; 69-92 years; 41 blood samples, five pretreatment scans, 19 post-treatment scans); and (iii) 18F-fallypride imaging of an antipsychotic free Alzheimer's disease control group (n = 10, 78-92 years), to provide additional pretreatment data. Non-linear mixed effects modelling was used to describe pharmacokinetic-occupancy curves in caudate, putamen and thalamus. Model outputs were used to estimate threshold steady state blood concentration and occupancy required to elicit a clinically relevant response (>25% reduction in scores on delusions, hallucinations and agitation domains of the Neuropsychiatric Inventory) and extrapyramidal side effects (Simpson Angus Scale scores > 3). Average steady state blood levels were low (71 ± 30 ng/ml), and associated with high D2/3 occupancies (65 ± 8%, caudate; 67 ± 11%, thalamus; 52 ± 11%, putamen). Antipsychotic clinical response occurred at a threshold concentration of 20 ng/ml and D2/3 occupancies of 43% (caudate), 25% (putamen), 43% (thalamus). Extrapyramidal side effects (n = 7) emerged at a threshold concentration of 60 ng/ml, and D2/3 occupancies of 61% (caudate), 49% (putamen) and 69% (thalamus). This study has established that, as in schizophrenia, there is a therapeutic window of D2/3 receptor occupancy for optimal treatment of psychosis in Alzheimer's disease. We have also shown that occupancies within and beyond this window are achieved at very low amisulpride doses in Alzheimer's disease due to higher than anticipated occupancies for a given blood drug concentration. Our findings support a central pharmacokinetic contribution to antipsychotic sensitivity in Alzheimer's disease and implicate the blood-brain barrier, which controls central drug access. Whether high D2/3 receptor occupancies are primarily accounted for by age- or disease-specific blood-brain barrier disruption is unclear, and this is an important future area of future investigation, as it has implications beyond antipsychotic prescribing. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Effects of aripiprazole and haloperidol on neural activation during the n-back in healthy individuals: A functional MRI study.

PubMed

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.

Therapeutic equivalence of antipsychotics and antidepressants - A systematic review.

PubMed

Cessak, Grzegorz; Rokita, Konrad; Dąbrowska, Marta; Sejbuk-Rozbicka, Katarzyna; Zaremba, Anna; Mirowska-Guzel, Dagmara; Bałkowiec-Iskra, Ewa

2016-04-01

The number of newly approved generic psychotropic drugs increases every year and, in many countries, their sales exceed the sales of brand-name counterparts. In order for any generic drug to receive an approval of regulatory authorities, its bioequivalence with the corresponding reference product must be demonstrated. Moreover, generic drugs must meet the same quality standards as reference drugs. However, many psychiatrists express concerns about use of generic drugs. We carried out a systematic analysis of the relevant literature indexed in PubMed and Cochrane databases. The MeSH term "generic" was combined with terms describing antipsychotic and antidepressive drugs, including their pharmaceutical names and relevant mental disorders. All 26 articles including either clinical studies or case reports have been qualified for a detailed analysis. No cases describing switches between two generics were found. Therapeutic equivalence studies evaluating antipsychotics included clozapine, olanzapine, and risperidone. The clinical status was judged to have worsened in 15.7% patients treated with clozapine. The number of relapses before and after the switch was not significantly different in patients treated with olanzapine. Two case reports showed clinical state deterioration after switch to generic risperidone. The clinical outcome after conversion to a generic antidepressant was evaluated only in one retrospective study. That study analyzed the outcomes of treatment with citalopram and revealed mental state deterioration in 11.6% of patients. Only single reports describe cases of impaired efficacy or adverse events after the switch to a generic antidepressant, including fluoxetine, mirtazapine, and venlafaxine. No cases of suicidal attempt after the switch were reported. Although the overall number of described cases is rather modest, health professionals should be aware of possible changes in the therapeutic effectiveness after changing to a generic medicine. Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Epilepsy and psychosis: a practical approach.

PubMed

Maguire, Melissa; Singh, Jasvinder; Marson, Anthony

2018-04-01

The psychoses of epilepsy can be classified according to their temporal relationship with seizures, namely as ictal, postictal and interictal psychosis. Interictal psychosis is the most common and may resemble schizophrenia. They can be challenging to diagnose and to manage, especially given the perception that some antipsychotic drugs may exacerbate seizures, while some antiepileptic medications may worsen psychosis. The current uncertainty around their best management means that some patients may not receive appropriate care. We propose a practical stepwise approach to managing psychosis in patients with epilepsy, summarising the key clinical features. We provide a framework for diagnosis, investigation and management of psychosis in the acute and long term. We also summarise the available evidence on the risk of psychosis with current antiepileptic drugs and the risk of seizures with antipsychotic drugs. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Paliperidone for the treatment of ketamine-induced psychosis: a case report.

PubMed

Zuccoli, M L; Muscella, A; Fucile, C; Carrozzino, R; Mattioli, F; Martelli, A; Orengo, S

2014-01-01

Ketamine is an anaesthetic and analgesic drug synthesized in the 1960s from phencyclidine. The recreational use of ketamine increased among the dance culture of techno and house music, in particular in clubs, discotheques, and rave parties. The psychotropic effects of ketamine are now well known and they range from dissociation to positive, negative, and cognitive schizophrenia-like symptoms. We report a case of a chronic oral consumption of ketamine which induced agitation, behavioral abnormalities, and loss of contact with reality in a poly-drug abuser; these symptoms persisted more than two weeks after the drug consumption had stopped. Antipsychotic treatment with paliperidone led to a successful management of the psychosis, getting a complete resolution of the clinical picture. Paliperidone has proven to be very effective in the treatment of ketamine-induced disorders. Moreover, the pharmacological action and metabolism of paliperidone are poorly dependent from the activity of liver enzymes, so that it seems to be one of the best second generation antipsychotics for the treatment of smokers and alcohol abusers.

Paradoxes of evidence in Russian addiction medicine.

PubMed

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.

Dried Blood Spots Combined With Ultra-High-Performance Liquid Chromatography-Mass Spectrometry for the Quantification of the Antipsychotics Risperidone, Aripiprazole, Pipamperone, and Their Major Metabolites.

PubMed

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.

Validation and pharmacological characterisation of MK-801-induced locomotor hyperactivity in BALB/C mice as an assay for detection of novel antipsychotics.

PubMed

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.

Neural basis of the potentiated inhibition of repeated haloperidol and clozapine treatment on the phencyclidine-induced hyperlocomotion

PubMed Central

Zhao, Changjiu; Sun, Tao; Li, Ming

2012-01-01

Clinical observations suggest that antipsychotic effect starts early and increases progressively over time. This time course of antipsychotic effect can be captured in a rat phencyclidine (PCP)-induced hyperlocomotion model, as repeated antipsychotic treatment progressively increases its inhibition of the repeated PCP-induced hyperlocomotion. Although the neural basis of acute antipsychotic action has been studied extensively, the system that mediates the potentiated effect of repeated antipsychotic treatment has not been elucidated. In the present study, we investigated the neuroanatomical basis of the potentiated action of haloperidol (HAL) and clozapine (CLZ) treatment in the repeated PCP-induced hyperlocomotion. Once daily for five consecutive days, adult Sprague-Dawley male rats were first injected with HAL (0.05 mg/kg, sc), CLZ (10.0 mg/kg, sc) or saline, followed by an injection of PCP (3.2 mg/kg, sc) or saline 30 min later, and motor activity was measured for 90 min after the PCP injection. C-Fos immunoreactivity was assessed either after the acute (day 1) or repeated (day 5) drug tests. Behaviorally, repeated HAL or CLZ treatment progressively increased the inhibition of PCP-induced hyperlocomotion throughout the five days of drug testing. Neuroanatomically, both acute and repeated treatment of HAL significantly increased PCP-induced c-Fos expression in the nucleus accumbens shell (NAs) and the ventral tegmental area (VTA), but reduced it in the central amygdaloid nucleus (CeA). Acute and repeated CLZ treatment significantly increased PCP-induced c-Fos expression in the ventral part of lateral septal nucleus (LSv) and VTA, but reduced it in the medial prefrontal cortex (mPFC). More importantly, the effects of HAL and CLZ in these brain areas underwent a time-dependent reduction from day 1 to day 5. These findings suggest that repeated HAL achieves its potentiated inhibition of the PCP-induced hyperlocomotion by acting on the NAs, CeA and VTA, while CLZ does so by acting on the mPFC, LSv and VTA. PMID:22476004

A study on the quality of outpatient prescription of psychopharmaceuticals in the City of Zagreb 2006-2009.

PubMed

Zivković, Kresimir; Zelić-Kerep, Ana; Stimac, Danijela; Ozić, Sanja; Zivković, Nikica

2014-06-01

The lack of Croatian studies which could determine the justifiability of excessive psychopharmaceutical utilization was an encouragement to conduct this research. Furthermore, regarding the conduction of this study, it would be possible to determine whether the trend of drug utilization has increased, decreased or perhaps stabilized. The data on the outpatient utilization of psycholeptics and psychoanaleptics were collected from all Zagreb pharmacies, 2006-2009. Based on the collected data for all N05 and N06 groups of drugs, the defined daily doses (DDD) and DDD per thousand inhabitants per day (DDD/TID) have been calculated using the Anatomical-Therapeutic-Chemical classification (ATC) for 2006, 2007, 2008 and 2009. To indicate the quality of drug prescription the Drug Utilization 90% (DU 90%) method was used. Moreover, in order to determine a more precise quality of individual drug group prescriptions, the indicators have been calculated by determining the proportion of the total utilization of individual therapeutic and pharmacological therapeutic subgroups in DDD/TID a day. The utilization of anxiolytics (N05B) accounts for most of the psycholeptic utilization in the City of Zagreb throughout the entire study period. In the study period, the utilization of antidepressants has slightly increased, by 10.5%, taking the first and the last years of the period into account. In 2006, 5 benzodiazepines and the hypnotic zolpidem, as well as 5 selective serotonin reuptake inhibitors (SSRIs) and 1 third generation antipsychotic (olanzapin) were found in the DU 90% segment. In 2009, the DU 90% segment also comprised 5 benzodiazepines and the hypnotic zolpidem, as well as 6 SSRIs and 1 third generation antipsychotic (olanzapin). In the City of Zagreb, a general insight into the quality of psychopharmaceutical prescriptions indicates stability in comparison to earlier studies. The ratio index of the first generation antipsychotic utilization, compared to the third generation antipsychotics, shows an increase in the quality of prescription. Also, the ratio index of total tricyclic antidepressants (TCA) and SSRI utilization indicates improvement in quality of prescription. The ratio index of the entire outpatient utilization of anxiolytics and antidepressants expressed in DDD/TID unfortunately shows a very mild increase of prescription quality. Benzodiazepines accounted for more than 50% of the outpatient utilization of psychopharmaceuticals throughout the study period, which proves the need for precise guidelines as the most significant means of drug rationalization and utilization. It is necessary to identify priorities and problems in order to solve them successfully, by monitoring drug utilization and prescription on a national level. Results demonstrate that within the primary health care system, there is a need for constant education on rational prescription of this drug group.

Patient, Physician and Organizational Influences on Variation in Antipsychotic Prescribing Behavior

PubMed Central

Tang, Yan; Chang, Chung-Chou H.; Lave, Judith R.; Gellad, Walid F.; Huskamp, Haiden A.; Donohue, Julie M.

2016-01-01

Background Physicians face the choice of multiple ingredients when prescribing drugs in many therapeutic categories. For conditions with considerable patient heterogeneity in treatment response, customizing treatment to individual patient needs and preferences may improve outcomes. Aims of the Study To assess variation in the diversity of antipsychotic prescribing for mental health conditions, a necessary although not sufficient condition for personalizing treatment. To identify patient caseload, physician, and organizational factors associated with the diversity of antipsychotic prescribing. Methods Using 2011 data from Pennsylvania’s Medicaid program, IMS Health’s HCOS™ database, and the AMA Masterfile, we identified 764 psychiatrists who prescribed antipsychotics to ≥10 patients. We constructed three physician-level measures of diversity/concentration of antipsychotic prescribing: number of ingredients prescribed, share of prescriptions for most preferred ingredient, and Herfindahl-Hirschman index (HHI). We used multiple membership linear mixed models to examine patient caseload, physician, and healthcare organizational predictors of physician concentration of antipsychotic prescribing. Results There was substantial variability in antipsychotic prescribing concentration among psychiatrists, with number of ingredients ranging from 2-17, share for most preferred ingredient from 16%-85%, and HHI from 1,088-7,270. On average, psychiatrist prescribing behavior was relatively diversified; however, 11% of psychiatrists wrote an average of 55% of their prescriptions for their most preferred ingredient. Female prescribers and those with smaller shares of disabled or serious mental illness patients had more concentrated prescribing behavior on average. Discussion Antipsychotic prescribing by individual psychiatrists in a large state Medicaid program varied substantially across psychiatrists. Our findings illustrate the importance of understanding physicians’ prescribing behavior and indicate that even among specialties regularly prescribing a therapeutic category, some physicians rely heavily on a small number of agents. Implications for Health Policies, Health Care Provision and Use Health systems may need to offer educational interventions to clinicians in order to improve their ability to tailor treatment decisions to the needs of individual patients. Implications for Future Research Future studies should examine the impact of the diversity of antipsychotic prescribing to determine whether more diversified prescribing improves patient adherence and outcomes. PMID:27084793

Appropriate prescribing in nursing homes demonstration project (APDP) study protocol: pragmatic, cluster-randomized trial and mixed methods process evaluation of an Ontario policy-maker initiative to improve appropriate prescribing of antipsychotics.

PubMed

Desveaux, Laura; Gomes, Tara; Tadrous, Mina; Jeffs, Lianne; Taljaard, Monica; Rogers, Jess; Bell, Chaim M; Ivers, Noah M

2016-03-29

Antipsychotic medications are routinely prescribed in nursing homes to address the behavioral and psychological symptoms of dementia. Unfortunately, inappropriate prescribing of antipsychotic medications is common and associated with increased morbidity, adverse drug events, and hospitalizations. Multifaceted interventions can achieve a 12-20 % reduction in antipsychotic prescribing levels in nursing homes. Effective interventions have featured educational outreach and ongoing performance feedback. This pragmatic, cluster-randomized control trial and embedded process evaluation seeks to determine the effect of adding academic detailing to audit and feedback on prescribing of antipsychotic medications in nursing homes, compared with audit and feedback alone. Nursing homes within pre-determined regions of Ontario, Canada, are eligible if they express an interest in the intervention. The academic detailing intervention will be delivered by registered health professionals following an intensive training program including relevant clinical issues and techniques to support health professional behavior change. Physicians in both groups will have the opportunity to access confidential reports summarizing their prescribing patterns for antipsychotics in comparison to the local and provincial average. Participating homes will be allocated to one of the two arms of the study (active/full intervention versus standard audit and feedback) in two waves, with a 2:1 allocation ratio. Homes will be randomized after stratifying for geography, baseline antipsychotic prescription rates, and size, to ensure a balance of characteristics. The primary outcome is antipsychotic dispensing in nursing homes, measured 6 months after allocation; secondary outcomes include clinical outcomes and healthcare utilization. Policy-makers and the public have taken note that antipsychotics are used in nursing homes in Ontario far more than other jurisdictions. Academic detailing can be an effective technique to address challenges in appropriate prescribing in nursing homes, but effect sizes vary widely. This opportunistic, policy-driven evaluation, embedded within a government-initiated demonstration project, was designed to ensure policy-makers receive the best evidence possible regarding whether and how to scale up the intervention. ClinicalTrials.gov NLM Identifier: NCT02604056 .

The impact of the 1987 federal regulations on the use of psychotropic drugs in Minnesota nursing homes.

PubMed Central

Garrard, J; Chen, V; Dowd, B

1995-01-01

OBJECTIVES. The purpose of this study was to examine prevalence rates of psychotropic drug use by elderly nursing home residents 3 years before and 1 year after implementation of the 1987 Omnibus Budget Reconciliation Act drug regulations throughout the United States on October 1, 1990. METHODS. A cohort study was conducted of elderly nursing home residents, for each of 4 study years (approximately 33,000 residents per year), of all nursing homes (n = 372) in Minnesota certified by Medicare and Medicaid. Data included (1) health status assessment and psychotropic drug use; (2) nursing home and care characteristics; and (3) county geographic and population characteristics. RESULTS. Annual rates of antipsychotic drug use declined by one third over the 4-year period (23%, 22%, 19%, and 15% from 3 years before enforcement of the regulations to 1 year afterward). All differences were statistically significant. Antianxiety use rates were 11%, 12%, 12%, and 12%, respectively, and antidepressant use rates were 14%, 15%, 16%, 16%, respectively, for the 4 years. The latter two classes of drugs were not affected directly by the regulations. CONCLUSIONS. Declines in the rates of antipsychotic drug use appear to be associated with anticipation of the regulations the year before and as the result of the regulations the year after the October 1990 implementation. A hypothesized medication shift to benzodiazepine drugs was not observed. PMID:7762708

The impact of reference pricing and extension of generic substitution on the daily cost of antipsychotic medication in Finland.

PubMed

Koskinen, Hanna; Ahola, Elina; Saastamoinen, Leena K; Mikkola, Hennamari; Martikainen, Jaana E

2014-12-01

To assess the impact of reference pricing and extension of generic substitution on the daily cost of antipsychotic drugs in Finland during the first year after its launch. Furthermore, the additional impact of reference pricing on prior implemented generic substitution is assessed. A retrospective analysis was performed between 2006 and 2010. A segmented linear regression analysis of interrupted time series was used to estimate changes in the levels and trends in the cost of one day of treatment. Of the study drugs, clozapine belonged to generic substitution already at the start of the study period while olanzapine and quetiapine were included in generic substitution alongside with reference pricing in 2009. Risperidone was included in generic substitution in 2008, before reference pricing. A substantial decrease in the daily cost of all four antipsychotic substances was seen after one year of the implementation of reference pricing and the extension of generic substitution. The impact ranged from -29.9% to -66.3%, and it was most substantial on the daily cost of olanzapine. Also in the daily cost of risperidone a substantial decrease of -43.3% was observed. However, most of these savings, -32.6%, were generated by generic substitution which had been adopted prior. Reference pricing and the extension of generic substitution produced substantial savings on antipsychotic medication costs during the first year after its launch, but the intensity of the impact differed between active substances. Furthermore, our results suggest that the additional cost savings from reference pricing after prior implemented generic substitution, are comparatively low.

