Sample records for long-acting injectable antipsychotic
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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.
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Citrome, Leslie
2017-10-01
Long-acting injectable (LAI) antipsychotics are a useful but underutilized option in the management of schizophrenia. Areas covered: This is a narrative review of newer LAI antipsychotics approved by the US Food and Drug Administration and is an update to a previously published review from 2013. Emphasized are new indications and new dosing intervals. Expert commentary: Ensuring that persons receiving oral antipsychotics are aware that LAI antipsychotics are available is important. The use of LAI antipsychotics can decrease the risk of relapse in both first-episode and chronic schizophrenia. Available treatments differ in terms of specific indications, approved injection sites, needle gauge, injection volume, injection interval, requirements for oral supplementation, availability of pre-filled syringes, storage needs, and post-injection observation period, as well as potential drug-drug interactions and commonly encountered adverse reactions. Approved indications have expanded beyond schizophrenia to also include bipolar maintenance (risperidone microspheres and aripiprazole monohydrate) and schizoaffective disorder (paliperidone palmitate monthly). Intervals between injections can be longer than one month (six-week or two-month aripiprazole lauroxil, and three-month paliperidone palmitate). After a review of the evidence-base, guidance is offered on the appropriate selection among the LAI formulations of both first and second-generation antipsychotics.
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Achilla, Evanthia; McCrone, Paul
2013-04-01
Antipsychotic medication is the mainstay of treatment in schizophrenia. Long-acting medication has potential advantages over daily medication in improving compliance and thus reducing hospitalization and relapse rates. The high acquisition and administration costs of such formulations raise the need for pharmacoeconomic evaluation. The aim of this article is to provide a comprehensive review of the available evidence on the cost effectiveness of long-acting/extended-release antipsychotic medication and critically appraise the strength of evidence reported in the studies from a methodological viewpoint. Relevant studies were identified by searching five electronic databases: PsycINFO, MEDLINE, EMBASE, the NHS Economic Evaluation Database and the Health Technology Assessment database (HTA). Search terms included, but were not limited to, 'long-acting injection', 'economic evaluation', 'cost-effectiveness' and 'cost-utility'. No limits were applied for publication dates and language. Full economic evaluations on long-acting/extended-release antipsychotics were eligible for inclusion. Observational studies and clinical trials were also checked for cost-effectiveness information. Conference abstracts and poster presentations on the cost effectiveness of long-acting antipsychotics were excluded. Thirty-two percent of identified studies met the selection criteria. Pertinent abstracts were reviewed independently by two reviewers. Relevant studies underwent data extraction by one reviewer and were checked by a second, with any discrepancies being clarified during consensus meetings. Eligible studies were assessed for methodological quality using the quality checklist for economic studies recommended by the NICE guideline on interventions in the treatment and management of schizophrenia. After applying the selection criteria, the final sample consisted of 28 studies. The majority of studies demonstrated that risperidone long-acting injection, relative to oral or other long-acting injectable drugs, was associated with cost savings and additional clinical benefits and was the dominant strategy in terms of cost effectiveness. However, olanzapine in either oral or long-acting injectable formulation dominated risperidone long-acting injection in a Slovenian and a US study. Furthermore, in two UK studies, the use of long-acting risperidone increased the hospitalization days and overall healthcare costs, relative to other atypical or typical long-acting antipsychotics. Finally, paliperidone extended-release was the most cost-effective treatment compared with atypical oral or typical long-acting formulations. From a methodological viewpoint, most studies employed decision analytic models, presented results using average cost-effectiveness ratios and conducted comprehensive sensitivity analyses to test the robustness of the results. Variations in study methodologies restrict consistent and direct comparisons across countries. The exclusion of a large body of potentially relevant conference abstracts as well as some papers being unobtainable may have increased the likelihood of misrepresenting the overall cost effectiveness of long-acting antipsychotics. Finally, the review process was restricted to qualitative assessment rather than a quantitative synthesis of results, which could provide more robust conclusions. Atypical long-acting (especially risperidone)/extended-release antipsychotic medication is likely to be a cost-effective, first-line strategy for managing schizophrenia, compared with long-acting haloperidol and other oral or depot formulations, irrespective of country-specific differences. However, inconsistencies in study methodologies and in the reporting of study findings suggest caution needs to be applied in interpreting these findings.
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Mah, Greg T; Dumontet, Jane; Lakhani, Anisha; Corrigan, Susan
2010-01-01
Background Long-acting risperidone for injection is a second-generation antipsychotic indicated for the treatment of schizophrenia and related psychotic disorders. It is a relatively new agent with pharmacokinetic and dosing properties unlike those of conventional long-acting antipsychotic drugs administered by injection. Objective To determine the proportion of patients for whom long-acting risperidone for injection was prescribed appropriately in acute care settings in the Fraser Health Authority of British Columbia, according to the following 4 criteria: approved indication for therapy, 2-week dosing intervals, dose increases no sooner than every 4 weeks, and initial overlap supplementation with another antipsychotic for at least 3 weeks. A variety of other variables, including documented approval under special authority from the provincial drug coverage program, length of hospital stay, initial dose of risperidone, and total number of doses, were assessed as secondary outcomes. Methods A chart review was conducted for all patients for whom therapy with long-acting risperidone for injection was prescribed during stays in 8 acute care hospitals between July 1, 2007, and July 22, 2008. The appropriateness of prescribing was assessed according to the 4 prespecified criteria. Results Long-acting risperidone for injection was prescribed for 116 patients during the study period, and 82 of these started therapy and were included in the evaluation. The primary outcome could not be assessed for 27 of these 82 patients, because they were discharged early, and data for some or all of the 4 criteria were not available. For 33 (60%) of the 55 remaining patients, long-acting risperidone for injection had been prescribed appropriately. In contrast, for 22 (40%) of the patients, prescription of risperidone was deemed inappropriate because of failure to meet at least 1 of the 4 criteria. Premature escalation of the dose and inadequate overlap with antipsychotic supplementation were the most common reasons for designation of the prescription as inappropriate. Conclusions Opportunities exist to improve prescribing practices for long-acting risperidone for injection in acute care institutions in this health authority. PMID:22479015
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Making the leap from daily oral dosing to long-acting injectables: lessons from the antipsychotics.
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.
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Risperidone long-acting injection: a review of its long term safety and efficacy
Rainer, Michael K
2008-01-01
A long-acting form of the second-generation antipsychotic drug risperidone is now broadly available for the treatment of schizophrenia and closely related psychiatric conditions. It combines the advantage of previously available depot formulations for first-generation drugs with the favorable characteristics of the modern “atypical” antipsychotics, namely higher efficacy in the treatment of the negative symptoms of schizophrenia and reduced motor disturbances. Published clinical studies show an objective clinical efficacy (as per psychiatric symptom scores and relapse data) that exceeds that of oral atypical antipsychotics when patients are switched to the long-acting injectable form, a low incidence of treatment-emergent extrapyramidal side effects, and very good acceptance by patients. Available data for maintenance treatment of bipolar disorder show equivalence with the oral form instead of superiority, but are still limited. As it seems likely that efficacy benefits are mostly due to the fact that the injectable form reduces the demand for patient compliance to one physician visit every 2 weeks instead of self-administration on a daily or twice-daily basis, additional potential could exist in other psychiatric disorders where atypical antipsychotic drugs are of benefit but where patient adherence to treatment schedules is typically low. PMID:19183782
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Nystazaki, Maria; Pikouli, Katerina; Tsapakis, Eva-Maria; Karanikola, Maria; Ploumpidis, Dimitrios; Alevizopoulos, Giorgos
2018-04-01
Providing informed, consent requires patients' Decision-Making Capacity for treatment. We evaluated the Decision Making Capacity of outpatients diagnosed with schizophrenia and schizoaffective disorder on treatment with Long Acting Injectable Antipsychotic medication. This is a retrospective, cross-sectional, correlational study conducted at two Depot Clinics in Athens, Greece. Participants included 65 outpatients diagnosed with schizophrenia and schizoaffective disorder on treatment with Long Acting Injectable Antipsychotics. Over half of the participants showed poor understanding of the information given regarding their disease and treatment (Understanding subscale), however >70% seemed to comprehend the relevance of this information to their medical condition (Appreciation subscale). Moreover, half of the participants reported adequate reasoning ability (Reasoning subscale), whilst patients who gained >7% of their body weight scored statistically significantly higher in the subscales of Understanding and Appreciation. Our results suggest that there is a proportion of patients with significantly diminished Decision Making Capacity, hence a full assessment is recommended in order to track them down. Further research is needed to better interpret the association between antipsychotic induced weight gain and Decision Making Capacity in patients suffering from schizophrenia or schizoaffective disorder. Copyright © 2017 Elsevier Inc. All rights reserved.
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Aggarwal, Arpit; Gopalakrishna, Ganesh; Lauriello, John
2016-01-01
Antipsychotics have long been the mainstay for the treatment of schizophrenia and other psychotic disorders. Long-acting injectables (LAI) of antipsychotics-provided once every two weeks to once every three months-promise to reduce the incidence of nonadherence. ARISTADA(™) (aripiprazole lauroxil; ALLAI) extended-release injectable suspension was approved by the U.S. Food and Drug Administration in October 2015 for the treatment of schizophrenia, and is the newest entrant in the LAI market. ALLAI is available as a single-use, pre-filled syringe, can be started in three different dosages, and also has the option of every six-week dosing. Treatment with oral aripiprazole is recommended for the first twenty-one days after the first ALLAI injection, which is a potential disadvantage. Adverse effects include sensitivity to extrapyramidal symptoms, especially akathisia, which is well documented in other aripiprazole preparations. There is no available data comparing ALLAI to other antipsychotics, and more head-to-head trials comparing different LAI formulations are needed. Based on the available data, ALLAI is an effective and safe option for treatment of schizophrenia. Further studies and post-marketing data will provide better understanding of this formulation.
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Sermon, Jan; Geerts, Paul; Denee, Tom R.; De Vos, Cedric; Malfait, Bart; Lamotte, Mark; Mulder, Cornelis L.
2017-01-01
Achieving greater continuation of treatment is a key element to improve treatment outcomes in schizophrenia patients. However, reported treatment continuation can differ markedly depending on the study design. In a retrospective setting, treatment continuation remains overall poor among patients using antipsychotics. This study aimed to document the difference in treatment continuation between four long-acting injectable antipsychotics based on the QuintilesIMS LRx databases, national, longitudinal, panel based prescription databases of retail pharmacies, in the Netherlands and Belgium. Paliperidone palmitate once monthly, risperidone microspheres, haloperidol decanoate, and olanzapine pamoate were studied. This study demonstrated significantly higher treatment continuation of paliperidone palmitate once monthly compared to risperidone microspheres (p-value<0,01) and haloperidol decanoate (p-value<0,01) in both countries, a significantly higher treatment continuation of paliperidone palmitate once monthly compared to olanzapine pamoate in the Netherlands (p-value<0,01), and a general trend towards better treatment continuation versus olanzapine pamoate in Belgium. Analysing the subgroup of patients without previous exposure to long-acting antipsychotic treatment revealed the positive impact of previous exposure on treatment continuation with a subsequent long acting treatment. Additionally, the probability of restarting the index therapy was higher among patients treated with paliperidone palmitate once monthly compared to patients treated with risperidone microspheres and haloperidol decanoate. The data source used and the methodology defined ensured for the first time a comparison of treatment continuation in a non-interventional study design for the four long-acting injectable antipsychotics studied. PMID:28614404
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Emerging pharmacological therapies in schizophrenia: what's new, what's different, what's next?
Citrome, Leslie
2016-12-01
There are several new and emerging medication interventions for both the acute and maintenance treatment phases of schizophrenia. Recently approved are 2 new dopamine receptor partial agonists, brexpiprazole and cariprazine, as well as 2 new long-acting injectable antipsychotic formulations, aripiprazole lauroxil and 3-month paliperidone palmitate. Although differences in efficacy compared to other available choices are not expected, the new oral options offer different tolerability profiles that may be attractive for individual patients who have had difficulties with older medications. The new long-acting injectable options provide additional flexibility in terms of increasing the time interval between injections. In Phase III of clinical development is a novel antipsychotic, lumateperone (ITI-007), that appears to have little in the way of significant adverse effects. Deutetrabenazine and valbenazine are agents in Phase III for the treatment of tardive dyskinesia, a condition that can be found among persons receiving chronic antipsychotic therapy. On the horizon are additional injectable formulations of familiar antipsychotics, aripiprazole and risperidone, that may be more convenient than what is presently available.
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Aripiprazole once-monthly long-acting injectable for the treatment of schizophrenia.
Potkin, Steven G; Preda, Adrian
2016-01-01
Patient non-adherence increases the risk for relapse and the long-term care of schizophrenia. Long-acting injectable (LAI) antipsychotics can decrease this risk by ensuring adherence. An extended formulation, aripiprazole 400 mg once-monthly (AOM 400) LAI (AOM LAI), received regulatory approval in the year 2013 for the treatment of schizophrenia. AOM LAI is the first dopamine D2 partial agonist available in a long-acting formulation for the treatment of schizophrenia. This review covers data on the efficacy and tolerability/safety of AOM LAI. AOM LAI is a lyophilized powder of aripiprazole, with an elimination half-life of 29.9 - 46.5 days, allowing for a 4-week injection interval. Antipsychotic efficacy was documented in a 12-week double-blind trial (n = 340) and in two maintenance-of-effect trials: a 38-week trial (n = 662) and a 52-week trial (n = 403). The side effect profile is similar to that of oral aripiprazole. Adverse events (≥5% and at least twice that for placebo) were typically mild or moderate and did not lead to discontinuation: increased weight, akathisia, injection site pain and sedation. The 400 mg dose is tolerated by >90% of patients. Injection does not require additional training of health personnel or post-injection observation. AOM LAI is an efficacious and well-tolerated antipsychotic treatment for schizophrenia.
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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.
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Lee, Lik Hang N; Choi, Charles; Collier, Abby C; Barr, Alasdair M; Honer, William G; Procyshyn, Ric M
2015-12-01
Product monographs (also known by terms such as Summary of Product Characteristics and Highlights of Prescribing Information, depending on the jurisdiction) provide essential information to ensure the safe and effective use of a drug. Medical practitioners often rely on these monographs for guidance on matters related to pharmacokinetics as well as indications, contraindications, clinical pharmacology, and adverse reactions. The clinical and scientific information found within these documents, forming the basis for decision making, are presumed to be derived from well-designed studies. The objective of this review is to examine the source and validity of the pharmacokinetic data used in establishing the half-lives and times to steady-state reported in the product monographs of second-generation long-acting injectable antipsychotics. Thus, we have critically evaluated the clinical trials from which the pharmacokinetic parameters listed in the product monographs were determined. In many cases, the pharmacokinetic information presented in product monographs is of limited use to clinicians wishing to optimize the effectiveness and tolerability of second-generation long-acting injectable antipsychotics. Under such circumstances, off-label prescribing practices may actually produce better clinical outcomes than if decisions were made based on the product monographs alone.
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Si, Tianmei; Li, Nan; Lu, Huafei; Cai, Shangli; Zhuo, Jianmin; Correll, Christoph U; Zhang, Lili; Feng, Yu
2018-06-01
Limited data are available to help identify patients with schizophrenia who are most likely to benefit from long-acting injectable antipsychotics. To investigate the efficacy of long-acting injectable antipsychotic paliperidone palmitate one-month formulation for preventing relapses, factors influencing time to first relapse, and the effect of different antipsychotic adherence levels on time to first relapse in Chinese patients with schizophrenia. This was a post-hoc analysis from an open-label, single-arm study of stable patients (Positive and Negative Syndrome Scale total score <70; n=367) receiving paliperidone palmitate one-month formulation at the end of an acute 13-week treatment phase, who entered a naturalistic one-year follow-up period, either continuing with flexibly dosed paliperidone palmitate one-month formulation (75-150 mg eq.) or switching to another antipsychotic(s). There were 362/367 patients (age=31.4±10.75 years) included in the analysis of time to first relapse (primary outcome) and 327/362 patients (39/327, poor antipsychotic adherence (<80%)) willing to receive antipsychotics were included in the exposure/adherence analysis. Overall, 84.6% (95% confidence interval=79.2-88.7) patients remained relapse-free. Poor adherence during follow-up (hazard ratio=2.97, 95% confidence interval=1.48-5.98, p=0.002) and frequent hospitalizations in the previous year (hazard ratio=1.29, 95% confidence interval=1.02-1.62, p=0.03) were associated with a significant risk of shorter time to first relapse in the univariate analysis. In patients with poor adherence, 'no use' (hazard ratio=13.13, 95% confidence interval=1.33-129.96, p=0.03) and 'interrupted use' (hazard ratio=11.04, 95% confidence interval=1.03-118.60, p=0.047) of paliperidone palmitate one-month formulation (vs continued use) showed a significantly higher risk of relapse; this was not observed in patients with good (≥80%) antipsychotic adherence. No new safety concerns were identified. Continued use of paliperidone palmitate one-month formulation/long-acting injectable antipsychotic was effective in preventing schizophrenia relapses, especially in patients with suboptimal antipsychotic adherence.
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Cordiner, Matthew; Shajahan, Polash; McAvoy, Sarah; Bashir, Muhammad; Taylor, Mark
2016-01-01
Objectives: In the UK, nine different compounds are available as long-acting antipsychotic injections (LAIs). There are few clinical guidelines for determining which LAIs are most effective in specific patient groups. To measure the clinical effectiveness of LAIs we aimed to determine the now-established concept of antipsychotic discontinuation rates and measure Clinical Global Impression (CGI) outcomes. Method: The population (n was approximately 560,000) was a secondary care NHS adult mental health service in Lanarkshire, Scotland, UK. This was a retrospective, electronic case note search of LAI-naïve patients commenced on paliperidone palmitate (n = 31), risperidone long-acting injection (RLAI) (n = 102) or zuclopenthixol decanoate (n = 105), with an 18-month follow up. Kaplan–Meier survival statistics for discontinuation rates and hospital admission were calculated. CGI severity and improvement scores were retrospectively assigned by the investigating team. Results: Paliperidone palmitate performed less favourably than risperidone long-acting injection (RLAI) or zuclopenthixol decanoate. Paliperidone palmitate had higher discontinuation rates due to any cause, inefficacy and increased hospitalization risk. Paliperidone palmitate had the smallest proportion of patients assigned a clinically desirable CGI-I score of 1 (very much improved) or 2 (much improved). Conclusions: Paliperidone palmitate had less favourable discontinuation and CGI outcomes compared with RLAI and zuclopenthixol decanoate. This could not be adequately explained by patients in the paliperidone group being more chronically or severely unwell, nor by the presence of comorbidities such as alcohol or substance misuse, or by the use of lower mean dosages compared with RLAI or zuclopenthixol decanoate. We considered that prescribers are familiarizing themselves with paliperidone and outcomes may improve over time. PMID:26913175
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Mesones-Peral, Jesús E; Gurillo-Muñoz, Pedro; Sánchez-Sicilia, Mari Paz; Miller, Adam; Griñant-Fernández, Alejandra
Prevent hospitalizations in psychotic disorders is an important aim, so long-acting antipsychotic is a good option that can control better the correct adherence. Moreover, in the current economic context pharmacoeconomic studies are necessary. We estimate the effect in prevention of paliperidone palmitate long-acting injection (PP-LAI) and calculate the economic cost in the 12 months preceding the start of treatment with PP-LAI and 12 months later. Mirror image study of 71 outpatients diagnosed with psychotic disorders and treated with PP-LAI. In a first analysis, we measured along one year: number of hospitalizations/year, number of hospitalization in days, number of emergency assists/year and if there is antipsychotics associated to long-acting treatment. After this phase, we applied Fees Act of Valencia for economic analysis and estimate of the cost per hospitalization (€ 5,640.41) and hospital emergency (€ 187.61). After one year of treatment with PP-LAI (mean dose=130.65mg/month), we obtained greater numbers in assistance variables: total hospitalizations decrease, 78.8% (P=.009); shortening in hospitalization days, 89.4% (P=.009); abridgement of number of emergency assists, 79.1% (P=.002); decrease of rate of antipsychotics associated to long-acting treatment, 21% (P<.0001); increase in monotherapy, 53.8% (P<.0001). Therefore, after 12 months of treatment with PP-LAI we obtained a reduction in inpatient spending (savings of € 175,766.54) and increased spending on antipsychotics 32% (equivalent to € 151,126.92). PP-LAI can be an effective therapy for the treatment of patients with severe psychotic disorders: improves symptomatic stability and can prevent hospitalizations with cost-effective symptom control. Copyright © 2016 SEP y SEPB. Publicado por Elsevier España, S.L.U. All rights reserved.
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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.
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2013-01-01
Background Discontinuation of antipsychotic treatment for schizophrenia can interrupt improvement and exacerbate the illness. Reasons for discontinuing treatment are multifactorial and include adherence, efficacy and tolerability issues. Poor adherence may be addressed through non-pharmacological approaches as well as through pharmacological ones, ie ensured delivery of medication, such as that achieved with long-acting injectable (LAI) antipsychotics. However, attitudes of healthcare professionals (HCPs) towards LAI antipsychotics may influence their prescribing decisions and may influence medication choices offered to patients. We therefore conducted a survey to investigate factors driving LAI use as well as physician and nurse attitudes to LAI antipsychotics and to different injection sites. Methods An independent market research agency conducted the survey of HCPs across Europe. Participants were recruited by telephone and completed the survey online. Using conjoint analyses (a multivariate statistical technique analysing preferences on the basis of ranking a limited number of attributes which are presented repetitively), attitudes to oral versus LAI medication and gluteal versus deltoid injection routes were assessed. Results A total of 891 HCPs across Europe were surveyed. Of these, 40% would choose LAI antipsychotics for first episode patients whereas 90% would select LAI antipsychotics for chronic patients with two to five psychotic episodes. Dominant elements in antipsychotic choice were low sedation but no tardive dyskinesia, no or mild pain at injection and low risk of embarrassment or impact upon therapeutic alliance. Eighty-six per cent of respondents considered that having the choice of a deltoid as well as gluteal administration site was beneficial over not having that choice. Two thirds of respondents said they agreed that medication administration via the deltoid muscle may reduce social embarrassment associated with LAI antipsychotics and most respondents (61%) believed that administration of LAI antipsychotics into the deltoid muscle as opposed to the gluteal muscle may be more respectful to the patient. Conclusions In this survey of physicians and nurses, attitudes towards LAI antipsychotics compared with oral medication were generally positive. Respondents considered that the availability of a deltoid administration route would offer increased choice in LAI antipsychotic administration and may be perceived as more respectful and less socially embarrassing. PMID:23414331
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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.
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Weiden, Peter J; Du, Yangchun; Liu, Chih-Chin; Stanford, Arielle D
2018-06-26
Switching antipsychotic medications is common in patients with schizophrenia who are experiencing persistent symptoms or tolerability issues associated with their current drug regimen. This analysis assessed the safety of switching from an oral antipsychotic to the long-acting injectable antipsychotic aripiprazole lauroxil (AL). This was a post hoc analysis of outpatients with schizophrenia who were prescribed an oral antipsychotic and who enrolled in an international, open-label, long-term (52-week) safety study of AL. The analysis focused on the first 3 injections of AL 882 mg over 12 weeks, divided into the immediate 4-week crossover period between the first and second AL injections (initiation phase) and the subsequent 8 weeks (stabilization phase). Patients were grouped by preswitch oral antipsychotic medication, and safety and clinical symptoms were assessed. In total, 190 patients had switched from one of the following oral antipsychotic medications: aripiprazole, conventional antipsychotics, risperidone/paliperidone, olanzapine, or quetiapine. The 12-week completion rate was high (92.1%) and similar across the different preswitch oral antipsychotic groups. Overall, adverse event (AE) rates experienced over 12 weeks were modest; no AEs were considered serious. The most common AEs in the initiation phase were injection site pain (5.8%), insomnia (5.8%), and akathisia (3.2%). No apparent relationship was observed between preswitch medication and early-onset AEs. Mean Positive and Negative Syndrome Scale total scores remained stable during this period across preswitch antipsychotic groups. Switching from an oral antipsychotic to AL was feasible in an outpatient setting for patients with schizophrenia, and the 12-week retention rate was favorable.
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Sajatovic, Martha; Ross, Ruth; Legacy, Susan N; Byerly, Matthew; Kane, John M; DiBiasi, Faith; Fitzgerald, Heather; Correll, Christoph U
2018-01-01
The aim of this study was to provide recommendations on initiating and maintaining long-acting injectable antipsychotics (LAIs) in individuals with schizophrenia/schizoaffective or bipolar disorder. A 50-question survey comprising 916 response options was completed by 34 expert researchers and high prescribers with extensive LAI experience, rating relative appropriateness/importance on a 9-point scale. Consensus was determined using chi-square test of score distributions. Results of 21 questions comprising 339 response options regarding LAI initiation, maintenance treatment, adequate trial definition, identifying treatment nonresponse, and switching are reported. Experts agreed that the most important LAI selection factor was patient response/tolerability to previous antipsychotics. An adequate therapeutic LAI trial was defined as the time to steady state ± 1-2 injection cycles. Experts suggested that oral efficacy and tolerability should be established before switching to an LAI, without consensus on the required time, and that the time for oral supplementation and next injection interval should be determined by the time to attainment of therapeutic LAI levels. Most experts agreed that ≥1 adequate LAI trial is needed to identify the lack of efficacy. There was little agreement about strategies for switching between LAIs. Expert guidance may aid clinicians in their decisions regarding initiating/maintaining LAIs in individuals with schizophrenia/schizoaffective or bipolar disorder.
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Singh, Sourabh Moti; Haddad, Peter M.; Husain, Nusrat; Heaney, Eamonn; Tomenson, Barbara; Chaudhry, Imran B.
2016-01-01
Objectives: The objective of this study was to compare patients’ attitudes and satisfaction with medication and patient-rated tolerability between those prescribed a first-generation antipsychotic long-acting injection (FGA-LAI) and those prescribed risperidone long-acting injection (RLAI). Method: A cross-sectional study of a representative sample of outpatients prescribed an FGA-LAI or RLAI for a minimum of 6 months and attending a depot clinic. Attitudes to medication were assessed by the Drug Attitude Inventory (DAI-30), tolerability was measured by the Liverpool University Neuroleptic Side Effect Rating Scale (LUNSERS) and satisfaction with antipsychotic medication was assessed by the Satisfaction with Antipsychotic Medication (SWAM) scale. Results: The RLAI (n = 28) and FGA-LAI (n = 39) groups did not differ in terms of mean age, sex, diagnosis and ethnicity. All individual LAIs were prescribed within British National Formulary limits. The most commonly prescribed FGA-LAI was flupentixol decanoate (n = 22). There was no significant difference between the RLAI and FGA-LAI groups in terms of mean total scores on the DAI-30, LUNSERS and SWAM or the tolerability subscales of the LUNSERS or the two subscales (treatment acceptability and medication insight) of the SWAM. In both LAI groups there was a low level of side effects (LUNSERS) and a generally positive attitude (DAI-30) and reasonable satisfaction (SWAM) with medication. Conclusions: Patients treated with FGA-LAI and RLAI for at least 6 months did not differ in terms of patient-rated tolerability, attitudes and satisfaction with medication. The current design cannot determine whether differences would have been evident earlier on during treatment. These results should be regarded as preliminary and are subject to prescribing bias. Randomized studies avoid prescribing bias and are a superior way to compare specific LAIs. Ideally randomized studies should include patient-rated outcome measures including medication tolerability; assessment of side effects, efficacy and quality of life made by blinded raters; and additional objective side-effect data including changes in weight and key blood parameters. PMID:27354904
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Bioque, Miquel; Llerena, Adrián; Cabrera, Bibiana; Mezquida, Gisela; Lobo, Antonio; González-Pinto, Ana; Díaz-Caneja, Covadonga M.; Corripio, Iluminada; Aguilar, Eduardo J.; Bulbena, Antoni; Castro-Fornieles, Josefina; Vieta, Eduard; Lafuente, Amàlia; Mas, Sergi; Parellada, Mara; Saiz-Ruiz, Jerónimo; Cuesta, Manuel J.
2016-01-01
Background: The characterization of the first episode of psychosis and how it should be treated are principal issues in actual research. Realistic, naturalistic studies are necessary to represent the entire population of first episode of psychosis attended in daily practice. Methods: Sixteen participating centers from the PEPs project recruited 335 first episode of psychosis patients, aged 7 to 35 years. This article describes and discusses the psychopharmacological interventions and safety profiles at baseline and during a 60-day pharmacovigilance period. Results: The majority of first episode of psychosis patients received a second-generation antipsychotic (96.3%), orally (95%), and in adjusted doses according to the product specifications (87.2%). A total of 24% were receiving an antipsychotic polytherapy pattern at baseline, frequently associated with lower or higher doses of antipsychotics than the recommended ones. Eight patients were taking clozapine, all in monotherapy. Males received higher doses of antipsychotic (P=.043). A total of 5.2% of the patients were being treated with long-acting injectable antipsychotics; 12.2% of the patients received anticholinergic drugs, 12.2% antidepressants, and 13.7% mood stabilizers, while almost 40% received benzodiazepines; and 35.52% reported at least one adverse drug reaction during the pharmacovigilance period, more frequently associated with higher antipsychotic doses and antipsychotic polytherapy (85.2% vs 45.5%, P<.001). Conclusions: These data indicate that the overall pharmacologic prescription for treating a first episode of psychosis in Spain follows the clinical practice guideline recommendations, and, together with security issues, support future research of determinate pharmacological strategies for the treatment of early phases of psychosis, such as the role of clozapine, long-acting injectable antipsychotics, antipsychotic combination, and the use of benzodiazepines. PMID:26506856
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History and therapeutic rationale of long acting antipsychotics.
De Risio, Alessandro; Lang, Antonella P
2014-02-01
Despite their widespread use, long acting antipsychotics, are often regarded with prejudice, due to fears of punishment, control and insufficient evolution towards psychosocial development of psychotic patients raised by their improper utilization. Another major shortcoming of long-acting antipsychotics is the impossibility of altering their dosage if side-effects appear. However, long-acting antipsychotics proved effective in schizophrenia and other severe psychotic disorders as a consequence of stable dose administration, leading to reduction of relapses and increased treatment adherence. Therapeutic opportunities have also risen after introduction of newer long acting second generation antipsychotics in recent years. Newer long-acting antipsychotics were developed to tackle the need for pharmacotherapy enhancing adherence in integrated rehabilitation programmes. This review is an outline of the development and introduction of older and newer long-acting antipsychotics in the treatment of schizophrenia and other psychoses, with considerations on past and present pharmacological and therapeutic issues.