Effects of haloperidol and aripiprazole on the human mesolimbic motivational system: A pharmacological fMRI study.

PubMed

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.

Plasma BDNFs level initially and post treatment in acute mania: comparison between ECT and atypical antipsychotic treatment and healthy controls.

PubMed

Karamustafalioglu, Nesrin; Genc, Abdullah; Kalelioglu, Tevfik; Tasdemir, Akif; Umut, Gokhan; Incir, Said; Akkuş, Mustafa; Emul, Murat

2015-08-01

Inconsistent findings concerning brain-derived neurotrophic factor (BDNF) levels across different episodes in bipolar disorder have been reported, which is also in line with the treatment effects on BDNF levels in acute mania. We aimed to compare plasma BDNF level alterations after pure antipsychotic drug or ECT plus antipsychotic drug treatment in acute mania. Sixty-eight patients with mania were divided into two treatment arms: the antipsychotic treatment arm (AP) and electroconvulsive therapy (ECT)+AP arm. In addition, 30 healthy controls were included in the study. There was no significant statistical difference according to mean age, education level, marital and working status between patients and healthy controls. The initial serum BDNF level in patients with acute mania was significantly lower than healthy controls. The initial BDNF level between the ECT arm and AP arm was not significant. The BDNF level decreased significantly after reaching remission in patients with acute mania. The change in BDNF level in the AP arm was not significant while in the ECT arm it was significant after treatment. In this study, for the first time we revealed a significant decrease in BDNF levels after ECT sessions in acute manic patients. Besides clinical remission after treatment in acute mania, the decrement in BDNF levels does not seem to be related to clinical response. Thus cumulative effects of mood episodes for the ongoing decrease in BDNF levels might be borne in mind despite the achievement of remission and/or more time being required for an increase in BDNF levels after treatment. © The Author(s) 2015.

A novel approach to measuring response and remission in schizophrenia in clinical trials.

PubMed

Aboraya, Ahmed; Leucht, Stefan; Nasrallah, Henry A; Samara, Myrto; Haro, Josep Maria; Elshazly, Ahmed; Zangeneh, Masood

2017-12-01

Pharmaceutical companies conduct clinical trials to show the efficacy and safety of new medications for the treatment of schizophrenia. After the new medications are marketed, clinicians treating patients with schizophrenia discover that a considerable number of patients do not respond to these new medications. The goals of the review are to examine the methodology and design of recent antipsychotic clinical trials, identify common flaws, and propose guidelines to fix the flaws and improve the quality of future clinical trials of antipsychotic medications. A review of recent antipsychotic clinical trials was conducted using a PubMed search. Ten recent trials published in the past four years were reviewed and their methods analyzed and critiqued. The authors identified six major methodological flaws that may explain the suboptimal response in many patients after a drug is approved. Most of the flaws are related to eligibility criteria, the misuse of the Positive and Negative Syndromes Scale (PANSS) and the lack of consensus on how to define remission, response and exacerbation in schizophrenia. Proposed guidelines for a more rigorous use of the PANSS are presented and recommendations are proposed for using uniform criteria for remission, response and exacerbation in schizophrenia. The authors recommend using standardized diagnostic interviews to screen patients for eligibility criteria and using the PANSS according to the author's recommendations and the proposed guidelines. Uniform criteria to define remission, response and exacerbation are recommended for clinical trials examining the efficacy and safety of antipsychotic drugs in schizophrenia. Copyright © 2017 Elsevier B.V. All rights reserved.

Publication Bias in Antipsychotic Trials: An Analysis of Efficacy Comparing the Published Literature to the US Food and Drug Administration Database

PubMed Central

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

Recurrent rhabdomyolysis in a teenager with psychosis-intermittent hyponatremia-polydipsia syndrome.

PubMed

Shenoi, Asha N; Stockwell, Jana

2015-04-01

To report a case of recurrent hyponatremia and rhabdomyolysis in a teenager with psychogenic polydipsia. A 16-year-old boy was admitted with recurrent episodes of hyponatremia and rhabdomyolysis secondary to psychogenic polydipsia. He was treated with hypertonic saline, intravenous fluids, and supportive care. Psychogenic polydipsia is a condition characterized by compulsive drinking. Severe hyponatremia is a rare, but serious complication in patients with psychogenic polydipsia. Failure in cell volume regulatory mechanisms, defective osmoregulation, defective urinary dilution, and enhanced secretion of vasopressin are believed to play a role in the development of hyponatremia. Rhabdomyolysis can complicate severe hyponatremia, although the exact mechanism is not known. Antipsychotic drugs are also implicated in rhabdomyolysis. Severe hyponatremia and rhabdomyolysis can complicate psychogenic polydipsia. Patients receiving antipsychotic drugs with concomitant severe hyponatremia need to be monitored for rhabdomyolysis.

Repeated administration of aripiprazole produces a sensitization effect in the suppression of avoidance responding and phencyclidine-induced hyperlocomotion and increases D2 receptor-mediated behavioral function.

PubMed

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.

Repeated administration of aripiprazole produces a sensitization effect in the suppression of avoidance responding and phencyclidine-induced hyperlocomotion and increases D2 receptor-mediated behavioral function

PubMed Central

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

Efficacy and Tolerability of Pharmacotherapy Options for the Treatment of Irritability in Autistic Children

PubMed Central

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

Metabolic effects of antipsychotics in prepubertal children: a retrospective chart review.

PubMed

Ebert, Tanya; Midbari, Yael; Shmilovitz, Ronen; Kosov, Ira; Kotler, Moshe; Weizman, Abraham; Ram, Anca

2014-05-01

Antipsychotics, especially atypical ones, are in common use in children and adolescents with psychotic or affective spectrum disorders, as well as in various other psychopathologies. The adverse effects of atypical antipsychotics in children and adolescents are similar to those seen in adults, and include weight gain, elevated blood glucose levels, and hyperlipidemia. In this retrospective chart review, we compared these adverse events in children who were treated with typical, atypical, or no antipsychotic treatment. The medical charts of 72 children, 65 boys and 7 girls, were reviewed. All children were 6-13 years old (mean age 9.5±1.7 years). In total, 48 children received antipsychotic treatment, and 24 children were in the control group. Data were extracted from the medical charts, including weight, height, body mass index (BMI), blood pressure, aspartate transaminase (AST), alanine transaminase (ALT), triglycerides, total cholesterol, and glucose blood levels. We examined the values in the beginning of the antipsychotic treatment and at release from the hospital in the study group, and at admission and in the end of the drug-free period or at release from the hospital (a duration of at least 4 weeks) in the control group. The average weight gain was 3.9±3.8 kg in the atypical antipsychotic treatment (AAT) group, 1.1±4.4 kg in the typical antipsychotic treatment (TAT) group, and 0.23±2.9 kg in the control group. The average increase in BMI was 15.1±22.0 percentiles in the AAT group, 6.4±14.2 percentiles in the TAT group, and 1.6±12.5 percentiles in the control group. No statistically significant difference was found in the increase in height percentile. There were no significant differences in the rates of elevated values of serum triglycerides, cholesterol, AST, ALT, or fasting blood glucose. We found a significant increase in both absolute weight gain and BMI percentile following atypical antipsychotic treatment. In contrast, typical antipsychotic treatment did not affect weight gain significantly, and the same was true for the control group. In addition, the rates of elevated values of biochemical parameters (AST, ALT, total cholesterol, triglycerides, and fasting blood glucose levels) were very low at the beginning of the study, and were not significantly altered by the various treatments.

Comprehensive DNA methylation analysis of human neuroblastoma cells treated with blonanserin.

PubMed

Murata, Yui; Nishioka, Masaki; Bundo, Miki; Sunaga, Fumiko; Kasai, Kiyoto; Iwamoto, Kazuya

2014-03-20

Blonanserin is a second-generation antipsychotic drug for schizophrenia. The pharmacological actions of blonanserin are shown to be the antagonism of dopamine receptor 2 and serotonin receptors. However, its molecular mechanisms in brain cells have not been fully characterized. Accumulating evidence suggests that antipsychotic drugs and mood stabilizers show epigenetic effects on a wide range of genes in animal and cellular models. We performed genome-wide DNA methylation analysis targeting 479,814 CpG sites of cultured human neuroblastoma cells administered with blonanserin. We found that 3,057 CpG sites showed statistically significant changes in DNA methylation at two different doses of blonanserin (1.36 nM and 13.6 nM). These included hypermethylated CpG sites that were enriched in genes related to axonogenesis and cell morphogenesis involved in neuron differentiation. We also showed that the global effect on DNA methylome depends on the concentration of the drug. With a high dose of blonanserin, the overall methylation levels across all CpG sites significantly increased. These increases in DNA methylation were prominent in the CpG sites distant from promoter regions. We further examined DNA methylation changes in specific genes implicated for the actions of antipsychotic drugs, such as the dopamine receptor 2 (DRD2) gene and the serotonin receptor 2A (HTR2A) gene. We observed that CpG sites that were located within DRD2 and HTR2A genes were significantly hypermethylated by blonanserin. The DNA methylation changes induced by the treatment with blonanserin will be useful for understanding its pharmacological actions at the cellular level. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

A comparison of the central nervous system effects of haloperidol, chlorpromazine and sulpiride in normal volunteers.

PubMed Central

McClelland, G R; Cooper, S M; Pilgrim, A J

1990-01-01

1. Twelve healthy male volunteers participated in four experimental occasions during each of which they were dosed with one of the following anti-psychotic drugs: chlorpromazine (50 mg), haloperidol (3 mg), sulpiride (400 mg) and placebo. Drugs were allocated to subjects in a double-blind, crossover fashion. 2. The subject's mood state, psychometric performance and electroencephalogram (EEG) were assessed pre-dose, and at 2, 4, 6, 8, 24 and 48 h post-dose. Mood states were assessed using 16 visual analogue scales and psychomotor performance was measured using the following tests: elapsed time estimation, tapping rate, choice reaction times, a rapid information processing task, flash fusion threshold, a manipulative motor task, digit span, body sway and tremor. 3. Chlorpromazine and haloperidol significantly reduced subjective ratings of 'alertness' and 'contentedness', and haloperidol significantly reduced feelings of 'calmness'. Sulpiride did not significantly affect any of the visual analogue scales. 4. All three anti-psychotic drugs had similar EEG effects with peak effect 2 to 4 h postdose. The profile was characterised by an increase in the proportion of slow wave activity (delta and theta) as well as decreased alpha (8-14 Hz) and faster (beta) wave activity. 5. Chlorpromazine reduced tapping rate and increased choice reaction movement times. Haloperidol reduced the flash fusion threshold frequency at 6 h post-dose. Sulpiride prolonged the duration of the manipulative motor task, particularly at 48 h post-dose. 6. All three anti-psychotic drugs impaired performance on the rapid information processing task. Chlorpromazine significantly reduced the number of correct letter pair identifications at 2, 4 and 6 h post-dose, haloperidol at 4, 6, 8, 24 and 48 h post-dose, and sulpiride at 24 h post-dose.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2288826

Gene expression in dopamine and GABA systems in an animal model of schizophrenia: effects of antipsychotic drugs.

PubMed

Lipska, Barbara K; Lerman, Daniel N; Khaing, Zin Z; Weickert, Cynthia Shannon; Weinberger, Daniel R

2003-07-01

We used in situ hybridization histochemistry to assess expression of dopamine receptors (D1R, D2R and D3R), neurotensin, proenkephalin and glutamate decarboxylase-67 (GAD67) in the prefrontal cortex, striatum, and/or nucleus accumbens in adult rats with neonatal ventral hippocampal (VH) lesions and in control animals after acute and chronic treatment with antipsychotic drugs clozapine and haloperidol. We also acquired these measures in a separate cohort of treatment-naïve sham and neonatally VH-lesioned rats used as an animal model of schizophrenia. Our results indicate that the neonatal VH lesion did not alter expression of D1R, D3R, neurotensin or proenkephalin expression in any brain region examined. However, D2R mRNA expression was down-regulated in the striatum, GAD67 mRNA was down-regulated in the prefrontal cortex and prodynorphin mRNA was up-regulated in the striatum of the VH-lesioned rats as compared with sham controls. Antipsychotic drugs did not alter expression of D1R, D2R or D3R receptor mRNAs but elevated neurotensin and proenkephalin expression in both groups of rats; patterns of changes were dependent on the duration of treatment and brain area examined. GAD67 mRNA was up-regulated by chronic antispychotics in the nucleus accumbens and the striatum and by chronic haloperidol in the prefrontal cortex in both sham and lesioned rats. These results indicate that the developmental VH lesion changed the striatal expression of D2R and prodynorphin and robustly compromised prefrontal GAD67 expression but did not modify drug-induced expression of any genes examined in this study.

Molindone for schizophrenia and severe mental illness.

PubMed

Bagnall, A; Fenton, M; Kleijnen, J; Lewis, R

2007-01-24

Antipsychotic therapy is the mainstay of treatment for people with schizophrenia. In recent years new or atypical antipsychotics have been introduced. These are less likely to produce movement disorders and raise serum prolactin. Researchers have suggested that molindone should be classified as an atypical antipsychotic. To determine the effects of molindone compared with placebo, typical and other atypical antipsychotic drugs for schizophrenia and related psychoses. For the original search we searched the following databases: 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). We also searched pharmaceutical databases on the Dialog Corporation Datastar and Dialog and the references of all identified studies for further trials. Finally, we contacted the manufacturer of molindone and the authors of any relevant trials. For the update of this review, we searched The Cochrane Schizophrenia Group's Trials Register (August 2005). We included all randomised controlled trials that compared molindone to other treatments for schizophrenia and schizophrenia-like psychoses. We extracted data independently and analysed on an intention to treat basis calculating, for binary data, the fixed effect relative risk (RR), their 95% confidence intervals (CI), and the number needed to treat or harm (NNT or NNH). We excluded data if loss to follow up was greater than 50%. We included fourteen studies. Duration ranged from very short (10 days) studies of the intramuscular preparation, to trials lasting over three months. For measures of global assessment, available data do not justify any conclusions on the comparative efficacy of molindone and placebo. When compared to other typical antipsychotics we found no evidence of a difference in effectiveness (doctors' 4 RCTs n=150, RR 1.13, CI 0.69 to 1.86; nurses 4RCTs n=146, RR 1.23, CI 0.82 to 1.86). Molindone is no more or less likely than typical drugs to cause movement disorders, but it does cause significantly more weight loss (2RCTs n=60 RR 2.78, CI 1.10 to 6.99, NNH 5 CI 2 to 77). 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 but its adverse effect profile does not differ significantly from that of typical antipsychotics (apart from the event of weight loss). Data from this review suggest, at present, there is no evidence to suggest that it may have an atypical profile.

Pharmacological Strategies to Counteract Antipsychotic-Induced Weight Gain and Metabolic Adverse Effects in Schizophrenia: A Systematic Review and Meta-analysis

PubMed Central

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

Perampanel and Challenging Behaviour in Intellectual Disability and Epilepsy: A Management Dilemma

PubMed Central

Choudry, Ansar

2014-01-01

We describe a case of a patient with a diagnosis of moderate learning disability with challenging behaviour and treatment refractory epilepsy. Antiepileptics can increase challenging behaviour; however, antipsychotics can provoke seizures. This results in a difficult balance for patient care. Due to worsening seizures, the patient was prescribed perampanel. This increased her aggression and agitation resulting in admission. We trialled four antipsychotic drugs to reduce her challenging behaviour, two of which worsened her seizures. It was necessary to continue antiepileptic medication to maintain adequate seizure control. However, the resulting uncontrolled challenging behaviour persisted, meaning she was unable to return to her family home on discharge. This case emphasises the difficult scenario clinician's encounter when balancing the use of antipsychotics and antiepileptics. The case demonstrates the significant functional loss due to challenging behaviour, balanced against controlling life threatening seizures. PMID:25580340

Risk of underdiagnosis of hypertension in schizophrenia patients.

PubMed

Castillo-Sánchez, Miguel; Fàbregas-Escurriola, Mireia; Bergè-Baquero, Daniel; Fernández-San Martín, MªIsabel; Boreu, Quintí Foguet; Goday-Arno, Albert

2018-01-01

Arterial hypertension requires proper screening and management, and its underdiagnosis in patients with schizophrenia (SZ) and/or antipsychotic treatment has been postulated. The objective of the study is to assess whether there are differences in the proportion of screened patients with a blood pressure >140/90 mmHg that are undiagnosed or not confirmed later (risk of underdiagnosis). Cross-sectional study of clinical records from SIDIAPQ (Spain) during the 2006-2011 period. Three groups were studied: SZ, no SZ but under antipsychotic treatment, and control groups. Patients with established hypertension, cardiovascular disease, dementia, or diagnosis of SZ or starting with antipsychotic treatment during this period were excluded. The SZ group had a lower risk of underdiagnosis than the control group (OR 0.91; 95% CI: 0.83-0.99; p < 0.05), at the expense of men (OR 0.8; 95% CI: 0.71-0.9; p < 0.001) and patients younger than 50 years of age (OR: 0.84; 95% CI: 0.74-0.93; p < 0.003). In the no SZ but under antipsychotic treatment group there were some differences, but not in the overall results. Preventive management of hypertension seemed to be sufficient for SZ and antipsychotic treatment patients. The lower prevalence of hypertension found in these groups may be due to other factors (blood pressure-lowering effect of psychoactive drugs or smoking) but these hypotheses must be evaluated with specific studies.

[Positive and negative aspects of pharmaceutical services in Spain: about antidepressants and antipsychotics].

PubMed

Girona-Brumós, Lourdes; Ribera-Montañá, Ramón; Juárez-Giménez, Juan Carlos; Pilar Lalueza-Broto, María

2006-03-01

Mental disorders mortality rates are low but they are extremely disabling so that the diagnosis and treatment of mental illness is an important task for public health and it is central in current therapy strategies and sanitary policy. The aim of this study is to analyse conditions influencing antidepressants and antipsychotics use in Spain from 1997 to 2004. Tryciclic antidepressants have been of first-choice in depression treatment for many years but their side effects profile are related to a lack of treatment adherence. Trying to increase tolerance, new antidepressants have been developed and research into new therapeutic uses is being done. These are some of the reasons causing an increase in medical utilization and costs. Medical boxes sold have increased from 14,14 million in 1997 to 26,76 million in 2004, meaning 168,61 and 447,11 million euros respectively. Antipsychotic use has been maintained, 11,74 million boxes in 1997 and 12,65 in 2004; however, there has been a rise in price from 61,84 to 317,46 million euros due to second generation antipsychotics prescription (mainly risperidone and olanzapine) Some conditions have contributed to current situation: increased number of diagnosed patients with depression and other mental disorders, new approved therapeutic uses and a rise in elderly people receiving new antipsychotic agents. Moreover, promotional marketing is causing an increase in new recently commercialised drugs use.

Blonanserin, an antipsychotic and dopamine D₂/D₃receptor antagonist, and ameliorated alcohol dependence.

PubMed

Takaki, Manabu; Ujike, Hiroshi

2013-01-01

Blonanserin (BNS) is used for treatment of both positive and negative symptoms of schizophrenia in Japan and Korea. Because BNS has weak α1 receptor blocking activities and is almost devoid of histamine H1 and muscarinic M1 antagonist activity, BNS is better tolerated than other atypical antipsychotics. A high degree of D₃ receptor blockage is reported to be predictive of drug abuse and alcoholism, and BNS has strong D₃ receptor antagonism. Thus, BNS may be useful in the treatment of alcoholism. We present a case in which BNS ameliorated alcohol dependence.

Can a digital medicine system improve adherence to antipsychotic treatment?

PubMed

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.

Olanzapine-induced hyperphagia and weight gain associate with orexigenic hypothalamic neuropeptide signaling without concomitant AMPK phosphorylation.

PubMed

Fernø, Johan; Varela, Luis; Skrede, Silje; Vázquez, María Jesús; Nogueiras, Rubén; Diéguez, Carlos; Vidal-Puig, Antonio; Steen, Vidar M; López, Miguel

2011-01-01

The success of antipsychotic drug treatment in patients with schizophrenia is limited by the propensity of these drugs to induce hyperphagia, weight gain and other metabolic disturbances, particularly evident for olanzapine and clozapine. However, the molecular mechanisms involved in antipsychotic-induced hyperphagia remain unclear. Here, we investigate the effect of olanzapine administration on the regulation of hypothalamic mechanisms controlling food intake, namely neuropeptide expression and AMP-activated protein kinase (AMPK) phosphorylation in rats. Our results show that subchronic exposure to olanzapine upregulates neuropeptide Y (NPY) and agouti related protein (AgRP) and downregulates proopiomelanocortin (POMC) in the arcuate nucleus of the hypothalamus (ARC). This effect was evident both in rats fed ad libitum and in pair-fed rats. Of note, despite weight gain and increased expression of orexigenic neuropeptides, subchronic administration of olanzapine decreased AMPK phosphorylation levels. This reduction in AMPK was not observed after acute administration of either olanzapine or clozapine. Overall, our data suggest that olanzapine-induced hyperphagia is mediated through appropriate changes in hypothalamic neuropeptides, and that this effect does not require concomitant AMPK activation. Our data shed new light on the hypothalamic mechanism underlying antipsychotic-induced hyperphagia and weight gain, and provide the basis for alternative targets to control energy balance.

Olanzapine-Induced Hyperphagia and Weight Gain Associate with Orexigenic Hypothalamic Neuropeptide Signaling without Concomitant AMPK Phosphorylation

PubMed Central

Fernø, Johan; Vázquez, María Jesús; Nogueiras, Rubén; Diéguez, Carlos; Vidal-Puig, Antonio; Steen, Vidar M.; López, Miguel

2011-01-01

The success of antipsychotic drug treatment in patients with schizophrenia is limited by the propensity of these drugs to induce hyperphagia, weight gain and other metabolic disturbances, particularly evident for olanzapine and clozapine. However, the molecular mechanisms involved in antipsychotic-induced hyperphagia remain unclear. Here, we investigate the effect of olanzapine administration on the regulation of hypothalamic mechanisms controlling food intake, namely neuropeptide expression and AMP-activated protein kinase (AMPK) phosphorylation in rats. Our results show that subchronic exposure to olanzapine upregulates neuropeptide Y (NPY) and agouti related protein (AgRP) and downregulates proopiomelanocortin (POMC) in the arcuate nucleus of the hypothalamus (ARC). This effect was evident both in rats fed ad libitum and in pair-fed rats. Of note, despite weight gain and increased expression of orexigenic neuropeptides, subchronic administration of olanzapine decreased AMPK phosphorylation levels. This reduction in AMPK was not observed after acute administration of either olanzapine or clozapine. Overall, our data suggest that olanzapine-induced hyperphagia is mediated through appropriate changes in hypothalamic neuropeptides, and that this effect does not require concomitant AMPK activation. Our data shed new light on the hypothalamic mechanism underlying antipsychotic-induced hyperphagia and weight gain, and provide the basis for alternative targets to control energy balance. PMID:21695181

Is cerebrovascular disease a silent condition in patients with chronic schizophrenia-related disorders?

PubMed

Berrocal-Izquierdo, Nuria; Bioque, Miquel; Bernardo, Miguel

2017-03-01

Patients with chronic schizophrenia-related disorders are at a heightened risk of developing cardiovascular disease. The presence and interpretation of cerebral vascular lesions in neuroimaging tests in these patients represents a common clinical challenge. Nevertheless, the literature on cerebrovascular disease in this population is scarce and contradictory. The aim of this study was to analyse the relationship between schizophrenia-related disorders and cerebrovascular morbidity. A case-control study compared cerebrovascular morbidity in a group of patients with schizophrenia-related disorder versus a group of patients with another severe mental illness. The risk of presenting cerebrovascular morbidity was four times higher and statistically significant in patients with schizophrenia-related disorders compared with controls, paired by age and sex. However, both groups were homogeneous in terms of cardiovascular risk factors. There were significant differences between the two groups only in the time using first-generation antipsychotic drugs and taking two or more antipsychotic medications simultaneously. The relationship between chronic schizophrenia-related disorders and cerebrovascular disease may be beyond the classic cardiovascular risk factors and related to certain medications. This is one of the first studies to focus on the relation among cerebrovascular morbidity, antipsychotic drugs and disorders related to schizophrenia in middle-aged and elderly adults.

Improving outcome in schizophrenia: the potential importance of EPS and neuroleptic dysphoria.

PubMed

Gerlach, Jes

2002-03-01

Despite half a century of antipsychotic drug treatment, the outcome of therapy in schizophrenia remains disappointing. Relapse, rehospitalization, limited fulfilment of social roles, and suicide remain frequent, and the economic costs are high. Current relapse rates may be two to three times higher than those that could be achieved with optimal use of therapy. Poor compliance with treatment is considered to be a significant preventable cause of poor outcome and is in turn likely to be influenced by the patient's experience of drug treatment. There is some evidence that extrapyramidal symptoms (EPS), particularly akathisia and neuroleptic dysphoria, are associated with poor compliance and poor treatment outcome. Atypical antipsychotics have a lower risk of EPS than do standard antipsychotics. Some (risperidone, olanzapine, and ziprasidone) show evidence of a dose-related increase in EPS, but clozapine and quetiapine have demonstrated a placebo-level incidence of EPS across the dose range. Quetiapine does not require the regular blood monitoring mandated for clozapine, and results from a patient survey indicate a high degree of patient satisfaction with treatment. While further research is needed, it is possible that wider use of medications with low EPS and high patient acceptability could promote better compliance and improve the outcome of schizophrenia treatment.

Current status of atypical antipsychotics for the treatment of fibromyalgia.

PubMed

Rico-Villademoros, F; Calandre, E P; Slim, M

2014-06-01

The treatment of fibromyalgia requires pharmacological and nonpharmacological therapies. The pharmacological treatment of fibromyalgia is limited to a few drugs that have been demonstrated to be moderately effective in some but not all dimensions of the disease. Therefore, the search for new drugs to treat this condition is warranted. Atypical antipsychotics offered an attractive alternative because they had been shown to be active against several key symptoms of fibromyalgia. The results of open-label studies, however, appear to indicate that atypical antipsychotics are poorly tolerated in patients with fibromyalgia, and only quetiapine XR has been studied in randomized controlled trials. Quetiapine XR has demonstrated effectiveness in treating comorbid major depression, anxiety and sleep disturbance. However, in two randomized controlled trials, quetiapine XR was not differentiated from placebo and failed to demonstrate noninferiority to amitriptyline in terms of improving overall symptomatology. The effect of quetiapine XR on pain and its usefulness as part of a combination pharmacological regimen should be further evaluated. Overall, the use of quetiapine (initiated at a low dose and slowly titrated) in fibromyalgia should be limited to patients with comorbid major depression or patients who are currently receiving other treatments and have unresolved and disabling depressive and/or anxiety symptoms. Copyright 2014 Prous Science, S.A.U. or its licensors. All rights reserved.

[Minocycline as a therapeutic drug for methamphetamine use disorders].

PubMed

Hashimoto, Kenji

2008-02-01

Use of methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) is an extremely serious and growing problem throughout the world, including Japan. Antipsychotic drugs have been used for psychotic symptoms associated with these abused drugs. However, there are currently no particular pharmacological treatments for the wide range of symptoms associated with these abused drugs. Recently, we reported that the second generation antibiotic drug minocycline can attenuate behavioral abnormalities and neurotoxicity in the brain after administration of methamphetamine or MDMA. In this review, we discuss minocycline as a new potential therapeutic drug for schizophrenia as well as psychosis associated with these abused drugs.

Autism and Obesity: Co-Occurring Conditions or Drug Side Effects

DTIC Science & Technology

2015-10-01

Antipsychotic-Induced Weight Gain ASD: Autism Spectrum Disorder BMI: Body Mass Index SSC: Simons Simplex Collection SNP: Single Nucleotide Polymorphism...AWARD NUMBER: W81XWH-14-1-0374 TITLE: Autism and Obesity: Co-Occurring Conditions or Drug Side Effects? PRINCIPAL INVESTIGATOR: Zohreh...SUBTITLE Autism and Obesity: Co-Occurring Conditions or Drug Side Effects? 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-14-1-0374 5c. PROGRAM ELEMENT

Novel antipsychotics activate recombinant human and native rat serotonin 5-HT1A receptors: affinity, efficacy and potential implications for treatment of schizophrenia.

PubMed

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.

Treatment pathway and patterns of clozapine prescribing for schizophrenia in New Zealand.

PubMed

Wheeler, Amanda J

2008-06-01

To describe the treatment pathway and patterns of clozapine use in patients with schizophrenia, including coprescribed psychotropic medications, and compare the extent of coprescribing of clozapine with that of non-clozapine schizophrenia treatment in community mental health services in the Auckland and Northland regions of New Zealand. A retrospective chart review was conducted for adult outpatients receiving care from community mental health services on October 31, 2004. Data collected for all patients prescribed an antipsychotic included demographics (sex, age, ethnicity); principal diagnosis (Diagnostic and Statistical Manual of Mental Disorders, 4th edition); comorbid conditions; duration of mental illness; psychiatric admissions; and treatment information (psychotropic medications, with dose and route of administration). If clozapine had been started after the introduction of full government prescription subsidy (February 1999), additional data, including year of initiation and prior antipsychotic history, were collected. Analysis included all outpatients with a diagnosis of schizophrenia (including schizoaffective disorder). Antipsychotics were prescribed for 2796 schizophrenia patients; 32.8% were prescribed clozapine, with a mean dose of 372 mg/day and an average duration of illness of 9.7 years before starting clozapine. Patients who had started treatment after clozapine was funded by the government (59.3%) had received a median of 3 antipsychotic drugs prior to starting clozapine; most of the treatment regimens included 1 second-generation antipsychotic (91.2%). Clozapine patients were less likely to be coprescribed another antipsychotic compared with non-clozapine patients (11.7% vs 17.6%; p < 0.001). Both the clozapine and non-clozapine groups had a low total number of psychotropic medications prescribed (median 2); for clozapine patients, the second drug was most likely to be for treatment of hypersalivation. Outpatients with treatment-resistant schizophrenia were prescribed clozapine at expected rates; however, treatment was delayed longer than recommended. There is some evidence that access to clozapine for treatment-resistant schizophrenia has improved, possibly as the result of the introduction of government subsidy, guideline dissemination, or increasing experience of clinicians with use of clozapine. In this real-world environment, the number of concomitant psychotropic medications for outpatients with schizophrenia was found to be low; when used concomitantly with clozapine, they were most commonly used to manage adverse effects.

Rationale and design of the PLACID study: a randomised trial comparing the efficacy and safety of inhaled loxapine versus IM aripiprazole in acutely agitated patients with schizophrenia or bipolar disorder.

PubMed

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 ).

Blonanserin Augmentation for Treatment-Resistant Somatic Symptom Disorder: A Case Series.

PubMed

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.

[Atypical antipsychotic-induced weight gain].

PubMed

Godlewska, Beata R; Olajossy-Hilkesberger, Luiza; Marmurowska-Michałowska, Halina; Olajossy, Marcin; Landowski, Jerzy

2006-01-01

Introduction of a new group of antipsychotic drugs, called atypical because of the proprieties differing them from classical neuroleptics, gave hope for the beginning of a new era in treatment of psychoses, including schizophrenia. Different mechanisms of action not only resulted in a broader spectrum of action and high efficacy but also in a relative lack of extrapiramidal symptoms. However, atypical neuroleptics are not totally free from adverse effects. Symptoms such as sedation, metabolic changes and weight gain, often very quick and severe - present also in the case of classical drugs, but put to the background by extrapiramidal symptoms--have become prominent. Weight gain is important both from the clinical and subjective point of view--as associated with serious somatic consequences and as a source of enormous mental distress. These problems are addressed in this review, with the focus on weight gain associated with the use of specific atypical neuroleptics.

Proposing the Use of Partial AUC as an Adjunctive Measure in Establishing Bioequivalence Between Deltoid and Gluteal Administration of Long-Acting Injectable Antipsychotics.

PubMed

Lee, Lik Hang N; Choi, Charles; Gershkovich, Pavel; Barr, Alasdair M; Honer, William G; Procyshyn, Ric M

2016-12-01

The maximum plasma concentration (C max ) and the area under the plasma concentration-time curve (AUC) are commonly used to establish bioequivalence between two formulations of the same oral medication. Similarly, these pharmacokinetic parameters have also been used to establish bioequivalence between two sites of administration for the same injectable formulation. However, these conventional methods of establishing bioequivalence are of limited use when comparing modified-release formulations of a drug, particularly those with rates of absorption that are amenable to change with the site of injection. Inherent differences in the rate of absorption can result in clinically significant differences in early exposure and drug response. Here, we propose the use of the partial AUC (pAUC) as a measure of early exposure to aid in the assessment of bioequivalence between the gluteal and the deltoid site of administration for long-acting injectable antipsychotics.

Clozapine in schizophrenia patients with recurrent catatonia: report of two cases.

PubMed

Hung, Yi-Yung; Yang, Ping-Suen; Huang, Tiao-Lai

2006-04-01

Prolonged catatonia can be a source of extremely serious morbidity and mortality. Lorazepam is effective in rapidly relieving most cases of catatonia. Reports have also shown that second-generation antipsychotic drugs are also efficacious in relieving catatonia. This report describes two schizophrenia patients who demonstrated recurrent catatonic features mutism and stupor. Both patients were treated with lorazepam, diazepam or electroconvulsive therapy (ECT). Patient 1 responded well and rapidly to lorazepam each time catatonia happened; but catatonia recurred once a year under treatment with many antipsychotic drugs. Patient 2 had catatonia features associated with discontinuing or decreasing clozapine. With each recurrent episode, the duration of catatonia increased, requiring an increased dosage of benzodiazepine. The patient's response to lorazepam and ECT gradually decreased, until the patient had almost no response to lorazepam, diazepam or ECT. Both patients had no recurrence during a period of 2-year follow up with continuous clozapine therapy.

Effectiveness of blonanserin for patients with drug treatment-resistant schizophrenia and dopamine supersensitivity: A retrospective analysis.

PubMed

Tachibana, Masumi; Niitsu, Tomihisa; Watanabe, Motoki; Hashimoto, Tasuku; Kanahara, Nobuhisa; Ishikawa, Masatomo; Iyo, Masaomi

2016-12-01

Dopamine supersensitivity psychosis (DSP) is one of the key factors contributing to the development of antipsychotic treatment-resistant schizophrenia (TRS). We investigated the efficacy of blonanserin, an atypical antipsychotic, for patients with TRS and DSP. In this 12-month retrospective follow-up study, we investigated the cases of eight consecutive patients with unstable TRS and DSP treated with blonanserin as an add-on therapy. We examined changes in scores for the Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression-Severity of Illness (CGI-S) scale and the Global Assessment of Functioning scale (GAF) during the 12 months after the administration of blonanserin. The patients' total scores on the BPRS and GAF scores were significantly improved by 3 months at the latest. Positive BPRS and CGI-S scores were also improved by 6 months at the latest. The total chlorpromazine-equivalent doses of antipsychotics were significantly reduced from 1462.3±499.6mg to 794.1±642.8mg (p=0.001) after 12 months of blonanserin treatment, with a favorable safety and tolerability profile. Blonanserin may be a promising antipsychotic for the treatment of TRS and DSP. Copyright © 2016 Elsevier B.V. All rights reserved.

Movement Disorders Induced by the "Atypical" Antipsychotic Aripiprazole.

PubMed

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.

Long-acting atypical injectable antipsychotics in the treatment of schizophrenia: safety and tolerability review.

PubMed

Cañas, Fernando; Möller, Hans-Jürgen

2010-09-01

Although atypical antipsychotics have beneficial efficacy and tolerance, non-adherence and partial adherence remain in patients treated for schizophrenia. Long-acting injectable or depot atypical antipsychotics offer better medication adherence and tolerability advantages. Currently, two drugs are available for the treatment of schizophrenia, risperidone long-acting injectable (RLAI) and olanzapine pamoate (OP). Short- and long-term safety and tolerability data on RLAI and OP from January 2006 through September 2009 were reviewed by performing Medline and PubMed searches, reviewing abstracts and poster presentations, and viewing available material from the FDA and European Medicines Agency. RLAI and OP show good short- and long-term safety when treating patients with schizophrenia, with uncommon discontinuation due to adverse effects. RLAI and OP data show rare problems with injection site reactions and patients exposed to injectable treatments prefer to continue injections. Infrequent but serious post-injection delirium sedation syndrome occurred after 1% of OP injections. Weight gain was generally higher among patients treated with OP versus RLAI. Healthcare providers, patients and family members should be made aware of the safety and benefits of long-acting injectable atypical antipsychotics in order to diminish the unnecessary restrictions of these therapies for patients with schizophrenia.