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The role of long-acting injectable antipsychotics in schizophrenia: a critical appraisal.
Brissos, Sofia; Veguilla, Miguel Ruiz; Taylor, David; Balanzá-Martinez, Vicent
2014-10-01
Despite their widespread use, long-acting injectable (LAI) antipsychotics (APs) are often regarded with some negativity because of the assumption of punishment, control and insufficient evolution towards psychosocial development of patients. However, LAI APs have proved effective in schizophrenia and other severe psychotic disorders because they assure stable blood levels, leading to a reduction of the risk of relapse. Therapeutic opportunities have also arisen after introduction of newer, second-generation LAI APs in recent years. Newer LAI APs are more readily dosed optimally, may be better tolerated and are better suited to integrated rehabilitation programmes. This review outlines the older and newer LAI APs available for the treatment of schizophrenia, with considerations of past and present pharmacological and therapeutic issues. Traditional, evidence-based approaches to systematic reviews and randomized clinical trials are of limited utility in this area so this paper's blending of experimental trials with observational research is particularly appropriate and effective.
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Tempest, Michael; Sapin, Christophe; Beillat, Maud; Robinson, Paul; Treur, Maarten
2015-12-01
Schizophrenia is a severe and debilitating psychiatric disorder. Pharmacological interventions aim to ameliorate symptoms and reduce the risk of relapse and costly hospitalisation. Despite the established efficacy of antipsychotic medication, compliance to treatment is poor, particularly with oral formulation. The emergence of long acting injectable (LAI) antipsychotic formulations in recent years has aimed to counteract the poor compliance rates observed and optimise long term patient outcomes. To estimate the cost-effectiveness of aripiprazole once-monthly 400mg (AOM 400) vs. risperidone long acting injectable (RLAI), paliperidone long acting injectable (PLAI) and olanzapine long acting injectable (OLAI) in the maintenance treatment of chronic, stable schizophrenia patients in the United Kingdom. A Markov model was developed to emulate the treatment pathway of a hypothetical cohort of patients initiating maintenance treatment with LAI antipsychotics. The economic analysis was conducted from a National Health Service (NHS) and Personal Social Services (PSS) perspective over a 10 year time horizon. Efficacy and safety probabilities were derived from mixed treatment comparisons (MTCs) where possible. Analyses were conducted assuming pooled dosing from randomised clinical trials included in the MTCs. The model estimates that AOM 400 improves clinical outcomes by reducing relapses per patient comparative to other LAIs over the model time horizon (2.38, 2.53, 2.70, and 2.67 for AOM 400, RLAI, PLAI and OLAI respectively). In the deterministic analysis, AOM 400 dominated PLAI and OLAI; an incremental cost-effectiveness ratio (ICER) of GBP 3,686 per QALY gained was observed against RLAI. Results from the univariate sensitivity analyses highlighted the probability and cost of relapse as main drivers for cost-effectiveness. In the probabilistic sensitivity analysis, AOM 400 demonstrated a marginally higher probability of being cost-effective (51%) than RLAI, PLAI and OLAI (48%, 1% and 0%, respectively) at a willingness to pay threshold of GBP 20,000. The model was built to accommodate results of an adjusted MTC analysis. Furthermore the model effectively captures repercussions of deteriorating compliance to treatment by incorporating three levels of compliance with elevated risks of relapse for partial compliance and non-compliance. Limitations of the analysis include the limited number of studies incorporated in the MTC, the extrapolation of short term clinical data and the exclusion of the wider societal burden. Comparative to other atypical antipsychotics, AOM 400 represents value for money in the maintenance treatment of chronic, stable schizophrenia; however, in light of the PSA findings and comparable cost-effectiveness (i.e. against RLAI), the product profile and wider benefits of the respective treatments must be taken into account when prescribing antipsychotics. Future research should assess the use of LAI antipsychotics earlier in the disease course of schizophrenia to see whether improved compliance and outcomes shortly following the onset of psychosis has the potential to alter the disease trajectory. Moreover it should be assessed whether changes in the disease trajectory can alleviate cost and resource pressures placed on national health services.
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Brugnoli, Roberto; Rapinesi, Chiara; Kotzalidis, Georgios D; Marcellusi, Andrea; Mennini, Francesco S; De Filippis, Sergio; Carrus, Dario; Ballerini, Andrea; Francomano, Antonio; Ducci, Giuseppe; Del Casale, Antonio; Girardi, Paolo
2016-01-01
Schizophrenia is a severe mental disease that affects approximately 1% of the population with a relevant chronic impact on social and occupational functioning and daily activities. People with schizophrenia are 2-2.5 times more likely to die early than the general population. Non-adherence to antipsychotic medications, both in chronic and first episode schizophrenia, is one of the most important risk factors for relapse and hospitalization, that consequently contributes to increased costs due to psychiatric hospitalization. Atypical long-acting injectable (LAI) antipsychotics can improve treatment adherence and decrease re-hospitalization rates in patients with schizophrenia since its onset. The primary goals in the management of schizophrenia are directed not only at symptom reduction in the short and long term, but also at maintaining physical and mental functioning, improving quality of life, and promoting patient recovery. To propose a scientific evidence-based integrated model that provides an algorithm for recovery of patients with schizophrenia and to investigate the effectiveness and safety of antipsychotics LAI in the treatment, maintenance, relapse prevention, and recovery of schizophrenia. After an accurate literature review we identified, collected and analyzed the crucial points in taking care schizophrenia patients, through which we defined the steps described in the model of management and the choice of the better treatment option. Results. In the management model we propose, the choice of a second generation long acting antipsychotic, could allow from the earliest stages of illness better patient management, especially for young individuals with schizophrenia onset, a better recovery and significant reductions of relapse and health care costs. LAI formulations of antipsychotics are valuable, because they help patients to remain adherent to their medication through regular contact with healthcare professionals and to prevent covert non-adherence. The proposed schizophrenia model of management could allow better patient management and recovery, in which the treatment with LAI formulation is a safe and effective therapeutic option. This new therapeutic approach could change the cost structure of schizophrenia by decreasing costs with efficient economic resource allocation guaranteed from efficient diagnostic and therapeutic pathways.
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Increased use of antipsychotic long-acting injections with community treatment orders.
Patel, Maxine X; Matonhodze, Jane; Baig, Mirza K; Gilleen, James; Boydell, Jane; Holloway, Frank; Taylor, David; Szmukler, George; Lambert, Tim; David, Anthony S
2011-04-01
Community treatment orders (CTOs) are increasingly being used, despite a weak evidence base, and problems continue regarding Second Opinion Appointed Doctor (SOAD) certification of medication. The aim of the current study was to describe current CTO usage regarding patient characteristics, prescribed medication and CTO conditions. A 1-year prospective cohort study with consecutive sampling was conducted for all patients whose CTO was registered in a large mental health trust. Only the first CTO for each patient was included. Measures included sociodemographic variables, psychiatric diagnosis, CTO date of initiation and conditions, psychotropic medication and date of SOAD certification for medication. This study was conducted in the first year of CTO legislation in England and Wales. A total of195 patients were sampled (mean age 40.6 years, 65% male, 52% black ethnic origin). There was significant geographical variability in rates of CTO use (χ(2) = 11.3, p = 0.012). A total of 53% had their place of residence specified as a condition and 29% were required to allow access into their homes. Of those with schizophrenia, 64% were prescribed an antipsychotic long-acting injection (LAI). Of the total group, 7% received high-dose antipsychotics, 10% were prescribed two antipsychotics and only 15% received SOAD certification in time. There was geographical and ethnic variation in CTO use but higher rates of hospital detention in minority ethnic groups may be contributory. Most patients were prescribed antipsychotic LAIs and CTO conditions may not follow the least restrictive principle.
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Tachycardia in patients treated with clozapine versus antipsychotic long-acting injections.
Nilsson, Björn M; Edström, Oscar; Lindström, Leif; Wernegren, Petter; Bodén, Robert
2017-07-01
Tachycardia is a known adverse effect during clozapine treatment. However, prevalence reported differs widely between studies and hitherto there are no studies comparing clozapine-treated patients with a similar control group. The present study was carried out to assess the prevalence of tachycardia in patients treated with clozapine and antipsychotic long-acting injections (LAI). Data on heart rate (HR), concomitant medication, and relevant anthropometric and laboratory measurements were collected for all clozapine-treated patients (n=174) in a defined catchment area and compared with data on patients treated with LAI (n=87). In total, 33% of patients on long-term clozapine treatment had tachycardia (HR>100) compared with 16% in the LAI group (P<0.001). The mean HR was 91 in the clozapine group and 82 in the LAI group (P<0.001). Clozapine dose correlated with HR. The majority of patients with HR more than 100 received no specific treatment for tachycardia. In conclusion, the prevalence of tachycardia was twice as high in patients treated with clozapine as in a similar patient group with severe schizophrenia spectrum disorder. The tachycardia was in many cases clinically unnoticed. Tachycardia during antipsychotic treatment is a common phenomenon that must be monitored for actively and, when noticed, further investigated and treated.
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Gundugurti, Prasad Rao; Nagpal, Rajesh; Sheth, Ashit; Narang, Prashant; Gawande, Sonal; Singh, Vikram
2017-12-01
Schizophrenia is associated with functional challenges for patients; relapses in schizophrenia may lead to increased treatment costs and poor quality of life. This SUSTAIN-I study was conducted to establish psychiatrists' perspective on impact of long-acting injectables (LAIs) antipsychotics on the socio-economic and functional burden of schizophrenia. This cross-sectional, survey-based study was conducted in 5 cities in India. Psychiatrists (≥5years of experience) working in clinics, psychiatric, government hospitals and rehabilitation centers were included and administered a specially designed questionnaire to elicit information on their clinical practice and prescription patterns. Perceived treatment costs for LAI versus oral antipsychotic treatments (OATs) and relapse rates were assessed. Descriptive statistics were used to summarize results. Total 31 physicians completed this survey. In acute phase, OAT prescription was higher whereas chronic patients were treated with either OATs or LAIs. Treatment with LAIs was the preferred treatment in 9% of chronic cases. Reduced relapse rates were observed with LAI treatment: 12% patients on LAIs relapsed as compared with 60% patients on OATs. Monthly medication cost for oral medications was lower ($8-$17) than short-acting injectables ($22-$50). For chronic cases, atypical antipsychotics cost (oral: $11.7-25, LAI: $150-167) was higher than typical antipsychotics (oral: $4-5, LAI: $5-25). Of the total expenses incurred, cost for hospital admissions was the largest component (78%). Despite enhanced treatment adherence and potential to lower risk of rehospitalizations from relapse, LAIs are not the preferred treatment choice for patients with schizophrenia in India, owing to their perceived high costs. Copyright © 2017 Elsevier B.V. All rights reserved.
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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.
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A review of aripiprazole long-acting injection.
Chue, Pierre; Chue, James
2016-01-01
To review the published literature on aripiprazole once monthly, a second generation antipsychotic (SGA) recently developed as a long-acting injection (LAI), in the form of a suspension of lyophilized aripiprazole reconstituted with an aqueous diluent, for intramuscular administration. An electronic database search was conducted using the key words; relevant articles were then hand searched and websites (FDA, EMA, Otsuka, Lundbeck, NIH) reviewed. Efficacy has been demonstrated in preventing relapse in a 52 week study versus placebo, and non-inferiority to oral aripiprazole in a 38 week study, as well as in the treatment of hospitalized adult patients with acutely relapsed schizophrenia. Aripiprazole LAI appears cost-effective versus other SGA-LAIs, with improved health-related quality of life and functioning in a head-to-head study with paliperidone LAI. A 6 month (pre and post), mirror-image switch study demonstrated a reduction in hospitalization and associated costs compared with previous antipsychotic treatment. Safety and tolerability are comparable to oral aripiprazole with no new safety signals. Experience with oral aripiprazole and the current availability of the long-acting formulation suggest a potential benefit in a variety of clinical scenarios and therefore consideration as a treatment option in the treatment of schizophrenia.
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Kane, John M; Kishimoto, Taishiro; Correll, Christoph U
2013-08-01
As psychopathology and social functioning can worsen with repeated psychotic episodes in schizophrenia, relapse prevention is critical. Because high nonadherence rates limit the efficacy of pharmacotherapy, the use of long-acting injectable (LAI) antipsychotics is considered an important treatment option. To date, many studies comparing LAIs and oral antipsychotics have been conducted; however, the results are mixed, and careful interpretation of the data is required. Selective review of existing literature regarding LAIs. We especially focused the discussion on the impact of the design of studies with different approaches comparing LAIs and oral antipsychotics in preventing relapse. The results were diverse and were influenced by the design used, that is, randomized controlled trials (RCTs) showed LAIs and oral antipsychotics to have similar effects, whereas mirror-image and some large cohort studies showed LAIs to be superior to oral antipsychotics. Divergent results from studies using different methodologies create a dilemma for comparative effectiveness research, and LAI studies may serve as an example of a situation in which a conventional RCT is not the gold standard. Traditional RCTs generally increase adherence compared with clinical practice and, therefore, might not be well suited to detect differences between LAIs and oral medications, because any increase in adherence affects patients on oral medications more than those on LAIs and thus leads to an underestimation of any potential difference in effectiveness. A possible solution would be the implementation of a true effectiveness trial in which post-randomization involvement would be kept to a minimum to better reflect routine practice. Copyright © 2013 Elsevier Inc. All rights reserved.
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The role of long-acting injectable antipsychotics in schizophrenia: a critical appraisal
Veguilla, Miguel Ruiz; Taylor, David; Balanzá-Martinez, Vicent
2014-01-01
Despite their widespread use, long-acting injectable (LAI) antipsychotics (APs) are often regarded with some negativity because of the assumption of punishment, control and insufficient evolution towards psychosocial development of patients. However, LAI APs have proved effective in schizophrenia and other severe psychotic disorders because they assure stable blood levels, leading to a reduction of the risk of relapse. Therapeutic opportunities have also arisen after introduction of newer, second-generation LAI APs in recent years. Newer LAI APs are more readily dosed optimally, may be better tolerated and are better suited to integrated rehabilitation programmes. This review outlines the older and newer LAI APs available for the treatment of schizophrenia, with considerations of past and present pharmacological and therapeutic issues. Traditional, evidence-based approaches to systematic reviews and randomized clinical trials are of limited utility in this area so this paper’s blending of experimental trials with observational research is particularly appropriate and effective. PMID:25360245
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Olivares, J M; Rodriguez-Morales, A; Diels, J; Povey, M; Jacobs, A; Zhao, Z; Lam, A; Villalobos Vega, J C; Cuéllar, J Alonso; de Castro, F J Alberca; Quintero, C Morillo-Velarde; Martíin, J F Román; Domínguez, P Tabares; Ojeda, J L Prados; Cortés, S Sanz; Cala, F I Mata; Marín, C Gutiérrez; Castro, L Moyano; Duaso, M A Haza; Albarracín, J Requena; Vergara, G Narbona; Benítez, A Fernández; Cleries, F Mayoral; Pérez-Brian, J M García-Herrera; Aragón, A Bordallo; Navarro, J C Rodríguez; Biedma, J A Algarra; de Pedro, R Bravo; González, J F Delgado; López, M E Jaén; Moreno, H Díaz; López, J A Soto; Rodríguez, E Ojeda; de Hoyos, C Martínez; Sacristán, M Pardilla; Martín, M D Molina; Ballesteros, E Martín; Rodríguez, P A Sopelana; Menéndez, L Fernández; Rivas, R Santos; del Pino Cuadrado, P; Lauffer, J Correas; Solano, J J Rodríguez; Martínez, J M Fernández; Solano, F García; Rodríguez, P García-Lamberde; Rodríguez, J A Romero; Cano, T Rodríguez; Fortacin, M Ducaju; Lobeiras, J M Blanco; Sampedro, J M Piñeiro; Bravo, A Pérez; Pellicer, A Fernández; López, M D Alonso; Liste, J Fraga; Fernández, M Riobo; Losada, A Casas; Mendez, R Vazquez-Noguerol; Romero, S Agra; Blanco, J J Blanco; Bonaselt, I Tortajada; Mahia, M C García; del Valle, E Ferrer Gómez; Yañez, P Quiroga; Camarasa, M Gelabert; Alonso, J A Barbado; Mendez, G Florez; Feliz, F Doce; Lamela, M A López; Piñero, M Vega; Alvarado, P Fuentes; Gómez, I López; Martín, P Fadon; Gómez, J L Santos; López, A García; Jiménez, A Rodríguez; Nafs, A Escudero; Barquero, N Casas; Ortiz, R Fernández-Villamor; Noguera, J L Velez; Carrasco, P Ruiz; Muñoz, J Martín; Palma, M Masegoza; Hortelano, C Marín; Bonome, L Sánchez; Sevilla, J Sánchez; Juan, J M Mongil San; Ramos, J M García; Muñoz, J L Vallejo; Guisasola, J Elorza; Vazquez, L Santamaria; Guerras, F Campo; Nebot, F J Arrufat; Fernández, F J Baron; Nicolau, A L Palomo; Subirats, R Catala; Kidias, M Messays; Navarro, V Fabregat; García, B Frades; del Rosal, F Mejias; de Vicente Muñoz, T; Ballester, J Año; Lieb, P Malabia; Martel, A Delgado; Bea, E Roca; Joaquim, I Grau; Enjuanes, F Boatas; Piñol, M Bañuelos; Carbonell, E Fontova I; Muñoz, R Martín; Giribets, C Argila; Sans, L Albages; Blanco, A Serrano; Felipe, M Arcega; Muñoz, P González; Villanueva, A Pons; Arroyo, M Bernardo; Borri, R Coronas; Fallada, S Miret; Merola, M Celma; Rodon, E Parellada; Palmes, J R Pigem; Martínez, E Pérez; Catala, J Matarredona; Coca, A Sandoval; Ferrandiz, F Pascual; Paya, E Ferrandiz; Caballero, G Iturri; Bonet, A Franco; Figueras, J Fluvia; Pagador, P Moreno; Garibo, M Medina; Camo, V Pérez; Carrillo, C Sanz; Valero, C Pelegrin; Rebollo, F J Caro; García Campayo, J; Sala Ayma, J M Sala; Roig, M Martínez; de Uña Mateos, M A; Bertolin, R García; García, A Martín; Mazo, F Jiménez; Velasco, J L Galvez; Pérez, L Santa Maria; Casado, C Jiménez; Barba, J J Mancheño; Diaz, M Conde; Rubio, J P Alcon; Mandoli, A Soler; Herrero, A Uson; Martínez, A Rodríguez; Serrano, P Salgado; Rodríguez, E Nieto; Montesinos, J Segui; Macia, J Ferragud; Mateos Marcos, A Mateos; Soto, J V Pérez-Fuster; Dumont, M Verdaguer; Pagan, J Parra; Martínez, V Balanza; Santiuste de Pablos, M; Delgado, C Espinosa; Quiles, M D Martínez; López, F J Manzanera; Navarro, P Pozo; Torres, A Micol; Ingles, F J Martínez; Arias-Camison, J M Salmeron; Manzano, J C López; Peña, R Villanueva; Guitarte, G Petersen; Fontecilla, H Blasco; Romero, J Barjau; Gil, R Sanz; Lozano, J Marín; Adanez, L Donaire; Zarranz Herrera-Oria, I; Jiménez, J Pérez; Vaz, F Carrato; García, O Sanz; Anton, C Contreras; Casula, R Reixach; Hernandez, M C Natividad; Escabias, F Teba; Torresano, J Rodríguez; Pérez-Villamil, A Huidobro; Estevez, L; Figuero, M Aragües; Muñoz de Morales, A; Calvin, J L Rodríguez; Criado, M Delgado; Rodríguez, V Molina; Ambrosolio, E Balbo; Madera, P M Holgado; Alfaro, G Ponce; Vidal, M M Rojas; Valtuille, A García; Ruiz, O; Cabornero, G Lucas; Echevarria Martínez de Bujo, M; Mallen, M J Maicas; Puigros, J Santandreu; Martorell, A Liñana; Forteza, A Clar; Arrebola, E Rodríguez; Rodríguez de la Torre, M; Saiz, C G Anton; Bardolet I Casas, C; Linde, E Rodríguez; De Arce Cordon, R; Molina, E M Padial; Carazo, F J Ruiz; Romero, J J Muro; Cano, D Vico; Dorado, M Soria; Velazquez, S Campos; Sánchez, A J Rodríguez; Leon, S Ocio; Sánchez, K Pachas; Benitez, M Henry; Zugarramurai, A Intxausti; Contreras, M A; De la Varga González, M; Marín, P Barreiro; Robina, F Gómez; García, M Sánchez; Pérez, F J Otero; Bros, P Cubero; Gómez, A Carrillo; de Dios Molina Martín, J; Perera, J L Carrasco; Averbach, M C; Perera, J L Carrasco; Palancares, E Goenaga; Gallego de Dios, M T; Rojo, C Fernández; Iglesias, S Sánchez; Merino, M I Rubio; Mestre, N Prieto; Urdaniz, A Pérez; Sánchez, J M Martínez; Seco, R Gordo; Muñoz, J Franco; Agut, M Mateos; Lozano, M L Blanco; Herguedas, F Martín; Pena, A Torcal; García, J Vicente; Martínez, A Varona; Sanz Granado, O Sanz; Fernández, M A Medina; Canseco, J M Moran; López, P A Megia; Martín, M A Franco; Barrio, J A Espina; Ubago, J Giner; Bennassar, M Roca; Díez, J M Olivares; Fleta, J L Hernandez; Fortes, F Porras; López, C Arango; Medina, O; Alvarez, D Figuera; Roca, J M Peña; Valladolid, G Rubio; Tavera, J A Furquet; García-Castrillon Sales, J A; Llordes, I Batalla; Melgarejo, C Anchuistegui; Cañas de la Paz, F; Callol, V Vallés; García, M Bousoño; García, J Bobes; Leal, F J Vaz; Corrales, E Cáceres; Iglesias, E Sánchez; Gómez, M A Carreiras; Serrano, G García; Chillarón, E G Román; Aguado, F J Samino; Castillo, J J Molina; González, A González; Vázquez, J Gallardo; Peralvarez, M Bolivar; Diaz, M Rios; Mesa, M Ybarzabal; Artiles, F J Acosta; Chao, M Ajoy; Mesa, M Ybarzabal; del Rosario Santana, P; Escudero, M A García; Berenguer, M Molla; Llacer, J M Bonete; Berna, J A Juan; Ortiz, J Barragán; Pardell, L Tost; Hernández-Alvarez de Sotomayor, C; Méndez, M R Cejas; Garate, R Cabrera; Múgica, B Díaz; González, M Caballero; Domingo, J Pujol; Navarro, C Sáez; Vera, G Selva; Cuquerella, M A; Monzo, J Lonjedo; Boada, P Cervera; Pérez, M F Martín; Parrado, E Carrasco; Sánchez, J J Yañez; Fernández, J Calvo
2009-06-01
The electronic Schizophrenia Treatment Adherence Registry (e-STAR) is a prospective, observational study of patients with schizophrenia designed to evaluate long-term treatment outcomes in routine clinical practice. Parameters were assessed at baseline and at 3 month intervals for 2 years in patients initiated on risperidone long-acting injection (RLAI) (n=1345) or a new oral antipsychotic (AP) (n=277; 35.7% and 36.5% on risperidone and olanzapine, respectively) in Spain. Hospitalization prior to therapy was assessed by a retrospective chart review. At 24 months, treatment retention (81.8% for RLAI versus 63.4% for oral APs, p<0.0001) and reduction in Clinical Global Impression Severity scores (-1.14 for RLAI versus -0.94 for APs, p=0.0165) were significantly higher with RLAI. Compared to the pre-switch period, RLAI patients had greater reductions in the number (reduction of 0.37 stays per patient versus 0.2, p<0.05) and days (18.74 versus 13.02, p<0.01) of hospitalizations at 24 months than oral AP patients. This 2 year, prospective, observational study showed that, compared to oral antipsychotics, RLAI was associated with better treatment retention, greater improvement in clinical symptoms and functioning, and greater reduction in hospital stays and days in hospital in patients with schizophrenia. Improved treatment adherence, increased efficacy and reduced hospitalization with RLAI offer the opportunity of substantial therapeutic improvement in schizophrenia.
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Barrio, Pablo; Batalla, Albert; Castellví, Pere; Hidalgo, Diego; García, Marta; Ortiz, Ana; Grande, Iria; Pons, Alexandre; Parellada, Eduard
2013-07-01
Long-acting injectable antipsychotics may offer a relevant improvement in treatment adherence in recent-onset psychosis, leading to a decreased rate of hospital readmission, a better rate of clinical remission and improved psychosocial adjustment. The aim of the study was to compare the clinical remission rates, number of hospital readmissions and personal and social functioning after 2 years between patients with recent-onset schizophrenia (<2 years) in treatment with risperidone long-acting injectable (RLAI) and patients with recent-onset schizophrenia receiving oral antipsychotics. This is a case-control study comparing patients with recent-onset schizophrenia who initiated RLAI treatment between 2004 and 2008 (n=26) with a control group matched for age and sex, diagnosed with recent-onset schizophrenia and treated with oral antipsychotics (n=26). Study assessments included sociodemographic variables, the Positive and Negative Syndrome Scale, the Personal and Social Functioning Scale, the number of hospital readmissions and the Andreasen remission criteria. To assess the effect of treatment on each dependent variable, separate generalized estimating equations models were constructed. After 2 years of treatment, and adjusting for educational level, the RLAI group showed a greater reduction in the Positive and Negative Syndrome Scale total scale [mean (SD)=47.7 (12.0) vs. 66.2 (18.5); mean difference =-17.56; 95% confidence interval (CI)=-27.11 to -8.00; P<0.001], as well as in the negative [mean (SD) 14.3 (6.1) vs. 19.4 (6.4); mean difference=-5.02; 95% CI=-8.28 to -1.77; P=0.002] and general psychopathology [mean (SD)=23.4 (6.3) vs. 32.7 (8.1); mean difference=-9.16; 95% CI=-13.3 to -5.03; P<0.001] subscales compared with the oral antipsychotic group. Personal and Social Functioning Scale scores were also higher in the RLAI group [mean (SD)=72.4 (14.8) vs. 59.7 (13.5); mean difference=13.41; 95% CI=5.65-21.18; P<0.001]. Although not statistically significant, there were fewer readmissions (adjusted odds ratio 0.28; 95% CI=0.06-1.35; P=0.114) and more illness remissions (adjusted odds ratio 3.24; 95% CI=0.20-11.93; P=0.077) in the RLAI group. Treatment with RLAI instead of oral antipsychotics in recent-onset schizophrenia might improve clinical symptoms and social functioning. The efficacy of RLAI treatment on remission and readmission rates should be researched further.
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Brenzel, Allen
2016-01-01
Intravenous haloperidol has been associated with torsades de pointes (TdP). These two sudden deaths were probable adverse drug reactions (ADRs) following intramuscular (IM) antipsychotics. The autopsies described lack of heart pathology and were highly compatible with the possibility of TdP in the absence of risk factors other than the accumulation of antipsychotics with a high serum peak after the last injection, leading to death within hours. The first case was a 27-year-old African-American male with schizophrenia but no medical issues. His death was probably caused by repeated IM haloperidol injections of 10 mg (totaling 35 mg in 2 days). The second case involves a 42-year-old African-American female with metabolic syndrome. Her probable cause of death was the last ziprasidone IM injection of 20 mg in addition to (1) three extra haloperidol doses (2 hours before the ziprasidone injection, 5 mg oral haloperidol; approximately 21 hours earlier, 5 mg oral haloperidol; and 2 days prior, one 10 mg IM haloperidol injection), (2) 10 mg/day of scheduled oral haloperidol for 6 days before death, and (3) a long-acting paliperidone injection of 156 mg 18 days before death. The study of haloperidol glucuronidation and its impairment in some African-Americans is urgently recommended. PMID:27597919
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Dilemma of treating schizophrenia during pregnancy: a Case series and a review of literature.
Teodorescu, Andreea; Ifteni, Petru; Moga, Marius Alexandru; Burtea, Victoria; Bigiu, Nicusor
2017-08-29
The choice of antipsychotic treatment during pregnancy remains controversial, mainly due to a lack of exposure and outcome data. Randomized clinical trials are practically impossible due to ethical reasons. Our reports describe three cases of closely monitored female patients with schizophrenia who were treated with olanzapine during pregnancy. The novelty of reports is that all patients were previously treated with olanzapine long acting injectable (LAI) for an average period of 3.8 years. During the LAI treatment period they were in remission and then refused to continue with LAI mainly due to treatment modality (injectable administration). The patients were relatively young, diagnosed with schizophrenia and were previously successfully treated with long acting injectable. The women were pregnant for the first time. In two cases, the patients had become pregnant during remission and they continued treatment with oral olanzapine. In the third case, olanzapine treatment was initiated during admission for a relapse. There are no controlled studies for the use of olanzapine therapy in pregnant women. More studies are needed to determine the effects of antipsychotics, including olanzapine, on pregnant women and the developing fetus. Schizophrenia relapse during pregnancy may expose the mother and the fetus to high risk if olanzapine is stopped. It is important to assess the risks and benefits of treating pregnant or breastfeeding women with antipsychotics, and weigh these against possible risks of anomalies and developmental problems to the fetus or child.
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Suicide Prevention in Schizophrenia: Do Long-Acting Injectable Antipsychotics (LAIs) have a Role?