One patient with schizophrenia showed reduced drug-induced extrapyramidal symptoms as a result of an alternative regimen of treatment with paliperidone 3 and 6 mg every other day.

PubMed

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. Antipsychotic drugs are given by tapering their dose, extending the dosing interval, and so on, as part of a treatment strategy to minimize the adverse effects while at the same time maintaining efficacy. We report the case of one patient with schizophrenia in whom the clinical symptoms were alleviated after treatment with 6 mg paliperidone. However, the patient developed extrapyramidal syndrome, for which 3 and 6 mg paliperidone were administered alternately every other day. Extrapyramidal syndrome was assessed using the Drug-Induced Extrapyramidal Symptoms Scale, Abnormal Involuntary Movement Scale, or Barnes Akathisia Scale. There was improvement in Drug-Induced Extrapyramidal Symptoms Scale score and Abnormal Involuntary Movement Scale score. However, there was almost no change in the Positive and Negative Syndrome Scale total score, positive score, negative score, or general score. The results indicate the possibility of lessened adverse effects as a result of an alternative regimen of treatment with paliperidone 3 and 6 mg every other day in the maintenance phase.

What do large scale studies of medication in schizophrenia add to our management strategies?

PubMed

Agius, Mark; Davis, Abigail; Gilhooley, Michael; Chapman, Shelley; Zaman, Rashid

2010-06-01

A number of large naturalistic trials have reported in recent years comparing second generation antipsychotic drugs with their predecessors. The conclusions they draw have rightly sparked much debate, but are these studies truly comparable? If not, which of them are most methodologically robust and are these the studies most suitable as a foundation for clinical care guidelines with a strong evidence base. We aimed to conduct a review of the current literature to establish the appropriateness of several recent major clinical studies being used as the basis for clinical guidelines. A literature search using the PUBMED database was carried out. Five major studies comparing antipsychotic efficacy were selected as possible candidates and subjected to further analysis. The studies were: * CUTLASS (Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia study); * CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness study); * SOHO (Schizophrenia outpatients Health Outcomes study); * CAFE (Comparison of Atypicals in First Episode study); * EUFEST (European First Episode Schizophrenia Trial). The trials: * CAFE - the trial, although well randomised and blinded, uses discontinuation as a primary endpoint - this is hard to draw conclusions from: patients may discontinue due to side effects, due to lack of efficacy or with against medical advice for a multitude of reasons. As a secondary endpoint, the study does make use of a PANSS scoring system to measure efficacy, adding some weight to the conclusion that olanzapine, quetiaine and risperidone in early psychosis patients have equivalent efficacies. * CATIE - This trial was a comparative study, and so lacked a control arm and used discontinuation of medication an inverse measure of efficacy - an easily quantifiable event, but making for difficult interpretation. However most criticism has been directed at the unusually low (quitiapine, ziprasidone) and high (olanzapine and perphenazine) doses of drug used, which were reflected in their differing rates of efficacy. * CUtLASS This trial allows for less generalisation of its findings to the general population as it makes use a specific sub-population (those switching from one medication to another after a period of treatment). Also some patients were prescribed oral medications and some depot injections - making comparisons difficult due to possible differences in compliance. * EUFEST This trial makes use of discontinuation as an endpoint with the weaknesses we have described. Treatment of first episodes of psychosis is shown to be feasible, but it could not suggest if haloperidol or second generation drugs may be more efficacious. * SOHO - This trial hindered by the observational design of the study and small numbers reaching the primary end point (4%) caution should be exercised in the conclusion that olanzapine is superior to risperidone, quetiapine or typical antipsychotics. There is much information useful for clinical practice to be gathered from the results of these major studies, however, interpretation is hampered by both variations and weakness in study design. On balance it does appear that different antipsychotics possess differing efficacy, but also of relevance to the development of sound clinical guidelines is their differing side effects profile.

Methylene Blue: The Long and Winding Road From Stain to Brain: Part 2.

PubMed

Howland, Robert H

2016-10-01

Methylene blue was the first synthetic drug ever used in medicine, having been used to treat clinical pain syndromes, malaria, and psychotic disorders more than one century ago. Methylene blue is a cationic thiazine dye with redox-cycling properties and a selective affinity for the nervous system. This drug also inhibits the activity of monoamine oxidase, nitric oxide synthase, and guanylyl cyclase, as well as tau protein aggregation; increases the release of neurotransmitters, such as serotonin and norepinephrine; reduces amyloid-beta levels; and increases cholinergic transmission. The action of methylene blue on multiple cellular and molecular targets justifies its investigation in various neuropsychiatric disorders. Investigations of methylene blue were instrumental in the serendipitous development of phenothiazine antipsychotic drugs. Although chlorpromazine is heralded as the first antipsychotic drug used in psychiatry, methylene blue is a phenothiazine drug that had been used to treat psychotic patients half a century earlier. It has also been studied in bipolar disorder and deserves further investigation for the treatment of unipolar and bipolar disorders. More recently, methylene blue has been the subject of preclinical and clinical investigations for cognitive dysfunction, dementia, and other neurodegenerative disorders. [Journal of Psychosocial Nursing and Mental Health Services, 54(10), 21-26.]. Copyright 2016, SLACK Incorporated.

Augmentation by escitalopram, but not citalopram or R-citalopram, of the effects of low-dose risperidone: behavioral, biochemical, and electrophysiological evidence.

PubMed

Marcus, Monica M; Jardemark, Kent; Malmerfelt, Anna; Gertow, Jens; Konradsson-Geuken, Asa; Svensson, Torgny H

2012-04-01

Antidepressant drugs are frequently used to treat affective symptoms in schizophrenia. We have recently shown that escitalopram, but not citalopram or R-citalopram, increases firing rate and burst firing of midbrain dopamine neurons, potentiates cortical N-methyl-D-aspartate (NMDA) receptor-mediated transmission and enhances cognition, effects that might influence the outcome of concomitant antipsychotic medication. Here, we studied, in rats, the behavioral and neurobiological effects of adding escitalopram, citalopram, or R-citalopram to the second-generation antipsychotic drug risperidone. We examined antipsychotic efficacy using the conditioned avoidance response (CAR) test, extrapyramidal side effect (EPS) liability using a catalepsy test, dopamine outflow in the medial prefrontal cortex (mPFC) and nucleus accumbens using in vivo microdialysis in freely moving animals, and NMDA receptor-mediated transmission in the mPFC using intracellular electrophysiological recording in vitro. Only escitalopram (5 mg/kg), but not citalopram (10 mg/kg), or R-citalopram (10 mg/kg), dramatically enhanced the antipsychotic-like effect of a low dose of risperidone (0.25 mg/kg), without increasing catalepsy. Given alone, escitalopram, but not citalopram or R-citalopram, markedly enhanced both cortical dopamine output and NMDA receptor-mediated transmission. Addition of escitalopram and to some extent R-citalopram, but not citalopram, significantly enhanced both cortical dopamine output and cortical NMDA receptor-mediated transmission induced by a suboptimal dose/concentration of risperidone. These results suggest that adjunct treatment with escitalopram, but not citalopram, may enhance the effect of a subtherapeutic dose of risperidone on positive, negative, cognitive, and depressive symptoms in schizophrenia, yet without increased EPS liability. Copyright © 2011 Wiley Periodicals, Inc.

Oral haloperidol or olanzapine intake produces distinct and region-specific increase in cannabinoid receptor levels that is prevented by high fat diet.

PubMed

Delis, Foteini; Rosko, Lauren; Shroff, Aditya; Leonard, Kenneth E; Thanos, Panayotis K

2017-10-03

Clinical studies show higher levels of cannabinoid CB1 receptors (CB1R) in the brain of schizophrenic patients while preclinical studies report a significant functional interaction between dopamine D2 receptors and CB1Rs as well as an upregulation of CB1Rs after antipsychotic treatment. These findings prompted us to study the effects of chronic oral intake of a first and a second generation antipsychotic, haloperidol and olanzapine, on the levels and distribution of CB1Rs in the rat brain. Rats consumed either regular chow or high-fat food and drank water, haloperidol drinking solution (1.5mg/kg), or olanzapine drinking solution (10mg/kg) for four weeks. Motor and cognitive functions were tested at the end of treatment week 3 and upon drug discontinuation. Two days after drug discontinuation, rats were euthanized and brains were processed for in vitro receptor autoradiography. In chow-fed animals, haloperidol and olanzapine increased CB1R levels in the basal ganglia and the hippocampus, in a similar, but not identical pattern. In addition, olanzapine had unique effects in CB1R upregulation in higher order cognitive areas, in the secondary somatosensory cortex, in the visual and auditory cortices and the geniculate nuclei, as well as in the hypothalamus. High fat food consumption prevented antipsychotic-induced increase in CB1R levels in all regions examined, with one exception, the globus pallidus, in which they were higher in haloperidol-treated rats. The results point towards the hypothesis that increased CB1R levels could be a confounding effect of antipsychotic medication in schizophrenia that is circumveneted by high fat feeding. Copyright © 2017 Elsevier Inc. All rights reserved.

Alterations in brain extracellular dopamine and glycine levels following combined administration of the glycine transporter type-1 inhibitor Org-24461 and risperidone.

PubMed

Nagy, Katalin; Marko, Bernadett; Zsilla, Gabriella; Matyus, Peter; Pallagi, Katalin; Szabo, Geza; Juranyi, Zsolt; Barkoczy, Jozsef; Levay, Gyorgy; Harsing, Laszlo G

2010-12-01

The most dominant hypotheses for the pathogenesis of schizophrenia have focused primarily upon hyperfunctional dopaminergic and hypofunctional glutamatergic neurotransmission in the central nervous system. The therapeutic efficacy of all atypical antipsychotics is explained in part by antagonism of the dopaminergic neurotransmission, mainly by blockade of D(2) dopamine receptors. N-methyl-D-aspartate (NMDA) receptor hypofunction in schizophrenia can be reversed by glycine transporter type-1 (GlyT-1) inhibitors, which regulate glycine concentrations at the vicinity of NMDA receptors. Combined drug administration with D(2) dopamine receptor blockade and activation of hypofunctional NMDA receptors may be needed for a more effective treatment of positive and negative symptoms and the accompanied cognitive deficit in schizophrenia. To investigate this type of combined drug administration, rats were treated with the atypical antipsychotic risperidone together with the GlyT-1 inhibitor Org-24461. Brain microdialysis was applied in the striatum of conscious rats and determinations of extracellular dopamine, DOPAC, HVA, glycine, glutamate, and serine concentrations were carried out using HPLC/electrochemistry. Risperidone increased extracellular concentrations of dopamine but failed to influence those of glycine or glutamate measured in microdialysis samples. Org-24461 injection reduced extracellular dopamine concentrations and elevated extracellular glycine levels but the concentrations of serine and glutamate were not changed. When risperidone and Org-24461 were added in combination, a decrease in extracellular dopamine concentrations was accompanied with sustained elevation of extracellular glycine levels. Interestingly, the extracellular concentrations of glutamate were also enhanced. Our data indicate that coadministration of an antipsychotic with a GlyT-1 inhibitor may normalize hypofunctional NMDA receptor-mediated glutamatergic neurotransmission with reduced dopaminergic side effects characteristic for antipsychotic medication.

Clinical characteristics of patients who overdose on multiple psychotropic drugs in Tokyo.

PubMed

Hori, Satoshi; Kinoshita, Kosaku

2016-01-01

The purpose of this study was to identify the clinical aspects leading to overdose of multiple psychotropic drugs, in order to determine areas which need attention in the proper treatment of overdose patients. Patients who were treated for overdose of psychotropic drugs at our emergency and critical center over two years were targeted. The clinical data was gathered from the medical records and database of all patients, including age, gender, vital signs, and laboratory data, drugs, and medical complications during hospital stay. In addition primary patient care at the emergency department was examined. Among the 277 patients treated during this study period, 255 (74.0%) used two or more types of psychotropic drugs. Risk factors associated with endotracheal intubation and aspiration pneumonitis included the use of antipsychotics and/or barbiturates as types of overdose drugs. The mean number of days in the ICU was 3.4 days. Seventy-four patients (26.7%) stayed 4 days or more in the ICU of which 16 patients (5.8%) still had suicidal thoughts. A significantly higher incidence of extended ICU stay or endotracheal intubation and aspiration pneumonitis was observed in the group who overdosed on more than 50 or 60 tablets of psychotropic drugs, respectively. Patients who ingested an overdose of more than 60 tablets of psychotropic drugs should be considered a high-risk group requiring intensive care with extended ICU stay. In case of including antipsychotics and/or barbiturates, the patient should be observed carefully due to a higher risk of medical complications.

Adverse drug reactions induced by valproic acid.

PubMed

Nanau, Radu M; Neuman, Manuela G

2013-10-01

Valproic acid is a widely-used first-generation antiepileptic drug, prescribed predominantly in epilepsy and psychiatric disorders. VPA has good efficacy and pharmacoeconomic profiles, as well as a relatively favorable safety profile. However, adverse drug reactions have been reported in relation with valproic acid use, either as monotherapy or polytherapy with other antiepileptic drugs or antipsychotic drugs. This systematic review discusses valproic acid adverse drug reactions, in terms of hepatotoxicity, mitochondrial toxicity, hyperammonemic encephalopathy, hypersensitivity syndrome reactions, neurological toxicity, metabolic and endocrine adverse events, and teratogenicity. Copyright © 2013 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

[Drug safety warnings in psychiatry: adverse drug reactions' signaling from 2002 to 2014].

PubMed

Prisco, Vincenzo; Iannaccone, Teresa; Tusciano, Adriano; Boccardi, Mariangela; Perris, Francesco; Capuano, Annalisa; Catapano, Francesco; Fabrazzo, Michele

2016-01-01

Monitoring drug-related side effects in psychiatric patients is highly recommended. In fact, frequent exposure to long-term polipharmacotherapy, poor compliance to pharmachological treatment and comorbidity with organic illnesses requiring the prescription of other drugs are causes of pharmacokinetic/pharmacodynamic interactions. These vulnerability factors result in a certain increase in adverse drug reactions (ADRs). This study performes an analysis of Italian Medicine Agency data, in the section "signal analysis", to attempt an assessment of the safety warnings among the different psychotropic drug classes, belonging to the ATC class: N03 (antiepileptics), N05 (antipsychotics), N06 (psycho-analectic drugs). Then we analysed, in a descriptive way, the different association between the drug and the related ADR, evaluating the different safety profiles, in relation to experimental studies, supporting the importance of the signal. In the last years, among the new 25 ADRs, 10 were related to antidepressant drugs (8 SSRI, 1 mirtazapine, 1 agomelatine). In relation to antipsychotic drugs, 6 new correlations were found between drug and ADR onset, mainly among atypical antispychotics. Other correlations (6 above all) were found among antiepileptic drugs. Among benzodiazepines, a signal linked to rabdomylysis onset was found. It is also recommended an evaluation of safety profile in relation to zolpidem prescription. The results of our systematic review are a motivational input, considering the continuous increase of safety warnings, to attentively monitor drug's prescription. Spontaneous ADRs' signaling is a classical system to provide the required attention in relation to a potential risk. The clinician in charge must report this because he is the key figure in the drugs' safety process. In psychiatry, in which a long-term pharmachological therapy is frequent, clinicians are requested to find and signal ADRs to the competent authority.

Attribution style as a factor in psychosis and symptom resolution.

PubMed

Mizrahi, Romina; Addington, Jean; Remington, Gary; Kapur, Shitij

2008-09-01

Attribution (AT) style theory provides a framework for understanding the causal explanations that individuals give for their own behaviour and the behaviour of others. It has been suggested that patients with persecutory delusions excessively attribute hypothetical positive events to internal causes (self) and hypothetical negative events to external personal causes. Despite this, how AT associates with psychotic symptoms (not only persecutory delusions) and how it changes with the resolution of psychosis has never been investigated. We conducted a cross-sectional study to investigate how AT is associated with psychopathology and a longitudinal study to examine the change of AT during the first 6 weeks of antipsychotic treatment and the relationship with psychopathology improvement. 86 patients meeting DSM-IV criteria for schizophrenia and related psychotic disorders were included in the cross-sectional study, and 17 patients in the longitudinal study. The longitudinal group were free of antipsychotic drugs at baseline and followed for 6 weeks after being started on antipsychotic medication by their psychiatrist. We used the Internal, Personal and Situational Attributions Questionnaire (IPSAQ) as a measure of AT. Patients that tend to internalize (i.e. less self-serving bias), showed greater overall psychopathology, as measured by PANSS-Total (F(2,83)=6.59, p=0.002), with a trend toward significance for PANSS-Positive (F(2,83)=2.62 p=0.07). Longitudinally, having a low self-serving bias was associated with poorer response to antipsychotic treatment. Further, externalizing bias seems to change early on in treatment (F=9.65 df=1,15 p=0.007) and reach ceiling effects thereafter. AT is related to overall symptom severity, with internalizing style linked to higher global psychopathology. Antipsychotic treatment has little effect on AT, at least within 6 weeks of antipsychotic exposure, and only a modest effect is on EB which plateaus within 2 weeks. Finally, internalizing style appears associated with poorer response to antipsychotic treatment.

Polypharmacy with antipsychotic drugs in patients with schizophrenia: trends in multiple health care systems

PubMed Central

Sun, FangFang; Stock, Eileen M.; Copeland, Laurel A.; Zeber, John E.; Ahmedani, Brian K.; Morissette, Sandra B.

2015-01-01

Purpose To investigate patterns in pharmacological treatment for patients with schizophrenia, we examined antipsychotic polypharmacy across multiple outpatient healthcare settings and their association with hospital admission. Methods This multi-system study utilized data on patients diagnosed with schizophrenia, including 119,662 Veterans in the Department of Veterans Affairs (VA) healthcare system, 553 and 4,887 patients in two private, integrated health systems (HMO), and outpatients (17,596,617 visits in 1-week look-back) from a nationally representative sample of U.S. residents seeking care outside federal systems (National Ambulatory Medical Care Survey, NAMCS). Antipsychotic polypharmacy was defined as the use of more than one antipsychotic agent during the covered period (week, year). The prevalence and trend of antipsychotic polypharmacy was assessed in each system (2002-2009 or 2005-2009) and their association with one-year hospital admission using multivariable logistic regression. Results Annual antipsychotic treatment in the VA ranged 74-78% each year, with the lowest rates observed in the HMO (49-67% site 1, 22-41% site 2) per pharmacy fill data; NAMCS ranged 69-84% per clinician-reported prescriptions. Polypharmacy rates depended on the defined covered period. The VA had lower polypharmacy rates when data were restricted to the one-week covered period used in non-federal systems (20-22% vs. 19-31% NAMCS). In each system, polypharmacy was associated with increased odds of admission (odds ratio ranging 1.4-2.4). Conclusions The unadjusted longitudinal trends suggest tremendous system variations in antipsychotic use among patients with schizophrenia. Cross-system comparisons are inherently subject to uncertainty due to variation in the amount and type of data collected. Given the current debate over healthcare access and costs, electronic systems to signal polypharmacy could assist in identifying patients requiring more complex clinical and pharmacy management, individuals at substantially higher risk for adverse events. Such enhanced sentinel detection and follow-up care could ultimately lead to improved clinical practice and fiscal well-being. PMID:24733136

The expert consensus guideline series. Optimizing pharmacologic treatment of psychotic disorders. Introduction: methods, commentary, and summary.