Pompili, Maurizio; Orsolini, Laura; Lamis, Dorian A; Goldsmith, David R; Nardella, Adele; Falcone, Giulia; Corigliano, Valentina; Luciano, Mario; Fiorillo, Andrea
2017-01-01
Suicide risk is a major cause of death among patients with schizophrenia. Death by suicide has been reported in approximately 5% of schizophrenia patients although this figure appears to be an underestimate of the problem. A number of risk factors are routinely reported as associated with suicide risk among these patients, some of which are modifiable by targeted therapeutic strategies. Clozapine is the only compound that gathered evidence as an effective treatment for reducing suicide risk in schizophrenia. Long-Acting Injectable Antipsychotics (LAIs) have a range of advantages in terms of efficacy, safety and tolerability in the treatment of schizophrenia, and one area of interest is whether LAI-treatment may decrease suicidality by indirectly acting on a range of risk factors for suicide specific to schizophrenia patients. This background encouraged the present review of research pertaining to LAIs in relation to modifiable risk factors for suicide in schizophrenia. We viewed our task as gathering, speculating and critically appraising the available research relevant to the topic, with the aim of formulating a hypothesis to be tested with further research. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
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Atypical psychotic symptoms and Dandy-Walker variant.
Williams, Aislinn J; Wang, Zhenni; Taylor, Stephan F
2016-10-01
New-onset psychotic symptoms often respond well to antipsychotic treatment; however, symptoms may be difficult to treat when an underlying brain malformation is present. Here, we present a case of atypical psychotic symptoms in the context of a congenital cerebellar malformation (Dandy-Walker variant). The patient ultimately improved with paliperidone palmitate after multiple antipsychotic medication trials (both oral and one long-acting injectable) were ineffective. Neuroimaging may provide valuable diagnostic and prognostic information in cases of new-onset psychosis with atypical features and treatment resistance, even in the absence of neurologic signs and symptoms.
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2013-01-01
Background The research goal is to better understand prescriber, patient, and caregiver perspectives about long-acting injectable (LAI) antipsychotic therapy and how these perspectives affect LAI use. Addressing these perspectives in the clinic may lead to greater success in achieving therapeutic goals for the patient with schizophrenia. Methods Ethnographic information was collected from a non-random sample of 69 prescriber-patient conversations (60 with community mental health center [CMHC] psychiatrists; 9 with nurse-practitioners) recorded during treatment visits from August 2011 to February 2012, transcribed and analyzed. Discussions were categorized according to 11 predetermined CMHC topics. In-person observations were also conducted at 4 CMHCs, including home visits by researchers (n = 15 patients) prior to the CMHC visit and observations of patients receiving injections and interacting with staff. Telephone in-depth interviews with psychiatrists, patients, and caregivers to gather additional information on LAI discussion, prescription, or use were conducted. Results Antipsychotic treatment decisions were made without patient or caregiver input in 40 of 60 (67%) of psychiatrist-patient conversations. Involvement of patients or caregivers in treatment decisions was greater when discussing LAI (15 of 60 [25%]) vs oral antipsychotic treatment (5 of 60 [8%]). LAIs were not discussed by psychiatrists in 11 of 22 (50%) patients taking oral antipsychotics. When offered, more LAI-naïve patients expressed neutral (9 of 19 [47%]) rather than favorable (3 of 19 [16%]) or unfavorable (7 of 19 [37%]) responses. Prescribers were most concerned about potentially damaging the therapeutic relationship and side-effects when discussing LAIs while patient resistance was often related to negative feelings about injections. Psychiatrists had some success in overcoming patient objections to LAIs by addressing and decomposing initial resistance. More than half (11 of 19 [58%]) of LAI-naïve patients agreed to start LAI treatment following office visits. Patient-described benefits of LAIs vs orals included perceived rapid symptom improvement and greater overall efficacy. Conclusions In this study, many psychiatrists did not offer LAIs and most patients and caregivers were not involved in antipsychotic treatment decision making. Opportunities to increase active patient engagement, address resistances, guide patient drug-formulation selection, and provide better LAI-relevant information for more individualized approaches to treating the patient with schizophrenia were present. PMID:24131801
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Fagiolini, Andrea; Alfonsi, Emilia; Amodeo, Giovanni; Cenci, Mario; Di Lella, Michele; Farinella, Francesco; Ferraiuolo, Fabrizio; Fraguas, David; Loparco, Natale; Gutierrez-Rojas, Luis; Mignone, Maria Laura; Pataracchia, Giuseppe; Pillai, Gianluca; Russo, Felicia; Sanchez-Gistau, Vanessa; Spinogatti, Franco; Toscano, Marco; Villari, Vincenzo; De Filippis, Sergio
2016-01-01
Aripiprazole long acting once-monthly (AOM) is a long acting atypical antipsychotic with proven efficacy in schizophrenia and with a pharmacological and a side effect profile that is different from other antipsychotics. These and other characteristics make AOM a possible alternative in patients requiring a change in long acting antipsychotic treatment due to issues such as lack of efficacy or persistent side effects. Both clinical and pharmacological factors should be considered when switching antipsychotics, and specific guidelines for long acting antipsychotic switching that address all these factors are needed. A panel of Italian and Spanish experts in psychiatry met to discuss the strategies for the switch to AOM in patients with schizophrenia. Real life clinical experiences were shared and the clinical strategies to improve the likelihood of success were discussed. Due to its specific pharmacological and tolerability profile, AOM represents a suitable alternative for patients with schizophrenia requiring a switch to a new LAI treatment because of lack of efficacy or persistent side effects from another LAI. Possible strategies for the switch to AOM are presented in this expert consensus paper in an attempt to provide guidance throughout the entire switching process.
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Atkins, Susan; Detke, Holland C; McDonnell, David P; Case, Michael G; Wang, Shufang
2014-01-14
Depot antipsychotic injections are an important tool for the management of patients with schizophrenia who have difficulty with adherence to oral medication. However, pain and discomfort at the injection site can be a potential impediment to the use of these long-acting formulations. We report here the results of a pooled analysis of injection site-related adverse events (AEs) collected during treatment with the olanzapine long-acting injection (olanzapine LAI). Unsolicited injection site-related AEs were pooled from 7 olanzapine LAI clinical trials conducted in patients between March 2001 and December 2010. All patients had a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) or Fourth Edition, Text Revision (DSM-IV-TR) diagnosis of schizophrenia or schizoaffective disorder and were between the ages of 18 and 75. Doses ranged from 45 to 405 mg olanzapine LAI, and injection intervals were 2, 3, or 4 weeks. Events were evaluated for severity, timing, possible risk factors, and outcome. A criterion of p < .05 for statistical significance was used for all tests. A total of 1752 patients received at least 1 olanzapine LAI injection. Of these, 92 patients (5.3%) reported at least 1 injection site-related AE, with "pain" being the most common type (2.9%). Most events were mild (81.4%) and the median duration was 3 days. Four patients (0.2%) discontinued due to injection site-related AEs. Dose volume and body mass index did not appear to affect the probability of injection site-related AEs. However, patients who experienced a post-injection delirium/sedation syndrome event (n = 37) were more likely to have or have had an injection site-related AE at some time during the study. Incidence of injection site-related AEs appeared to decrease over time. In 94.2% of the injection site-related AEs, no specific treatment or concomitant medication was reported; in 9 cases, patients received pharmacologic treatment for reaction, mass, abscess, rash, or pain. Injection site-related AEs with olanzapine LAI were generally mild. The incidence and nature of these injection site-related AEs were generally similar to those occurring during treatment with other injectable antipsychotics. ClinicalTrials.gov ID; URL: NCT00094640, NCT00088478, NCT00088491, NCT00088465, and NCT00320489.
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Subotnik, Kenneth L; Casaus, Laurie R; Ventura, Joseph; Luo, John S; Hellemann, Gerhard S; Gretchen-Doorly, Denise; Marder, Stephen; Nuechterlein, Keith H
2015-08-01
Long-acting, injectable, second-generation antipsychotic medication has tremendous potential to bring clinical stability to persons with schizophrenia. However, long-acting medications are rarely used following a first episode of schizophrenia. To compare the clinical efficacy of the long-acting injectable formulation of risperidone with the oral formulation in the early course of schizophrenia. A randomized clinical trial performed at a university-based research clinic, between 2005 and 2012. Eighty-six patients with recent onset of schizophrenia were randomized to receive long-acting injectable risperidone or oral risperidone. Half of each group was simultaneously randomized to receive cognitive remediation to improve cognitive functioning or healthy-behaviors training to improve lifestyle habits and well-being. An intent-to-treat analysis was performed between October 4, 2012, and November 12, 2014. A 12-month trial comparing the long-acting injectable vs oral risperidone and cognitive remediation vs healthy-behaviors training. Psychotic relapse and control of breakthrough psychotic symptoms. Of the 86 patients randomized, 3 refused treatment in the long-acting injectable risperidone group. The psychotic exacerbation and/or relapse rate was lower for the long-acting risperidone group compared with the oral group (5% vs 33%; χ21 = 11.1; P < .001; relative risk reduction, 84.7%). Long-acting injectable risperidone better controlled mean levels of hallucinations and delusions throughout follow-up (β = -0.30; t68 = -2.6, P = .01). The cognitive remediation and healthy-behaviors training groups did not differ significantly regarding psychotic relapse, psychotic symptom control, or hospitalization rates, and there were no significant interactions between the 2 medications and the 2 psychosocial treatments. Discontinuations owing to inadequate clinical response were more common in the oral group than in the long-acting risperidone group (χ21 = 6.1; P = .01). Adherence to oral risperidone did not appear to differ before randomization but was better for the long-acting risperidone group compared with the oral group (t80 = 5.3; P < .001). Medication adherence was associated with prevention of exacerbation and/or relapse (χ21 =11.1; P = .003) and control of breakthrough psychotic symptoms (β = 0.2; t79 = 2.1; P = .04). The use of long-acting injectable risperidone after a first episode of schizophrenia has notable advantages for clinical outcomes. The key clinical advantages are apparently owing to the more consistent administration of the long-acting injectable. Such formulations should be offered earlier in the course of illness. clinicaltrials.gov Identifier: NCT00333177.
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Rosenheck, Robert A; Leslie, Douglas L; Sint, Kyaw J; Lin, Haiqun; Li, Yue; McEvoy, Joseph P; Byerly, Matthew J; Hamer, Robert M; Swartz, Marvin S; Stroup, T Scott
2016-10-01
This study assessed the relative cost-effectiveness of haloperidol decanoate (HD), a first-generation long-acting injectable (LAI) antipsychotic, and paliperidone palmitate (PP), a second-generation LAI antipsychotic. A double-blind, randomized 18-month clinical trial conducted at 22 clinical research sites in the United States compared the cost-effectiveness of HD and PP among 311 adults with schizophrenia or schizoaffective disorder who had been clinically assessed as likely to benefit from an LAI antipsychotic. Patients were randomly assigned to monthly intramuscular injections of HD (25-200 mg) or PP (39-234 mg) for up to 24 months. Quality-adjusted life years (QALYs) were measured by a schizophrenia-specific algorithm based on the Positive and Negative Syndrome Scale and side-effect assessments; total health care costs were assessed from the perspective of the health system. Mixed-model analysis showed that PP was associated with .0297 greater QALYs over 18 months (p=.03) and with $2,100 more in average costs per quarter for inpatient and outpatient services and medication compared with HD (p<.001). Bootstrap analysis with 5,000 replications showed an incremental cost-effectiveness ratio for PP of $508,241 per QALY (95% confidence interval=$122,390-$1,582,711). Net health benefits analysis showed a .98 probability of greater cost-effectiveness for HD compared with PP at an estimated value of $150,000 per QALY and a .50 probability of greater cost-effectiveness at $500,000 per QALY. HD was more cost-effective than PP, suggesting that PP's slightly greater benefits did not justify its markedly higher costs, which are likely to fall once the medication's patent expires.
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Chue, Pierre; Chue, James
2016-01-01
Schizoaffective disorder (SCA) is a chronic and disabling mental illness that presents with mixed symptoms of schizophrenia and affective disorders. SCA is recognized as a discrete disorder, but with greater heterogeneity and symptom overlap, leading to difficulty and delay in diagnosis. Although the overall prognosis is intermediate between schizophrenia and mood disorders, SCA is associated with higher rates of suicide and hospitalization than schizophrenia. No treatment guidelines exist for SCA, and treatment is frequently complex, involving off-label use and polypharmacy (typically combinations of antipsychotics, mood stabilizers, and antidepressants). Oral paliperidone extended-release was the first agent to be approved for the treatment of SCA. As in schizophrenia and bipolar disorder, adherence to oral medications is poor, further contributing to suboptimal outcomes. The use of an antipsychotic in a long-acting injection (LAI) addresses adherence issues, thus potentially reducing relapse. Paliperidone palmitate represents the LAI formulation of paliperidone. In a long-term, double-blind, randomized, controlled trial of adult patients (n=334; intent-to-treat [ITT]) with SCA, paliperidone long-acting injection (PLAI) significantly delayed risk of relapse compared to placebo (hazard ratio 2.49, 95% confidence interval, 1.55–3.99; P<0.001). This study demonstrated the efficacy and safety of PLAI when used as either monotherapy or adjunctive therapy for the maintenance treatment of SCA. The results are consistent with a similarly designed study conducted in patients with schizophrenia, which suggests a benefit in the long-term control of not only psychotic but also affective symptoms. No new safety signals were observed. When used in monotherapy, PLAI simplifies treatment by reducing complex pharmacotherapy and obviating the necessity for daily oral medications. PLAI is the second agent, and the first LAI, to be approved for the treatment of SCA; as an LAI formulation, there is the advantage of improved adherence and simplified treatment in the long-term management of SCA. PMID:26869795
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Chue, Pierre; Chue, James
2016-01-01
Schizoaffective disorder (SCA) is a chronic and disabling mental illness that presents with mixed symptoms of schizophrenia and affective disorders. SCA is recognized as a discrete disorder, but with greater heterogeneity and symptom overlap, leading to difficulty and delay in diagnosis. Although the overall prognosis is intermediate between schizophrenia and mood disorders, SCA is associated with higher rates of suicide and hospitalization than schizophrenia. No treatment guidelines exist for SCA, and treatment is frequently complex, involving off-label use and polypharmacy (typically combinations of antipsychotics, mood stabilizers, and antidepressants). Oral paliperidone extended-release was the first agent to be approved for the treatment of SCA. As in schizophrenia and bipolar disorder, adherence to oral medications is poor, further contributing to suboptimal outcomes. The use of an antipsychotic in a long-acting injection (LAI) addresses adherence issues, thus potentially reducing relapse. Paliperidone palmitate represents the LAI formulation of paliperidone. In a long-term, double-blind, randomized, controlled trial of adult patients (n=334; intent-to-treat [ITT]) with SCA, paliperidone long-acting injection (PLAI) significantly delayed risk of relapse compared to placebo (hazard ratio 2.49, 95% confidence interval, 1.55-3.99; P<0.001). This study demonstrated the efficacy and safety of PLAI when used as either monotherapy or adjunctive therapy for the maintenance treatment of SCA. The results are consistent with a similarly designed study conducted in patients with schizophrenia, which suggests a benefit in the long-term control of not only psychotic but also affective symptoms. No new safety signals were observed. When used in monotherapy, PLAI simplifies treatment by reducing complex pharmacotherapy and obviating the necessity for daily oral medications. PLAI is the second agent, and the first LAI, to be approved for the treatment of SCA; as an LAI formulation, there is the advantage of improved adherence and simplified treatment in the long-term management of SCA.
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Antipsychotic-Induced Dopamine Supersensitivity Psychosis: Pharmacology, Criteria, and Therapy.
Chouinard, Guy; Samaha, Anne-Noël; Chouinard, Virginie-Anne; Peretti, Charles-Siegfried; Kanahara, Nobuhisa; Takase, Masayuki; Iyo, Masaomi
2017-01-01
The first-line treatment for psychotic disorders remains antipsychotic drugs with receptor antagonist properties at D2-like dopamine receptors. However, long-term administration of antipsychotics can upregulate D2 receptors and produce receptor supersensitivity manifested by behavioral supersensitivity to dopamine stimulation in animals, and movement disorders and supersensitivity psychosis (SP) in patients. Antipsychotic-induced SP was first described as the emergence of psychotic symptoms with tardive dyskinesia (TD) and a fall in prolactin levels following drug discontinuation. In the era of first-generation antipsychotics, 4 clinical features characterized drug-induced SP: rapid relapse after drug discontinuation/dose reduction/switch of antipsychotics, tolerance to previously observed therapeutic effects, co-occurring TD, and psychotic exacerbation by life stressors. We review 3 recent studies on the prevalence rates of SP, and the link to treatment resistance and psychotic relapse in the era of second-generation antipsychotics (risperidone, paliperidone, perospirone, and long-acting injectable risperidone, olanzapine, quetiapine, and aripiprazole). These studies show that the prevalence rates of SP remain high in schizophrenia (30%) and higher (70%) in treatment-resistant schizophrenia. We then present neurobehavioral findings on antipsychotic-induced supersensitivity to dopamine from animal studies. Next, we propose criteria for SP, which describe psychotic symptoms and co-occurring movement disorders more precisely. Detection of mild/borderline drug-induced movement disorders permits early recognition of overblockade of D2 receptors, responsible for SP and TD. Finally, we describe 3 antipsychotic withdrawal syndromes, similar to those seen with other CNS drugs, and we propose approaches to treat, potentially prevent, or temporarily manage SP. © 2017 S. Karger AG, Basel.
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Intramuscular preparations of antipsychotics: uses and relevance in clinical practice.
Altamura, A Cario; Sassella, Francesca; Santini, Annalisa; Montresor, Clauno; Fumagalli, Sara; Mundo, Emanuela
2003-01-01
Intramuscular formulations of antipsychotics can be sub-divided into two groups on the basis of their pharmacokinetic features: short-acting preparations and long-acting or depot preparations. Short-acting intramuscular formulations are used to manage acute psychotic episodes. On the other hand, long-acting compounds, also called "depot", are administered as antipsychotic maintenance treatment to ensure compliance and to eliminate bioavailability problems related to absorption and first pass metabolism. Adverse effects of antipsychotics have been studied with particular respect to oral versus short- and long-acting intramuscular formulations of the different compounds. For short-term intramuscular preparations the main risk with classical compounds are hypotension and extrapyramidal side effects (EPS). Data on the incidence of EPS with depot formulations are controversial: some studies point out that the incidence of EPS is significantly higher in patients receiving depot preparations, whereas others show no difference between oral and depot antipsychotics. Studies on the strategies for switching patients from oral to depot treatment suggest that this procedure is reasonably well tolerated, so that in clinical practice depot antipsychotic therapy is usually begun while the oral treatment is still being administered, with gradual tapering of the oral dose. Efficacy, pharmacodynamics and clinical pharmacokinetics of haloperidol decanoate, fluphenazine enanthate and decanoate, clopenthixol decanoate, zuclopenthixol decanoate and acutard, flupenthixol decanoate, perphenazine enanthate, pipothiazine palmitate and undecylenate, and fluspirilene are reviewed. In addition, the intramuscular preparations of atypical antipsychotics and clinical uses are reviewed. Olanzapine and ziprasidone are available only as short-acting preparations, while risperidone is to date the only novel antipsychotic available as depot formulation. To date, acutely ill, agitated psychotic patients have been treated with high parenteral doses of typical antipsychotics, which often cause serious EPS, especially dystonic reactions. Intramuscular formulations of novel antipsychotics (olanzapine and ziprasidone), which appear to have a better tolerability profile than typical compounds, showed an equivalent efficacy to parenteral typical agents in the acute treatment of psychoses. However, parenteral or depot formulations of atypical antipsychotics are not yet widely available.
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Sajatovic, Martha; Ross, Ruth; Legacy, Susan N; Correll, Christoph U; Kane, John M; DiBiasi, Faith; Fitzgerald, Heather; Byerly, Matthew
2018-01-01
To assess expert consensus on barriers and facilitators for long-acting injectable antipsychotic (LAI) use and provide clinical recommendations on issues where clinical evidence is lacking, including identifying appropriate clinical situations for LAI use. A 50-question survey comprising 916 response options was distributed to 42 research experts and high prescribers with extensive LAI experience. Respondents rated options on relative appropriateness/importance using a 9-point scale. Consensus was determined using chi-square test of score distributions. Mean (standard deviation) ratings were calculated. Responses to 29 questions (577 options) relating to appropriate patients and clinical scenarios for LAI use are reported. Recommendations aligned with research on risk factors for nonadherence and poor outcomes for patients with schizophrenia/schizoaffective or bipolar disorder. Findings suggested, contrary to general practice patterns, that LAI use may be appropriate earlier in the disease course and in younger patients. Results for bipolar disorder were similar to those for schizophrenia but with less consensus. Numerous facilitators of LAI prescribing were considered important, particularly that LAIs may reduce relapses and improve outcomes. Findings support wider use of LAIs in patients with schizophrenia/schizoaffective and bipolar disorders beyond the setting of poor adherence and earlier use in the disease course.
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Alphs, Larry; Mao, Lian; Rodriguez, Stephen C; Hulihan, Joe; Starr, H Lynn
2014-12-01
Public health considerations require that clinical trials address the complex "real-world" needs of patients with chronic illnesses. This is particularly true for persons with schizophrenia, whose management is frequently complicated by factors such as comorbid substance abuse, homelessness, and contact with the criminal justice system. In addition, barriers to obtaining health care in the United States often prevent successful community reentry and optimal patient management. Further, nonadherence to treatment is common, and this reinforces cycles of relapse and recidivism. Long-acting injectable antipsychotic therapy may facilitate continuity of treatment and support better outcomes, particularly in patients who face these challenges. Clinical trials with classical explanatory designs may not be the best approaches for evaluating these considerations. We describe the design and rationale of a novel trial that combines both explanatory and pragmatic design features and studies persons with schizophrenia who face these challenges. The Paliperidone Palmitate Research in Demonstrating Effectiveness (PRIDE) study is a prospective, open-label, randomized, 15-month study conducted between May 5, 2010, and December 9, 2013, comparing long-acting injectable paliperidone palmitate and oral antipsychotic medications in subjects with schizophrenia (according to DSM-IV criteria). Investigators and subjects had broad flexibility for treatment decision-making, thus making it a model that better reflects real-world practice. The primary end point was time to treatment failure, defined as arrest/incarceration psychiatric hospitalization; suicide; treatment discontinuation or supplementation due to inadequate efficacy, safety, or tolerability; or increased psychiatric services to prevent hospitalization. This end point was adjudicated by a blinded event monitoring board. Patients were followed to the 15-month end point, regardless of whether they were maintained on their initial randomized treatment. This article provides some of the reasoning behind the authors' choices when combining features from both explanatory and pragmatic approaches to this trial's design. The PRIDE study incorporates real-world design features in a novel, prospective, comparative study of long-acting injectable and oral antipsychotics in persons with schizophrenia who have had recent contact with the criminal justice system. Insights provided should help the reader to better understand the need for more real-world approaches for clinical studies and how a broader approach can better aid clinical treatment and public health decision-making. ClinicalTrials.gov identifier: NCT01157351. © Copyright 2014 Physicians Postgraduate Press, Inc.
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Hard, Marjie L; Mills, Richard J; Sadler, Brian M; Turncliff, Ryan Z; Citrome, Leslie
2017-06-01
Aripiprazole lauroxil is an extended-release prodrug of aripiprazole for intramuscular injection, approved for schizophrenia treatment. We developed a population pharmacokinetic (PopPK) model to characterize aripiprazole lauroxil PK and evaluate dosing scenarios likely to be encountered in clinical practice. Data from 616 patients with schizophrenia, collected from 5 clinical studies, were used to construct the PopPK model. The model was subsequently used to evaluate various dose levels and frequency and the impact of dosing delay on aripiprazole concentrations. The results of the model indicate that aripiprazole is released into the systemic circulation after 5 to 6 days, and release continues for an additional 36 days. The slow increase in aripiprazole concentration after injection necessitates the coadministration of oral aripiprazole for 21 days with the first injection. Based on the PopPK model simulations, a dosing interval of 882 mg every 6 weeks results in aripiprazole concentrations that fall within the concentration range associated with the efficacious aripiprazole lauroxil dose range (441-882 mg dosed monthly). A 662-mg monthly dose also resulted in aripiprazole concentrations within the efficacious dose range. Aripiprazole lauroxil administration results in prolonged exposure, such that dose delays of 2 to 4 weeks, depending on the dose regimen, do not require oral aripiprazole supplementation upon resumption of dosing. This PopPK model and model-based simulations were effective means for evaluating aripiprazole lauroxil dosing regimens and management of missed doses. Such analyses play an important role in determining the use of this long-acting antipsychotic in clinical practice.
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Ju, Po-Chung; Chou, Frank Huang-Chih; Lai, Te-Jen; Chuang, Po-Ya; Lin, Yung-Jung; Yang, Ching-Wen Wendy; Tang, Chao-Hsiun
2014-02-01
We aimed at evaluating the relationship between medication and treatment effectiveness in a home care setting among patients with schizophrenia. Patients with schizophrenia hospitalized between 2004 and 2009 with a primary International Classification of Diseases, Ninth Revision, Clinical Modification code of 295 were identified from Psychiatric Inpatient Medical Claims Data released by the National Health Research Institute in Taiwan. Patients who joined the home care program after discharge and were prescribed long-acting injection (LAI) (the LAI group) or oral antipsychotic medications (the oral group) were included as study subjects. The final sample for the study included 810 participants in the LAI group and 945 in the oral group. Logistic regression was performed to examine the independent effect of LAI medication on the risk for rehospitalization within the 12-month observation window after controlling for patient and hospital characteristics and propensity score quintile adjustment. The unadjusted odds ratio for rehospitalization risk was 0.80 (confidence interval, 0.65-0.98) for the LAI group compared to the oral group. The adjusted odds ratio was further reduced to 0.78 (confidence interval, 0.63-0.97). Results remained unchanged when the propensity score quintiles were entered into the regression for further adjustment. In a home care setting, patients treated with long-acting antipsychotic agents are at a significantly lower risk for psychiatric rehospitalization than those treated with oral medication. Consequently, LAI home-based treatment for the prevention of schizophrenia relapse may lead to substantial clinical and economic benefits.
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Emsley, Robin; Alptekin, Koksal; Azorin, Jean-Michel; Cañas, Fernando; Dubois, Vincent; Gorwood, Philip; Haddad, Peter M; Naber, Dieter; Olivares, José Manuel; Papageorgiou, Georgios; Roca, Miguel; Thomas, Pierre; Hargarter, Ludger; Schreiner, Andreas
2015-12-01
Poor adherence to antipsychotic treatment is a widespread problem within schizophrenia therapy with serious consequences including increased risks of relapse and rehospitalization. Mounting evidence supports the key roles that nurses play in monitoring patient progress and facilitating long-term treatment adherence. The Adherencia Terapéutica en la Esquizofrenia (ADHES) nurses' survey was designed to assess the opinions of nurses on the causes and management of partial/nonadherence to antipsychotic medication. A questionnaire-based cross-sectional survey of 4120 nurses from Europe, the Middle East and Africa. Interpretation of results was based on a descriptive comparison of responses. Nurses perceived 54% of patients seen in the preceding month to be partially/nonadherent to treatment. Most nurses (90%) reported some level of experience with administration of long-acting injectable (LAI) antipsychotics, with 24% of nurses administering >10 injections per month. The majority (85%) of nurses surveyed believed that improving adherence would improve patient outcomes. Nearly half (49%) reported that most of their patients depend on a family member or other nonprofessional carer to remind them to take their medication as prescribed. A similar proportion of nurses (43%) reported that most of their patients relied on a professional to remind them to take medication. Most nurses (92%) felt that ensuring continuous medication with LAI antipsychotics would yield long-term benefits for patients, but their opinion was that over a third of patients were unaware of LAI antipsychotic treatments. In a series of forced options, the strategy used most often by respondents (89%) to promote medication adherence was to build trusting relationships with patients while listening to and interpreting their needs and concerns. Respondents also rated this as the most effective strategy that they used (48%). Nurses are highly aware of adherence issues faced by their patients; further patient education on treatment options is needed.
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Emsley, Robin; Alptekin, Koksal; Azorin, Jean-Michel; Cañas, Fernando; Dubois, Vincent; Gorwood, Philip; Haddad, Peter M.; Naber, Dieter; Olivares, José Manuel; Papageorgiou, Georgios; Roca, Miguel; Thomas, Pierre; Hargarter, Ludger; Schreiner, Andreas
2015-01-01
Objectives: Poor adherence to antipsychotic treatment is a widespread problem within schizophrenia therapy with serious consequences including increased risks of relapse and rehospitalization. Mounting evidence supports the key roles that nurses play in monitoring patient progress and facilitating long-term treatment adherence. The Adherencia Terapéutica en la Esquizofrenia (ADHES) nurses’ survey was designed to assess the opinions of nurses on the causes and management of partial/nonadherence to antipsychotic medication. Methods: A questionnaire-based cross-sectional survey of 4120 nurses from Europe, the Middle East and Africa. Interpretation of results was based on a descriptive comparison of responses. Results: Nurses perceived 54% of patients seen in the preceding month to be partially/nonadherent to treatment. Most nurses (90%) reported some level of experience with administration of long-acting injectable (LAI) antipsychotics, with 24% of nurses administering >10 injections per month. The majority (85%) of nurses surveyed believed that improving adherence would improve patient outcomes. Nearly half (49%) reported that most of their patients depend on a family member or other nonprofessional carer to remind them to take their medication as prescribed. A similar proportion of nurses (43%) reported that most of their patients relied on a professional to remind them to take medication. Most nurses (92%) felt that ensuring continuous medication with LAI antipsychotics would yield long-term benefits for patients, but their opinion was that over a third of patients were unaware of LAI antipsychotic treatments. In a series of forced options, the strategy used most often by respondents (89%) to promote medication adherence was to build trusting relationships with patients while listening to and interpreting their needs and concerns. Respondents also rated this as the most effective strategy that they used (48%). Conclusion: Nurses are highly aware of adherence issues faced by their patients; further patient education on treatment options is needed. PMID:26834967
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[Treatment of Adult Schizophrenic Patients With Depot Antipsychotics].