PubMed

Kane, John M; Leucht, Stefan; Carpenter, Daniel; Docherty, John P

2003-01-01

A growing number of atypical antipsychotics are available for clinicians to choose from in the treatment of psychotic disorders. However, a number of important questions concerning medication selection, dosing and dose equivalence, and the management of inadequate response, compliance problems, and relapse have not been adequately addressed by clinical trials. To aid clinical decision-making, a consensus survey of expert opinion on the pharmacologic treatment of psychotic disorders was undertaken to address questions not definitively answered in the research literature. Based on a literature review, a written survey was developed with 60 questions and 994 options. Approximately half of the options were scored using a modified version of the RAND 9-point scale for rating the appropriateness of medical decisions. For the other options, the experts were asked to write in answers (e.g., average doses) or check a box to indicate their preferred answer. The survey was sent to 50 national experts on the pharmacologic treatment of psychotic disorders, 47 (94%) of whom completed it. In analyzing the responses to items rated on the 9-point scale, consensus on each option was defined as a non random distribution of scores by chi-square "goodness-of-fit"test. We assigned a categorical rank (first line/preferred choice,second line/alternate choice, third line/usually inappropriate) to each option based on the 95% confidence interval around the mean rating. Guideline tables indicating preferred treatment strategies were then developed for key clinical situations. The expert panel reached consensus on 88% of the options rated on the 9-point scale. The experts overwhelmingly endorsed the atypical antipsychotics for the treatment of psychotic disorders. Risperidone was the top choice for first-episode and multi-episode patients, with the other newer atypicals rated first line or high second line depending on the clinical situation. Clozapine and a long-acting injectable atypical (when available)were other high second line options for multi-episode patients. The expert's dosing recommendations agreed closely with the package inserts for the drugs, and their estimates of dose equivalence among the antipsychotics followed a linear pattern. The experts considered 3-6 weeks an adequate antipsychotic trial, but would wait a little longer (4-10 weeks) before making a major change in treatment regimen if there is a partial response. The experts recommended trying to improve response by increasing the dose of atypical and depot antipsychotics before switching to a different agent; there was less agreement about increasing the dose of conventional antipsychotics before switching, probably because of concern about side effects at higher doses. If it is decided to switch because of inadequate response, risperidone was the expert's first choice to switch to, no matter what drug was initially tried. Although there was some disparity in the expert's recommendations concerning how many agents to try before switching to clozapine, the expert's responses suggest that switching to clozapine should be Clozapine was also the antipsychotic of choice for patients with suicidal behavior. When switching oral antipsychotics,the experts considered cross-titration the preferred strategy. When switching to an injectable antipsychotic, the experts stressed the importance of continuing the oral antipsychotic until therapeutic levels of the injectable agent are achieved. The experts considered psychosocial interventions the first choice strategy for partially compliant patients, with pharmacologic interventions the first choice for patients with clear evidence of noncompliance. However, because it can be difficult to distinguish partially compliant from noncompliant patients, the editors recommended combining psychosocial and pharmacologic interventions to improve compliance whenever possible. When patients relapse because of compliance problems or if there is any doubt about compliance, the experts recommended the use of a long-acting injectable antipsychotic and would select an injectable atypical when this option becomes available. The experts would also consider using an injectable atypical antipsychotic (when available) in many clinical situations that do not involve compliance problems. The experts stressed the importance of monitoring for health problems-especially obesity, diabetes, cardiovascular problems,HIV risk behaviors, medical complications of substance abuse, heavy smoking and its effects, hypertension, and amenorrhea-in patients being treated with antipsychotics. Although many patients are prescribed adjunctive treatments,multiple antipsychotics, and combinations of different classes of drugs (e.g., antipsychotics plus mood stabilizers or antidepressants) in an effort to enhance response, the experts gave little support to any of these strategies, with the exception of antidepressants for patients with dysphoria/depression, antidepressants or ECT for patients with suicidal behavior, and mood stabilizers for patients with aggression/violence. When asked about indicators of remission and recovery, the experts considered acute improvement in psychotic symptoms the most important indicator of remission, whereas they considered more sustained improvement in multiple outcome domains (e.g., occupational/educational functioning, peer relationships,independent living) important in assessing recovery. The experts reached a high level of consensus on many of the key treatment questions in the survey. Within the limits of expert opinion and with the expectation that future research data will take precedence, these guidelines provide direction for addressing common clinical dilemmas that arise in the pharmacologic treatment of psychotic disorders. They can be used to inform clinicians and educate patients regarding the relative merits of a variety of interventions. Clinicians should keep in mind that no guidelines can address the complexities involved in the care of each individual patient and that sound clinical judgment based on clinical experience should be used in applying these recommendations.

Risperidone and aripiprazole alleviate prenatal valproic acid-induced abnormalities in behaviors and dendritic spine density in mice.

PubMed

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.

Effects of aripiprazole on caffeine-induced hyperlocomotion and neural activation in the striatum.

PubMed

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.

Hormonal and metabolic effects of olanzapine and clozapine related to body weight in rodents.

PubMed

Albaugh, Vance L; Henry, Cathy R; Bello, Nicholas T; Hajnal, Andras; Lynch, Susan L; Halle, Beth; Lynch, Christopher J

2006-01-01

To characterize a model of atypical antipsychotic drug-induced obesity and evaluate its mechanism. Chronically, olanzapine or clozapine was self-administered via cookie dough to rodents (Sprague-Dawley or Wistar rats; C57Bl/6J or A/J mice). Chronic studies measured food intake, body weight, adiponectin, active ghrelin, leptin, insulin, tissue wet weights, glucose, clinical chemistry endpoints, and brain dopaminergic D2 receptor density. Acute studies examined food intake, ghrelin, leptin, and glucose tolerance. Olanzapine (1 to 8 mg/kg), but not clozapine, increased body weight in female rats only. Weight changes were detectable within 2 to 3 days and were associated with hyperphagia starting approximately 24 hours after the first dose. Chronic administration (12 to 29 days) led to adiposity, hyperleptinemia, and mild insulin resistance; no lipid abnormalities or changes in D2 receptor density were observed. Topiramate, which has reversed weight gain from atypical antipsychotics in humans, attenuated weight gain in rats. Acutely, olanzapine, but not clozapine, lowered plasma glucose and leptin. Increases in glucose, insulin, and leptin following a glucose challenge were also blunted. A model of olanzapine-induced obesity was characterized which shares characteristics of patients with atypical antipsychotic drug-induced obesity; these characteristics include hyperphagia, hyperleptinemia, insulin resistance, and weight gain attenuation by topiramate. This model may be a useful and inexpensive model of uncomplicated obesity amenable to rapid screening of weight loss drugs. Olanzapine-induced weight gain may be secondary to hyperphagia associated with acute lowering of plasma glucose and leptin, as well as the inability to increase plasma glucose and leptin following a glucose challenge.

Serotonin-1A receptor gene polymorphism and the ability of antipsychotic drugs to improve attention in schizophrenia.

PubMed

Sumiyoshi, Tomiki; Tsunoda, Masahiko; Higuchi, Yuko; Itoh, Toru; Seo, Tomonori; Itoh, Hiroko; Suzuki, Michio; Kurachi, Masayoshi

2010-05-01

The purpose of this study was to determine if the functional single nucleotide polymorphisms of rs6259 C(-1019)G in the promoter region, which regulates serotonin 5-HT(1A) receptor transcription, affects the ability of antipsychotic drugs to improve attention in patients with schizophrenia. Subjects were neuroleptic-free and meeting DSM-IV-TR criteria for schizophrenia. Psychopathology and attention were evaluated with the Scale for the Assessment of Positive Symptoms (SAPS) and the Scale for the Assessment of Negative Symptoms (SANS) at baseline and 3 months after treatment with atypical antipsychotic drugs (AAPDs). DNA was extracted from peripheral blood following standard procedures. Genotyping was performed with HS-Taq assay (LaboPass). Data were available from 30 subjects (male/female=19/11), in which 17 had the CC genotype, three had the GG genotype, and 10 were heterozygous. The 3-month treatment with AAPDs was associated with significant improvements in positive and negative symptoms, but not attention as measured by SANS-Attention subscale in the entire subject group. There were no significant differences in the degree of improvements of SAPS and SANS scores between the CC genotype group and the (C/G plus G/G) combined group. On the other hand, improvement of attention was significantly greater for the former group compared to the latter group (P<0.016), suggesting a detrimental influence of the G-allele. These results provide additional support to the role of 5-HT(1A) receptors in some of the cognitive disturbances of schizophrenia. Further studies with a larger number of subjects are warranted.

Relationship between xerostomia and psychotropic drugs in patients with schizophrenia: evaluation using an oral moisture meter.

PubMed

Okamoto, A; Miyachi, H; Tanaka, K; Chikazu, D; Miyaoka, H

2016-12-01

Patients with schizophrenia are most commonly treated with antipsychotic medications, often with the addition of anxiolytics. This study used an oral moisture meter to evaluate xerostomia in patients with schizophrenia taking typical and atypical antipsychotics, anxiolytics and non-psychotropic medications. Patients diagnosed with schizophrenia according to ICD-10 criteria in the Department of Psychiatry, Kitasato University East, and affiliated hospitals were studied. All patients were on psychotropic medications. Patients with diseases associated with xerostomia, such as Sjögren's syndrome I, were excluded. A total of 127 patients were enrolled. Mean oral moisture was 27·81 ± 2·27% (normal, ≥30·0%). A significant association was observed between objective oral moisture and the subjective sense of dry mouth. Multivariate analysis revealed a negative correlation between the number of antipsychotics and, especially, anxiolytics, and the degree of oral moisture. Drug dosages themselves were not significantly correlated with dry mouth. These findings suggest that objective oral moisture measurements show decreased moisture in patients on these medications and that the degree of moisture shows a greater negative correlation with the number, as opposed to the dosages, of psychotropic drugs administered. When patients with schizophrenia visit a dental clinic, it is important for the dentist to accurately assess the degree of oral moisture and to determine the medications being taken. Based on these findings of the association of polypharmacy with xerostomia, dentists are encouraged to inform the psychiatrist of the need to actively manage patients' xerostomia. © 2016 John Wiley & Sons Ltd.

Post-marketing surveillance of sertindole.

PubMed

Toumi, Mondher

2002-01-01

The atypical antipsychotic drug, sertindole, like several other drugs, causes QT interval prolongation. Prolongation of the QT interval on the electrocardiogram has been associated with an increased risk of ventricular arrhythmia, including the more serious form, torsades de pointes, and is thus a safety concern for the authorities. In the case of sertindole, however, the available pharmacoepidemiological studies gathering data from about 10 000 patients documented the lack of increased risk associated to sertindole in comparison to other atypical antipsychotics. On the basis of these data, as well as non-clinical and clinical safety data, the CPMP expert group concluded that, although sertindole has the potential to prolong the QT interval, ¤ ¤ QT interval prolongation does not seem to be a reliable proxy for the risk of severe cardiac arrhythmias'', and there are no clinical data suggesting that sertindole is more arrhythmogenic than are other atypical antipsychotics. To further substantiate this conclusion, two post-marketing surveillance studies have been initiated. One is a randomized comparison of sertindole and risperidone under normal conditions of use. Randomization minimizes selection bias and the intention is that allocation to the two treatment arms will yield comparable treatment groups. While the two drugs will be given in an open-label fashion, all safety data will be blinded and reviewed by an independent safety committee. The other study is an observational study that includes all patients prescribed sertindole who, for whatever reason, will not be included in the randomized study. In all, 10 000 patients are expected to take part in the studies, which will run for at least 1 year.

Differential long-term effects of haloperidol and risperidone on the acquisition and performance of tasks of spatial working and short-term memory and sustained attention in rats.

PubMed

Hutchings, Elizabeth J; Waller, Jennifer L; Terry, Alvin V

2013-12-01

A common feature of the neuropsychiatric disorders for which antipsychotic drugs are prescribed is cognitive dysfunction, yet the effects of long-term antipsychotic treatment on cognition are largely unknown. In the current study, we evaluated the effects of long-term oral treatment with the first-generation antipsychotic haloperidol (1.0 and 2.0 mg/kg daily) and the second-generation antipsychotic risperidone (1.25 and 2.5 mg/kg daily) on the acquisition and performance of two radial-arm maze (RAM) tasks and a five-choice serial reaction-time task (5C-SRTT) in rats during days 15-60 and 84-320 days of treatment, respectively. In the RAM, neither antipsychotic significantly affected the acquisition or performance of a spatial win shift or a delayed non-match-to-position task. Conversely, in the rats administered 5C-SRTT, haloperidol was associated with profound deficits in performance, and the subjects were not able to progress through all stages of task acquisition. Depending on the dose, risperidone was associated with a greater number of trials to meet specific performance criteria during task acquisition compared with vehicle-treated controls; however, most subjects were eventually able to achieve all levels of task acquisition. Both haloperidol and risperidone also increased the number of perseverative and time-out responses during certain stages of task acquisition, and the response and reward latencies were slightly higher than controls during several stages of the study. These results in rats suggest that while long-term treatment with haloperidol or risperidone may not significantly affect spatial working or short-term memory, both antipsychotics can (depending on dose) impair sustained attention, decrease psychomotor speed, increase compulsive-type behaviors, and impair cognitive flexibility.

A Study of the Impact of Cannabis on Doses of Discharge Antipsychotic Medication in Individuals with Schizophrenia or Schizoaffective Disorder.

PubMed

Babatope, Taiwo; Chotalia, Jigar; Elkhatib, Rania; Mohite, Satyajit; Shah, Joel; Goddu, Sumana; Patel, Ruchir Arvind; Aimienwanu, Osarhiemen Ruth; Patel, Devanshu; Makanjuola, Titilayo; Okusaga, Olaoluwa O

2016-12-01

Patients with schizophrenia or schizoaffective disorder have a high prevalence of comorbid cannabis use disorder (CUD). CUD has been associated with poorer outcomes in patients. We compared doses of antipsychotic medications at the time of discharge from hospital among inpatients with schizophrenia or schizoaffective disorder with or without concurrent cannabis use. We reviewed the medical records of patients (N = 8157) with schizophrenia or schizoaffective disorder discharged from the hospital between 2008 and 2012. The patients were divided into two groups; those with urine drug tests positive for cannabis and those negative for cannabis. Doses of antipsychotic medications were converted to chlorpromazine equivalents. Bivariate analyses were done with Student's t test for continuous variables and χ 2 test for categorical variables. Linear regression was carried out to adjust for potential confounders. Unadjusted analysis revealed that the cannabis positive group was discharged on lower doses of antipsychotic medication compared with the cannabis negative group (geometric mean chlorpromazine equivalent doses 431.22 ± 2.20 vs 485.18 ± 2.21; P < 0.001). However, the difference in geometric mean chlorpromazine equivalent doses between the two groups was no longer significant after adjusting for sex, age, race, and length of stay (geometric mean difference 0.99; 95 % CI 0.92-1.10). Though limited by lack of information on duration, amount and severity of cannabis use, as well as inability to control for other non-antipsychotic medications, our study suggests that cannabis use did not significantly impact on doses of antipsychotics required during the periods of acute exacerbation in patients with schizophrenia or schizoaffective disorder.

Differential Long-Term Effects of Haloperidol and Risperidone on the Acquisition and Performance of Tasks of Spatial Working and Short-Term Memory and Sustained Attention in Rats

PubMed Central

Hutchings, Elizabeth J.; Waller, Jennifer L.

2013-01-01

A common feature of the neuropsychiatric disorders for which antipsychotic drugs are prescribed is cognitive dysfunction, yet the effects of long-term antipsychotic treatment on cognition are largely unknown. In the current study, we evaluated the effects of long-term oral treatment with the first-generation antipsychotic haloperidol (1.0 and 2.0 mg/kg daily) and the second-generation antipsychotic risperidone (1.25 and 2.5 mg/kg daily) on the acquisition and performance of two radial-arm maze (RAM) tasks and a five-choice serial reaction-time task (5C-SRTT) in rats during days 15–60 and 84–320 days of treatment, respectively. In the RAM, neither antipsychotic significantly affected the acquisition or performance of a spatial win shift or a delayed non–match-to-position task. Conversely, in the rats administered 5C-SRTT, haloperidol was associated with profound deficits in performance, and the subjects were not able to progress through all stages of task acquisition. Depending on the dose, risperidone was associated with a greater number of trials to meet specific performance criteria during task acquisition compared with vehicle-treated controls; however, most subjects were eventually able to achieve all levels of task acquisition. Both haloperidol and risperidone also increased the number of perseverative and time-out responses during certain stages of task acquisition, and the response and reward latencies were slightly higher than controls during several stages of the study. These results in rats suggest that while long-term treatment with haloperidol or risperidone may not significantly affect spatial working or short-term memory, both antipsychotics can (depending on dose) impair sustained attention, decrease psychomotor speed, increase compulsive-type behaviors, and impair cognitive flexibility. PMID:24042161

Treatment of antipsychotic-associated obesity with a GLP-1 receptor agonist--protocol for an investigator-initiated prospective, randomised, placebo-controlled, double-blinded intervention study: the TAO study protocol.

PubMed

Ishøy, Pelle L; Knop, Filip K; Broberg, Brian V; Baandrup, Lone; Fagerlund, Birgitte; Jørgensen, Niklas R; Andersen, Ulrik B; Rostrup, Egill; Glenthøj, Birte Y; Ebdrup, Bjørn H

2014-01-08

Antipsychotic medication is widely associated with dysmetabolism including obesity and type 2 diabetes, cardiovascular-related diseases and early death. Obesity is considered the single most important risk factor for cardiovascular morbidity and mortality. Interventions against antipsychotic-associated obesity are limited and insufficient. Glucagon-like peptide-1 (GLP-1) receptor agonists are approved for the treatment of type 2 diabetes, but their bodyweight-lowering effects have also been recognised in patients with non-diabetes. The primary endpoint of this trial is weight loss after 3 months of treatment with a GLP-1 receptor agonist (exenatide once weekly) in patients with non-diabetic schizophrenia with antipsychotic-associated obesity. Secondary endpoints include physiological and metabolic measurements, various psychopathological and cognitive measures, and structural and functional brain MRI. 40 obese patients with schizophrenia or schizoaffective disorder treated with antipsychotic drugs will be randomised to subcutaneous injection of exenatide once weekly (2 mg) or placebo for 3 months, adjunctive to their antipsychotic treatment. The trial has been approved by the Danish Health and Medicines Authority, the National Committee on Health Research Ethics and the Danish Data Protection Agency. Trial participation presupposes theoral and written patient informed consent. An external, independent monitoring committee (Good Clinical Practice Unit at Copenhagen University Hospital) will monitor the study according to the GCP Guidelines. Trial data, including positive, negative and inconclusive results, will be presented at national and international scientific meetings and conferences. Papers will be submitted to peer-reviewed journals. ClinicalTrials.gov identifier: NCT01794429; National Committee on Health Research Ethics project number: 36378; EudraCT nr: 2012-005404-17; The Danish Data Protection Agency project number: RHP-2012-027.

Worsening of myasthenia gravis after administration of injectable long-acting risperidone for treatment of schizophrenia; first case report and a call for caution.

PubMed

Al-Hashel, Jasem Y; Ismail, Ismail Ibrahim; John, John K; Ibrahim, Mohammed; Ali, Mahmoud

2016-01-01

Myasthenia gravis is an autoimmune disease characterized by muscle weakness due to autoantibodies affecting the neuromuscular junction. Co-occurrence of myasthenia gravis and schizophrenia is very rare and raises a challenge in management of both diseases. Antipsychotic drugs exhibit anticholinergic side effects and have the potentials of worsening myasthenia. Long-acting risperidone is an injectable atypical antipsychotic drug that has not been previously reported to worsen myasthenia gravis in literature. We report the first case report of worsening of myasthenia after receiving long-acting risperidone injection for schizophrenia in a 29-year-old female with both diseases. She started to have worsening 2 weeks following the first injection and her symptoms persisted despite receiving plasma exchange. This could be explained by the pharmacokinetics of the drug. We recommend that long-acting risperidone should be used with caution in patients with myasthenia gravis, and clinicians must be aware of the potential risks of this therapy. Copyright © 2016 Elsevier B.V. All rights reserved.

Comparison of psychotropic prescriptions between oncology and cardiology inpatients: result from a pharmacy database in a teaching hospital in Malaysia.

PubMed

Ng, Chong Guan; Mohamed, Salina; Wern, Tai Yi; Haris, Azwa; Zainal, Nor Zuraida; Sulaiman, Ahmad Hatim

2014-01-01

To examine the prescription rates in cancer patients of three common psychotropic drugs: anxiolytic/ hypnotic, antidepressant and antipsychotic. In this retrospective cohort study, data were extracted from the pharmacy database of University Malaya Medical Center (UMMC) responsible for dispensing records of patients stored in the pharmacy's Medication Management and Use System (Ascribe). We analyzed the use of psychotropics in patients from the oncology ward and cardiology from 2008 to 2012. Odds ratios (ORs) were adjusted for age, gender and ethnicity. A total of 3,345 oncology patients and 8,980 cardiology patients were included. Oncology patients were significantly more often prescribed psychotropic drugs (adjusted OR: anxiolytic/hypnotic=5.55 (CI: 4.64-6.63); antidepressants=6.08 (CI: 4.83-7.64) and antipsychotics=5.41 (CI: 4.17-7.02). Non-Malay female cancer patients were at significantly higher risk of anxiolytic/hypnotic use. Psychotropic drugs prescription is common in cancer patients. Anxiolytic/hypnotic prescription rates are significantly higher in non-Malay female patients in Malaysia.

The effect of switching from oral low-dose aripiprazole to aripiprazole once-monthly 300 mg on the quality of life in three patients with schizophrenia.

PubMed

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.

Caring for people with dementia and challenging behaviors in nursing homes: A needs assessment geriatric nursing.

PubMed

Daly, Jeanette M; Bay, Camden P; Levy, Barcey T; Carnahan, Ryan M

2015-01-01

An estimated 50% of nursing home residents have a dementia diagnosis. The purpose of this research was to conduct a needs assessment of directors of nursing (DON) in Iowa nursing homes in relation to caring for patients with Behavioral and Psychological Symptoms of Dementia. DON responses were linked to Online Survey Certification and Reporting/Certification and Survey Provider Enhanced Reporting (OSCAR/CASPER) data to examine how facility characteristics may be associated with use of and confidence in non-drug management strategies. From 431 questionnaires mailed to DONs, 160 (37%) were returned. Regression analysis showed that those who were more confident in managing challenging behavior were more likely to have satisfaction with current training on managing challenging behaviors and had a psychiatrist available to visit the facility. Facilities with a larger proportion of patients with challenging behaviors being treated with non-drug approaches instead of antipsychotics had DONs who were more likely to be confident in non-drug management strategies and have knowledge about the FDA antipsychotic medications risks. Copyright © 2015 Elsevier Inc. All rights reserved.

The serotonergic hallucinogen 5-methoxy-N,N-dimethyltryptamine disrupts cortical activity in a regionally-selective manner via 5-HT(1A) and 5-HT(2A) receptors.

PubMed

Riga, Maurizio S; Bortolozzi, Analia; Campa, Letizia; Artigas, Francesc; Celada, Pau

2016-02-01

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a natural hallucinogen, acting as a non-selective serotonin 5-HT(1A)/5-HT(2A)-R agonist. Psychotomimetic agents such as the non-competitive NMDA-R antagonist phencyclidine and serotonergic hallucinogens (DOI and 5-MeO-DMT) disrupt cortical synchrony in the low frequency range (<4 Hz) in rat prefrontal cortex (PFC), an effect reversed by antipsychotic drugs. Here we extend these observations by examining the effect of 5-MeO-DMT on low frequency cortical oscillations (LFCO, <4 Hz) in PFC, visual (V1), somatosensory (S1) and auditory (Au1) cortices, as well as the dependence of these effects on 5-HT(1A)-R and 5-HT(2A)-R, using wild type (WT) and 5-HT(2A)-R knockout (KO2A) anesthetized mice. 5-MeO-DMT reduced LFCO in the PFC of WT and KO2A mice. The effect in KO2A mice was fully prevented by the 5-HT(1A)-R antagonist WAY-100635. Systemic and local 5-MeO-DMT reduced 5-HT release in PFC mainly via 5-HT(1A)-R. Moreover, 5-MeO-DMT reduced LFCO in S1, Au1 and V1 of WT mice and only in V1 of KO2A mice, suggesting the involvement of 5-HT(1A)-R activation in the 5-MeO-DMT-induced disruption of V1 activity. In addition, antipsychotic drugs reversed 5-MeO-DMT effects in WT mice. The present results suggest that the hallucinogen action of 5-MeO-DMT is mediated by simultaneous alterations of the activity of sensory (S1, Au1, V1) and associative (PFC) cortical areas, also supporting a role of 5-HT(1A)-R stimulation in V1 and PFC, in addition to the well-known action on 5-HT(2A)-R. Moreover, the reversal by antipsychotic drugs of 5-MeO-DMT effects adds to previous literature supporting the usefulness of the present model in antipsychotic drug development. Copyright © 2015 Elsevier Ltd. All rights reserved.

Drug interactions between hormonal contraceptives and psychotropic drugs: a systematic review.

PubMed

Berry-Bibee, Erin N; Kim, Myong-Jin; Simmons, Katharine B; Tepper, Naomi K; Riley, Halley E M; Pagano, H Pamela; Curtis, Kathryn M

2016-12-01

To examine whether the co-administration of hormonal contraceptives (HC) and psychotropic drugs commonly used to treat anxiety and/or depression results in safety or efficacy concerns for either drug. We searched PubMed and Cochrane libraries for clinical or pharmacokinetic (PK) studies that examined co-administration of any HC with psychotropic drugs [selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), oral benzodiazepines, bupropion, mirtazapine, trazadone, buspirone, hydroxyzine, monoamine oxidase inhibitors (MAOIs), or atypical antipsychotics] in reproductive aged women. Of 555 articles identified, 22 articles (18 studies) met inclusion criteria. We identified 5 studies on SSRIs, four on TCAs, one on bupropion, three on atypical antipsychotics and five on oral benzodiazepines. No articles met inclusion criteria for SNRIs, mirtazapine, trazadone, buspirone, hydroxyzine or MAOIs. Overall, clinical studies did not demonstrate differences in unintended pregnancy rates when HCs were administered with and without psychotropic drugs or in psychotropic drug treatment outcomes when psychotropic drugs were administered with and without HCs. PK studies did not demonstrate changes in drug exposure related to contraceptive safety, contraceptive effectiveness or psychotropic drug effectiveness for most classes of psychotropic drugs. However, limited PK data raise concern for HCs increasing systemic exposure of amitriptyline and imipramine (both TCAs), theoretically posing safety concerns. Limited quality and quantity evidence on use of psychotropic drugs and HCs suggests low concern for clinically significant interactions, though no data exist specifically for non-oral formulations of HC. Given the high frequency of use for both HCs and psychotropic drugs among reproductive-age women in the US, this review highlights a need for further research in this area. Copyright © 2016 Elsevier Inc. All rights reserved.

A pilot randomised controlled trial of community-led ANtipsychotic Drug REduction for Adults with Learning Disabilities.

PubMed Central

McNamara, Rachel; Randell, Elizabeth; Gillespie, David; Wood, Fiona; Felce, David; Romeo, Renee; Angel, Lianna; Espinasse, Aude; Hood, Kerry; Davies, Amy; Meek, Andrea; Addison, Katy; Jones, Glyn; Deslandes, Paul; Allen, David; Knapp, Martin; Thapar, Ajay; Kerr, Michael

2017-01-01

BACKGROUND Data suggest that approximately 50,000 adults with learning disabilities (LDs) in England and Wales are currently prescribed antipsychotic medication. Illness in this population is common, including significant rates of challenging behaviour and mental illness, but there is particular concern over the use of antipsychotics prescribed for reasons other than the treatment of psychosis. Control of challenging behaviour is the primary reason why such medications are prescribed despite the absence of good evidence for any therapeutic effect for this purpose. OBJECTIVES To assess the feasibility of recruitment and retention and to explore non-efficacy-based barriers to a blinded antipsychotic medication withdrawal programme for adults with LDs without psychosis compared with treatment as usual. A secondary objective was to compare trial arms regarding clinical outcomes. DESIGN A two-arm individually randomised double-blind placebo-controlled drug reduction trial. SETTING Recruitment was through community learning disability teams (CLDTs) in south Wales and south-west England. PARTICIPANTS Adults with LDs who are prescribed risperidone for treatment of challenging behaviour with no known current psychosis or previous recurrence of psychosis following prior drug reduction. INTERVENTION A double-blind drug reduction programme leading to full withdrawal within 6 months. Treatment in the intervention group was gradually reduced over a 6-month period and then maintained at the same level for a further 3 months, still under blind conditions. In the control group, the baseline level of medication was maintained throughout the 9-month period. The blind was broken at 9 months, following final data collection. MAIN OUTCOME MEASURES Feasibility outcomes were (1) the number and proportion of general practices/CLDTs that progressed from initial approach to recruitment of participants and (2) the number and proportion of recruited participants who progressed through the various stages of the study. Trial arms were also compared regarding clinical outcomes, the Modified Overt Aggression Scale, the Aberrant Behaviour Checklist, the Psychiatric Assessment Schedule for Adults with Developmental Disability checklist, the Antipsychotic Side-effect Checklist, the Dyskinesia Identification System Condensed User Scale, the Client Service Receipt Inventory, use of other interventions to manage challenging behaviour, use of as-required (pro re nata) medication and level of psychotropic medication use. RESULTS Of the 22 participants randomised (intervention, n = 11; control, n = 11), 13 (59%) achieved progression through all four stages of reduction. Follow-up data at 6 and 9 months were obtained for 17 participants (intervention, n = 10; and control, n = 7; 77% of those randomised). There were no clinically important changes in participants' levels of aggression or challenging behaviour at the end of the study. There were no expedited safety reports. Four adverse events and one serious adverse event were reported during the trial. LIMITATIONS Recruitment was challenging, which was largely a result of difficulty in identifying appropriate persons to consent and carer concerns regarding re-emergence of challenging behaviour. Reduced recruitment meant that the full trial became an exploratory pilot study. CONCLUSIONS The results indicate that drug reduction is possible and safe. However, concerns about taking part were probably exacerbated by limited availability of alternative (behavioural) interventions to manage behaviour; therefore, focused support and alternative interventions are required. The results of the qualitative study provide important insights into the experiences of people taking part in drug reduction studies that should influence future trial development. FUTURE WORK We recommend that further work focuses on support for practitioners, carers and patients in reducing antipsychotic medication. TRIAL REGISTRATION Current Controlled Trials ISRCTN38126962. FUNDING This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 47. See the NIHR Journals Library website for further project information. PMID:28857740

Borderline Personality Disorder: Bipolarity, Mood Stabilizers and Atypical Antipsychotics in Treatment

PubMed Central

Belli, Hasan; Ural, Cenk; Akbudak, Mahir

2012-01-01

In this article, it is aimed to review the efficacies of mood stabilizers and atypical antipsychotics, which are used commonly in psychopharmacological treatments of bipolar and borderline personality disorders. In this context, common phenomenology between borderline personality and bipolar disorders and differential features of clinical diagnosis will be reviewed in line with the literature. Both disorders can demonstrate common features in the diagnostic aspect, and can overlap phenomenologically. Concomitance rate of both disorders is quite high. In order to differentiate these two disorders from each other, quality of mood fluctuations, impulsivity types and linear progression of disorders should be carefully considered. There are various studies in mood stabilizer use, like lithium, carbamazepine, oxcarbazepine, sodium valproate and lamotrigine, in the treatment of borderline personality disorder. Moreover, there are also studies, which have revealed efficacies of risperidone, olanzapine and quetiapine as atypical antipsychotics. It is not easy to differentiate borderline personality disorder from the bipolar disorders. An intensively careful evaluation should be performed. This differentiation may be helpful also for the treatment. There are many studies about efficacy of valproate and lamotrigine in treatment of borderline personality disorder. However, findings related to other mood stabilizers are inadequate. Olanzapine and quetiapine are reported to be more effective among atypical antipsychotics. No drug is approved for the treatment of borderline personality disorder by the entitled authorities, yet. Psychotherapeutic approaches have preserved their significant places in treatment of borderline personality disorder. Moreover, symptom based approach is recommended in use of mood stabilizers and atypical antipsychotics. PMID:23024731

Performance of a neuro-fuzzy model in predicting weight changes of chronic schizophrenic patients exposed to antipsychotics.

PubMed

Lan, T H; Loh, E W; Wu, M S; Hu, T M; Chou, P; Lan, T Y; Chiu, H-J

2008-12-01

Artificial intelligence has become a possible solution to resolve the problem of loss of information when complexity of a disease increases. Obesity phenotypes are observable clinical features of drug-naive schizophrenic patients. In addition, atypical antipsychotic medications may cause these unwanted effects. Here we examined the performance of neuro-fuzzy modeling (NFM) in predicting weight changes in chronic schizophrenic patients exposed to antipsychotics. Two hundred and twenty inpatients meeting DSMIV diagnosis of schizophrenia, treated with antipsychotics, either typical or atypical, for more than 2 years, were recruited. All subjects were assessed in the same study period between mid-November 2003 and mid-April 2004. The baseline and first visit's physical data including weight, height and circumference were used in this study. Clinical information (Clinical Global Impression and Life Style Survey) and genotype data of five single nucleotide polymorphisms were also included as predictors. The subjects were randomly assigned into the first group (105 subjects) and second group (115 subjects), and NFM was performed by using the FuzzyTECH 5.54 software package, with a network-type structure constructed in the rule block. A complete learned model trained from merged data of the first and second groups demonstrates that, at a prediction error of 5, 93% subjects with weight gain were identified. Our study suggests that NFM is a feasible prediction tool for obesity in schizophrenic patients exposed to antipsychotics, with further improvements required.

Use of Sedatives, Antidepressants and Antipsychotic Medicine among Seventh-day Adventists and Baptists in Denmark.

PubMed

Rasmussen, Peter; Johansen, Christoffer; Hvidt, Niels Christian; Kørup, Alex Kappel; Søndergaard, Jens; Thygesen, Lau Caspar

2017-10-01

Earlier it has been found that female Seventh-day Adventists (SDA) and Baptists have an increased incidence of psychiatric affective disorders, in contrast to findings that religious practice is associated with better health. In this study, we examined whether the increase in incidence is due to less use of prescribed antidepressants, sedatives and antipsychotics by members of these religious societies than by the general population. In a cohort study, we examined records of all drugs redeemed by 3121 SDA and 2888 Baptists and 29,817 age- and gender-matched members of the general population between 1995 and 2010 in the Danish Prescription Register and compared the prevalence and incidence of use of antidepressants, sedatives and antipsychotics. The prevalence of antidepressant use by women was lower in 1998 but no different from that in controls in 2003 and 2008; the prevalence of antidepressant use by men was higher in both 1998 and 2008 than in the Danish population. The incidence of antidepressant use was lower for female members in 1996-2000, but no difference was observed in the other periods. The prevalence and incidence of use of sedatives and antipsychotics did not consistently differ from those of the general population. The prevalence and incidence of use of antidepressants, sedatives and antipsychotics by female SDA and Baptists were not consistently lower than in the general Danish population. Our findings hence do not explain the increased incidence of psychiatric disorders among female members of these Danish religious societies.

Partial regimen replacement with aripiprazole reduces serum prolactin in patients with a long history of schizophrenia: A case series.

PubMed

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.

[The influence of antipsychotic therapy on the cognitive functions of schizophrenic patients].