Jaramillo González, Luis Eduardo; Gómez Restrepo, Carlos; García Valencia, Jenny; de la Hoz Bradford, Ana María; Ávila-Guerra, Mauricio; Bohórquez Peñaranda, Adriana
2014-01-01
To determine the indications of long-acting antipsychotic injection and what its effectiveness and safety in adult patients with schizophrenia during the treatment maintenance phase. 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. The evidence of NICE guide 82 was adopted and updated. The evidence was presented to the Guideline Developing Group and recommendations, employing the GRADE system, were produced. The literature review shows that the evidence has moderate to low quality. 8 articles were used. The risk of relapse was lower with depot risperidone and paliperidone palmitate when compared with placebo. For the risk of hospitalizations comparing depot antipsychotics (APD) versus oral AP, the result is inconclusive. Globally the second-generation APD had a lower risk of discontinuation when compared with placebo. The second generation AP had higher risk of extrapyramidal syndromes than placebo, as in the use of antiparkinsonian. The comparison of second-generation AP injections versus placebo showed an increased risk of early weight gain. The use of depot antipsychotics in the maintenance phase of adult patients diagnosed with schizophrenia is recommended if there is no adherence to oral antipsychotics as the patient's preference. It is not recommended depot antipsychotics in the acute phase of schizophrenia in adults. Copyright © 2014 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.
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Health resource utilization associated with switching to risperidone long-acting injection.
Young, C L; Taylor, D M
2006-07-01
Studies have shown oral risperidone and conventional depot antipsychotics decrease direct healthcare costs largely by reducing hospitalization. Our aim was to assess the effect on bed stay of risperidone injection prescribed in normal clinical practice. Patients prescribed risperidone long-acting injection (RLAI) were identified and followed-up for 1 year. Resource use data were collected for 3 years before and for 1 year after the initiation of RLAI. The main outcome measure was bed stay before and after the prescription of RLAI. Outcome data were available for 250 subjects. Eighty-one subjects (32.4%) completed 1 year's treatment. Days spent in hospital increased from (mean number/patient) 31 in year -3 to 44 in year -2 to 90 in year -1 to 141 in year +1. Direct healthcare costs increased accordingly. Outcome for RLAI continuers was similar to that of discontinuers. Switching to RLAI was associated with a continuation of the trend for increased bed stay and use of healthcare resources.
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Pesa, Jacqueline A; Muser, Erik; Montejano, Leslie B; Smith, David M; Meyers, Oren I
Non-adherence to antipsychotic therapy among patients with schizophrenia is a key driver of relapse, which can lead to costly inpatient stays. Long-acting injectables (LAIs) may improve adherence, thus reducing hospitalizations, but inpatient cost reductions need to be balanced against higher drug acquisition costs of LAIs. Real-world evidence is needed to help quantify the economic value of oral atypical antipsychotics compared with LAIs. The objective of this study was to compare healthcare costs and resource utilization between once-monthly paliperidone palmitate (PP) and oral antipsychotic therapy (OAT) in a population of Medicaid beneficiaries with schizophrenia. A retrospective, observational study was performed using Truven Health MarketScan Medicaid claims data from 2009 to 2012. Marginal structural modeling, a form of weighted repeated measures analysis to control for differences between cohorts and time-varying confounding, was used to estimate monthly costs of care in 2012 US dollars and resource utilization over a 12-month period for patients in each cohort. While per-month mental-health prescription costs were US$1019 higher in the PP cohort, approximately 55 % of this premium was offset by lower inpatient and outpatient care costs, producing a mean monthly total cost differential of US$434 (95 % CI 298-569, p < 0.0001) for all-cause costs and US$463 (95 % CI 374-552, p < 0.0001) for mental-health-related costs. Use of PP also resulted in a 0.44 and 0.47 reduction in the odds of all-cause and mental-health-related hospitalizations and a 0.09 reduction in the odds of all-cause emergency department visits ( p < 0.0001, p < 0.0001, and p = 0.0134, respectively) over the 12-month follow-up period. Treatment with long-acting injectable antipsychotics, such as PP, may reduce inpatient and outpatient healthcare services utilization and associated costs. These findings also suggest that patients with schizophrenia taking once-monthly PP may stand a lower risk of hospitalization than patients on OAT.
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Moran, Katherine; Priebe, Stefan
2016-08-01
In a randomised controlled trial, patients were offered financial incentives to improve their adherence to anti-psychotic maintenance medication. Compared to a control group without the incentives, they had an improved adherence and also better subjective quality of life (SQOL) after 1 year. This paper explores the question as to whether this improvement in SQOL was associated with the amount of money received or with the improved adherence itself. A secondary analysis was performed using data of the experimental group in the trial. Adherence was assessed as the percentage of all prescribed long-acting anti-psychotic injections that were taken by the patient. In regression models, we tested whether changes in medication adherence and/or the amount of incentives received over the 12-month period was associated with SQOL, as rated on the DIALOG scale. Adherence changed from 68.49 % at baseline to 88.23 % (mean difference in adherence = 19.59 %, SD = 17.52 %). The total amount of incentives received within the 1-year study period varied between £75 and £735, depending on the treatment cycle and the number of long-acting injections taken. Improvement in adherence was found to be a significant predictor of better subjective quality of life (β = 0.014, 95 % CI 0.003-0.025, p = 0.014), whilst the amount of incentives received was not (β = 0.0002, 95 % CI -0.002 to 0.002, p = 0.818). Improved medication adherence is associated with a more favourable SQOL. This underlines the clinical relevance of improved adherence in response to financial incentives in this patient group.
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Joshi, Kruti; Lin, Jay; Lingohr-Smith, Melissa; Fu, Dong-Jing; Muser, Erik
2016-01-01
Abstract This study assessed real-world treatment patterns and antipsychotic (AP) medication adherence among commercially insured US patients with schizoaffective disorder (SCA). Continuously insured adults aged 18 years or older with a diagnosis of SCA from January 1, 2009, to December 31, 2012, were identified from the Clinformatics Data Mart database. Patients were categorized into 2 cohorts: incident or prevalent SCA. Demographics and clinical characteristics were evaluated during the baseline period. Use of psychiatric medications and adherence to AP medications were evaluated during a 12-month follow-up period after index diagnosis of SCA. Of the overall study population (N = 2713; mean age, 40.2 y; 52.7% female), 1961 patients (72.3%) (mean age, 38.7 y; 51.3% female) had incident SCA, and 752 patients (27.7%) (mean age, 43.9 y; 56.5% female) had prevalent SCA. Antipsychotics were used by 74.8% of patients in the overall study population during the follow-up period. The most commonly prescribed oral AP was risperidone (23.9%), followed by quetiapine (21.4%) and aripiprazole (20.4%). Use of any long-acting injectable APs in the overall study population during the follow-up period was less than 3%. A total of 49.0% and 38.0% of the overall study population had medication possession ratios and proportion of days covered for APs of 80% or greater, respectively. Overall use of long-acting injectable APs for the treatment of SCA is low, and adherence to AP medications, measured by both medication possession ratio and proportion of days covered, is suboptimal among patients with SCA in the real-world setting. PMID:27525965
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Naudin, J; Dassa, D; Cermolacce, M
2009-09-01
This paper focuses on the questions asked to practitioners regarding compliance to new long-acting atypical antipsychotics (LAAA): how does the comprehensive approach of patients' and carers' attitudes facing treatment challenge it? A review of recent literature shows that LAAA, are still suffering from an "image problem". We aim to describe these negative beliefs and suggest that LAAA indications be reconsidered. Following a comprehensive approach, we interpreted our review on the basis of anthropological criteria. We focused on value-based health and disease models that organize the attitude of patients and carers regarding the depot injection. Multiple negative beliefs attached to the pain, side-effects, and stigmas are well-known to impair adhesion to treatment. Carers understand disease as a lack of insight. Patients experience it as a threat for the Self and a loss of autonomy. The nurse-patient relationship involving injections is an important factor of compliance. When time is devoted by the carer to paying attention to the patient's experience, in order to perceive the patient as a participant, patients are more likely to adopt the injectable route themselves. By doing so, the patient considers the injection as a "protective net" a "lesser evil" by integrating it within his(her) biography. A comprehensive approach links the lack of insight to the patient's perception of stigma. Hope for recovery is related by the person him(her)self to his(her) own ability for autonomy. Persons with schizophrenia usually struggle for norms (agonomia). This trend has to be taken into account. LAAA are better indicated when patients are compliant. There is no indication when patients are "pure agonomics" and fight to deny both stigma and medication.
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Matthew, Binoj J; Gedzior, Joanna S
2015-01-01
This report attempts to highlight that use of an antipsychotic and concurrent chronic use of methamphetamine can cause drug-induced parkinsonism. Methamphetamine is usually not encountered in the list of agents that induce drug-induced parkinsonism and so its consideration particularly during chronic use by a patient who is also on an antipsychotic is worthwhile because of its popularity as an illegal narcotic. This case report describes just such a case of drug-induced parkinsonism which is a subacute syndrome that mimics Parkinson's disease. Although less alarming than dystonia, it is more common, more difficult to treat and can be the cause of significant disability during maintenance treatment especially in the elderly. In most cases, symptoms are reversible in days or weeks, but occasionally, especially in the elderly, or if long-acting injectable antipsychotics are used-as in this case-symptoms may last for weeks or months. The report also illustrates the neuronal workings due to chronic methamphetamine-use and the additive effects of dopamine blockade by antipsychotics such as haloperidol. © The Author(s) 2015.
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Si, Tianmei; Zhuo, Jianmin; Turkoz, Ibrahim; Mathews, Maju; Tan, Wilson; Feng, Yu
2017-12-01
The use of long-acting injectable antipsychotics in recently diagnosed schizophrenia remains less explored. We evaluated the efficacy and safety of paliperidone palmitate once-monthly (PP1M) treatment in adult patients with recently diagnosed vs. chronic schizophrenia. These post-hoc analyses included two multicenter studies. Study 1 (NCT01527305) enrolled recently diagnosed (≤5 years) and chronic (>5 years) patients; Study 2 (NCT01051531) enrolled recently diagnosed patients only. Recently diagnosed patients were further sub-grouped into ≤2 years or 2-5 years. The primary efficacy endpoint was the change from baseline in Positive and Negative Syndrome Scale (PANSS) total score. In Study 1, 41.5% patients had recent diagnosis (≤2 years: 56.8%; 2-5 years: 43.2%); 58.5% had chronic schizophrenia. In Study 2, 52.8% and 47.2% patients were grouped into ≤2 years and 2-5 years, respectively. PANSS total score showed significantly greater improvement in patients with recently diagnosed vs. chronic schizophrenia. Similar results were obtained for PANSS responder rate, improvements in PANSS, and CGI-S scores. PP1M was efficacious in both recently diagnosed and chronic schizophrenia, with the benefits being more pronounced in patients with recently diagnosed schizophrenia. This adds to growing evidence recommending long-acting antipsychotic interventions at early stages of schizophrenia.
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Sajatovic, Martha; Levin, Jennifer; Ramirez, Luis F.; Hahn, David Y.; Tatsuoka, Curtis; Bialko, Christopher S.; Cassidy, Kristin A.; Fuentes-Casiano, Edna; Williams, Tiffany D.
2014-01-01
Background Treatment non-adherence in people with schizophrenia is associated with relapse and homelessness. Building upon the usefulness of long-acting medication, and our work in psychosocial interventions to enhance adherence, we conducted a prospective uncontrolled trial of customized adherence enhancement (CAE) plus long-acting injectable antipsychotic (LAI) using haloperidol decanoate in 30 homeless or recently homeless individuals with schizophrenia and schizoaffective disorder. Methods Participants received monthly CAE and LAI (CAE-L) for 6 months. Primary outcomes were adherence as measured by the Tablets Routine Questionnaire (TRQ) and housing status. Secondary outcomes included psychiatric symptoms, functioning, side effects, and hospitalizations. Results Mean age of participants was 41.8 years (SD 8.6), mainly minorities (90% African-American) and mainly single/never married (70%). Most (97%) had past or current substance abuse, and had been incarcerated (97%). Ten individuals (33%) terminated the study prematurely. CAE-L was associated with good adherence to LAI (76% at 6 months) and dramatic improvement in oral medication adherence, which changed from missing 46% of medication at study enrollment to missing only 10% at study end (p = 0.03). There were significant improvements in psychiatric symptoms (p<.001) and functioning (p<.001). Akathisia was a major side effect with LAI. Conclusion While interpretation of findings must be tempered by the methodological limitations, CAE-L appears to be associated with improved adherence, symptoms, and functioning in homeless or recently homeless individuals with schizophrenia or schizoaffective disorder. Additional research is needed on effective and practical approaches to improving health outcomes for homeless people with serious mental illness. PMID:24434094
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Constantine, Robert J; Andel, Ross; McPherson, Marie; Tandon, Rajiv
2015-08-01
Despite little evidence to support its use and practice guidelines discouraging the practice, antipsychotic polypharmacy is widely prevalent in schizophrenia. This randomized controlled trial studied the effects of switching patients stable on two antipsychotic medications to one antipsychotic medication. 104 adult outpatients with schizophrenia from 7 community mental health centers clinically stable on concurrent treatment with 2 antipsychotics were randomly assigned to stay on polypharmacy or to switch to antipsychotic monotherapy. Participants were followed for 1-year with assessments of symptoms and side effects occurring every 60days (7 total assessments). We examined differences in time trajectories in symptoms (PANSS, CGI) and side effects (EPS, metabolic, other) as a function of group assignment (switch vs. stay) and time, using intention-to-treat analysis. Participants who switched to antipsychotic monotherapy experienced greater increases in symptoms than stay patients. These differences emerged in the second 6months of the trial. All-cause discontinuation rates over the 1-year trial were higher in the switch-to-monotherapy group than in the stay-on-polypharmacy group (42% vs. 13%; p<0.01). There were no differences in change over time in any of the side effect measures, except that stay patients experienced a greater decrease in Simpson Angus total scores than switch patients. Clinicians should be cautious in switching patients with chronic schizophrenia who are stable on 2 antipsychotics to one antipsychotic. Given the challenges in discontinuing antipsychotic polypharmacy, adequate trials of evidence-based treatments such as clozapine and long-acting injectable antipsychotics should be undertaken in inadequately responsive schizophrenia patients before moving to antipsychotic polypharmacy. Copyright © 2015 Elsevier B.V. All rights reserved.
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Eum, Seenae; Schneiderhan, Mark E; Brown, Jacob T; Lee, Adam M; Bishop, Jeffrey R
2017-07-03
Given the complex nature of symptom presentation and medication regimens, psychiatric clinics may benefit from additional tools to personalize treatments. Utilizing pharmacogenetic information may be helpful in assessing unique responses to therapy. We report herein a case of wearing-off phenomena during treatment with aripiprazole long-acting injectable (LAI) and a proof of concept strategy of how pharmacogenetic information may be used to assess possible genetic factors and also hypothesize potential mechanisms for further study. A 51-year-old African American male with schizoaffective disorder was referred to a psychiatric clinic for medication management. After unsuccessful trials of multiple antipsychotics, oral aripiprazole was initiated (up to 30 mg/day) and transitioned to aripiprazole LAI with symptom improvement. At a high dose of aripiprazole LAI (400 mg Q3wks), the patient experienced breakthrough symptoms approximately 3 days prior to his next injection. Various considerations were examined to explain his atypical dose requirements, including but not limited to pharmacogenetic influences. Pharmacogenetic testing ruled out genetic influences on drug metabolism but noted a -141C Del variant in the dopamine-D2 receptor (DRD2) gene associated in prior studies of poor-response to antipsychotics. At this time, a new formulation, aripiprazole lauroxil, was explored due to its availability in higher dose options. Transition to the new formulation (882 mg Q4wks) greatly improved and stabilized the patient's symptoms with no breakthrough psychosis. Comparable daily dose equivalents were achieved with two different formulations due to the Q3wks vs Q4wks dosing strategies, although the two agents have some differences in pharmacokinetic profiles. We report a case of a patient experiencing wearing-off symptoms with aripiprazole LAI who benefited from switching to aripiprazole lauroxil. Pharmacogenetic testing revealed normal activity for relevant metabolism pathways but a DRD2 -141C variant that may influence brain D2 expression and antipsychotic responsiveness. The clinical utility of DRD2 information and what to do with genotyping results has not been previously addressed, despite availability on clinical test panels. Our case report suggests further investigations of altered dosing strategies and receptor genotype sensitivities to pharmacokinetic factors may be helpful in understanding symptom re-emergence observed in some patients taking LAI antipsychotics.
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Brandon Bookstaver, P; Miller, A D
2011-06-01
Thermodysregulation, including hypothermia, is recognized as a potential adverse effect secondary to atypical antipsychotics. We report the first known case of hypothermia possibly associated with long-acting risperidone depot injection, precipitating further adverse events secondary to supratherapeutic phenytoin concentrations. A 75-year-old African-American female presented as a transfer from an outpatient psychiatric center with hypothermia (35·1 °C), bradycardia, altered mental status and a series of witnessed tonic-clonic seizures. The patient was discovered to be profoundly neutropenic (absolute neutrophil count = 266 × 10(9) /L) and a corrected phenytoin concentration was 147·708 μm. During the 3 months preceding admission, phenytoin dosing was stable and consecutive therapeutic concentrations were documented. The only recent change in medication regimen was a switch from oral risperidone to the long-acting injectable formulation. Upon discontinuation of the risperidone and phenytoin, the patient's mental status and laboratory abnormalities returned to baseline. The patient did not experience additional seizure activity. This unintentional significant drop in core body temperature may have resulted in altered metabolism of phenytoin leading to supratherapeutic concentrations and subsequent tonic-clonic seizures, bradycardia and neutropenia. Low core body temperatures can alter the pharmacokinetic profiles of hepatically metabolized medications, prompting careful patient assessment especially in those receiving medications with a narrow-therapeutic index. Hypothermia should be recognized as a potential adverse event with the long-acting injectable formulation of risperidone. © 2010 The Authors. JCPT © 2010 Blackwell Publishing Ltd.
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Mahlich, Jörg; Nishi, Masamichi; Saito, Yoshimichi
2015-01-01
Background The cost of schizophrenia in Japan is high and new long-acting injectable (LAI) antipsychotics might be able to reduce costs by causing a reduction of hospital stays. We aim to estimate budget effects of the introduction of a new 1-month LAI, paliperidone palmitate, in Japan. Methods A budget impact analysis was conducted from a payer perspective. The model took direct costs of illness into account (ie, costs for inpatient and outpatient services, as well as drug costs). The robustness of the model was checked using a sensitivity analysis. Results According to our calculations, direct total costs of schizophrenia reach 710,500 million yen a year (US$6 billion). These costs decrease to 691,000 million yen (US$5.9 billion) 3 years after the introduction of paliperidone palmitate. Conclusion From a payer point of view, the introduction of a new treatment for schizophrenia in Japan helps to save resources and is not associated with a higher financial burden. PMID:26045674
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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.
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Kane, John M.; Zhao, Cathy; Johnson, Brian R.; Baker, Ross A.; Eramo, Anna; McQuade, Robert D.; Duca, Anna R.; Sanchez, Raymond; Peters-Strickland, Timothy
2015-01-01
Abstract Objective: To compare hospitalization rates in patients with schizophrenia treated prospectively with aripiprazole once-monthly 400 mg (AOM 400; an extended-release injectable suspension) vs the same patients’ retrospective rates with their prior oral anti-psychotic therapy. Research design and methods: Multi-center, open-label, mirror-image, naturalistic study in a community setting in North America. Patients who required a change in treatment and/or would benefit from long-acting injectable anti-psychotic therapy were treated prospectively for 6 months with AOM 400. Retrospective data on hospitalization rates were obtained. Clinical trial registration: ClinicalTrials.gov: NCT01432444. Main outcome measures: The proportion of patients with ≥1 psychiatric inpatient hospitalization with oral anti-psychotic therapy examined retrospectively (months –4 to –1 before oral conversion) and after switching to AOM 400 (months 4–6 after initiating AOM 400). Results: Psychiatric hospitalization rates were significantly lower when patients were treated with AOM 400 compared with oral anti-psychotic therapy both in the 3-month primary efficacy sample (2.7% [n = 9/336] vs 27.1% [n = 91/336], respectively; p < 0.0001) and in the total sample (6-month prospective rate: 8.8% [n = 38/433] vs 6-month retrospective rate: 38.1% [n = 165/433]; p < 0.0001). Discontinuations due to adverse events (AEs) during cross-titration were lower in patients cross-titrated on oral aripiprazole for >1 and <4 weeks (2.9% [n = 7/239]) compared with patients cross-titrated for ≤1 week (10.4% [n = 5/48]). The most common treatment-emergent AEs during the prospective treatment phase were insomnia (6.7% [n = 29/431]) and akathisia (6.5% [n = 28/431]). Patient-rated injection-site pain decreased from the first injection to the last visit. Conclusions: In a community setting, patients with schizophrenia demonstrated significantly lower psychiatric hospitalization rates after switching from their prior oral anti-psychotic therapy to AOM 400. Patients served as their own control, and thus an active control group was not included in this study. Confounding factors, such as insurance coverage and availability of hospital beds, were not examined here and deserve further consideration. PMID:25347448
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Suzuki, Hidenobu; Hibino, Hiroyuki; Inoue, Yuichi; Matsumoto, Hideo; Mikami, Katsunaka
2017-01-01
Schizophrenia is a chronic disease that requires long-term management with antipsychotics; however, an important barrier to the success of long-term treatment is drug noncompliance, which increases the risk of recurrence and hospitalization. Second-generation long-acting injectable antipsychotics have improved drug adherence, and the pharmacological effects of the drugs, and therefore, have become useful treatment options. We report on three schizophrenia patients who switched from oral low-dose aripiprazole to aripiprazole once-monthly 300 mg. We examined the efficacy and safety of aripiprazole once-monthly 300 mg, as well as its influence on quality of life, from baseline to 20 weeks after aripiprazole once-monthly 300 mg treatment. Aripiprazole once-monthly 300 mg did not exacerbate the depressive and negative symptoms, and extrapyramidal symptoms were improved, which may have helped improve the quality of life. The results suggest the efficacy of aripiprazole once-monthly 300 mg in maintenance treatment for schizophrenia when mental symptoms are stable.
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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.
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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.
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Samalin, L; Abbar, M; Courtet, P; Guillaume, S; Lancrenon, S; Llorca, P-M
2013-12-01
Compliance is often partial with oral antipsychotics and underestimated for patients with serious mental illness. Despite their demonstrated advantages in terms of relapse prevention, depot formulations are still poorly used in routine. As part of a process to improve the quality of care, French Association for Biological Psychiatry and Neuropsychopharmacology (AFPBN) Task Force elaborated a Formal Consensus for the prescription of depot antipsychotics in clinical practice. The Task Force recommends as first-line choice, the use of long-acting injectable (LAI) second-generation antipsychotics in patients with schizophrenia, schizoaffective disorder and delusional disorder. They can be considered as a second-line option as a monotherapy to prevent manic recurrence or in combination with mood stabilizer to prevent depressive recurrence in the maintenance treatment of bipolar disorder. LAI second-generation antipsychotics can also be used after a first episode of schizophrenia. Depot neuroleptics are not recommended during the early course of schizophrenia and are not appropriate in bipolar disorder. They are considered as a second-line option for maintenance treatment in schizophrenia. LAI formulations should be systematically proposed to any patients for whom maintenance antipsychotic treatment is indicated. LAI antipsychotics can be used preferentially for non-compliant patients with frequent relapses or aggressive behaviors. A specific information concerning the advantages and inconveniences of the LAI formulations, in the framework of shared-decision making must be delivered to each patient. Recommendations for switching from one oral/LAI form to another LAI and for using LAI antipsychotics in specific populations (pregnant women, elderly patients, subjects in a precarious situation, and subjects having to be treated in a prison establishment) are also proposed. Copyright © 2013 L’Encéphale. Published by Elsevier Masson SAS.. All rights reserved.
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McCreath, James; Larson, Essie; Bharatiya, Purabi; Labanieh, Hisham A; Weiss, Zvi; Lozovatsky, Michael
2017-02-23
Long-acting injectable (LAI) antipsychotic medications are employed universally for the treatment of schizophrenia. This study retrospectively assessed the variables that factor into an individual's adherence to LAIs. The data sample was obtained from the adult ambulatory services of a large general hospital mental health center located in Elizabeth, New Jersey. Reports were run in November 2015 to identify patients who had received at least 1 LAI between January 1, 2014, and October 14, 2015. In September 2016, an additional report was run to collect follow-up data. The sample included 120 women and 178 men, ranging in age from 18-81 years, who received at least 1 LAI during a 23-month period. A hazard analysis for single-decrement, nonrepeatable events was used to assess the risk of discontinuation of LAIs during the study period. Separate χ² analyses were conducted to assess differences in discontinuation rates for sociodemographic variables, program type variables, type of long-acting medication, and time effects. The cumulative continuation rate across the study period was 73%. Main effect differences were found in continuation rates for program type (χ²₂undefined= 10.252, P = .006), LAI type (χ²₅ = 23.365, P < .000), and prescribed frequency of LAI (χ²₂ = 7.622, P = .022). In addition, multiple time-dependent effect differences were found. No significant main effect results were found for LAI continuation rates and patient age (χ²₃ = 3.689, P = .297), sex (χ²₁ = 0.904, P = .342), race (χ²₃ = 5.785, P = .123), or enrollment in involuntary outpatient commitment (χ²₁ = 2.989, P = .084). The findings of the current research suggest that medication type, frequency of medication appointments, and program type may be key in increasing and maintaining LAI adherence. © Copyright 2017 Physicians Postgraduate Press, Inc.
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Practical guidelines on the use of paliperidone palmitate in schizophrenia.
Newton, Richard; Hustig, Harry; Lakshmana, Raju; Lee, Joseph; Motamarri, Balaji; Norrie, Peter; Parker, Robert; Schreiner, Andreas
2012-04-01
Paliperidone palmitate is an atypical long-acting injectable (LAI) antipsychotic that has been approved for use in the US, EU, Australia and numerous other countries for acute and maintenance therapy of schizophrenia. LAI antipsychotics are often viewed as a 'last-resort' treatment for difficult-to-treat patients, however this article considers their role more broadly in the management of partial or non-adherence in schizophrenia. A search of MedLine, CTR and PsychInfo was conducted to identify relevant publications and clinical trials (search term 'paliperidone palmitate', up to December 2010). The findings were discussed in a number of teleconferences and the manuscript was finalized with a face-to-face meeting of the authors group. Relapse prevention in schizophrenia requires a comprehensive approach to treatment, which includes antipsychotic medication and psychosocial measures as well as family and/or carer involvement. Good symptom control and the interconnected issue of treatment adherence are arguably the most crucial factors for success. Carer and patient feedback should be carefully considered. Negotiation about commencing LAI therapy done early in course of disease is easier than many clinicians believe, although it is not often attempted in practice. Paliperidone palmitate is useful in both the acute and maintenance phases of treatment. A case-based approach is presented to suggest various opportunities where use of paliperidone palmitate could be considered within the disease course of schizophrenia. Paliperidone palmitate offers some advantages in terms of tolerability, simplicity of treatment initiation and long duration between injections. The consensus of the authors is that rather than reserving paliperidone palmitate for use in difficult-to-treat or refractory patients, it could be used to promote adherence and prevent relapse earlier in the course of the illness.
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Ganesan, Soma; McKenna, Mario; Procyshyn, Ric M.; Zipursky, Sheldon
2007-01-01
Background: Schizophrenia is a chronic debilitating disease that affects ~110,000 Canadians (0.55% lifetime prevalence). Risperidone long-acting injection (RLAI) is the first injectable, long-acting, atypical antipsychotic drug marketed in Canada. Objective: The aim of this study was to assess the clinical effectiveness and hospitalization rates of patients with schizophrenia, schizoaffective disorder, or schizophreniform disorder treated with RLAI in a community mental health care setting. Methods: Data were collected between August 1, 2006 and September 30, 2006 via a retrospective chart review of outpatients diagnosed with schizophrenia, schizoaffective disorder, or schizophreniform disorder who received treatment from 1 of the 8 mental health teams within the Vancouver Community Mental Health Organization (VCMHO) in Vancouver, British Columbia, Canada. Collected data included: frequency and duration of institutional care, discharge and relapse rates, demographic variables, diagnosis history, RLAI medication history, and history of other medications. The overall severity of symptoms before and after RLAI treatment and the improvement in symptoms during treatment were evaluated using the Clinical Global Impression Scales for severity (CGI-S)(1 = not ill to 7 = extremely ill) and improvement (CGI-I)(1 = very much improved to 7 = very much worse). Results: Forty-four patients were identified as having received RLAI. The charts of 19 patients (10 men, 9 women; mean [SD] age at time of chart audit, 36.7 [11.7] years; mean [SD] age at primary diagnosis, 23.6 [7.4] years; race: white, 10 [52.6%]; Asian, 6 [31.6%]; American Indian, 1 [5.3%]; black, 1 [5.3%]; other, 1 [5.3%]) were included in the analysis. The majority of patients (78%) had been treated with another antipsychotic drug prior to treatment with RLAI: risperidone (77%), quetiapine (47%), zuclopenthixol (43%), olanzapine (43%), and loxapine (17%). Mean (SD) CGI-S Scale score declined significantly from 5.29 (1.3) before treatment initiation to 3.05 (1.0) posttreatment (P < 0.001). Mean (SD) CGI-I Scale score was 2.58 (0.71) (P < 0.001); 94% of patients had a CGI-I score ≤3. Mean (SD) duration of hospitalization decreased significantly from 15.7 (19.7) days before treatment to 2.4 (6.0) days after treatment (P < 0.05). Mean (SD) number of hospializations also decreased significantly from 2.0 (1.8) before treatment to 0.5 (1.3) after treatment (P < 0.01). Conclusions: The results of this pilot study suggest that use of the atypical-antipsychotic medication RLAI significantly decreased duration and rates of hospitalization, compared with baseline, in these VCMHO patients with schizophrenia spectrum illnesses. PMID:24692772
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Paliperidone for the treatment of schizoaffective disorder.
Alphs, Larry; Fu, Dong-Jing; Turkoz, Ibrahim
2016-01-01
Schizoaffective disorder (SCA) is a complex mental illness characterized by psychosis and affective symptoms. Treatment usually involves concomitant therapy with antipsychotics, mood stabilizers, and/or antidepressants. Effective treatment must address acute symptoms, maintain long-term stability, promote recovery, and improve patient functioning. Data from 3 pivotal studies evaluating the acute and maintenance treatment of SCA with paliperidone are reviewed. Two formulations of paliperidone have been studied for these indications: an extended-release oral formulation (NCT00397033, NCT00412373) and long-acting injectable once-monthly paliperidone palmitate (NCT01193153). The reported effects of these formulations on psychotic, depressive, and manic symptoms are discussed. Both formulations were found to be safe and effective for the acute and maintenance treatment of SCA. Of critical importance for this treatment population is that rapid improvement was seen in all major symptoms of SCA, including psychosis, depression, and mania. Mediation analyses suggest that the known antipsychotic effects of paliperidone occur independently of its antidepressant effects. Both formulations of the drug are effective when used as monotherapy or adjunctively with antidepressants or mood stabilizers. Beyond symptom control, both formulations improved patient functioning and increased patient satisfaction.