PubMed

Tybura, Piotr; Mak, Monika; Samochowiec, Agnieszka; Pełka-Wysiecka, Justyna; Grzywacz, Anna; Grochans, Elzbieta; Zaremba-Pechmann, Liliana; Samochowiec, Jerzy

2013-01-01

The aim of the present study was twofold: 1. to compare the efficacy of three antipsychotics (ziprasidone, olanzapine and perazine) in schizophrenia 2. to compare the improvement in cognitive functioning between groups treated with the three different neuroleptics. A total of 58 Caucasian patients diagnosed with paranoid schizophrenia were recruited into the study group. We used the Polish version of the CIDI (Composite International Diagnostic Interview) to obtain ICD-10 diagnoses. The intensity of psychopathological symptoms was examined using the PANSS. The patients were randomly assigned to treatment with perazine, olanzapine or ziprasidone administered as monotherapy for 3 months. The treatment efficacy was measured as a change in the PANSS (Positive and Negative Syndrome Scale) total score from baseline (T0) to 3 months (T1). The WCST (The Wisconsin Card Sorting Test) was used to measure working memory and executive functions in the evaluated patients. Wilcoxon's and Kruskal-Wallis tests were applied to compare changes in the PANSS scores between the treatment groups. To analyze the cognitive functions, Kruskal-Wallis test for the WCST parameters was used. The three antipsychotics similarly reduced the total PANSS score. The WCST parameters in the 3 groups of examined patients using the Kruskal-Wallis test revealed some differences between the three administered antipsychotics. Results suggest that the short-term efficacy of the atypical (olanzapine, ziprasidone) and typical (perazine) antipsychotic drugs did not differ. Based on the analysis, a conclusion can be drawn that the three neuroleptics provided similar improvements in cognitive functioning.

The effect of second-generation antipsychotic drugs on sleep parameters in patients with unipolar or bipolar disorder.

PubMed

Monti, Jaime M

2016-07-01

Sleep disturbances predominantly take the form of insomnia in patients with unipolar disorder, while patients with bipolar disorder show a decreased need for sleep. Sleep impairment in these patients is a risk factor for the development of a major depressive episode and suicidal behavior. Administration of second-generation antipsychotics (SGAs) olanzapine, quetiapine, and ziprasidone as augmentation therapy or monotherapy to unipolar and bipolar disorder patients, respectively, has been shown to improve sleep continuity and sleep architecture. Thus, their use by these patients could ameliorate their sleep disorder. Copyright © 2016. Published by Elsevier B.V.

Novel Antipsychotics in the Treatment of Behavioral Disturbances and Psychoses Associated With Neurodegenerative Disorders

PubMed Central

Masand, Prakash S.

2000-01-01

Behavioral disturbances and psychosis are common features of neurodegenerative disorders and may be drug induced, intrinsic to the underlying pathology, or both. These disturbances, including psychotic and mood symptoms, apathy, aggression and other behavioral symptoms, and superimposed delirium, cause a great amount of disability to the patient and stress on the caregiver. Conventional neuroleptics have been shown to be effective in the treatment of these symptoms, but unacceptable side effects may occur. However, the novel antipsychotics, with their lower risk of inducing extrapyramidal symptoms, have shown promise in the treatment of behavioral disturbances and psychosis associated with neurodegenerative disorders. PMID:15014653

[Antipsychotic Treatment of the Adult Patient in the Acute Phase of Schizophrenia].

PubMed

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.

Frequency of sexual dysfunction and other reproductive side-effects in patients with schizophrenia treated with risperidone, olanzapine, quetiapine, or haloperidol: the results of the EIRE study.

PubMed

Bobes, J; Garc A-Portilla, M P; Rejas, J; Hern Ndez, G; Garcia-Garcia, M; Rico-Villademoros, F; Porras, A

2003-01-01

Atypical antipsychotics seem to differ mainly in their tolerability profile. The aim of this cross-sectional study, the Estudio de Investigaci n de Resultados en Esquizofrenia (Outcomes Research Study in Schizophrenia; EIRE study), was to assess in a clinical setting the frequency of several side-effects related to haloperidol, risperidone, olanzapine, and quetiapine. This article addresses sexual dysfunction and other reproductive side-effects (gynecomastia, menorrhage, amenorrhea, and galactorrhea). We recruited outpatients diagnosed with schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders (DSM-IV; American Psychiatric Association, 1994) criteria and who had received a single antipsychotic (risperidone, olanzapine, quetiapine, or haloperidol) for at least 4 weeks. During a single visit, we collected data, including demographic and clinical characteristics, current antipsychotic and concomitant treatment, and adverse effects listed in a modified version of the UKU Scale. We used a Chi-squared test to determine pairs comparisons of the frequency of adverse reactions between treatments. To estimate risk of a given adverse reaction with a given treatment, we used a logistic regression method. We assessed 636 evaluable patients out of 669 recruited. Frequency of sexual dysfunction was high with haloperidol (38.1%) and also with olanzapine (35.3%), quetiapine (18.2%), and risperidone (43.2%). We found the frequency of other reproductive side-effects to be relatively low with all four drugs: haloperidol (6.9%), olanzapine (6.4%), quetiapine (2.7%), and risperidone (11.7%). Sexual dysfunction appeared to be dose-related with haloperidol, risperidone, and olanzapine. Risperidone and olanzapine showed a higher risk of sexual dysfunction and other reproductive sideeffects than haloperidol. Quetiapine showed a lower risk of sexual dysfunction during short-term treatment (< 12 weeks). However, data on longer-term treatment (> 12 weeks) are lacking. Our results suggest that none of the atypical antipsychotics that we studied significantly improved sexual dysfunction and other reproductive side-effects of the conventional antipsychotic, haloperidol, in stabilized patients during long-term treatment. Quetiapine appears to improve this profile during short-term treatment; however, longterm data, with larger samples, are required with this latter drug.

CASE REPORT : GRAVE'S DISEASE PRESENTING AS PARANOID SCHIZOPHRENIA

PubMed Central

Singh, S.K.; Hatwal, A.; Agarwal, J.K.; Bajpai, H.S.; Sharma, I.

1989-01-01

SUMMARY The case of a 37 year old male is described who initially presented as paranoid schizophrenia unresponsive to anti-psychotic drug treatment and subsequently developed features of Grave's disease. Treatment with carbimazole alone improved his psychiatric symptoms. PMID:21927380

Pharmacotherapy in the Developmental Disabilities: New Developments.

ERIC Educational Resources Information Center

Aman, Michael G.

1991-01-01

This paper identifies and evaluates emerging developments in the behavioral pharmacotherapy of people with developmental disabilities, including such medications as the opiate antagonists, fenfluramine, beta adrenergic blockers, buspirone, antipsychotics, amantadine hydrochloride, and antilibidinal drugs. The need for more well-designed drug…

Can authorities appreciably enhance the prescribing of oral generic risperidone to conserve resources? Findings from across Europe and their implications.

PubMed

Godman, Brian; Petzold, Max; Bennett, Kathleen; Bennie, Marion; Bucsics, Anna; Finlayson, Alexander E; Martin, Andrew; Persson, Marie; Piessnegger, Jutta; Raschi, Emanuel; Simoens, Steven; Zara, Corinne; Barbui, Corrado

2014-06-13

Generic atypical antipsychotic drugs offer health authorities opportunities for considerable savings. However, schizophrenia and bipolar disorders are complex diseases that require tailored treatments. Consequently, generally there have been limited demand-side measures by health authorities to encourage the preferential prescribing of generics. This is unlike the situation with hypertension, hypercholaesterolaemia or acid-related stomach disorders.The objectives of this study were to compare the effect of the limited demand-side measures in Western European countries and regions on the subsequent prescribing of risperidone following generics; to utilise the findings to provide future guidance to health authorities; and where possible, to investigate the utilisation of generic versus originator risperidone and the prices for generic risperidone. Principally, this was a segmented regression analysis of retrospective time-series data of the effect of the various initiatives in Belgium, Ireland, Scotland and Sweden following the introduction of generic risperidone. The study included patients prescribed at least one atypical antipsychotic drug up to 20 months before and up to 20 months after generic risperidone. In addition, retrospective observational studies were carried out in Austria and Spain (Catalonia) from 2005 to 2011 as well as one English primary care organisation (Bury Primary Care Trust (PCT)). There was a consistent steady reduction in risperidone as a percentage of total selected atypical antipsychotic utilisation following generics. A similar pattern was seen in Austria and Spain, with stable utilisation in one English PCT. However, there was considerable variation in the utilisation of generic risperidone, ranging from 98% of total risperidone in Scotland to only 14% in Ireland. Similarly, the price of generic risperidone varied considerably. In Scotland, generic risperidone was only 16% of pre-patent loss prices versus 72% in Ireland. Consistent findings of no increased prescribing of risperidone post generics with limited specific demand-side measures suggests no 'spillover' effect from one class to another encouraging the preferential prescribing of generic atypical antipsychotic drugs. This is exacerbated by the complexity of the disease area and differences in the side-effects between treatments. There appeared to be no clinical issues with generic risperidone, and prices inversely reflected measures to enhance their utilisation.

Effects of chronic antipsychotic drug exposure on the expression of Translocator Protein and inflammatory markers in rat adipose tissue.

PubMed

Calevro, Anita; Cotel, Marie-Caroline; Natesan, Sridhar; Modo, Michel; Vernon, Anthony C; Mondelli, Valeria

2018-05-16

The precise effect of antipsychotic drugs on either central or peripheral inflammation remains unclear. An important issue in this debate is to what extent the known peripheral metabolic effects of antipsychotics, including increased adiposity, may contribute to increased inflammation. Adipose tissue is known to contribute to the development of systemic inflammation, which can eventually lead to insulin resistance and metabolic dysregulation. As a first step to address this question, we evaluated whether chronic exposure to clinically comparable doses of haloperidol or olanzapine resulted in the immune activation of rat adipose tissue. Samples of visceral adipose tissue were sampled from male Sprague-Dawley rats exposed to, haloperidol, olanzapine or vehicle (all n = 8), for 8 weeks. From these we measured a cytokine profile, protein expression of F4/80 (a phenotypic macrophage marker) and translocator protein (TSPO), a target for radiotracers putatively indicating microgliosis in clinical neuroimaging studies. Chronic olanzapine exposure resulted in significantly higher adipose IL-6 levels compared with vehicle-controls (ANOVA p = 0.008, Bonferroni post-hoc test p = 0.006); in parallel, animals exposed to olanzapine had significantly higher F4/80 expression when compared with vehicle-controls (Mann Whitney Test, p = 0.014), whereas there was no difference between haloperidol and vehicle groups (Mann Whitney test, p = 0.1). There were no significant effects of either drug on adipose TSPO protein levels. Nevertheless, we found a positive correlation between F4/80 and TSPO adipose protein levels in the olanzapine-exposed rats (Spearman's rho = 0.76, p = 0.037). Our data suggest that chronic exposure to olanzapine, but not haloperidol, increases production of the pro-inflammatory cytokine IL-6 in adipose tissue and increased macrophages expression (F4/80), in the absence of measurable changes in TSPO with respect to vehicle. This may have potentially important consequences in terms of metabolic dysregulation associated with long-term antipsychotic treatment. Copyright © 2018. Published by Elsevier Ltd.

Community pharmacy loyalty among individuals with schizophrenia.

PubMed

Lauzier, Sophie; Grégoire, Jean-Pierre; Lesage, Alain; Moisan, Jocelyne

2013-01-01

Community pharmacists can use medication records to assist individuals who are loyal to their pharmacy in better managing their pharmacotherapy. However, the extent of community pharmacy loyalty among individuals with severe mental illness such as schizophrenia remains unknown. To assess the extent of community pharmacy loyalty among individuals with schizophrenia and identify factors associated with loyalty. Using the Quebec Health Insurance Board databases, a cohort study of individuals with schizophrenia who claimed an antipsychotic drug for the first time between January 1, 2001 and December 31, 2005 was conducted. Such individuals were considered loyal to their community pharmacy if they filled all their prescriptions for any drug at the same community pharmacy during the second year after antipsychotics initiation. Logistic regression models were used to identify factors associated with community pharmacy loyalty (measured in the first year after antipsychotics initiation). Of the 6159 individuals in the study, 57.8% were loyal to one pharmacy. Men were more likely to be loyal (Adjusted OR = 1.29; 95% CI = 1.16-1.44), as were individuals aged 30-64 years and those aged ≥65 years, when compared to individuals 20-29 years (1.70; 1.48-1.95 and 2.39; 1.97-2.90, respectively). Individuals who filled their antipsychotics on a weekly basis were also more likely to be loyal (1.39; 1.18-1.63). Factors associated with non-loyalty were welfare beneficiary status (0.79; 0.70-0.89), having substance-use disorder (0.69; 0.60-0.80), a greater number of different types of drugs (5-8 types = 0.76; 0.66-0.87; 9-51 = 0.59; 0.50-0.69), and emergency department visits (0.71; 0.60-0.82). Results suggest that medication records in community pharmacies are incomplete for 42.2% of individuals with schizophrenia. Individuals more likely to experience more severe illness were also those less likely to be loyal. Given the potentially severe consequences of medication-related problems in this latter population, strategies to further improve the comprehensiveness of medication information should be promoted. Copyright © 2013 Elsevier Inc. All rights reserved.

The PsyLOG mobile application: development of a tool for the assessment and monitoring of side effects of psychotropic medication.

PubMed

Kuzman, Martina Rojnic; Andlauer, Olivier; Burmeister, Kai; Dvoracek, Boris; Lencer, Rebekka; Koelkebeck, Katja; Nawka, Alexander; Riese, Florian

2017-06-01

Mobile health interventions are regarded as affordable and accessible tools that can enhance standard psychiatric care. As part of the mHealth Psycho-Educational Intervention Versus Antipsychotic-Induced Side Effects (mPIVAS) project (www.psylog.eu), we developed the mobile application "PsyLOG" based on mobile "smartphone" technology to monitor antipsychotic-induced side effects. The aim of this paper is to describe the rationale and development of the PsyLOG and its clinical use. The PsyLOG application runs on smartphones with Android operating system. The application is currently available in seven languages (Croatian, Czech, English, French, German, Japanese and Serbian). It consists of several categories: "My Drug Effects", "My Life Styles", "My Charts", "My Medication", "My Strategies", "My Supporters", "Settings" and "About". The main category "My Drug Effects" includes a list of 30 side effects with the possibility to add three additional side effects. Side effects are each accompanied by an appropriate description and the possibility to rate its severity on a visual analogue scale from 0-100%. The PsyLOG application is intended to enhance the link between patients and mental health professionals, serving as a tool that more objectively monitors side-effects over certain periods of time. To the best of our knowledge, no such applications have so far been developed for patients taking antipsychotic medication or for their therapists.

Differences in psychotropic drug prescriptions among ethnic groups in the Netherlands.

PubMed

Wittkampf, Laura Christina; Smeets, Hugo M; Knol, Mirjam J; Geerlings, Mirjam I; Braam, Arjan W; De Wit, Niek J

2010-08-01

Psychotropic drug use in Europe and the USA has increased in the past 20 years. The rise in mental health-care use instigated a debate about possible differences in prevalence rates between different ethnic groups in the Netherlands, although the exact differences were unknown. The aim of this study was to determine whether these minority groups were more or less likely than the native population to receive psychotropic drugs. A descriptive population study was conducted using the Agis Health Database, containing demographic and health-care consumption data of approximately 1.5 million inhabitants of the Netherlands. Rates of prescriptions of psychotropic drugs from 2001 to 2006 and adjusted odds ratios for psychotropic drug prescriptions among native Dutch, Turkish and Moroccan ethnic groups were calculated. These data were analysed using logistic regression, after being adjusted for age, gender and socioeconomic status. The mean year prevalence of psychotropic drug prescriptions from 2001 to 2006 was 14.0%. Except for a decrease in anxiolytic drugs, the prescriptions of psychotropic drugs increased from 2001 to 2006. These trends were the same for all of the ethnic groups considered. Among both the Moroccan and Turkish populations, there was a higher risk of antidepressant and antipsychotic drug prescriptions, and a pronounced lower risk of ADHD medication and lithium prescriptions compared to the native population. Among the Turkish population, the risk of anxiolytic drug prescriptions was greater than in the native population. Compared to the native population in the Netherlands, first- and second-generation Turkish and Moroccan immigrants had an increased risk of antidepressant and antipsychotic drug prescriptions and a decreased risk of ADHD medication and Lithium prescriptions. Further research is needed to clarify whether patients of different ethnic backgrounds with the same symptoms receive similar diagnosis and adequate treatment.

Impact of the Pharma Economic Act on Diffusion of Innovation and Reduction of Costs in the Hungarian Prescription Drug Market (2007-2010).

PubMed

Hren, Rok

In this study, we examined the impact of the Pharma Economic Act, which was introduced in Hungary in 2007. We used detailed data on the Hungarian prescription drug market, which had been made publicly available by the authorities. We evaluated the effect of the Pharma Economic Act on both dynamic and static efficiencies and also on equity, which has been historically a controversial issue in Hungary. We analyzed the overall prescription drug market and statin and atorvastatin markets; as a proxy for determining dynamic efficiency, we examined the oncology drug market for some specific products (e.g., bortezomib) and the long-acting atypical antipsychotic drugs market. There is no denying that the authorities managed to control the overall prescription drug costs; however, they were still paying excessive rents for off-patent drugs. Examples of oncology and long-acting atypical antipsychotic drugs showed that the diffusion of innovation was on per-capita basis at least comparable to G-5 countries. While the share of out-of-pocket co-payments markedly increased and the reimbursement was lowered, the concurrent price decreases often meant that the co-payment per milligram of a given dispensed drug was actually lower than that before the Act, thereby benefiting the patient. It appears that strong mechanisms to control volume rather than price on the supply side (marketing authorization holders) contained the drug expenditure, while offering enough room to strive for innovation. Making data on prescription drug expenditures and associated co-payments publicly available is an item that should be definitely followed by the surrounding jurisdictions. Copyright © 2013, International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc.

Psychotropic Drug Prescription in Adolescents: A Retrospective Study in a Swiss Psychiatric University Hospital.