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Heusler, Peter; Newman-Tancredi, Adrian; Castro-Fernandez, Annabelle; Cussac, Didier
2007-03-01
The D(2) dopaminergic receptor represents a major target of antipsychotic drugs. Using the coupling of the human D(2long) (hD(2L)) receptor to G protein-coupled inward rectifier potassium (GIRK) channels in Xenopus laevis oocytes, we examined the activity of antipsychotic agents of different classes - typical, atypical, and a "new generation" of compounds, exhibiting a preferential D(2) and 5-HT(1A) receptor profile. When the hD(2L) receptor was coexpressed with GIRK channels, a series of reference compounds exhibited full agonist (dopamine, and quinpirole), partial agonist (apomorphine, (-)3-PPP, and (+)-UH232) or inverse agonist (raclopride, and L741626) properties. Sarizotan exhibited only very weak partial agonist action. At higher levels of receptor cRNA injected per oocyte, both partial agonist activity and inverse agonist properties were generally more pronounced. The inverse agonist action of L741626 was reversed by interaction with sarizotan, thus confirming the constitutive activity of wild-type hD(2L) receptors in the oocyte expression system. When antipsychotic agents were tested for their actions at the hD(2L) receptor, typical (haloperidol) as well as atypical (nemonapride, ziprasidone, and clozapine) compounds acted as inverse agonists. In contrast, among D(2)/5-HT(1A) antipsychotics, only SLV313 and F15063 behaved as inverse agonists, whilst the other members of this group (bifeprunox, SSR181507 and the recently marketed antipsychotic, aripiprazole) exhibited partial agonist properties. Thus, the X. laevis oocyte expression system highlights markedly different activity of antipsychotics at the hD(2L) receptor. These differential properties may translate to distinct therapeutic potential of these compounds.
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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
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Llorca, P M; Miadi-Fargier, H; Lançon, C; Jasso Mosqueda, G; Casadebaig, F; Philippe, A; Guillon, P; Mehnert, A; Omnès, L F; Chicoye, A; Durand-Zaleski, I
2005-01-01
Schizophrenia is a disease affecting the young adults and amounts to approximately 300,000 people in France. The French public psychiatric sector takes care of approximately 150,000 adults schizophrenics: 50% benefit from ambulatory care, 50% are in partial or full-time hospitalization care. Schizophrenia represents the first diagnosis that psychiatric sectors take in charge. The costs associated with schizophrenia, mainly hospital costs, are important and were estimated at 2% of the total medical costs in France. In the French social welfare system, the social costs (pensions, allowances, managements of custody or guardianship by social workers) are also to be taken into account: it amounts to a third of the global direct cost. Schizophrenia also generates indirect costs (losses of productivity and premature deaths) which would be at least equal, or even more important, than direct medical costs. The non-compliance to the antipsychotic treatment is a major problem with people suffering from schizophrenia. Indeed the lack of compliance to the treatment, estimated at 20 to 40%, is a major handicap for schizophrenic patient stabilization. The poor level of compliance is due to many various causes: adverse effects that are considered unbearable, medicine viewed as persecutory, negation of the disease, nostalgia for the productive phases of the disease, lack of social support, complexity of the prescription, relapse itself. Compliance is thus influenced by the patient's clinical features, local provision of health care and the specific nature of the drug (adverse effects, pharmaceutical formulation). The atypical antipsychotics present fewer extrapyramidal side effects and reduce the cognitive deficits associated with the disease, which results in improved compliance. Long-acting injectable antipsychotics allow a better therapeutic compliance and thus better efficacy of the treatment. Several studies have shown a significant improvement in compliance related to the pharmaceutical formulation of antipsychotics. Hospitalization and relapse risks are lower in compliant than in non-compliant patients. The main objective of this pharmacoeconomic analysis is to evaluate the impact in terms of medical benefits and costs of the following strategies: 1. Risperidone long-acting injection: first long-acting injectable atypical antipsychotic; 2. Haloperidol depot: long-acting injectable conventional neuroleptic; 3. Olanzapine: atypical antipsychotic available commercially in oral formulation. The target population defined for the study are young schizophrenic patients treated for at least 1 year and whose disorder has not been diagnosed for longer than 5 years. The time horizon is 2 years. A cost-effectiveness analysis is performed. The perspective adopted is the French Health System. The main hypothesis of the model is that an increase in compliance linked to the use of long-acting injectable formulation could lead to an increased efficacy and a modification of the cost-effectiveness ratio. A decision tree was built. Six periods of follow-up are identified with a duration of 4-months per period. The tree contains 3 principal arms, each one corresponding to a specific treatment: risperidone LA injection, haloperidol decanoate and olanzapine. For each arm, at the chance node, two health states are identified: either the patient responds favourably to the treatment or does not respond favourably and requires a switch to another drug treatment. After a period of response, the patient can either remain in the same state or experiences a clinical deterioration. If the patient presents a clinical deterioration, he can either go back to a positive response state after a period of intensive follow-up or remain in an insufficient response state; in this case, a change of antipsychotic treatment is necessary. In the model, a patient should receive four different treatments before a long-term hospitalization takes put in place. According to the market authorization labelling, clozapine is proposed only as a 2nd or 3rd line therapeutic option, so when at least one or two successive neuroleptics have failed. The efficacy data used in the model are provided by clinical research recently published. These studies estimate the efficacy of oral risperidone, LA risperidone, olanzapine, and treatment by haloperidol. When available data in the literature were insufficient, the opinion of experts was sought. The effectiveness criteria is the rate of patients treated successfully: patients responding to the initial treatment with the possibility of experiencing one or two episodes of clinical deterioration but without requiring a switch to another drug during 2 years of follow-up. The base case is as follows: efficacy for oral risperidone is used for the LA risperidone strategy, increased by 10% within the first 4 months of follow-up; efficacy for oral haloperidol is used for haloperidol depot, increased by 5% within the first 4 months of follow-up; for olanzapine, observed data in clinical trials were applied. The hypotheses for long acting forms are rather conservative because the increase of efficacy which can be expected for the long-acting injectable formulations varies between 5% to more than 30% according to the literature data. The analysis of sensibility includes three scenarios: scenario 1: for LA risperidone, 5% of patients treated successfully improvement in regard to oral risperidone instead of 10% in the base case; scenario 2: for haloperidol depot, 10% of patients treated successfully improvement in regard of oral haloperidol instead of 5% in the base case; scenario 3: the results of an open trial conducted within the framework of the LA risperidone license are used, leading to an increase of up to 13,3% of the rate of successfully treated patients, compared to oral risperidone literature data. As for the side effects, only extrapyramidal symptoms were considered. Other side effects are described in the literature such as the obesity or the occurrence of a diabetes; these effects were not taken into account in the model, their impact on the cove-rage of schizophrenic patients and on resources utilisation being poorly known. Only direct medical costs were considered in the pharmaco-economic analysis. Two types of costs were identified: hospital costs and community care costs. The stays in overnight hospitalisation and day hospitalisation were derived from the Disease Related Groups (DRG) and valued from the data of the National Cost Study (Etude Nationale de Coûts; 1999). The DRGs corresponding to the diagnosis of schizophrenia are the DRG 627 (complete hospitalization) and DRG 819 (day hospitalisation). Ambulatory care: procedures and visits, were valued in euros in reference with the tariffs for reimbursement issued in the Naming General of the Professional Acts (NGAP) and published by the French National Health Insurance (Year 2001). Medication consumption was quantified by using the daily dosage specified in the the MAA and the French prescription database IMS-Dorema. The cost of medicines was valued from tariffs 2001 (SEMPEX). LA risperidone price being not fixed to date, the reserved hypothesis is a 141,62 Euro retail price. As schizophrenia is listed among the diseases reimbursed at a 100% rate by the Health insurance, out of pocket expenses by patient are not considered in the analysis. The cost for the extrapyramidal effects was attributed to all the strategies. This cost was calculated according to the rates of extrapyramidal effects occurrence collected in the literature. Globally, in the published studies, the incidence of the side effects for the patients treated by olanzapine or risperidone is similar. It was thus decided by the experts to use the same rate of occurrence for extrapyramidal effects for olanzapine and risperidone (20%). This rate is 40% for haloperidol decanoate, 10% for oral clozapine. For the cost estimation, the expenses for treating a schizophrenic patient for two years were taken into account. The results show that in two years, LA risperidone is more effective than the two other antipsychotics. After 2 years, the rate of patients treated successfully is 82,7% for LA risperidone, 74,8% for olanzapine and 57,3% for haloperidol depot. The 2 year-cost per patient treated by LA risperidone is 14,055 Euro. This cost is 14,351 Euro and 17,203 Euro respectively for the strategies olanzapine and haloperidol depot. The cost-efficacy ratios per patient successfully treated are 16,995 Euro for the strategy LA risperidone, 19,186 Euro for olanzapine and 30,023 Euro for haloperidol depot. LA risperidone is a dominant strategy compared with both olanzapine and haloperidol depot. Scenario 1 shows that LA risperidone strategy remains the most effective. Indeed, this strategy allows a response increase of 3,5% regarding olanzapine strategy and of 21% regarding haloperidol depot strategy. Under the hypothesis tested in scenario 1, LA risperidone is a partial dominant strategy against olanzapine and a total dominant strategy against haloperidol depot. In scenario 2, as efficacy is improved for haloperidol decanoate (61,10%), a decrease of 1,763 Euro in the cost per patient treated is observed for this strategy. Cost per patient treated successfully and efficacy for LA risperidone and olanzapine are the same than in the base case. LA risperidone is a total dominant strategy against olanzapine and haloperidol decanoate. In scenario 3, the rate of patients treated successfully at 2 years is 88,6% for LA risperidone with a cost per patient of 12,347 Euro. LA risperidone is dominant against olanzapine and haloperidol depot. The schizophrenia is a relatively frequent disease. (ABSTRACT TRUNCATED)
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Laux, Gerd; Heeg, Bart; van Hout, Ben A; Mehnert, Angelika
2005-01-01
Schizophrenia is one of the most expensive psychiatric conditions because of high direct and indirect costs associated with the nature of the illness, its resistance to treatment and the consequences of relapse. Long-acting risperidone is a new formulation of an atypical antipsychotic drug that also offers the improvements in compliance associated with haloperidol depot. The aim of this simulation study was to compare the benefits and costs of three pharmacological treatment strategies comprising first-line treatment with long-acting risperidone injection, a haloperidol depot or an oral atypical antipsychotic agent, over a 5-year period in Germany. A discrete event simulation model was developed to compare three treatment scenarios from the perspective of major third-party payers (sickness funds and social security 'Sozialversicherung'). The scenarios comprised first-line treatment with haloperidol depot (scenario 1), long-acting risperidone (scenario 2) and oral olanzapine (scenario 3). Switches to second or third-line options were allowed when side-effects occurred or a patient suffered more than a fixed number of relapses. The model accounted for fixed patient characteristics, and on the basis of these, simulated patient histories according to several time-dependent variables. The time horizon for this model was limited to 5 years, and in accordance with German guidelines, costs and effects were discounted by between 3 and 10%. Direct costs included medication, type of physician visits and treatment location. Indirect costs were not included. Information on treatment alternatives, transition probabilities, model structure and healthcare utilization were derived from the literature and an expert panel. Outcomes were expressed in terms of the number and duration of psychotic episodes, cumulative symptom scores, costs, and quality-adjusted life-years (QALY). Univariate sensitivity analyses were carried out, as were subgroup analyses based on disease severity and for patients at high risk of being non-compliant. The long-acting risperidone strategy was calculated to avoid 0.23 and 0.33 relapses per patient, decrease the cumulative symptom score by 25 and 33 points, and decrease the costs by 2017 Euro and 6096 Euro per patient (1608 Euro and 5422 Euro discounted), compared with the haloperidol depot and olanzapine strategies, respectively, over a 5-year period (year of costing 2004). Among high-risk non-compliant patients, long-acting risperidone was estimated to avoid 0.23 and 0.47 relapses and save 4822 Euro and 10,646 Euro per patient (4107 Euro and 9490 Euro discounted), compared with the haloperidol depot and olanzapine strategies, respectively. Sensitivity analyses showed that the results were robust and mainly sensitive to changes in the reported relative effectiveness of atypical and conventional formulations for preventing symptom recurrence, and in the relative compliance with oral and long-acting formulations. In this model, long-acting risperidone is a dominant strategy compared with a haloperidol depot or oral atypical antipsychotic agent, being both more effective and less costly over a 5-year period. Results for long-acting risperidone are even more favourable among patients at high risk of being noncompliant or with more severe disease.
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Majer, Istvan M; Gaughran, Fiona; Sapin, Christophe; Beillat, Maud; Treur, Maarten
2015-01-01
Treatment with long-acting injectable (LAI) antipsychotic medication is an important element of relapse prevention in schizophrenia. Recently, the intramuscular once-monthly formulation of aripiprazole received marketing approval in Europe and the United States for schizophrenia. This study aimed to compare aripiprazole once-monthly with other LAI antipsychotics in terms of efficacy, tolerability, and safety. A systematic literature review was conducted to identify relevant double-blind randomized clinical trials of LAIs conducted in the maintenance treatment of schizophrenia. MEDLINE, MEDLINE In-Process, Embase, the Cochrane Library, PsycINFO, conference proceedings, clinical trial registries, and the reference lists of key review articles were searched. The literature search covered studies dating from January 2002 to May 2013. Studies were required to have ≥24 weeks of follow-up. Patients had to be stable at randomization. Studies were not eligible for inclusion if efficacy of acute and maintenance phase treatment was not reported separately. Six trials were identified (0.5% of initially identified studies), allowing comparisons of aripiprazole once-monthly, risperidone LAI, paliperidone palmitate, olanzapine pamoate, haloperidol depot, and placebo. Data extracted included study details, study duration, the total number of patients in each treatment arm, efficacy, tolerability, and safety outcomes. The efficacy outcome contained the number of patients that experienced a relapse, tolerability outcomes included the number of patients that discontinued treatment due to treatment-related adverse events (AEs), and that discontinued treatment due to reasons other than AEs (e.g., loss to follow-up). Safety outcomes included the incidence of clinically relevant weight gain and extrapyramidal symptoms. Data were analyzed by applying a mixed treatment comparison competing risks model (efficacy) and using binary models (safety). There was no statistically significant difference between any study outcome, including the risk of relapse, the risk of discontinuations, and safety outcomes. Aripiprazole once-monthly is similarly efficacious to other LAIs with relatively low rates of discontinuation due to AEs and due to reasons other than AEs than other LAIs.
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Berrouiguet, Sofian; Barrigón, Maria Luisa; Brandt, Sara A; Ovejero-García, Santiago; Álvarez-García, Raquel; Carballo, Juan Jose; Lenca, Philippe; Courtet, Philippe; Baca-García, Enrique
2016-01-01
The emergence of electronic prescribing devices with clinical decision support systems (CDSS) is able to significantly improve management pharmacological treatments. We developed a web application available on smartphones in order to help clinicians monitor prescription and further propose CDSS. A web application (www.MEmind.net) was developed to assess patients and collect data regarding gender, age, diagnosis and treatment. We analyzed antipsychotic prescriptions in 4345 patients attended in five Psychiatric Community Mental Health Centers from June 2014 to October 2014. The web-application reported average daily dose prescribed for antipsychotics, prescribed daily dose (PDD), and the PDD to defined daily dose (DDD) ratio. The MEmind web-application reported that antipsychotics were used in 1116 patients out of the total sample, mostly in 486 (44%) patients with schizophrenia related disorders but also in other diagnoses. Second generation antipsychotics (quetiapine, aripiprazole and long-acting paliperidone) were preferably employed. Low doses were more frequently used than high doses. Long acting paliperidone and ziprasidone however, were the only two antipsychotics used at excessive dosing. Antipsychotic polypharmacy was used in 287 (26%) patients with classic depot drugs, clotiapine, amisulpride and clozapine. In this study we describe the first step of the development of a web application that is able to make polypharmacy, high dose usage and off label usage of antipsychotics visible to clinicians. Current development of the MEmind web application may help to improve prescription security via momentary feedback of prescription and clinical decision support system.
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Berrouiguet, Sofian; Barrigón, Maria Luisa; Brandt, Sara A.; Ovejero-García, Santiago; Álvarez-García, Raquel; Carballo, Juan Jose; Lenca, Philippe; Courtet, Philippe; Baca-García, Enrique
2016-01-01
Purpose The emergence of electronic prescribing devices with clinical decision support systems (CDSS) is able to significantly improve management pharmacological treatments. We developed a web application available on smartphones in order to help clinicians monitor prescription and further propose CDSS. Method A web application (www.MEmind.net) was developed to assess patients and collect data regarding gender, age, diagnosis and treatment. We analyzed antipsychotic prescriptions in 4345 patients attended in five Psychiatric Community Mental Health Centers from June 2014 to October 2014. The web-application reported average daily dose prescribed for antipsychotics, prescribed daily dose (PDD), and the PDD to defined daily dose (DDD) ratio. Results The MEmind web-application reported that antipsychotics were used in 1116 patients out of the total sample, mostly in 486 (44%) patients with schizophrenia related disorders but also in other diagnoses. Second generation antipsychotics (quetiapine, aripiprazole and long-acting paliperidone) were preferably employed. Low doses were more frequently used than high doses. Long acting paliperidone and ziprasidone however, were the only two antipsychotics used at excessive dosing. Antipsychotic polypharmacy was used in 287 (26%) patients with classic depot drugs, clotiapine, amisulpride and clozapine. Conclusions In this study we describe the first step of the development of a web application that is able to make polypharmacy, high dose usage and off label usage of antipsychotics visible to clinicians. Current development of the MEmind web application may help to improve prescription security via momentary feedback of prescription and clinical decision support system. PMID:27764107
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Edwards, Natalie C; Locklear, Julie C; Rupnow, Marcia F T; Diamond, Ronald J
2005-01-01
The availability of long-acting risperidone injection may increase adherence and lead to improved clinical and economic outcomes for individuals with schizophrenia. The objective of this study was to assess the cost effectiveness of long-acting risperidone, oral risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, and haloperidol depot in patients with schizophrenia over 1 year from a healthcare system perspective. Published medical literature, unpublished data from clinical trials and a consumer health database, and a clinical expert panel were utilized to populate a decision analytical model comparing the seven treatment alternatives. The model captured rates of patient compliance, the rates, frequency and duration of relapse, incidence of adverse events, and healthcare resource utilization and associated costs. Primary outcomes were expressed in terms of percentage of patients relapsing per year, number of relapse days per year (number and duration of relapses per patient per year), and total direct 2003 medical cost per patient per year. On the basis of model projections, the proportions of patients experiencing a relapse requiring hospitalization in 1 year were 66% for haloperidol depot, 41% for oral risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole, and 26% for long-acting risperidone, whereas the proportions of patients with an exacerbation not requiring hospitalization were 60% for haloperidol depot, 37% for oral risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole, and 24% for long-acting risperidone. The mean number of days of relapse requiring hospitalization per patient per year were 28 for haloperidol depot, 18 for oral risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole, and 11 for long-acting risperidone, whereas the mean number of days of exacerbation not requiring hospitalization were eight for haloperidol depot, five for oral risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole, and three for long-acting risperidone. This would translate into direct medical cost savings with long-acting risperidone compared with oral risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, and haloperidol depot of US dollars 161, 1425, 508, 259, 1068, and 8224, respectively. These findings were supported by sensitivity analyses. The utilization of long-acting risperidone is predicted to result in better clinical outcomes and lower total healthcare costs than its comparators, oral risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, and haloperidol depot. Long-acting risperidone may therefore be a cost saving therapeutic option for patients with schizophrenia.
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Druais, Sylvain; Doutriaux, Agathe; Cognet, Magali; Godet, Annabelle; Lançon, Christophe; Levy, Pierre; Samalin, Ludovic; Guillon, Pascal
2016-04-01
French clinical recommendations suggest prescribing long-acting injectable (LAI) antipsychotics to patients with a maintenance treatment indication in schizophrenia. Despite this, and due to their relatively high acquisition and administration costs, LAIs are still underused in clinical practice in France, thus highlighting the need for pharmacoeconomic evaluations. Our objective was to estimate the cost effectiveness of paliperidone LAI (or paliperidone palmitate), a once-monthly second-generation LAI antipsychotic, compared with the most common antipsychotic medications for the maintenance treatment of schizophrenia in France. A Markov model was developed to simulate the progression of a cohort of schizophrenic patients through four health states (stable treated, stable non-treated, relapse and death) and to consider up to three lines of treatment to account for changes in treatment management. Paliperidone LAI was compared with risperidone LAI, aripiprazole LAI, olanzapine LAI, haloperidol LAI (or haloperidol decanoate) and oral olanzapine. Costs, quality-adjusted life-years (QALYs) and number of relapses were assessed over 5 years based on 3-month cycles with a discount rate of 4% and from a French health insurance perspective. Patients were considered to be stabilised after a schizophrenic episode and would enter the model at an initiation phase, followed by a prevention of relapse phase if successful. Data (e.g. relapse or discontinuation rates) for the initiation phase came from randomised clinical trials, whereas relapse rates in the prevention phase were derived from hospitalisation risks based on real-life French data to capture adherence effects. Safety and utility data were derived from international publications. Additionally, costs were retrieved from French health insurance databases and publications. Finally, expert opinion was used for validation purposes or in case of gaps in data. The robustness of results was assessed through deterministic and probabilistic sensitivity analyses. All LAI antipsychotics were found to have similar costs over 5 years: approximatively €55,000, except for paliperidone LAI which had a discounted cost of €50,880. Oral olanzapine was less costly than LAIs (i.e. €50,379 after 5 years) but was associated with fewer QALYs gained and relapses avoided. Paliperidone LAI dominated aripiprazole LAI, olanzapine LAI and haloperidol LAI in terms of costs per QALY, and it was associated with slightly fewer QALYs when compared with risperidone LAI (i.e. 3.763 vs 3.764). This resulted in a high incremental cost-effectiveness ratio (ICER) (i.e. €4,770,018 per QALY gained) for risperidone LAI compared with paliperidone LAI. Paliperidone LAI was more costly than olanzapine oral but associated with more QALYs (i.e. ICER of €2411 per QALY gained for paliperidone LAI compared with oral olanzapine). Paliperidone LAI had a probability of being the optimal strategy in more than 50% of cases for a willingness-to-pay threshold of €8000 per QALY gained. This analysis, to the best of our knowledge, is the first of its kind to assess the cost effectiveness of antipsychotics based on French observational data. Paliperidone LAI appeared to be a cost-effective option in the treatment of schizophrenia from the French health insurance perspective.
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Hard, Marjie L; Wehr, Angela Y; Sadler, Brian M; Mills, Richard J; von Moltke, Lisa
2018-06-11
BACKGROUND AND OBJECTIVES: Aripiprazole lauroxil (AL), a long-acting injectable antipsychotic for the treatment of schizophrenia, requires 21 days of oral aripiprazole supplementation upon initiation (21-day initiation regimen). An alternative 1-day initiation regimen utilizing a nano-crystalline milled dispersion of AL (AL NCD ) plus a single 30 mg oral aripiprazole dose achieved aripiprazole concentrations associated with therapeutic doses of aripiprazole in the same time frame as the 21-day initiation regimen when starting AL (441 or 882 mg). A population pharmacokinetic (PopPK) model was developed to describe aripiprazole pharmacokinetics following administration of AL NCD , AL and oral aripiprazole, and evaluate dosing scenarios likely to be encountered in clinical practice. In total, 12,768 plasma aripiprazole concentrations from 343 patients (from 4 clinical studies) were included in the PopPK analysis and used to construct the model. Concomitant administration of the 1-day initiation regimen with all approved AL dosing regimens (441, 662, or 882 mg monthly, 882 mg every 6 weeks, or 1064 mg every 2 months) is predicted to achieve aripiprazole concentrations associated with therapeutic doses of AL using the 21-day initiation regimen within 4 days, maintaining these concentrations until the next AL dose. Administration of the first AL injection 10 days after the 1-day initiation regimen resulted in median aripiprazole concentrations just before the second dose of AL ≥ 77% of that when coadministered on the same day. Coadministration of AL with a single AL NCD injection was predicted to be effective in rapidly re-establishing concentrations associated with therapeutic doses of AL following dose delay. Model-based simulations demonstrate that the 1-day initiation regimen is suitable for starting treatment with all AL doses, allowing a window of ≤ 10 days between initiation and AL administration. AL NCD may also be used to re-establish concentrations associated with therapeutic doses of AL in conjunction with a delayed AL dose.
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Ishigooka, Jun; Noda, Takamasa; Nishiyama, Kosuke; Tamaru, Noriko; Shima, Tomoko; Yamasaki, Yumiko; Tadori, Yoshihiro
2016-06-01
Aripiprazole once-monthly (AOM) was previously approved for treatment of schizophrenia as monthly injections in the gluteal muscle. The deltoid muscle provides a more accessible injection site. The present study was conducted in Japanese schizophrenia patients as a 24-week, open-label trial that assessed the pharmacokinetics and safety of 5 sequential doses of AOM 400 mg (AOM 400) once every 4 weeks administered in the deltoid muscle. Patients treated with an oral atypical antipsychotic (other than aripiprazole) continued to receive their pre-study medication up to 14 days after the first AOM 400 injection. The completion rate was 76.5% (n = 13/17). Mean aripiprazole plasma C(min) almost reached steady-state by the fourth AOM 400 injection. After the fifth AOM 400 injection, mean aripiprazole AUC(28d), C(max) and C(min) were 165 μg x h/ml, 331 ng/ml and 201 ng/ml, respectively, which were similar to previously published pharmacokinetic parameters after the fifth gluteal injection of AOM 400. The most common treatment-emergent adverse event (TEAE) was injection site pain (35.3%). Most TEAEs were classified as mild in intensity. In conclusion, the deltoid injection of AOM can be considered an alternative route of administration, as deltoid and gluteal injections are interchangeable in terms of aripiprazole plasma concentrations, with no additional safety issues.
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Lafeuille, Marie-Hélène; Frois, Christian; Cloutier, Michel; Duh, Mei Sheng; Lefebvre, Patrick; Pesa, Jacqueline; Clancy, Zoe; Fastenau, John; Durkin, Mike
2016-01-01
Background Treatment continuity is a major challenge in the long-term management of patients with schizophrenia; poor patient adherence to antipsychotic drugs has been associated with negative clinical outcomes. Long-acting injectable therapies may improve adherence and lessen the risk for psychiatric-related relapse, often leading to rehospitalization and higher healthcare costs. Therefore, understanding the determinants of adherence to antipsychotics is critical in the management of patients with schizophrenia. Objective To assess the impact of baseline patient characteristics on adherence as measured by the Healthcare Effectiveness Data and Information Set (HEDIS) measure of continuity of antipsychotic medications among patients with Medicaid coverage. Methods Medicaid healthcare claims data between 2008 and 2011 from 5 states were used to identify patients who were diagnosed with schizophrenia (aged 25–64 years) and received ≥1 antipsychotic prescriptions in baseline year 2010 and in measurement year 2011. The HEDIS continuity of antipsychotic medications (ie, adherence) measure was defined as the proportion of days covered with any antipsychotic medication ≥80% during the measurement year. The 2 cohorts compared paliperidone palmitate with any other antipsychotics, including quetiapine, risperidone, and haloperidol. The baseline-year characteristics were evaluated as potential predictive factors of adherence in the measurement year using multivariate logistic regressions. The regression models incorporated the inverse probability of treatment weights to control for differences in baseline characteristics between the paliperidone palmitate and the other antipsychotics cohort. Results Among the 12,990 patients who received an antipsychotic during the study period, 48.6% successfully achieved the continuity criteria in the measurement year. After controlling for other covariates, the odds of adherence were improved by adherence at baseline (odds ratio [OR], 9.42; 95% confidence interval [CI], 8.55–10.39). The use of paliperidone palmitate was associated with a 26% increase in the odds of achieving adherence compared with the use of the other antipsychotics studied (OR, 1.26; 95% CI, 1.14–1.39). In addition, female sex (OR, 1.11; 95% CI, 1.01–1.22), age 55 to 64 years (OR, 1.26; 95% CI, 1.09–1.46) versus age 25 to 34 years, Hispanic race (OR, 1.37; 95% CI, 1.05–1.81) versus white race, and an increase of $10,000 in baseline inpatient costs (OR, 1.11; 95% CI, 1.08–1.15) were associated with greater odds of treatment continuity. Conclusions In addition to sex, age, and race, the baseline characteristics that were associated with achieving the HEDIS continuity of antipsychotic medication measure included previous-year adherence, inpatient costs, and the use of paliperidone palmitate. These findings offer insight to healthcare plans that cover Medicaid populations on the effects that patient characteristics and treatment types may have on adherence among patients with schizophrenia. PMID:27994714
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Early-life risperidone enhances locomotor responses to amphetamine during adulthood.
Lee Stubbeman, Bobbie; Brown, Clifford J; Yates, Justin R; Bardgett, Mark E
2017-10-05
Antipsychotic drug prescriptions for pediatric populations have increased over the past 20 years, particularly the use of atypical antipsychotic drugs such as risperidone. Most antipsychotic drugs target forebrain dopamine systems, and early-life antipsychotic drug exposure could conceivably reset forebrain neurotransmitter function in a permanent manner that persists into adulthood. This study determined whether chronic risperidone administration during development modified locomotor responses to the dopamine/norepinephrine agonist, D-amphetamine, in adult rats. Thirty-five male Long-Evans rats received an injection of one of four doses of risperidone (vehicle, .3, 1.0, 3.0mg/kg) each day from postnatal day 14 through 42. Locomotor activity was measured for 1h on postnatal days 46 and 47, and then for 24h once a week over the next two weeks. Beginning on postnatal day 75, rats received one of four doses of amphetamine (saline, .3, 1.0, 3.0mg/kg) once a week for four weeks. Locomotor activity was measured for 27h after amphetamine injection. Rats administered risperidone early in life demonstrated increased activity during the 1 and 24h test sessions conducted prior to postnatal day 75. Taking into account baseline group differences, these same rats exhibited significantly more locomotor activity in response to the moderate dose of amphetamine relative to controls. These results suggest that early-life treatment with atypical antipsychotic drugs, like risperidone, permanently alters forebrain catecholamine function and increases sensitivity to drugs that target such function. Copyright © 2017 Elsevier B.V. All rights reserved.
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Cameron, Chris; Zummo, Jacqueline; Desai, Dharmik N; Drake, Christine; Hutton, Brian; Kotb, Ahmed; Weiden, Peter J
Aripiprazole lauroxil (AL) is a long-acting injectable atypical antipsychotic recently approved for treatment of schizophrenia on the basis of a large-scale trial of two doses of AL versus placebo. There are no direct-comparison studies with paliperidone palmitate (PP; long-acting antipsychotic used most often in acute settings) for the acute psychotic episode. To indirectly compare efficacy and safety of the pivotal AL study with all PP studies meeting indirect comparison criteria. Systematic searches of MEDLINE, Embase, Cochrane CENTRAL, PsycINFO, ClinicalTrials.gov, International Clinical Trials Registry Platform, and gray literature were performed to identify randomized controlled trials of PP with similar designs to the AL trial. Bayesian network meta-analysis compared treatments with respect to symptom response and tolerability issues including weight gain, akathisia, parkinsonism, and likelihood of treatment-emergent adverse events. Three appropriate PP studies were identified for indirect comparison. Both doses of AL (441 mg and 882 mg monthly) were used and compared with two efficacious doses of PP (156 mg and 234 mg monthly). All four active-treatment conditions were associated with comparable reductions in acute symptoms (Positive and Negative Syndrome Scale) versus placebo and were of similar magnitude (range of mean difference -8.12 to -12.01, with overlapping 95% credible intervals). Between-group comparisons of active-treatment arms were associated with summary estimates of magnitude near 0. No clinically meaningful differences in selected safety or tolerability parameter incidence were found between active treatments. These results suggest that both AL and PP are effective for treatment of adults experiencing acute exacerbation of schizophrenia. Copyright © 2017 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.
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Joshi, Kruti; Mao, Lian; Biondi, David M; Millet, Robert
2018-01-29
Outpatient facilities, such as community behavioral health organizations (CBHOs), play a critical role in the care of patients with serious mental illness, but there is a paucity of "real-world" patient outcomes data from this health care setting. Therefore, we conducted The Research and Evaluation of Antipsychotic Treatment in Community Behavioral Health Organizations, Outcomes (REACH-OUT) trial, a real-world, prospective, noninterventional observational study of patients with mental illness treated at CBHOs across the United States. We describe demographic and clinical characteristics, antipsychotic therapy (APT) treatment patterns, and health care resource utilization in patients with schizophrenia undergoing medical care as usual. This study enrolled adults with schizophrenia or bipolar I disorder who initiated APT treatment at various time points: 1) within 8 weeks of initiating risperidone long-acting injectables (RLAIs) or other APTs except paliperidone palmitate (PP), 2) after more than 24 weeks of continuous RLAI treatment, or 3) at any time after initiating PP LAI treatment (schizophrenia only). Study assessments were performed via participant interview, medical chart abstraction, and clinical survey at enrollment and at month 12. A total of 1065 patients from 46 CBHOs were enrolled. Of these, 944 (88.6%) had a diagnosis of schizophrenia and 121 (11.4%) had bipolar I disorder. At enrollment, 599 (63.5%) of patients with schizophrenia were receiving RLAIs or PP LAI, 281 (29.8%) were receiving oral APTs, and 64 (6.8%) were receiving other injectable APTs. A number of differences in patient characteristics and outcomes were observed between patients in the LAI APT cohort and the oral APT cohort. Descriptive analyses from this observational study suggest differences in the patient characteristics, treatment patterns, and clinical and economic outcomes among those with schizophrenia treated at CBHOs with LAI APT or oral APTs. Additional analyses will be conducted to delineate the impact of LAI APT versus oral APTs on patient outcomes. Clinical Trial Registry: NCT01181960 . Registered 12 August 2010.
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Critical appraisal of 3-monthly paliperidone depot injections in the treatment of schizophrenia.
Carpiniello, Bernardo; Pinna, Federica
2016-01-01
Three-monthly injections of paliperidone palmitate (PP-3M) represent a new and recently introduced long-acting antipsychotic therapeutic option. This review focuses on available data relating to the efficacy and safety of PP-3M and its position in the current therapeutic scenario. An analysis of PubMed, Scopus, and ISI Web of Knowledge databases was conducted, and all available papers on PP-3M, including poster presentations, were selected and considered for the purpose of the present review. to date, three full papers have been published, the first, a Phase 1 randomized, open label study investigating the pharmacokinetics, safety, and tolerability of the drug; the second, a Phase 3 double blind study vs placebo focusing on efficacy and tolerability; and the last relating to the practical use of PP-3M. The five posters identified describe data reported in the above-cited papers. Overall, the pharmacokinetic findings obtained in these studies highlight the feasibility of administering PP-3M on a 3-monthly basis, subsequent to the administration of four 1-monthly injections of PP at doses 3.5 times higher than the stabilized dose of 1-monthly injections of PP (ie, 175, 300, 450, and 525 mgs). The published studies highlight a significantly longer time to relapse compared to placebo, and significantly better results compared to placebo for all secondary end-points (Positive and Negative Syndrome Scale, Clinical Global Impression-Severity Scale, Personal and Social Performance Scale scores), in addition to reasonably good safety and tolerability profiles. PP-3M emerges as a potential candidate for use as a first-line long-acting agent in the maintenance treatment of patients with schizophrenia. Further studies should however be conducted to confirm this expectation. In view of its efficacy, tolerability, and safety, together with the longer timespan between injections, PP-3M currently represents one of the best available options, and may contribute towards addressing the issue of poor adherence, even in early psychosis.
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Cabotegravir long acting injection protects macaques against intravenous challenge with SIVmac251.
Andrews, Chasity D; Bernard, Leslie St; Poon, Amanda Yee; Mohri, Hiroshi; Gettie, Natanya; Spreen, William R; Gettie, Agegnehu; Russell-Lodrigue, Kasi; Blanchard, James; Hong, Zhi; Ho, David D; Markowitz, Martin
2017-02-20
We evaluated the effectiveness of cabotegravir (CAB; GSK1265744 or GSK744) long acting as preexposure prophylaxis (PrEP) against intravenous simian immunodeficiency virus (SIV) challenge in a model that mimics blood transfusions based on the per-act probability of infection. CAB long acting is an integrase strand transfer inhibitor formulated as a 200 mg/ml injectable nanoparticle suspension that is an effective PrEP agent against rectal and vaginal simian/human immunodeficiency virus transmission in macaques. Three groups of rhesus macaques (n = 8 per group) were injected intramuscularly with CAB long acting and challenged intravenously with 17 animal infectious dose 50% SIVmac251 on week 2. Group 1 was injected with 50 mg/kg on week 0 and 4 to evaluate the protective efficacy of the CAB long-acting dose used in macaque studies mimicking sexual transmission. Group 2 was injected with 50 mg/kg on week 0 to evaluate the necessity of the second injection of CAB long acting for protection against intravenous challenge. Group 3 was injected with 25 mg/kg on week 0 and 50 mg/kg on week 4 to correlate CAB plasma concentrations at the time of challenge with protection. Five additional macaques remained untreated as controls. CAB long acting was highly protective with 21 of the 24 CAB long-acting-treated macaques remaining aviremic, resulting in 88% protection. The plasma CAB concentration at the time of virus challenge appeared to be more important for protection than sustaining therapeutic plasma concentrations with the second CAB long acting injection. These results support the clinical investigation of CAB long acting as PrEP in people who inject drugs.
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Development of near zero-order release PLGA-based microspheres of a novel antipsychotic.
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.
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Pilon, Dominic; Amos, Tony B; Germain, Guillaume; Lafeuille, Marie-Hélène; Lefebvre, Patrick; Benson, Carmela J
2017-04-01
The effective treatment of schizophrenia requires continuous antipsychotic maintenance therapy. However, poor persistence with treatment is common among patients with schizophrenia. The objective of this study was to compare persistence and hospitalization rates among patients with schizophrenia treated with long-acting injectable (LAI) antipsychotics (i.e. paliperidone palmitate and risperidone) and enrolled in a patient information program (program cohort) with patients treated with oral antipsychotics (OAs) who were not enrolled in a patient information program (nonprogram cohort). Using a quasi-experimental design, data from chart reviews (for program patients) and Medicaid claims (for nonprogram patients) was analyzed. Patients were eligible if they had ≥12 months of pre-index data, ≥6 months of post-index data, and no hospitalization at index. Persistence and hospitalization rates were assessed at 6 months post-index. Propensity score matching was used to control for observed differences in demographics and baseline clinical characteristics. Odds ratios (ORs) were calculated using generalized estimating equation models and adjusted for matched pairs and propensity score. A total of 102 program patients were matched to 408 nonprogram patients with similar baseline characteristics. Adjusted ORs indicated that the persistence rate at 6 months was significantly higher for the program cohort (88.2%) versus the nonprogram cohort (43.9%; OR: 9.70; P < .0001). The 6 month post-index hospitalization rate for the program cohort (14.7%) was significantly lower versus the nonprogram cohort after adjustments (22.5%; OR: 0.55; P = 0.0321). The data for the program and nonprogram patients were from two different and independent data sources (healthcare claims and chart reviews, respectively). Results were based on a relatively small number of program LAI patients. Program patients treated with LAI antipsychotics had higher persistence rates and significantly lower adjusted hospitalization rates compared with nonprogram patients treated with OAs.
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Deltoid Injections of Risperidone Long-acting Injectable in Patients with Schizophrenia
Quiroz, Jorge A.; Rusch, Sarah; Thyssen, An; Kushner, Stuart
2011-01-01
Background Risperidone long-acting injectable was previously approved for treatment of schizophrenia as biweekly injections in the gluteal muscle only. We present data on local injection-site tolerability and safety of risperidone long-acting injectable and comparability of systemic exposure of deltoid versus gluteal injections. Methods Risperidone long-acting injectable was administered in an open-label, single-dose, two-way crossover study, with patients randomized to receive either 25mg gluteal/37.5mg deltoid crossover in two treatment periods or 50mg gluteal/50mg deltoid injections crossover; each treatment period was separated by an 85-day observation period (Study 1) and an open-label, multiple-dose study (4 sequential 37.5mg or 50mg deltoid injections every 2 weeks) (Study 2). The pharmacokinetic results from both the studies have already been published. Results In Study 1 (n=170), the majority of patients had no local injection-site findings, based on investigator and patient-rated evaluations. In Study 2 (n=53), seven of the 51 patients who received at least two deltoid injections discontinued (primary endpoint). However, none of the discontinuations were due to injection-site related reasons. The 90-percent upper confidence limit of the true proportion of injection-site issue withdrawals was 5.7 percent. No moderate or severe injection-site reactions were reported. Conclusion Intramuscular injections via the deltoid and gluteal sites are equivalent routes of administration of risperidone long-acting injectable with respect to local injection-site tolerability. The overall safety and tolerability profile of risperidone long-acting injectable was comparable when administered as an intramuscular injection in the deltoid (37.5mg and 50mg) and gluteal (25mg and 50mg) sites. PMID:21779538
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Antipsychotics Activate mTORC1-Dependent Translation to Enhance Neuronal Morphological Complexity
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
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Long-acting injectable hormonal dosage forms for contraception.
Wu, Linfeng; Janagam, Dileep R; Mandrell, Timothy D; Johnson, James R; Lowe, Tao L
2015-07-01
Although great efforts have been made to develop long-acting injectable hormonal contraceptives for more than four decades, few long-acting injectable contraceptives have reached the pharmaceutical market or even entered clinical trials. On the other hand, in clinical practice there is an urgent need for injectable long-acting reversible contraceptives which can provide contraceptive protection for more than 3 months after one single injection. Availability of such products will offer great flexibility to women and resolve certain continuation issues currently occurring in clinics. Herein, we reviewed the strategies exploited in the past to develop injectable hormonal contraceptive dosages including drug microcrystal suspensions, drug-loaded microsphere suspensions and in situ forming depot systems for long-term contraception and discussed the potential solutions for remaining issues met in the previous development.
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A 12-week intramuscular toxicity study of risperidone-loaded microspheres in Beagle dogs.
Tian, J; Wang, W; Ye, L; Cen, X; Guan, X; Zhang, J; Yu, P; Du, G; Liu, W; Li, Y
2014-05-01
Long-acting formulations of antipsychotics are important treatment options to increase the compliance of schizophrenic patients. Risperidone, a 5-HT2 and dopaminergic D2 receptor antagonist, was developed as long-acting sustained-release microspheres with poly(lactide-co-glycolide) (PLGA) as a drug carrier for the treatment of schizophrenia. In the present study, the main objective is to determine the nonclinical safety profile of risperidone-loaded microspheres (RM) in Beagle dogs after intramuscular administration for 3 months, once in 2 weeks, followed by 8-week recovery phase. No animal death was found and no special toxicological findings were observed. The findings, such as hypoactivity, ptosis, increased heart rate, and elevated serum and pituitary prolactin levels, were observed and related to the pharmacological effects of risperidone. The changes in the reproductive system (uterus, ovary, vagina, cervix, and mammary gland) were considered secondary to the prolactin elevation, and the congestion of spleen was related to risperidone. The foreign body granulomas at injection sites might be caused by PLGA. At the end of recovery phase, the above changes mostly recovered to normal, and on administering 3 mg/kg dose level once in 2 weeks on Beagle dogs showed no observed adverse effect. Taken together, RM had exhibited the acceptable safety.
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Carswell, Christopher; Wheeler, Amanda; Vanderpyl, Jane; Robinson, Elizabeth
2010-01-01
Schizophrenia affects approximately 1% of the population and is associated with a considerable economic burden to society. The healthcare costs of the disorder are high and are compounded by substantial productivity losses. Failure to adhere to medication regimens, with subsequent relapse and hospitalization, is a key driver of these costs. A long-acting injectable formulation of the second generation antipsychotic risperidone (risperidone long-acting injection [risperidone LAI]) was licensed in New Zealand and received full government funding in October 2005. Second generation antipsychotics may have some efficacy advantages, be associated with fewer adverse effects and could improve adherence. However, the acquisition cost of risperidone LAI is higher than that of first generation antipsychotics and healthcare decision makers need information that allows them to determine whether risperidone LAI represents a cost-effective investment in terms of improved outcomes. To explore real-world outcomes and costs of patients treated with risperidone LAI within New Zealand. A mirror-image retrospective study was conducted comparing outcomes and costs 12 months post- versus 12 months pre-initiation of risperidone LAI in all adults receiving approval for risperidone LAI between 1 October 2005 and 31 October 2006 in five health services. Continuation rates, compulsory treatment status, psychiatric hospitalization (admission number, bed-stay and cost) and treatment data were collected from clinical files and patient information systems for the 12 months on either side of the first risperidone LAI prescription. Hospitalization costs were valued using estimates for cost per admission and cost per hospital day ($NZ, year 2009 values). 58.3% of patients remained on risperidone LAI 12 months after initiation. Compared with the pre-risperidone LAI treatment period the mean number of admissions for the total study population was significantly lower in the post-risperidone LAI treatment period (1.38 vs 0.61, p<0.001) but the mean length of bed-stay increased (37.2 vs 53.3 days, p<0.001), as did compulsory treatment use. Overall hospital bed-nights (hospitalization days) increased by 6877 in the post-index period, driven mostly by those who discontinued treatment. Patients who continued risperidone LAI had fewer admissions and days in hospital post-risperidone LAI than patients who discontinued risperidone LAI use in the first year. The reduction in total hospital admission rates between the two treatment periods was significantly greater in the continuation group and mean difference in bed-days between the two treatment periods was significantly less for continuers (5.4 vs 31.1 days, p<0.001). Applying a cost per admission, hospitalization costs reduced by approximately $NZ1.7 million in the post risperidone LAI-period. Applying a daily hospitalization cost resulted in an increase of approximately $NZ3.5 million in the post-risperidone LAI period. This study suggests that patients have reduced hospital admissions but longer bed-stay after starting risperidone LAI. Longer admissions were driven by those that discontinued treatment and continuation was associated with improved resource and cost outcomes compared with those who discontinued. These findings have potential implications for payers, providers and patients that require further investigation over a longer time frame.
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El Hage, Cynthia; Bédard, Anne-Marie; Samaha, Anne-Noël
2015-12-01
Chronic exposure to some antipsychotic medications can induce supersensitivity to dopamine receptor stimulation. This is linked to a worsening of clinical outcome and to antipsychotic treatment failure. Here we investigated the role of striatal subregions [nucleus accumbens (NAc) and caudate-putamen (CPu)] in the expression of antipsychotic-induced dopamine supersensitivity. We treated rats with haloperidol (HAL) or olanzapine (OLZ), using regimens that achieve clinically relevant kinetics of striatal D2 receptor occupancy. Under these conditions, HAL produces dopamine supersensitivity whereas OLZ does not. We then assessed behaviors evoked by the dopamine agonist amphetamine (AMPH). We either injected AMPH into the striatum or inhibited striatal function with microinjections of GABA receptor agonists prior to injecting AMPH systemically. HAL-treated rats were dopamine supersensitive, as indicated by sensitization to systemic AMPH-induced potentiation of both locomotor activity and operant responding for a conditioned reward (CR). Intra-CPu injections of AMPH had no effect on these behaviors, in any group. Intra-NAc injections of AMPH enhanced operant responding for CR in OLZ-treated and control rats, but not in HAL-treated rats. In HAL-treated rats, inhibition of the NAc also failed to disrupt systemic AMPH-induced potentiation of operant responding for CR. Furthermore, while intra-NAc AMPH enhanced locomotion in both HAL-treated and control animals, inhibition of the NAc disrupted systemic AMPH-induced locomotion only in control rats. Thus, antipsychotic-induced dopamine supersensitivity persistently disrupts NAc function, such that some behaviors that normally depend upon NAc dopamine no longer do so. This has implications for understanding dysfunctions in dopamine-mediated behaviors in patients undergoing chronic antipsychotic treatment. Copyright © 2015 Elsevier Ltd. All rights reserved.
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Bédard, Anne-Marie; Maheux, Jérôme; Lévesque, Daniel; Samaha, Anne-Noël
2011-05-01
Chronic exposure to antipsychotic medications can persistently change brain dopamine systems. Most studies on the functional significance of these neural changes have focused on motor behavior and few have addressed how long-term antipsychotic treatment might influence dopamine-mediated reward function. We asked, therefore, whether a clinically relevant antipsychotic treatment regimen would alter the incentive motivational properties of a reward cue. We assessed the ability of a Pavlovian-conditioned stimulus to function as a conditioned reward, as well as to elicit approach behavior in rats treated with haloperidol, either continuously (achieved via subcutaneous osmotic minipump) or intermittently (achieved via daily subcutaneous injections). Continuous, but not intermittent, treatment enhanced the ability of amphetamine to potentiate the conditioned reinforcing effects of a cue associated with water. This effect was not related to differences in the ability to attribute predictive value to a conditioned stimulus (as measured by conditioned approach behavior), but was potentially linked to the development of behavioral supersensitivity to amphetamine and to augmented amphetamine-induced immediate early-gene expression (c-fos and Nur77) in dorsal striatopallidal and striatonigral cells. By enhancing the ability of reward cues to control behavior and by intensifying dopamine-mediated striatopallidal and striatonigral cell activity, standard (ie, continuous) antipsychotic treatment regimens might exacerbate drug-seeking and drug-taking behavior in schizophrenia. Achieving regular but transiently high antipsychotic levels in the brain (as modeled in the intermittent condition) might be a viable option to prevent these changes. This possibility should be explored in the clinic.
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Antipsychotic Management of Schizoaffective Disorder: A Review.
Lindenmayer, Jean-Pierre; Kaur, Amandeep
2016-04-01
Schizoaffective disorder (SAD) is an incapacitating illness that presents clinicians with challenges in terms of both its diagnosis and its psychopharmacological management. Most studies conducted on the psychopharmacological treatment of SAD also include patients with schizophrenia or other psychotic illnesses, thereby providing an unspecific view to the clinician as to the best way of treating patients with SAD. The objective of this article is to review studies on evidence-based treatment of patients with SAD. We conducted a systematic literature search in MEDLINE/PubMed for full-text studies in the English language using the terms 'Schizoaffective and treatment' or 'antipsychotic schizoaffective'. Our review found relatively few studies with either an active comparator or placebo that examined the efficacy of antipsychotics for patients with SAD without an admixture of patients with schizophrenia. Only oral paliperidone extended release (ER), paliperidone long-acting injection (LAI), and risperidone have been shown to be effective and safe in reducing psychotic as well as affective components in acutely ill SAD patients in controlled studies. Paliperidone ER and LAI have also been shown to be efficacious in the maintenance treatment phase of SAD patients. While no supportive data exist, it is possible that other atypical antipsychotics may have similar efficacy to the two mentioned above. We conclude with a number of research recommendations for the study of treatment options for patients with SAD. First, there is a need for studies with patients specifically diagnosed with SAD for both the acute and the maintenance phase. The sample size needs to be adequate to allow a primary analysis of efficacy and to allow for analysis of the SAD subtypes: depressed and bipolar. Another recommendation is the need for studies of patients with SAD stratified into patients with and without mood stabilizers or antidepressants to allow the examination of the adjunctive role of these psychotropic medications. A third recommendation is to focus on specific co-morbid aspects of patients with SAD, such as suicidality and substance use disorders. Data from such studies will fill the gap of evidence-based treatment approaches and help clinicians in making important treatment decisions for patients with this complex condition.
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Diana, Mariana C; Peres, Fernanda F; Justi, Veronica; Bressan, Rodrigo A; Lacerda, Acioly L T; Crippa, José Alexandre; Hallak, Jaime E C; Abilio, Vanesssa Costhek
2018-04-14
The treatment of schizophrenia with antipsychotics is still unsatisfactory. Therefore, the search for new treatments and prevention is crucial, and animal models are fundamental tools for this objective. Preclinical and clinical data evidence the antipsychotic profile of sodium nitroprusside (SNP), a nitric oxide (NO) donor. We aimed to investigate SNP in treating and/or preventing the schizophrenia-related behaviors presented by the spontaneously hypertensive rats (SHR) strain. Wistar rats (WR) and SHRs were submitted to two schemes of treatment: (i) a single injection of SNP or vehicle in adulthood; (ii) a long-term early treatment from 30 to 60 postnatal day with SNP or vehicle. The following behaviors were evaluated 24 hours after the acute treatment or 30 days after the long-term treatment: locomotion, social interaction, and contextual fear conditioning. Spontaneously hypertensive rats presented hyperlocomotion, decreased social interaction, and impaired contextual fear conditioning. Single injection of SNP decreased social interaction in both strains and induced a deficit in contextual fear conditioning in WR. Oppositely, early treatment with SNP prevented the behavioral abnormalities in adult SHRs without promoting any effects in WR. Our preclinical data point to SNP as a preventive and safe strategy with a broad range of effectiveness to the positive, negative, and cognitive symptoms of schizophrenia. © 2018 John Wiley & Sons Ltd.
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Nicotine Reduces Antipsychotic-Induced Orofacial Dyskinesia in Rats
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
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Vermeulen, J; van Rooijen, G; Doedens, P; Numminen, E; van Tricht, M; de Haan, L
2017-10-01
Patients with schizophrenia have a higher mortality risk than patients suffering from any other psychiatric disorder. Previous research is inconclusive regarding the association of antipsychotic treatment with long-term mortality risk. To this aim, we systematically reviewed the literature and performed a meta-analysis on the relationship between long-term mortality and exposure to antipsychotic medication in patients with schizophrenia. The objectives were to (i) determine long-term mortality rates in patients with schizophrenia using any antipsychotic medication; (ii) compare these with mortality rates of patients using no antipsychotics; (iii) explore the relationship between cumulative exposure and mortality; and (iv) assess causes of death. We systematically searched the EMBASE, MEDLINE and PsycINFO databases for studies that reported on mortality and antipsychotic medication and that included adults with schizophrenia using a follow-up design of more than 1 year. A total of 20 studies fulfilled our inclusion criteria. These studies reported 23,353 deaths during 821,347 patient years in 133,929 unique patients. Mortality rates varied widely per study. Meta-analysis on a subgroup of four studies showed a consistent trend of an increased long-term mortality risk in schizophrenia patients who did not use antipsychotic medication during follow-up. We found a pooled risk ratio of 0.57 (LL:0.46 UL:0.76 p value <0.001) favouring any exposure to antipsychotics. Statiscal heterogeneity was found to be high (Q = 39.31, I 2 = 92.37%, p value < 0.001). Reasons for the increased risk of death for patients with schizophrenia without antipsychotic medication require further research. Prospective validation studies, uniform measures of antipsychotic exposure and classified causes of death are commendable.
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Nasrallah, Henry A; Newcomer, John W; Risinger, Robert; Du, Yangchun; Zummo, Jacqueline; Bose, Anjana; Stankovic, Srdjan; Silverman, Bernard L; Ehrich, Elliot W
2016-11-01
Aripiprazole lauroxil, a long-acting injectable antipsychotic, demonstrated safety and efficacy in treating symptoms of schizophrenia in a double-blind, placebo-controlled trial. Because the metabolic profile of antipsychotics is an important safety feature, the effects of aripiprazole lauroxil on body weight, endocrine and metabolic profiles, and safety were examined in a secondary analysis. Patients with schizophrenia (DSM-IV-TR criteria) were randomly assigned to aripiprazole lauroxil 441 mg, aripiprazole lauroxil 882 mg, or placebo intramuscularly once monthly between December 2011 and March 2014. Changes in body weight, body mass index, fasting blood glucose and serum lipids, glycosylated hemoglobin (HbA1c), and prolactin over 12 weeks were assessed. The incidence of treatment-emergent adverse events (AEs) was evaluated. Among 622 randomized patients, no clinically relevant changes from baseline to week 12 were observed for any serum lipid, lipoprotein, plasma glucose, or HbA1c value with placebo or either dose of aripiprazole lauroxil. Both doses of aripiprazole lauroxil were associated with reductions in mean prolactin levels, whereas placebo treatment was not. The mean (standard deviation) change from baseline for body weight was 0.74 (3.9) kg, 0.86 (3.7) kg, and 0.01 (3.6) kg for aripiprazole lauroxil 441 mg, aripiprazole lauroxil 882 mg, and placebo groups, respectively. AEs related to metabolic parameters were reported in 2.4%, 1.4%, and 2.4% of patients in the aripiprazole lauroxil 441 mg, aripiprazole lauroxil 882 mg, and placebo groups, respectively. Aripiprazole lauroxil was well tolerated, with a low-risk metabolic profile relative to published data for other antipsychotics. Changes similar to those observed with placebo were observed in the aripiprazole lauroxil groups for metabolic parameters, with modest weight gain in the active treatment groups over the 12-week course. ClinicalTrials.gov identifier: NCT01469039. © Copyright 2016 Physicians Postgraduate Press, Inc.
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Nonadherence with antipsychotic medication in schizophrenia: challenges and management strategies
Haddad, Peter M; Brain, Cecilia; Scott, Jan
2014-01-01
Nonadherence with medication occurs in all chronic medical disorders. It is a particular challenge in schizophrenia due to the illness’s association with social isolation, stigma, and comorbid substance misuse, plus the effect of symptom domains on adherence, including positive and negative symptoms, lack of insight, depression, and cognitive impairment. Nonadherence lies on a spectrum, is often covert, and is underestimated by clinicians, but affects more than one third of patients with schizophrenia per annum. It increases the risk of relapse, rehospitalization, and self-harm, increases inpatient costs, and lowers quality of life. It results from multiple patient, clinician, illness, medication, and service factors, but a useful distinction is between intentional and unintentional nonadherence. There is no gold standard approach to the measurement of adherence as all methods have pros and cons. Interventions to improve adherence include psychoeducation and other psychosocial interventions, antipsychotic long-acting injections, electronic reminders, service-based interventions, and financial incentives. These overlap, all have some evidence of effectiveness, and the intervention adopted should be tailored to the individual. Psychosocial interventions that utilize combined approaches seem more effective than unidimensional approaches. There is increasing interest in electronic reminders and monitoring systems to enhance adherence, eg, Short Message Service text messaging and real-time medication monitoring linked to smart pill containers or an electronic ingestible event marker. Financial incentives to enhance antipsychotic adherence raise ethical issues, and their place in practice remains unclear. Simple pragmatic strategies to improve medication adherence include shared decision-making, regular assessment of adherence, simplification of the medication regimen, ensuring that treatment is effective and that side effects are managed, and promoting a positive therapeutic alliance and good communication between the clinician and patient. These elements remain essential for all patients, not least for the small minority where vulnerability and risk issue dictate that compulsory treatment is necessary to ensure adherence. PMID:25061342
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Alphs, Larry; Bossie, Cynthia; Mao, Lian; Lee, Erin; Starr, H Lynn
2018-02-01
Long-acting injectable antipsychotics (APs) are not well studied in recent-onset schizophrenia. This exploratory analysis of a study designed to reflect real-world schizophrenia, as defined by patients, interventions and outcomes, compared relative treatment effect between once-monthly paliperidone palmitate (PP) and daily oral APs in patients with recent-onset or chronic illness METHODS: This randomized, open-label, event monitoring board-blinded study compared treatment response in subjects with schizophrenia and a history of criminal justice system involvement following treatment with PP or oral APs for 15 months (ClinicalTrials.gov identifier, NCT01157351). Event-free probabilities were estimated using Kaplan-Meier method; hazard ratios (HRs) were estimated using Cox proportional hazard models. This subgroup analysis analysed data by disease duration (≤5 (recent-onset) or >5 years (chronic illness) since first psychiatric diagnosis). Seventy-seven subjects met the criteria for recent-onset illness; 365 for chronic illness. HRs (95% CI) for treatment failure for oral APs versus PP were 1.73 (0.87-3.45; P = 0.121) for recent-onset and 1.37 (1.02-1.85; P = 0.039) for chronic illness. Most common adverse events for PP versus oral APs were injection site pain (recent-onset, 26% vs. 0%; chronic, 17% vs. 0%), increased weight (14% vs. 6%; 12% vs. 6%), akathisia (14% vs. 9%; 10% vs. 7%), insomnia (12% vs. 17%; 18% vs. 10%) and anxiety (12% vs. 6%; 10% vs. 8%). Although neither pre-planned nor adequately powered, the estimated HRs suggest that the relative advantage of PP over oral APs for reducing the risk for treatment failure may be greater in patients with recent-onset schizophrenia than in those with more chronic illness. © 2015 The Authors. Early Intervention in Psychiatry published by Wiley Publishing Asia Pty Ltd.