PubMed

Ansermot, Nicolas; Jordanov, Véronique; Smogur, Michal; Holzer, Laurent; Eap, Chin B

2018-04-01

This retrospective study aims to evaluate off-label prescriptions and administrations of psychotropic medications in adolescents in a university psychiatric hospital in Switzerland. Data were collected during the entire stays from the electronic database for 76 inpatients in 2008 and 76 inpatients in 2014. Data collected included gender, age, psychiatric diagnosis, duration of hospitalization, and psychotropic drug prescriptions and administrations. A total of 224 psychotropic drugs (mean 2.9 drugs/patient) were prescribed in 2008 and 268 (mean 3.5 drugs/patient) in 2014. Due to the prescriptions of some drugs as required, only 76% of the prescriptions were actually administered in 2008 (mean 2.3 drugs/patient) and 55% in 2014 (mean 1.9 drugs/patient). Antipsychotics were the most frequently prescribed drugs in 2008 (74% of patients) and 2014 (86% of patients). Anxiolytics were also highly prescribed in 2008 (54% of patients) and 2014 (66% of patients), as well as antidepressants in 2008 (30% of patients), but less in 2014 (13% of patients). Overall, 69% of prescriptions were found to be off label in 2008 and 68% in 2014, according to age, diagnosis, dose, or formulation as approved by Swissmedic. The medication classes with the highest rate of off-label prescriptions were antidepressants (100% for both years), antipsychotics (94% in 2008 and 92% in 2014), and hypnotics (67% in 2008 and 100% in 2014). For both study periods, at least one off-label psychotropic drug prescription and administration was recorded in 96% and 79% of the patients, respectively. The high rate of off-label psychotropic drug use strengthens the need for clinical trials to better evaluate the efficacy and safety of these treatments in adolescents.

Déjà vu experiences in schizophrenia: relations with psychopathology and antipsychotic medication.

PubMed

Adachi, Naoto; Adachi, Takuya; Akanuma, Nozomi; Matsubara, Ryouji; Ito, Masumi; Takekawa, Yoshikazu; Ikeda, Hiroshi; Arai, Heii

2007-01-01

To clarify why patients with schizophrenia show déjà vu experiences less frequently, we studied déjà vu experiences in 113 schizophrenic patients in relation to psychopathologies and antipsychotic medication. Déjà vu experiences were observed in 53.1% of the schizophrenic patients. Patients with increased negative symptoms (blunted affect, motor retardation, emotional withdrawal, conceptual disorganization, and mannerisms) had déjà vu experiences less frequently. The other psychopathologies were not significantly associated with presence of déjà vu experiences. The dosage of antipsychotic drugs was significantly correlated with the frequency of déjà vu experiences. This correlation was not affected by their psychopathologies at the time of examination. The decreased frequency of déjà vu experiences in patients with schizophrenia may be mainly due to the negative symptoms. The positive relation between frequency of déjà vu experiences and the dosage of neuroleptics remains uncertain.

[POISONING BY PSYCHOPHARMACOLOGICAL DRUGS IN AZERBAIJAN: THE RESULTS OF 8-YEAR PROSPECTIVE OBSERVATION].

PubMed

Afandiyev, I; Azizov, V

2017-11-01

Acute poisoning of chemical etiology is a significant global public health problem. The aim of this study was the analysis of the toxicoepidemiological structure of psychopharmacological drugs poisoning in Azerbaijan. We collected and analyzed the data on all cases of acute poisoning by psychopharmacological drugs (codes of categories T42/T43 ICD-10) undergoing inpatient treatment at the Center of Clinical Toxicology in Baku, Azerbaijan in 2009-2016. The total number of patients with acute intoxication by psychopharmacological drugs was 3,413, which was 48.3% of all cases of poisoning by drugs, medicaments and biological substances (T36-T50). The predominance of women was registered in all age groups. 1114 patients or 32.6% were in 15-24 years old age group. The highest percentage of poisonings at category T42 of ICD-10 were benzodiazepine-type drugs (35.8%), and at category T43 - antipsychotic and neuroleptic drugs (19.2%). In the structure of benzodiazepine poisoning, the first and second ranked places belonged to phenazepam (71.0%) and clonazepam - 16.6%. In addition, another 120 cases (5.5%) of poisonings in the T42 cohort were caused by "Z drugs", which have similar therapeutic effect to benzodiazepines (zolpidem and zopiclone). Among the antipsychotic and neuroleptic poisonings, thioridazine, trifluoperazine, levomepromazine, chlorpromazine, and periciazine accounted for 91% of all cases of intoxication in this cohort. Barbiturates, in view of their toxicity and narrow range of therapeutic dosages, now lost their importance as antiepileptic and hypnotic drugs. Only 4.9% of all cases of poisoning, classified under category T42, was due to the use of barbiturates (mainly phenobarbital). Poisonings with iminostilbenes were presented by carbamazepine poisoning only. Most patients in this cohort received this anticonvulsant drug as prescribed by a doctor. Acute intoxications by tricyclic antidepressants in 91.5% were presented by cases of amitriptyline poisoning. Intoxication by serotonin reuptake inhibitors antidepressants, were relatively rare (3.8% of all cases of poisoning in T43). Among the poisonings with butyrophenone and thioxanthene neuroleptics, the first ranked place was occupied by cases of haloperidol poisoning, which accounted for 82.6% in this cohort. In the group of intoxications with other antipsychotic and neuroleptic drugs, the first ranked place belonged to the poisoning with clozapine - a total of 83 cases or 47.2% in cohort. Poisonings by psychopharmacological drugs occupy the first ranking place among poisoning by drugs, medicaments and biological substances (T36-T50). Increased control over the prescription and sale of psychopharmacological drugs, a reduction the number of tablets in one package, as well as increased attention to vulnerable groups of the population could be help to reduce the percentage of these poisonings in Azerbaijan.

Predicting Pharmacokinetic Stability by Multiple Oral Administration of Atypical Antipsychotics

PubMed Central

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.)

Structure-activity relationships for serotonin transporter and dopamine receptor selectivity.

PubMed

Agatonovic-Kustrin, Snezana; Davies, Paul; Turner, Joseph V

2009-05-01

Antipsychotic medications have a diverse pharmacology with affinity for serotonergic, dopaminergic, adrenergic, histaminergic and cholinergic receptors. Their clinical use now also includes the treatment of mood disorders, thought to be mediated by serotonergic receptor activity. The aim of our study was to characterise the molecular properties of antipsychotic agents, and to develop a model that would indicate molecular specificity for the dopamine (D(2)) receptor and the serotonin (5-HT) transporter. Back-propagation artificial neural networks (ANNs) were trained on a dataset of 47 ligands categorically assigned antidepressant or antipsychotic utility. The structure of each compound was encoded with 63 calculated molecular descriptors. ANN parameters including hidden neurons and input descriptors were optimised based on sensitivity analyses, with optimum models containing between four and 14 descriptors. Predicted binding preferences were in excellent agreement with clinical antipsychotic or antidepressant utility. Validated models were further tested by use of an external prediction set of five drugs with unknown mechanism of action. The SAR models developed revealed the importance of simple molecular characteristics for differential binding to the D(2) receptor and the 5-HT transporter. These included molecular size and shape, solubility parameters, hydrogen donating potential, electrostatic parameters, stereochemistry and presence of nitrogen. The developed models and techniques employed are expected to be useful in the rational design of future therapeutic agents.

Potential antipsychotic properties of central cannabinoid (CB1) receptor antagonists.

PubMed

Roser, Patrik; Vollenweider, Franz X; Kawohl, Wolfram

2010-03-01

Delta(9)-Tetrahydrocannabinol (Delta(9)-THC), the principal psychoactive constituent of the Cannabis sativa plant, and other agonists at the central cannabinoid (CB(1)) receptor may induce characteristic psychomotor effects, psychotic reactions and cognitive impairment resembling schizophrenia. These effects of Delta(9)-THC can be reduced in animal and human models of psychopathology by two exogenous cannabinoids, cannabidiol (CBD) and SR141716. CBD is the second most abundant constituent of Cannabis sativa that has weak partial antagonistic properties at the CB(1) receptor. CBD inhibits the reuptake and hydrolysis of anandamide, the most important endogenous CB(1) receptor agonist, and exhibits neuroprotective antioxidant activity. SR141716 is a potent and selective CB(1) receptor antagonist. Since both CBD and SR141716 can reverse many of the biochemical, physiological and behavioural effects of CB(1) receptor agonists, it has been proposed that both CBD and SR141716 have antipsychotic properties. Various experimental studies in animals, healthy human volunteers, and schizophrenic patients support this notion. Moreover, recent studies suggest that cannabinoids such as CBD and SR141716 have a pharmacological profile similar to that of atypical antipsychotic drugs. In this review, both preclinical and clinical studies investigating the potential antipsychotic effects of both CBD and SR141716 are presented together with the possible underlying mechanisms of action.

Use of Medication in School Programs for Behaviorally Disordered Pupils.

ERIC Educational Resources Information Center

Epstein, Michael H.; Olinger, Ellen

1987-01-01

The article presents information on psychotrophic drugs used with behaviorally disordered students (stimulants, antidepressants, antipsychotics, and lithium), including desired effects and side effects. Guidelines for teachers and other school personnel who work with students on medication are also provided. (Author/JW)

Multi-psychotropic drug prescription and the association to neuropsychiatric symptoms in three Norwegian nursing home cohorts between 2004 and 2011.

PubMed

Gulla, Christine; Selbaek, Geir; Flo, Elisabeth; Kjome, Reidun; Kirkevold, Øyvind; Husebo, Bettina S

2016-06-01

Neuropsychiatric symptoms, such as affective symptoms, psychosis, agitation, and apathy are common among nursing home patients with and without dementia. Treatment with one or more psychotropic drug is often without explicit clinical indication, despite low treatment efficacy, and potential side effects. We aim to investigate the multi-psychotropic drug use to identify factors and patient characteristics associated with multi-use. We analysed three cohorts from 129 Norwegian nursing homes, collected between 2004 and 2011. Patients (N = 4739) were assessed with the Neuropsychiatric Inventory - Nursing Home version (NPI-NH), Clinical Dementia Rating scale, and Physical Self Maintenance Scale. We used ordinal logistic regression to analyse associations between psychotropics (antidepressants, antipsychotics, anxiolytics, hypnotics, and anti-dementia drugs), patient characteristics, and neuropsychiatric symptoms. Patients used on average 6.6 drugs; 27 % used no psychotropics, 32 % one, and 41 % multiple psychotropic drugs (24 % two, 17 % ≥3). Thirty-nine percent were prescribed antidepressants, 30 % sedatives, 24 % anxiolytics, and 20 % antipsychotics. The total NPI-NH score was associated with multi-use (OR 1.02, 95 % CI 1.02-1.03), and increased from a mean of 13.5 (SD 16.3) for patients using none, to 25.5 (21.8) for patients using ≥3 psychotropics. Affective symptoms (depression and anxiety) were most strongly associated with multi-psychotropic drug use (OR 1.10, 95 % CI: 1.09-1.12). Female gender, independency in daily living, younger age, dementia, and many regular drugs were also associated with multi-use. Forty-one percent were exposed to multi-psychotropic drug prescriptions. Contrary to current evidence and guidelines, there is an extensive use of multiple psychotropic drugs in patients with severe NPS and dementia.

Effects of various antipsychotic drugs upon the striatal concentrations of para-hydroxyphenylacetic acid and meta-hydroxyphenylacetic acid in the mouse.

PubMed Central

Juorio, A. V.; McQuade, P. S.

1983-01-01

The endogenous concentrations of p- and m-hydroxyphenylacetic acid in the mouse caudate nucleus were determined by a gas chromatographic or a gas chromatographic-mass spectrometric technique and the concentrations were about 30 and 11 ng g-1 respectively. The subcutaneous administration of (+)-butaclamol (1 mg kg-1), haloperidol (5 mg kg-1), molindone (100 mg kg-1), sulpiride (50 mg kg-1) or chlorpromazine (20 mg kg-1) increased the concentration of mouse striatal p- and m-hydroxyphenylacetic acid; the effects were observed at 2 h after drug administration. Lower doses of chlorpromazine (2 mg kg-1), haloperidol (0.2 mg kg-1) and molindone (2 mg kg-1) did not affect p- or m-hydroxyphenylacetic acid concentrations. The time course for the concentration changes produced by chlorpromazine (20 mg kg-1) revealed that the formation of the metabolites occurred within 30 min after its administration and that their efflux from the caudate nucleus took at least 4 h for p-hydroxyphenylacetic acid and more than 8 h for m-hydroxyphenylacetic acid. Promethazine and (-)-butaclamol which have chemical structures related to chlorpromazine or (+)-butaclamol respectively but which lack antipsychotic activity, produced no effect on striatal p- or m-hydroxyphenylacetic acid concentrations. The results suggest that antipsychotic drugs increase the utilization of mouse striatal p- and m-tyramine and that after use the amines are metabolized by monoamine oxidase to form p- or m-hydroxyphenylacetic acid. The synthesis of the acid metabolites occurs within 30 min after chlorpromazine administration and their efflux from the caudate nucleus takes from 4-8 h. PMID:6196070

Striatal cholinergic interneurons and D2 receptor-expressing GABAergic medium spiny neurons regulate tardive dyskinesia

PubMed Central

Bordia, Tanuja; Zhang, Danhui; Perez, Xiomara A.; Quik, Maryka

2016-01-01

Tardive dyskinesia (TD) is a drug-induced movement disorder that arises with antipsychotics. These drugs are the mainstay of treatment for schizophrenia and bipolar disorder, and are also prescribed for major depression, autism, attention deficit hyperactivity, obsessive compulsive and post-traumatic stress disorder. There is thus a need for therapies to reduce TD. The present studies and our previous work show that nicotine administration decreases haloperidol-induced vacuous chewing movements (VCMs) in rodent TD models, suggesting a role for the nicotinic cholinergic system. Extensive studies also show that D2 dopamine receptors are critical to TD. However, the precise involvement of striatal cholinergic interneurons and D2 medium spiny neurons (MSNs) in TD is uncertain. To elucidate their role, we used optogenetics with a focus on the striatum because of its close links to TD. Optical stimulation of striatal cholinergic interneurons using cholineacetyltransferase (ChAT)-Cre mice expressing channelrhodopsin2-eYFP decreased haloperidol-induced VCMs (~50%), with no effect in control-eYFP mice. Activation of striatal D2 MSNs using Adora2a-Cre mice expressing channelrhodopsin2-eYFP also diminished antipsychotic-induced VCMs, with no change in control-eYFP mice. In both ChAT-Cre and Adora2a-Cre mice, stimulation or mecamylamine alone similarly decreased VCMs with no further decline with combined treatment, suggesting nAChRs are involved. Striatal D2 MSN activation in haloperidol-treated Adora2a-Cre mice increased c-Fos+ D2 MSNs and decreased c-Fos+ non-D2 MSNs, suggesting a role for c-Fos. These studies provide the first evidence that optogenetic stimulation of striatal cholinergic interneurons and GABAergic MSNs modulates VCMs, and thus possibly TD. Moreover, they suggest nicotinic receptor drugs may reduce antipsychotic-induced TD. PMID:27658674

Hormonal and Metabolic Effects of Olanzapine and Clozapine Related to Body Weight in Rodents

PubMed Central

Albaugh, Vance L.; Henry, Cathy R.; Bello, Nicholas T.; Hajnal, Andras; Lynch, Susan L.; Halle, Beth; Lynch, Christopher J.

2009-01-01

Objective To characterize a model of atypical antipsychotic drug-induced obesity and evaluate its mechanism. Research Methods and Procedures Chronically, olanzapine or clozapine was self-administered via cookie dough to rodents (Sprague-Dawley or Wistar rats; C57Bl/6J or A/J mice). Chronic studies measured food intake, body weight, adiponectin, active ghrelin, leptin, insulin, tissue wet weights, glucose, clinical chemistry endpoints, and brain dopaminergic D2 receptor density. Acute studies examined food intake, ghrelin, leptin, and glucose tolerance. Results Olanzapine (1 to 8 mg/kg), but not clozapine, increased body weight in female rats only. Weight changes were detectable within 2 to 3 days and were associated with hyperphagia starting ~24 hours after the first dose. Chronic administration (12 to 29 days) led to adiposity, hyperleptinemia, and mild insulin resistance; no lipid abnormalities or changes in D2 receptor density were observed. Topiramate, which has reversed weight gain from atypical anti-psychotics in humans, attenuated weight gain in rats. Acutely, olanzapine, but not clozapine, lowered plasma glucose and leptin. Increases in glucose, insulin, and leptin following a glucose challenge were also blunted. Discussion A model of olanzapine-induced obesity was characterized which shares characteristics of patients with atypical antipsychotic drug-induced obesity; these characteristics include hyperphagia, hyperleptinemia, insulin resistance, and weight gain attenuation by topiramate. This model may be a useful and inexpensive model of uncomplicated obesity amenable to rapid screening of weight loss drugs. Olanzapine-induced weight gain may be secondary to hyperphagia associated with acute lowering of plasma glucose and leptin, as well as the inability to increase plasma glucose and leptin following a glucose challenge. PMID:16493121

Prenatal exposure to a novel antipsychotic quetiapine: impact on neuro-architecture, apoptotic neurodegeneration in fetal hippocampus and cognitive impairment in young rats.

PubMed

Singh, K P; Tripathi, Nidhi

2015-05-01

Reports on prenatal exposure to some of the first generation antipsychotic drugs like, haloperidol, their effects on fetal neurotoxicity and functional impairments in the offspring, are well documented. But studies on in utero exposure to second generation antipsychotics, especially quetiapine, and its effects on fetal neurotoxicity, apoptotic neurodegeneration, postnatal developmental delay and neurobehavioral consequences are lacking. Therefore, the present study was undertaken to evaluate the effect of prenatal administration to equivalent therapeutic doses of quetiapine on neuro-architectural abnormalities, neurohistopathological changes, apoptotic neurodegeneration in fetal hippocampus, and postnatal development and growth as well as its long-lasting imprint on cognitive impairment in young-adult offspring. Pregnant Wistar rats (n=24) were exposed to selected doses (55 mg, 80 mg and 100mg/kg) of quetiapine, equivalent to human therapeutic doses, from gestation day 6 to 21 orally with control subjects. Half of the pregnant subjects of each group were sacrificed at gestation day 21 for histopathological, confocal and electron microscopic studies and rest of the dams were allowed to deliver naturally. Their pups were reared postnatally up to 10 weeks of age for neurobehavioral observations. In quetiapine treated groups, there was significant alterations in total and differential thickness of three typical layers of hippocampus associated with neuronal cells deficit and enhanced apoptotic neurodegeneration in the CA1 area of fetal hippocampus. Prenatally drug treated rat offspring displayed post-natal developmental delay till postnatal day 70, and these young-adult rats displayed cognitive impairment in Morris water maze and passive avoidance regimes as long-lasting impact of the drug. Therefore, quetiapine should be used with cautions considering its developmental neurotoxicological and neurobehavioral potential in animal model, rat. Copyright © 2015 Elsevier Ltd. All rights reserved.