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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.
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Hard, Marjie L.; Mills, Richard J.; Sadler, Brian M.; Turncliff, Ryan Z.; Citrome, Leslie
2017-01-01
Abstract Background Aripiprazole lauroxil is an extended-release prodrug of aripiprazole for intramuscular injection, approved for schizophrenia treatment. We developed a population pharmacokinetic (PopPK) model to characterize aripiprazole lauroxil PK and evaluate dosing scenarios likely to be encountered in clinical practice. Methods Data from 616 patients with schizophrenia, collected from 5 clinical studies, were used to construct the PopPK model. The model was subsequently used to evaluate various dose levels and frequency and the impact of dosing delay on aripiprazole concentrations. Findings The results of the model indicate that aripiprazole is released into the systemic circulation after 5 to 6 days, and release continues for an additional 36 days. The slow increase in aripiprazole concentration after injection necessitates the coadministration of oral aripiprazole for 21 days with the first injection. Based on the PopPK model simulations, a dosing interval of 882 mg every 6 weeks results in aripiprazole concentrations that fall within the concentration range associated with the efficacious aripiprazole lauroxil dose range (441–882 mg dosed monthly). A 662-mg monthly dose also resulted in aripiprazole concentrations within the efficacious dose range. Aripiprazole lauroxil administration results in prolonged exposure, such that dose delays of 2 to 4 weeks, depending on the dose regimen, do not require oral aripiprazole supplementation upon resumption of dosing. Conclusions This PopPK model and model-based simulations were effective means for evaluating aripiprazole lauroxil dosing regimens and management of missed doses. Such analyses play an important role in determining the use of this long-acting antipsychotic in clinical practice. PMID:28350572
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Jessop, Tiffany; Harrison, Fleur; Cations, Monica; Draper, Brian; Chenoweth, Lynn; Hilmer, Sarah; Westbury, Juanita; Low, Lee-Fay; Heffernan, Megan; Sachdev, Perminder; Close, Jacqueline; Blennerhassett, Jenny; Marinkovich, Millicent; Shell, Allan; Brodaty, Henry
2017-08-01
Inappropriate use of antipsychotic medications to manage Behavioral and Psychological Symptoms of Dementia (BPSD) continues despite revised guidelines and evidence for the associated risks and side effects. The aim of the Halting Antipsychotic Use in Long-Term care (HALT) project is to identify residents of long-term care (LTC) facilities on antipsychotic medications, and undertake an intervention to deprescribe (or cease) these medicines and improve non-pharmacological behavior management. LTC facilities will be recruited across Sydney, Australia. Resident inclusion criteria will be aged over 60 years, on regular antipsychotic medication, and without a primary psychotic illness or very severe BPSD, as measured using the Neuropsychiatric Inventory (NPI). Data collection will take place one month and one week prior to commencement of deprescribing; and 3, 6 and 12 months later. During the period prior to deprescribing, training will be provided for care staff on how to reduce and manage BPSD using person-centered approaches, and general practitioners of participants will be provided academic detailing. The primary outcome measure will be reduction of regular antipsychotic medication without use of substitute psychotropic medications. Secondary outcome measures will be NPI total and domain scores, Cohen-Mansfield Agitation Inventory scores and adverse events, including falls and hospitalizations. While previous studies have described strategies to minimize inappropriate use of antipsychotic medications in people with dementia living in long-term care, sustainability and a culture of prescribing for BPSD in aged care remain challenges. The HALT project aims to evaluate the feasibility of a multi-disciplinary approach for deprescribing antipsychotics in this population.
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Brooks, Adam C; Comer, Sandra D; Sullivan, Maria A; Bisaga, Adam; Carpenter, Kenneth M; Raby, Wilfrid M; Yu, Elmer; O'Brien, Charles P; Nunes, Edward V
2010-10-01
To conduct a quasi-experimental comparison of early clinical outcomes between injectable, sustained-release, depot naltrexone formulation versus oral naltrexone maintenance therapy in individuals with opiate dependence. Early retention in treatment and urine-confirmed opiate use in the first 8 weeks postdetoxification were compared between patients (diagnosed as opiate-dependent according to DSM-IV criteria) participating in 2 concurrently run randomized clinical trials of oral (n = 69; patients treated from September 1999 to May 2002) and long-acting injectable (n = 42; patients treated from November 2000 to June 2003) naltrexone maintenance therapy with psychosocial therapy. Long-acting injectable naltrexone produced significantly better outcome than oral naltrexone on days retained in treatment (F(1,106) = 6.49, P = .012) and for 1 measure of opiate use (F(1,106) = 5.26, P = .024); other measures were not significantly different, but differences were in the same direction. In subanalyses, there were interaction effects between baseline heroin use severity and type of treatment. In subanalyses, heroin users with more severe baseline use showed better retention with oral naltrexone maintenance therapy combined with intensive psychotherapy (behavioral naltrexone therapy) as compared to retention shown by severe heroin users treated with long-acting naltrexone injections combined with standard cognitive-behavioral therapy (χ²(1)= 9.31, P = .002); less severe heroin users evidenced better outcomes when treated with long-acting injectable naltrexone. This quasi-experimental analysis provides tentative indications of superior outcomes for heroin-dependent patients treated with long-acting injectable naltrexone compared to oral naltrexone. The finding that heroin users with more severe baseline use achieved better outcomes with oral naltrexone is most probably attributable to the intensive nature of the psychosocial treatments provided and points to the opportunity for continued research in augmenting injectable naltrexone with psychosocial strategies to further improve outcome, especially in individuals with more severe use. The results should be considered exploratory given the quasi-experimental nature of the study. © Copyright 2010 Physicians Postgraduate Press, Inc.
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Hemodynamic Changes by Drug Interaction of Adrenaline With Chlorpromazine
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
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Hemodynamic changes by drug interaction of adrenaline with chlorpromazine.
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.
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Markowitz, Michael; Fu, Dong-Jing; Levitan, Bennett; Gopal, Srihari; Turkoz, Ibrahim; Alphs, Larry
2013-07-11
Increasing availability and use of long-acting injectable antipsychotics have generated a need to compare these formulations with their oral equivalents; however, a paucity of relevant data is available. This post hoc comparison of the long-term efficacy, safety and tolerability of maintenance treatment with paliperidone palmitate (PP) versus oral paliperidone extended release (ER) used data from two similarly designed, randomised, double-blind (DB), placebo-controlled schizophrenia relapse prevention trials. Assessments included measures of time to relapse, symptom changes/functioning and treatment-emergent adverse events (TEAEs). Time to relapse between treatment groups was evaluated using a Cox proportional hazards model. Between-group differences for continuous variables for change scores during the DB phase were assessed using analysis of co-variance models. Categorical variables were evaluated using Chi-square and Fisher's exact tests. No adjustment was made for multiplicity. Approximately 45% of enrolled subjects in both trials were stabilised and randomised to the DB relapse prevention phase. Risk of relapse was higher in subjects treated with paliperidone ER than in those treated with PP [paliperidone ER/PP hazard ratio (HR), 2.52; 95% confidence interval (CI), 1.46-4.35; p < 0.001]. Similarly, risk of relapse after withdrawal of paliperidone ER treatment (placebo group of the paliperidone ER study) was higher than after withdrawal of PP (paliperidone ER placebo/PP placebo HR, 2.25; 95% CI, 1.59-3.18; p < 0.001). Stabilised schizophrenic subjects treated with PP maintained functioning demonstrated by the same proportions of subjects with mild to no difficulties in functioning at DB baseline and end point [Personal and Social Performance (PSP) scale total score >70, both approximately 58.5%; p = 1.000] compared with a 10.9% decrease for paliperidone ER (58.5% vs 47.6%, respectively; p = 0.048). The least squares mean change for Positive and Negative Syndrome Scale (PANSS) total score at DB end point in these previously stabilised subjects was 3.5 points in favour of PP (6.0 vs 2.5; p = 0.025). The rates of TEAEs and AEs of interest appeared similar. This analysis supports maintenance of effect with the injectable compared with the oral formulation of paliperidone in patients with schizophrenia. The safety profile of PP was similar to that of paliperidone ER. Future studies are needed to confirm these findings.
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Reviewing depot injection efficacy in the treatment of schizophrenia.
Jones, Adrian; Jones, Martin
2016-04-13
Schizophrenia is a severe and enduring mental health disorder. Treatment includes antipsychotic medication and psychological interventions. Medication can be administered as a depot injection; these treatments reduce the risk of relapse in some people with schizophrenia who have difficulties adhering to oral medication regimens. This article outlines the types of depot and medications that are available for the treatment of schizophrenia, and discusses the evidence base supporting their efficacy. The role of antipsychotic medication as part of a treatment plan should be reinforced by enabling patients to make an informed choice about which medication best supports their health and wellbeing.
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Brexpiprazole: A Partial Dopamine Agonist for the Treatment of Schizophrenia.
Ekinci, Asli; Ekinci, Okan
2018-01-31
Schizophrenia is a chronic and debilitating mental disorder that affects the patient's and their family's life. The disease remains a complicated disorder that is challenging to treat, despite there being a large antipsychotic armamentarium. Brexpiprazole acts both as a partial agonist at the serotonin 5-HT1A and dopamine D2 receptors and as an antagonist at the serotonin 5- HT2A and noradrenaline alpha1B and alpha2C receptors, all with similar potency. This balanced receptor profile may produce promising antipsychotic effects on positive, negative and cognitive symptoms in schizophrenia with minimal adverse effects. This review summarizes the pharmacodynamics and pharmacokinetic profile of brexpiprazole and the clinical trial information pertaining to its effectiveness and safety and tolerability, discusses its best clinical use, and compares its clinical profile to those of other widely used antipsychotic agents. Brexpiprazole demonstrated significant clinical efficacy and had good safety and tolerability in well-designed trials with patients with schizophrenia. This agent may be a useful treatment alternative. However, it will be valuable to consider a long-term observational study that includes an active comparator, especially other second-generation antipsychotics (SGAs), to further evaluate the efficacy and safety of brexpiprazole in the treatment of schizophrenia. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
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Van Donkersgoed, J; VanderKop, M; Salisbury, C; Sears, L; Holowath, J
1999-01-01
Forty yearling cattle were injected intramuscularly with long-acting oxytetracycline and subcutaneously with tilmicosin by dart gun or by hand in a chute 28 days prior to slaughter. The drugs caused injection site lesions and antibiotic residues in the neck and thigh that varied by technique, dose, and site. PMID:12001341
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Brain site- and transmitter-dependent actions of methamphetamine, morphine and antipsychotics.
Mori, Tomohisa; Iwase, Yoshiyuki; Murata, Asami; Iwata, Noriyuki; Suzuki, Tsutomu
2016-06-01
While several methamphetamine- and morphine-induced psychotic states are ordinarily treated by antipsychotics, the therapeutic mechanisms of antipsychotic drugs have yet been elucidated. The present study was designed to investigate the mechanisms how antipsychotic drugs suppress the behavioral changes induced by psychoactive drugs in mice. Low to medium doses of methamphetamine produced hyperlocomotion, whereas high dose of methamphetamine induced hypolocomotion. Hyperlocomotion induced by methamphetamine was potently suppressed by clozapine and 5-HT2 receptor antagonists, but not by the intra-accumbens injection of haloperidol. On the other hand, microinjection of haloperidol into the ventrolateral striatum increased locomotor activity with high dose of methamphetamine. In contrast, morphine-induced hyperlocomotion was suppressed by systemic as well as intra-accumbens injection of haloperidol, whereas relatively resistant to clozapine, compared to its effects in the case of methamphetamine. It has been widely believed that methamphetamine-induced psychosis is an animal model of schizophrenia, which is mediated by activation of accumbal dopamine receptors. Our findings suggest that methamphetamine differentially regulate monoaminergic systems (e.g., dopaminergic vs. 5-HTnergic), and accumbal dopamine receptors are not involved in methamphetamine-induced hyperlocomotion in mice. Thus, our findings may lead to a better understanding of the therapeutic mechanisms that underlie the effects of antipsychotic drugs and behavioral effects of methamphetamine and morphine. Copyright © 2016 Elsevier B.V. All rights reserved.
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de Kuijper, Gerda; Mulder, Hans; Evenhuis, Heleen; Visser, Frank; Hoekstra, Pieter J
2013-08-01
Antipsychotics are frequently prescribed agents in individuals with intellectual disability, often for behavioral symptoms. Efficacy of antipsychotics for this is ambiguous, so discontinuation should be considered. Weight gain and metabolic dysregulation are well-known adverse effects of antipsychotics which increase the risk of the metabolic syndrome. We performed a discontinuation study in 99 adults with intellectual disability, living in residential facilities who used antipsychotics for behavioral symptoms for more than 1 year. The aim of the present study was to investigate the effects of discontinuation of long-term used antipsychotics on weight, body mass index (BMI), and parameters of the metabolic syndrome and to investigate the influence of genetic polymorphisms and medication factors on these outcomes. Discontinuation of antipsychotics led to a mean decrease of 4 cm waist circumference, of 3.5 kg weight, 1.4 kg/m2 BMI, and 7.1 mm Hg systolic blood pressure. In those participants who had not completely discontinued use of antipsychotics we found a decrease in weight and BMI and an increase in fasting glucose. The presence of the C-allele of serotonin 5-hydroxytryptamine receptor polymorphism rs141334 was associated with higher waist circumference and higher plasma levels of triglycerides and lower levels of high-density lipoprotein. Achievement of complete discontinuation predicted a larger decrease in waist circumference and BMI. In conclusion, results of the study show the beneficial effects of discontinuation of long-term used antipsychotics on metabolic outcomes.
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Aripiprazole Long-Acting Injectable for Maintenance Treatment of Bipolar I Disorder in Adults.
Aggarwal, Arpit; Schrimpf, Lindsey; Lauriello, John
2018-01-01
Bipolar I disorder is a serious and disabling psychiatric illness. It is associated with a significant reduction in quality of life and an increased risk for suicide. Pharmacotherapy is essential for both the acute and maintenance treatment of bi-polar I disorder. While multiple oral medications are recommended for the maintenance treatment, there are not many long-acting injectable medications approved for this indication. New treatments that would improve patient adherence have the potential for decreasing relapses and improving patients' ability to remain functional members of society. In this paper we discuss the available data for safety and efficacy of aripiprazole long-acting injectable in bipolar disorder.
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Root, Elisabeth Dowling; Thomas, Deborah S K; Campagna, Elizabeth J; Morrato, Elaine H
2014-08-27
Area-level variation in treatment and outcomes may be a potential source of confounding bias in observational comparative effectiveness studies. This paper demonstrates how to use exploratory spatial data analysis (ESDA) and spatial statistical methods to investigate and control for these potential biases. The case presented compares the effectiveness of two antipsychotic treatment strategies: oral second-generation antipsychotics (SGAs) vs. long-acting paliperiodone palmitate (PP). A new-start cohort study was conducted analyzing patient-level administrative claims data (8/1/2008-4/30/2011) from Missouri Medicaid. ESDA techniques were used to examine spatial patterns of antipsychotic prescriptions and outcomes (hospitalization and emergency department (ED) visits). Likelihood of mental health-related outcomes were compared between patients starting PP (N = 295) and oral SGAs (N = 8,626) using multilevel logistic regression models adjusting for patient composition (demographic and clinical factors) and geographic region. ESDA indicated significant spatial variation in antipsychotic prescription patterns and moderate variation in hospitalization and ED visits thereby indicating possible confounding by geography. In the multilevel models for this antipsychotic case example, patient composition represented a stronger source of confounding than geographic context. Because geographic variation in health care delivery is ubiquitous, it could be a comparative effectiveness research (CER) best practice to test for possible geographic confounding in observational data. Though the magnitude of the area-level geography effects were small in this case, they were still statistically significant and should therefore be examined as part of this observational CER study. More research is needed to better estimate the range of confounding due to geography across different types of observational comparative effectiveness studies and healthcare utilization outcomes.
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The prefrontal cortex: a target for antipsychotic drugs.
Artigas, F
2010-01-01
At therapeutic doses, classical antipsychotic drugs occupy a large proportion of subcortical dopamine D2 receptors, whereas atypical antipsychotics preferentially occupy cortical 5-HT(2) receptors. However, the exact cellular and network basis of their therapeutic action is not fully understood. To review the mechanism of action of antipsychotic drugs with a particular emphasis on their action in the prefrontal cortex (PFC). The PFC controls a large number of higher brain functions altered in schizophrenia. Histological studies indicate the presence of a large proportion of PFC neurons expressing monoaminergic receptors sensitive to the action of atypical- and to a lesser extentclassical antipsychotic drugs. Functional studies also indicate that both drug families act at PFC level. Atypical antipsychotic drugs likely exert their therapeutic activity by a preferential action on PFC neurons, thus modulating the PFC output to basal ganglia circuits. Classical antipsychotics also interact with these PFC targets in addition to blocking massively striatal D2 receptors.
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Impact of Atypical Antipsychotic Therapy on Leptin, Ghrelin, and Adiponectin
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
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Turner, Erick H.; Knoepflmacher, Daniel; Shapley, Lee
2012-01-01
Background Publication bias compromises the validity of evidence-based medicine, yet a growing body of research shows that this problem is widespread. Efficacy data from drug regulatory agencies, e.g., the US Food and Drug Administration (FDA), can serve as a benchmark or control against which data in journal articles can be checked. Thus one may determine whether publication bias is present and quantify the extent to which it inflates apparent drug efficacy. Methods and Findings FDA Drug Approval Packages for eight second-generation antipsychotics—aripiprazole, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, risperidone long-acting injection (risperidone LAI), and ziprasidone—were used to identify a cohort of 24 FDA-registered premarketing trials. The results of these trials according to the FDA were compared with the results conveyed in corresponding journal articles. The relationship between study outcome and publication status was examined, and effect sizes derived from the two data sources were compared. Among the 24 FDA-registered trials, four (17%) were unpublished. Of these, three failed to show that the study drug had a statistical advantage over placebo, and one showed the study drug was statistically inferior to the active comparator. Among the 20 published trials, the five that were not positive, according to the FDA, showed some evidence of outcome reporting bias. However, the association between trial outcome and publication status did not reach statistical significance. Further, the apparent increase in the effect size point estimate due to publication bias was modest (8%) and not statistically significant. On the other hand, the effect size for unpublished trials (0.23, 95% confidence interval 0.07 to 0.39) was less than half that for the published trials (0.47, 95% confidence interval 0.40 to 0.54), a difference that was significant. Conclusions The magnitude of publication bias found for antipsychotics was less than that found previously for antidepressants, possibly because antipsychotics demonstrate superiority to placebo more consistently. Without increased access to regulatory agency data, publication bias will continue to blur distinctions between effective and ineffective drugs. Please see later in the article for the Editors' Summary PMID:22448149
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Pavlickova, Hana; Bremner, Stephen A; Priebe, Stefan
2015-08-01
A recent cluster-randomized controlled trial found that offering financial incentives improves adherence to long-acting injectable antipsychotics (LAIs). The present study investigates whether the impact of incentives diminishes over time and whether the improvement in adherence is linked to the amount of incentives offered. Seventy-three teams with 141 patients with psychotic disorders (using ICD-10) were randomized to the intervention or control group. Over 1 year, patients in the intervention group received £15 (US $23) for each LAI, while control patients received treatment as usual. Adherence levels, ie, the percentage of prescribed LAIs that were received, were calculated for quarterly intervals. The amount of incentives offered was calculated from the treatment cycle at baseline. Multilevel models were used to examine the time course of the effect of incentives and the effect of the amount of incentives offered on adherence. Adherence increased in both the intervention and the control group over time by an average of 4.2% per quarterly interval (95% CI, 2.8%-5.6%; P < .001). Despite this general increase, adherence in the intervention group remained improved compared to the control group by between 11% and 14% per quarterly interval. There was no interaction effect between time and treatment group. Further, a higher total amount of incentives was associated with poorer adherence (βbootstrapped = -0.11; 95% CIbootstrapped, -0.20 to -0.01; P = .023). A substantial effect of financial incentives on adherence to LAIs occurs within the first 3 months of the intervention and is sustained over 1 year. A higher total amount of incentives does not increase the effect. ISRCTN.com identifier: ISRCTN77769281 and UKCRN.org identifier: 7033. © Copyright 2015 Physicians Postgraduate Press, Inc.
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Williams, Wesley; McKinney, Christopher; Martinez, Larry; Benson, Carmela
2016-01-01
This study evaluated the effect of paliperidone palmitate long-acting injectable (LAI) antipsychotic on recovery-oriented mental health outcomes from the perspective of healthcare providers and patients during the treatment of patients with schizophrenia or schizoaffective disorders. Archival data for patients with a primary diagnosis of schizophrenia or schizoaffective disorder receiving ≥6 months of paliperidone palmitate LAI were retrieved from the electronic medical records system at the Mental Health Center of Denver. Mental health recovery was assessed from both a provider's (Recovery Markers Inventory [RMI]) and patient's (Consumer Recovery Measure [CRM]) perspective. A three-level hierarchical linear model (HLM) was utilized to determine changes in CRM and RMI scores by including independent variables in the models: intercept, months from treatment (slope), treatment time period (pretreatment and treatment), age, gender, primary diagnosis, substance abuse diagnosis, concurrent medications, and adherence to paliperidone palmitate LAI. A total of 219 patients were identified and included in the study. Results of the final three-level HLMs indicated an overall increase in CRM scores (p < 0.05), an overall increase (p < 0.01), and an increased rate of change (p < 0.05) in RMI scores during the paliperidone palmitate LAI treatment period vs the pre-treatment period. This study contained a retrospective, non-comparative design, and did not adjust for multiplicity Conclusions: The current study demonstrates that changes in recovery-oriented mental health outcomes can be detected following the administration of a specific antipsychotic treatment in persons with schizophrenia or schizoaffective disorders. Furthermore, patients receiving paliperidone palmitate LAI can effectively improve recovery-oriented outcomes, thereby supporting the drug's use as schizophrenia treatment from a recovery-oriented perspective.
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... and vomiting that may occur after surgery. Granisetron extended-release (long-acting) injection is used with other ... be injected intravenously (into a vein) and granisetron extended-release injection comes as a liquid to be ...
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Fall-Risk-Increasing Drugs: A Systematic Review and Meta-Analysis: II. Psychotropics.
Seppala, Lotta J; Wermelink, Anne M A T; de Vries, Max; Ploegmakers, Kimberley J; van de Glind, Esther M M; Daams, Joost G; van der Velde, Nathalie
2018-04-01
Falls are a major public health problem in older adults. Earlier studies showed that psychotropic medication use increases the risk of falls. The aim of this study is to update the current knowledge by providing a comprehensive systematic review and meta-analysis on psychotropic medication use and falls in older adults. This study is a systematic review and meta-analysis. A search was conducted in Medline, PsycINFO, and Embase. Key search concepts were "falls," "aged," "medication," and "causality." Studies were included that investigated psychotropics (antipsychotics, antidepressants, anxiolytics, sedatives, and hypnotics) as risk factors for falls in participants ≥60 years of age or participants with a mean age of ≥70 years. Meta-analyses were performed using generic inverse variance method pooling unadjusted and adjusted odds ratio (OR) estimates separately. In total, 248 studies met the inclusion criteria for qualitative synthesis. Meta-analyses using adjusted data showed the following pooled ORs: antipsychotics 1.54 [95% confidence interval (CI) 1.28-1.85], antidepressants 1.57 (95% Cl 1.43-1.74), tricyclic antidepressants 1.41 (95% CI 1.07-1.86), selective serotonin reuptake inhibitors 2.02 (95% CI 1.85-2.20), benzodiazepines 1.42 (95%, CI 1.22-1.65), long-acting benzodiazepines 1.81 (95%, CI 1.05-3.16), and short-acting benzodiazepines 1.27 (95%, CI 1.04-1.56) Most of the meta-analyses resulted in substantial heterogeneity that did not disappear after stratification for population and healthcare setting. Antipsychotics, antidepressants, and benzodiazepines are consistently associated with a higher risk of falls. It is unclear whether specific subgroups such as short-acting benzodiazepines and selective serotonin reuptake inhibitors are safer in terms of fall risk. Prescription bias could not be accounted for. Future studies need to address pharmacologic subgroups as fall risk may differ depending on specific medication properties. Precise and uniform classification of target medication (Anatomical Therapeutic Chemical Classification) is essential for valid comparisons between studies. Copyright © 2018 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.
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Saquinavir Loaded Acetalated Dextran Microconfetti – a Long Acting Protease Inhibitor Injectable
Collier, Michael A.; Gallovic, Matthew D.; Bachelder, Eric M.; Sykes, Craig D.; Kashuba, Angela; Ainslie, Kristy M.
2018-01-01
Purpose Since the adoption of highly active antiretroviral therapy, HIV disease progression has slowed across the world; however, patients are often required to take multiple medications daily of poorly bioavailable drugs via the oral route, leading to gastrointestinal irritation. Recently, long acting antiretroviral injectables that deliver drug for months at a time have moved into late phase clinical trials. Unfortunately, these solid phase crystal formulations have inherent drawbacks in potential dose dumping and a greater likelihood for burst release of drug compared to polymeric formulations. Methods Using electrospinning, acetalated dextran scaffolds containing the protease inhibitor saquinavir were created. Grinding techniques were then used to process these scaffolds into injectables which are termed saquinavir microconfetti. Microconfetti was analyzed for in vitro and in vivo release kinetics. Results Highly saquinavir loaded acetalated dextran electrospun fibers were able to be formed and processed into saquinavir microconfetti while other polymers such as poly lactic-co-glycolic acid and polycaprolactone were unable to do so. Saquinavir microconfetti release kinetics were able to be tuned via drug loading and polymer degradation rates. In vivo, a single subcutaneous injection of saquinavir microconfetti released drug for greater than a week with large tissue retention. Conclusions Microconfetti is a uniquely tunable long acting injectable that would reduce the formation of adherence related HIV resistance. Our findings suggest that the injectable microconfetti delivery system could be used for long acting controlled release of saquinavir and other hydrophobic small molecule drugs. PMID:27154460
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Gberindyer, Aondover F; Okpeh, Ene R; Semaka, Asaaga A
2015-12-01
Both short- and long-acting formulations of oxytetracycline are commonly used in veterinary medicine to treat animals infected with gram-negative and gram-positive bacteria, rickettsiae, mycoplasma, and chlamydiae. To compare pharmacokinetics of short- and long-acting oxytetracycline in chickens, injectable formulations from the same pharmaceutical company were administered to healthy 6-week-old broiler chickens in accordance to the labeled instructions. Fourteen chickens were separated into 2 groups: chickens in group A (n = 7) were administered the short-acting formulation (10 mg/kg IM q24h) for 4 consecutive days, whereas those in group B (n = 7) were treated with a single dose (20 mg/kg IM) of the long-acting formulation. Blood samples were collected into heparinized tubes before and at 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 10, and 24 hours after initial treatment. Thereafter, blood samples were taken every 24 hours up to 120 hours. Plasma concentrations of oxytetracycline were determined by competitive enzyme-linked immunoabsorbent assay, and pharmacokinetic parameters were obtained. Both formulations delivered therapeutic plasma concentrations of oxytetracycline for approximately 100% of their respective dosing intervals as recommended. However, considering the additional labor, patient stress, and mortalities associated with handling, in addition to rejection of the carcass due to tissue necrosis resulting from multiple injections, we recommend use of the long-acting instead of the short-acting injectable formulation in broiler chickens.
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Effects of the Antipsychotic Drug, Haloperidol, on Reproduction in the Fathead Minnow
Haloperidol is a butyrophenone antipsychotic drug used for the treatment of human hyperactive and manic disorders, agitation, and schizophrenia. The drug is thought to act through antagonism of dopaminergic receptors. We have studied a variety of endocrine-disrupting chemicals wi...
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Anticholinergics in the era of atypical antipsychotics: short-term or long-term treatment?
Desmarais, Julie Eve; Beauclair, Linda; Margolese, Howard C
2012-09-01
Anticholinergic agents are usually prescribed to prevent or treat antipsychotic-induced extrapyramidal symptoms. Their long-term benefits are questionable and they carry diverse adverse effects, including cognitive impairment and worsening of tardive dyskinesia. This literature review explores the impact of anticholinergic medication discontinuation on movement disorders, cognition and psychopathology in patients receiving antipsychotics. Medline, Embase and PsycInfo were searched from 1950 to July 2011 using "cessation /withdrawal /discontinuation /stopping" with "anticholinergic*" or "antiparkinson*" and "neuroleptic*" or "antipsychotic*". Additional articles were obtained by searching the bibliographies of relevant references. Earlier studies of anticholinergic agent discontinuation in patients receiving first-generation antipsychotics reported relapse rates of extrapyramidal symptoms between 4% and 80%, reflecting the heterogeneity of the studies. Two recent studies of patients prescribed second-generation antipsychotics obtained relapse rates of 4% and 33%. Some studies suggest improvement in tardive dyskinesia with cessation of anticholinergics. Four studies examined the effects of anticholinergic agent discontinuation on cognition and all observed an improvement post-discontinuation. Changes in symptoms of schizophrenia with anticholinergic discontinuation are conflicting, with more recent studies suggesting an improvement. Given their questionable benefit with continued use, clinicians should consider a gradual withdrawal of anticholinergic agents in stable patients receiving antipsychotics.
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Lafeuille, Marie-Hélène; Grittner, Amanda Melina; Fortier, Jonathan; Muser, Erik; Fasteneau, John; Duh, Mei Sheng; Lefebvre, Patrick
2015-03-01
Comparative data on rehospitalization patterns and associated institutional costs after inpatient treatment with paliperidone palmitate or oral antipsychotic therapy are reported. A retrospective cohort study was conducted using discharge and billing records from a large hospital database. Selected clinical and cost outcomes were compared in a cohort of adult patients who received the long-acting antipsychotic paliperidone palmitate during a schizophrenia-related index hospital stay and a cohort of patients who received oral antipsychotic therapy during their index admission. Inverse probability-of-treatment weights based on propensity scores were used to reduce confounding. Rates of all-cause and schizophrenia-related rehospitalization and emergency room (ER) use in the two cohorts over periods of up to 12 months were analyzed using a multivariate Cox proportional hazard model. Institutional costs for the evaluated postdischarge events were compared via multivariate linear regression analysis. In the first 12 months after index hospital discharge, the risk of all-cause rehospitalization and ER use was significantly lower in the paliperidone palmitate cohort than in the oral antipsychotic cohort (hazard ratio, 0.61; 95% confidence interval [CI], 0.59-0.63; p < 0.0001); institutional costs during the first 6 months after discharge were significantly lower in the paliperidone palmitate cohort than in the comparator group (adjusted mean monthly cost difference -$404; 95% CI, -$781 to -$148; p < 0.0001). The use of paliperidone palmitate therapy during patients' index hospital admission for schizophrenia was associated with a reduced risk of hospital readmission or ER use and lower postdischarge institutional costs. Copyright © 2015 by the American Society of Health-System Pharmacists, Inc. All rights reserved.
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Hulkko, A P; Murray, G K; Moilanen, J; Haapea, M; Rannikko, I; Jones, P B; Barnett, J H; Huhtaniska, S; Isohanni, M K; Koponen, H; Jääskeläinen, E; Miettunen, J
2017-09-01
Higher lifetime antipsychotic exposure has been associated with poorer cognition in schizophrenia. The cognitive effects of adjunctive psychiatric medications and lifetime trends of antipsychotic use remain largely unclear. We aimed to study how lifetime and current benzodiazepine and antidepressant medications, lifetime trends of antipsychotic use and antipsychotic polypharmacy are associated with cognitive performance in midlife schizophrenia. Sixty participants with DSM-IV schizophrenia from the Northern Finland Birth Cohort 1966 were examined at 43years of age with an extensive cognitive test battery. Cumulative lifetime and current use of psychiatric medications were collected from medical records and interviews. The associations between medication and principal component analysis-based cognitive composite score were analysed using linear regression. Lifetime cumulative DDD years of benzodiazepine and antidepressant medications were not significantly associated with global cognition. Being without antipsychotic medication (for minimum 11months) before the cognitive examination was associated with better cognitive performance (P=0.007) and higher lifetime cumulative DDD years of antipsychotics with poorer cognition (P=0.020), when adjusted for gender, onset age and lifetime hospital treatment days. Other lifetime trends of antipsychotic use, such as a long antipsychotic-free period earlier in the treatment history, and antipsychotic polypharmacy, were not significantly associated with cognition. Based on these naturalistic data, low exposure to adjunctive benzodiazepine and antidepressant medications does not seem to affect cognition nor explain the possible negative effects of high dose long-term antipsychotic medication on cognition in schizophrenia. Copyright © 2017 Elsevier Masson SAS. All rights reserved.
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Citraro, Rita; Leo, Antonio; De Fazio, Pasquale; De Sarro, Giovambattista; Russo, Emilio
2015-01-01
Background and Purpose Two of the most relevant unmet needs in epilepsy are represented by the development of disease-modifying drugs able to affect epileptogenesis and/or the study of related neuropsychiatric comorbidities. No systematic study has investigated the effects of chronic treatment with antipsychotics or antidepressants on epileptogenesis. However, such drugs are known to influence seizure threshold. Experimental Approach We evaluated the effects of an early long-term treatment (ELTT; 17 weeks), started before seizure onset (P45), with fluoxetine (selective 5-HT-reuptake inhibitor), duloxetine (dual-acting 5-HT-noradrenaline reuptake inhibitor), haloperidol (typical antipsychotic drug), risperidone and quetiapine (atypical antipsychotic drugs) on the development of absence seizures and comorbid depressive-like behaviour in the WAG/Rij rat model. Furthermore, we studied the effects of these drugs on established absence seizures in adult (6-month-old) rats after a chronic 7 weeks treatment. Key Results ELTT with all antipsychotics did not affect the development of seizures, whereas, both ELTT haloperidol (1 mg·kg−1 day−1) and risperidone (0.5 mg·kg−1 day−1) increased immobility time in the forced swimming test and increased absence seizures only in adult rats (7 weeks treatment). In contrast, both fluoxetine (30 mg·kg−1 day−1) and duloxetine (10–30 mg·kg−1 day−1) exhibited clear antiepileptogenic effects. Duloxetine decreased and fluoxetine increased absence seizures in adult rats. Duloxetine did not affect immobility time; fluoxetine 30 mg·kg−1 day−1 reduced immobility time while at 10 mg·kg−1 day−1 an increase was observed. Conclusions and Implications In this animal model, antipsychotics had no antiepileptogenic effects and might worsen depressive-like comorbidity, while antidepressants have potential antiepileptogenic effects even though they have limited effects on comorbid depressive-like behaviour. PMID:25754610
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Do antipsychotic drugs affect brain structure? A systematic and critical review of MRI findings.
Navari, S; Dazzan, P
2009-11-01
The potential effects of antipsychotic drugs on brain structure represent a key factor in understanding neuroanatomical changes in psychosis. This review addresses two issues: (1) do antipsychotic medications induce changes in total or regional human brain volumes and (2) do such effects depend on antipsychotic type? A systematic review of studies reporting structural brain magnetic resonance imaging (MRI) measures: (1) directly in association with antipsychotic use; and (2) in patients receiving lifetime treatment with antipsychotics in comparison with drug-naive patients or healthy controls. We searched Medline and EMBASE databases using the medical subject heading terms: 'antipsychotics' AND 'brain' AND (MRI NOT functional). The search included studies published up to 31 January 2007. Wherever possible, we reported the effect size of the difference observed. Thirty-three studies met our inclusion criteria. The results suggest that antipsychotics act regionally rather than globally on the brain. These volumetric changes are of a greater magnitude in association with typical than with atypical antipsychotic use. Indeed, there is evidence of a specific effect of antipsychotic type on the basal ganglia, with typicals specifically increasing the volume of these structures. Differential effects of antipsychotic type may also be present on the thalamus and the cortex, but data on these and other brain areas are more equivocal. Antipsychotic treatment potentially contributes to the brain structural changes observed in psychosis. Future research should take into account these potential effects, and use adequate sample sizes, to allow improved interpretation of neuroimaging findings in these disorders.
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Bortolato, Marco; Faravelli, Laura; Anand, Ravi
2018-01-01
Abstract Background The lack of adequate benefit with current 5HT2 / D2 antipsychotics in large proportions of schizophrenic patients suggests it is essential to modulate other mechanisms for improving symptoms of schizophrenia (SCZ). Increasing evidence implicates NMDAr hypofunction, and hippocampal hyperactivity, in the dysregulation not only of mesolimbic DA neurons but also of Glu neurons, leading to increasing synaptic activity of Glu in the PFC. Injection of NMDAr antagonists (PCP, ketamine) at doses that produce psychotomimetic effects lead to a downstream increase of Glu neurotransmission at non-NMDAr. The excessive firing and the hyper-glutamatergic tone represent alternative targets of treatment for SCZ ultimately affecting positive, negative, cognitive symptoms. The addition of Glu release inhibitors may augment the benefits of the antipsychotics in patients showing inadequate response. Evenamide uniquely does not interact with monoaminergic (DA, 5-HT, NA, H) pathways affected by current antipsychotics, or with more than 130 different targets that are involved in CNS activity, except sodium channels. Preclinical data suggests that by the modulation of the firing abnormalities, evenamide normalizes the aberrant spread of Glu excitatory transmission that occurs in the brains of patients with SCZ. Evenamide showed efficacy in animal models relevant to SCZ (sensory motor gating, mania, psychosis, depression, impulse control, cognition, social interaction), in monotherapy and as an add on to first or second generation antipsychotics irrespective of whether impairment was either spontaneous, induced by amphetamine or NMDAr antagonists or stress. Evenamide, has also shown significant benefit in a p.c phase 2 trial as an add-on to risperidone and aripiprazole in patients worsening on dopaminergic/serotoninergic antagonist medication, suggesting it acts through other mechanisms. New animal data further confirm evenamide’s activity in reducing SCZ symptoms provoked by Glu alteration. Methods Effects of evenamide (EVE 1.25, 5, 15 mg/kg PO) to restore the impaired information processing (a deficit observed in SCZ), were evaluated in the rat model of the Pre-Pulse Inhibition (PPI) deficit induced by injection of the NMDAr antagonist ketamine (KET 6 mg/kg, SC). Clozapine (CLO 7.5 mg/kg, IP) was used as a positive control. Results PPI analysis showed significant main effects for KET to lower PPI levels [F(1,264)=139.67, P<0.0001], for EVE [F(3,264)=3.14, P<0.05] and CLO to enhance PPI levels [F(1,98)=30.89, P<0.001]. Notably, significant EVE x KET [F(3,264)=2.79, P<0.05] and CLO x KET interactions [F(1,98)=5.45, P<0.05] were found. Post-hoc analyses (Tukey’s) revealed that KET significantly lowered PPI (P<0.0001) for each group; both EVE (5 mg/kg) and CLO significantly increased PPI in KET-treated rats (P=0.02; p<0.001). Discussion Evenamide as monotherapy has similar effect to clozapine in reversing ketamine- induced worsening of PPI. Together with previously demonstrated effects to reverse PCP-induced PPI and social interaction deficits, this further supports its potential to affect both positive and negative symptoms of SCZ by targeting altered Glu transmission. Efficacy of evenamide as an add-on to antipsychotics would revolutionize development of novel antipsychotics that would target aberrant firing and Glu transmission in SCZ. Two clinical trials have been planned to support the hypothesis that the addition of evenamide should add a non-dopaminergic mechanism for augmenting antipsychotic efficacy in patients who are not responding adequately to current antipsychotic, and in patients with treatment resistant SCZ who are not responding/worsening on clozapine.
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Einarson, Thomas R; Pudas, Hanna; Zilbershtein, Roman; Jensen, Rasmus; Vicente, Colin; Piwko, Charles; Hemels, Michiel E H
2013-09-01
In Finland, regional rates of schizophrenia exceed those in most countries, impacting the healthcare burden. This study determined the cost-effectiveness of long-acting antipsychotic (LAI) drugs paliperidone palmitate (PP-LAI), olanzapine pamoate (OLZ-LAI), and risperidone (RIS-LAI) for chronic schizophrenia. This study adapted a decision tree analysis from Norway for the Finnish National Health Service. Country-specific data were sought from the literature and public documents, guided by clinical experts. Costs of health services and products were retrieved from literature sources and current price lists. This simulation study estimated average 1-year costs for treating patients with each LAI, average remission days, rates of hospitalization and emergency room visits and quality-adjusted life-years (QALY). PP-LAI was dominant. Its estimated annual average cost was €10,380/patient and was associated with 0.817 QALY; OLZ-LAI cost €12,145 with 0.810 QALY; RIS-LAI cost €12,074 with 0.809 QALY. PP-LAI had the lowest rates of hospitalization, emergency room visits, and relapse days. This analysis was robust against most variations in input values except adherence rates. PP-LAI was dominant over OLZ-LAI and RIS-LAI in 77.8% and 85.9% of simulations, respectively. Limitations include the 1-year time horizon (as opposed to lifetime costs), omission of the costs of adverse events, and the assumption of universal accessibility. In Finland, PP-LAI dominated the other LAIs as it was associated with a lower cost and better clinical outcomes.
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Rhee, Taeho Greg; Mohamed, Somaia; Rosenheck, Robert A
A recent moderately long-term study found an antipsychotic to be more effective than an antidepressant as the next-step treatment of unresponsive major depressive disorder (MDD). It is thus timely to examine recent trends in the pharmacoepidemiology of antipsychotic treatment of MDD. Data from the 2006-2015 National Ambulatory Medical Care Survey, nationally representative samples of office-based outpatient visits in adults with MDD (ICD-9-CM codes 296.20-296.26 and 296.30-296.36) (n = 4,044 unweighted), were used to estimate rates of antipsychotic prescribing over these 10 years. Multivariable logistic regression analysis identified demographic and clinical factors independently associated with antipsychotic use in MDD. Antipsychotic prescribing for MDD increased from 18.5% in 2006-2007 to 24.9% in 2008-2009 and then declined to 18.9% in 2014-2015. Visits with adults 75 years or older showed the greatest decline from 27.0% in 2006-2007 to 10.7% in 2014-2015 (OR for overall trend = 0.73; 95% CI, 0.56-0.95). The most commonly prescribed antipsychotic agents were aripiprazole, olanzapine, quetiapine, and risperidone. Antipsychotic prescription was associated with being black or Hispanic, having Medicare among adults under 65 years or Medicaid as a primary source of payment, and receiving mental health counseling, 3 or more concomitant medications, and diagnosis of cannabis use disorder (P < .01). Antipsychotics, prescribed for about one-fifth of adults with MDD, increased and then declined from 2006 to 2015, reflecting, first, FDA approval and then concern about adverse effects in the elderly. Future research should track evolving trends following the publication of evidence of greater long-term effectiveness of antipsychotic than antidepressant next-step therapy in adults with MDD. © Copyright 2018 Physicians Postgraduate Press, Inc.
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McGregor, Nathaniel; Thompson, Nicole; O'Connell, Kevin Sean; Emsley, Robin; van der Merwe, Lize; Warnich, Louise
2018-04-01
Antipsychotics remain the most effective, and wide used option for ameliorating the symptoms of schizophrenia. However, inter-individual differences in treatment outcome are vast and suggest a role for genetic and environmental factors in affording favourable outcomes. A notable epigenetic relationship which has gained considerable traction in recent literature is the way in which the severity of childhood trauma can modify associations seen between genetic variation and antipsychotic treatment response. A potential mechanism of action which may facilitate this relationship is synaptic plasticity. This study investigated the role of variants in matrix metallopeptidase 9 (MMP9), a gene involved in synaptic plasticity, with treatment outcome considering the severity of childhood trauma as an interacting variable. The cohort comprised South African first episode schizophrenia patients treated with a single injectable antipsychotic, flupenthixol decanoate, monitored over 12 months. Relationships between novel and previously described variants, and haplotypes, with antipsychotic treatment response were found to be modified when considering childhood trauma as an interacting variable. This study provides the first evidence for the involvement of polymorphisms within MMP9 and the severity of childhood trauma in antipsychotic treatment response, and warrants further investigation into the role gene-environment interactions may play in the betterment of antipsychotic treatment strategies. Copyright © 2018 Elsevier B.V. All rights reserved.
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Effects of aripiprazole on caffeine-induced hyperlocomotion and neural activation in the striatum.
Batista, Luara A; Viana, Thércia G; Silveira, Vívian T; Aguiar, Daniele C; Moreira, Fabrício A
2016-01-01
Aripiprazole is an antipsychotic that acts as a partial agonist at dopamine D2 receptors. In addition to its antipsychotic activity, this compound blocks the effects of some psychostimulant drugs. It has not been verified, however, if aripiprazole interferes with the effects of caffeine. Hence, this study tested the hypothesis that aripiprazole prevents caffeine-induced hyperlocomotion and investigated the effects of these drugs on neural activity in the striatum. Male Swiss mice received injections of vehicle or antipsychotic drugs followed by vehicle or caffeine. Locomotion was analyzed in a circular arena and c-Fos protein expression was quantified in the dorsolateral, dorsomedial, and ventrolateral striatum, and in the core and shell regions of nucleus accumbens. Aripiprazole (0.1, 1, and 10 mg/kg) prevented caffeine (10 mg/kg)-induced hyperlocomotion at doses that do not change basal locomotion. Haloperidol (0.01, 0.03, and 0.1 mg/kg) also decreased caffeine-induced hyperlocomotion at all doses, although at the two higher doses, this compound reduced basal locomotion. Immunohistochemistry analysis showed that aripiprazole increases c-Fos protein expression in all regions studied, whereas caffeine did not alter c-Fos protein expression. Combined treatment of aripiprazole and caffeine resulted in a decrease in the number of c-Fos positive cells as compared to the group receiving aripiprazole alone. In conclusion, aripiprazole prevents caffeine-induced hyperlocomotion and increases neural activation in the striatum. This latter effect is reduced by subsequent administration of caffeine. These results advance our understanding on the pharmacological profile of aripiprazole.
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[Neurotensin-like oligopeptides as potential antipsychotics: effect on dopamine system].
Kost, N V; Meshavkin, V K; Batishcheva, E Iu; Sokolov, O Iu; Andreeva, L A; Miasoedov, N F
2011-01-01
According to published data, peptide neurotensin is considered as endogenous antipsychotic agent. A series of oligopeptides have been synthesized based on the proposed active center of neurotensin. These oligopeptides (called neurotensin-like peptides, NLPs) have been studied on behavioral models, in which the functional state of the dopamine system of animals was modified by apomorphine injections. The results of verticalization, stereotypy, and yawning tests revealed NLPs that behave as antagonists of dopamine receptors. Radioligand analysis showed that these peptides compete for specific binding to these receptors with sulpiride, which is a D2-type selective antagonist of dopamine receptors. The high degree of NLPs efficiency manifested in the behavioral tests and radioligand analysis suggests that the their antipsychotic action can be mediated by dopamine receptors.
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van den Wijngaard, L; Rodijk, I C M; van der Veen, F; Gooskens-van Erven, M H W; Koks, C A M; Verhoeve, H R; Mol, B W J; van Wely, M; Mochtar, M H
2015-02-01
What factors or attributes of a long-acting recombinant FSH (rFSH) or daily-administrated rFSH influence women's preferences IVF? Patients' preferences for rFSH products are primary influenced by the attribute 'number of injections', but a low 'number of injections' is exchanged for a high 'number of injections' at a 6.2% decrease in 'risk of cycle cancellation due to low response' and at a 4.5% decrease in 'chance of OHSS'. Injections of long-acting rFSH have been claimed to be preferred over daily-administrated rFSH injections, but patient preference studies to underpin this assumption have not been performed. A discrete choice experiment (DCE) was created to assess women's preference for long-acting or daily-administrated rFSH under varying attributes of efficiency, safety and burden. The selected attributes were the 'total number of injections', 'chance of ovarian hyperstimulation syndrome (OHSS)' and the 'risk of cycle cancellation due to low response'. Questionnaires were handed out during information gathering sessions in one academic hospital and two teaching hospitals in The Netherlands between April 2011 and April 2012. Women at the start of their first IVF treatment were asked to participate in this patient preference study. Participation was voluntary. We analysed the data by using mixed logit models to estimate the utility of each attribute. Questionnaires (n = 125) were handed out with a response rate of 77% (97/125). Four respondents did not complete the questionnaire. Hence, there were 93 questionnaires available for analysis. All attributes significantly influenced women's preference. Overall, the lower 'number of injections' was preferred above the higher 'number of injections' (mean coefficient 1.25; P < 0.001), while an increase of 1% in 'chance of OHSS' or 5% 'risk of cycle cancellation due to low response' was non-preferred (mean coefficients -0.31 and -0.24, respectively, P < 0.01). The majority of respondents was willing to trade-off a lower 'number of injections' for a higher 'number of injections' when gaining a 6.2% reduction in 'cycle cancellation due to low response', or a 4.5% reduction in 'chance of OHSS'. The generalizability of this DCE is limited in time-span. Women may choose differently when they have previous experience with long-acting rFSH, or when they have to pay for the medication, hospital visits and treatments themselves. The results of this DCE helps us to understand the trade-off women make in their preference for a long-acting rFSH product or a daily-administrated rFSH product in IVF and may support doctors when counselling patients. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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Prommer, Eric
2017-03-01
Delirium is a palliative care emergency where patients experience changes in perception, awareness, and behavior. Common features include changes in the sleep-wake cycle, emotional lability, delusional thinking, and language and thought disorders. Delirium results from neurotransmitter imbalances involving several neurotransmitters such as dopamine, glutamate, norepinephrine, acetylcholine, gamma-aminobutyric acid, and serotonin. Untreated delirium causes significant morbidity and mortality. Nonpharmacologic and pharmacologic approaches treat delirium. Current pharmacologic management of delirium involves using agents such as haloperidol or second-generation antipsychotics. Third-generation atypical antipsychotic drugs have emerged as a potential choice for delirium management. Aripiprazole is a third-generation antipsychotic with a dopamine receptor-binding profile distinct from other second-generation antipsychotics. Aripiprazole acts as partial agonist at dopamine D 2 and 5-hydroxytryptamine (5-HT) 1A receptors, stabilizing the dopamine receptor leading to improvement in symptoms. The article reviews the pharmacology, pharmacodynamics, metabolism, and evidence of clinical efficacy for this new antipsychotic agent. This article explores possible roles in palliative care.
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Commercial air travel after intraocular gas injection.
Houston, Stephen; Graf, Jürgen; Sharkey, James
2012-08-01
Passengers with intraocular gas are at risk of profound visual loss when exposed to reduced absolute pressure within the cabin of a typical commercial airliner. Information provided on the websites of the world's 10 largest airlines offer a considerable range of opinion as to when it might be safe to fly after gas injection. Physicians responsible for clearing pseassengers as 'fit to fly' should be aware modern retinal surgical techniques increasingly employ long-acting gases as vitreous substitutes. The kinetics of long-acting intraocular gases must be considered when deciding how long after surgery it is safe to travel. It is standard practice to advise passengers not to fly in aircraft until the gas is fully resorbed. To achieve this, it may be necessary to delay travel for approximately 2 wk after intraocular injection of sulfur hexafluoride (SF6) and for 6 wk after injection of perfluoropropane (C3F8).
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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.
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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
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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.
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Xiao, Yongling; Muser, Erik; Fu, Dong-Jing; Lafeuille, Marie-Hélène; Pilon, Dominic; Emond, Bruno; Wu, Allen; Duh, Mei Sheng; Lefebvre, Patrick
2016-01-01
Compared to oral atypical antipsychotics (OAAs), long-acting injectable antipsychotics require less frequent administration, and thus may improve adherence and reduce risk of relapse in schizoaffective disorder (SAD) patients. To evaluate the impact of once monthly paliperidone palmitate (PP) versus OAAs on healthcare resource utilization, Medicaid spending, and hospital readmission among SAD patients. Using FL, IA, KS, MS, MO, and NJ Medicaid data (January 2009-December 2013), adults with ≥2 SAD diagnoses initiated on PP or OAA (index date) were identified. Baseline characteristics and outcomes were assessed during the 12month pre- and post-index periods, respectively. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were used to reduce confounding and compare the estimated treatment effect for PP versus OAA. A total of 10,778 OAA-treated patients and 876 PP-treated patients were selected. Compared to OAAs, PP was associated with significantly lower medical costs (PSM: mean monthly cost difference [MMCD] = -$383, p < 0.001; IPTW: MMCD = -$403, p = 0.016), which offset the higher pharmacy costs associated with PP (PSM: MMCD = $270, p < 0.001; IPTW: MMCD = $350, p < 0.001) and resulted in similar total healthcare cost (PSM: MMCD = -$113, p = 0.414; IPTW: MMCD = -$53, p = 0.697) for PP versus OAA. Reduced risk of hospitalization (PSM: incidence rate ratio [IRR] = 0.85, p = 0.128; IPTW: IRR = 0.96, p = 0.004) and fewer hospitalization days (PSM: IRR = 0.74, p = 0.008; IPTW: IRR = 0.85, p < 0.001) were observed in PP versus OAA patients. Among hospitalized patients, PP was associated with a lower risk of 30 day hospital readmission compared to OAA (IPTW: odds ratio = 0.89, p = 0.041). Limitations The Medicaid data may not be representative of the nation or other states, and includes pre-rebate pharmacy costs (potentially over-estimated). Also changes in treatment over time were possible. Total healthcare costs associated with the use of once monthly PP versus OAAs appeared comparable; higher pharmacy costs for PP users were offset by lower medical costs related to fewer and shorter inpatients visits.
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Ballard, Clive; Thomas, Alan; Gerry, Stephen; Yu, Ly-Mee; Aarsland, Dag; Merritt, Claire; Corbett, Anne; Davison, Christopher; Sharma, Narenda; Khan, Zunera; Creese, Byron; Loughlin, Paul; Bannister, Carol; Burns, Alistair; Win, Soe Nyunt; Walker, Zuzana
2015-04-01
Neuropsychiatric symptoms in Alzheimer disease (AD) cause significant distress and present a complex clinical challenge for treatment. Pharmacological treatment options are limited to antipsychotics, which carry extensive safety issues. There is emerging evidence to support the potential benefits of memantine, currently licensed for moderate to severe AD, in the prophylaxis of neuropsychiatric symptoms. The MAIN-AD study is a double-blind randomized placebo-controlled withdrawal trial comparing memantine with antipsychotics for the treatment of neuropsychiatric symptoms over 24 weeks. A total of 199 people with probable AD living in care homes already receiving an antipsychotic were randomized to receive either memantine or to continue an antipsychotic. The primary outcomes were function (Bristol Activities of Daily Living Scale [BADLS]) and agitation (Cohen-Mansfield Agitation Inventory [CMAI]). Secondary outcomes were Neuropsychiatric Inventory (NPI), Mini-Mental State Examination (MMSE), and mortality. There was no significant difference between groups on the BADLS or CMAI. At 24 weeks, there was a nonsignificant adjusted difference in favor of memantine on the BADLS of 0.23 (95% CI -1.80-2.27; P = .82) and in favor of antipsychotic on the CMAI of 0.09 (95% CI -0.35-8.53; P = .07). Although there were no significant differences in total NPI, there were 5.01 (95% CI -1.68-11.70; P = .05) and 3.63 (95% CI -1.40-8.67; P = .16) point advantages favoring antipsychotics at weeks 12 and 24, respectively. In addition, in an exploratory analysis, individuals allocated to antipsychotics were significantly less likely to experience relapse of neuropsychiatric symptoms at all time points. The group receiving memantine had a nonsignificant 1.3-point advantage on the MMSE at 24 weeks. This study indicates no benefits for memantine in the long-term treatment and prophylaxis of clinically significant neuropsychiatric symptoms. The results did indicate some benefits for antipsychotic medications in reducing the relapse of neuropsychiatric symptoms, but this must be balanced against increased mortality risk. Copyright © 2015 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.
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Distiller, L A; Robertson, L I; Moore, R; Bonnici, F
1987-06-20
A trial was undertaken to ascertain the effect and acceptability of a multiple insulin injection regimen (MII) in patients with insulin-dependent diabetes mellitus using short-acting monocomponent human soluble insulin (Actrapid HM; Novo) for pre-meal bolus injections with the NovoPen injection device (Novo) and long-acting human insulin (Ultratard HM; Novo) at bedtime. Fifty-four patients, all previously on twice-daily short/intermediate-acting human insulin (Monotard HM; Novo) and Actrapid HM, were randomly selected. There was a significant overall improvement in diabetic control over the 12 weeks of the trial, the glycosylated haemoglobin (Hb A1) dropping from a mean of 9.8 +/- 2.2% to 8.6 +/- 1.7% (P less than 0.05). MII, using the NovoPen, was found to be more convenient than conventional insulin administration by 92% of the subjects. It is concluded that the NovoPen is a useful and convenient means of administering pre-meal boluses in an MII regimen, with a very high rate of acceptance by patients of all ages.
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C-fos mediates antipsychotic-induced neurotensin gene expression in the rodent striatum.
Robertson, G S; Tetzlaff, W; Bedard, A; St-Jean, M; Wigle, N
1995-07-01
The ubiquitous inducibility of the immediate-early gene c-fos in the central nervous system has led to the search for downstream genes which are regulated by its product, Fos. Recent evidence suggests that c-fos induction by a single injection of the classical antipsychotic haloperidol may contribute to the subsequent increase in neurotensin gene expression in the rodent striatum. Consistent with this proposal, in the present study haloperidol-induced Fos-like immunoreactivity and neurotensin/neuromedin N messenger RNA were found to be expressed by the same population of striatal neurons. Moreover, inhibition of haloperidol-induced c-fos expression by intrastriatal injection of antisense phosphorothioate oligodeoxynucleotides complimentary either to bases 109-126 or 127-144 of c-fos attenuated the subsequent increase in neurotensin/neuromedin N messenger RNA. However, injection of a sense phosphorothioate oligodeoxynucleotide corresponding to bases 127-144 of c-fos did not reduce haloperidol-induced c-fos or neurotensin/neuromedin N expression. Furthermore, constitutive expression of Jun-like immunoreactivity in the striatum was not reduced by either the sense or antisense phosphorothioate oligodeoxynucleotides. Similarly, the sense and antisense phosphorothioate oligodeoxynucleotide failed to reduce proenkephalin messenger RNA, which is located in the same striatal neurons that express haloperidol-induced neurotensin/neuromedin N messenger RNA, which is located in the same striatal neurons that express haloperidol-induced neurotensin/neuromedin N messenger RNA. Lastly, haloperidol-induced increases in nerve growth factor I-A-, JunB- and FosB-like immunoreactivity and fosB messenger RNA were not decreased by intrastriatal injection of either the sense or antisense phosphorothioate oligodeoxynucleotides. These results indicate that the antisense phosphorothioate oligodeoxynucleotides attenuated haloperidol-induced neurotensin/neuromedin N expression by selectively reducing c-fos expression and emphasize the potential importance of immediate-early gene induction in the mechanism of action of this antipsychotic drug.
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Druais, S; Doutriaux, A; Cognet, M; Godet, A; Lançon, C; Levy, P; Samalin, L; Guillon, P
2017-08-01
The course of schizophrenia can vary widely, and patients experience remission phases alternating with relapse episodes, which generally lead to hospitalisation and have a significant impact on the burden of disease. The prevalence of schizophrenia in France is estimated to be approximately 600,000 people, with an incidence of 10,000 new patients per year. Patients with schizophrenia represent the largest group of hospitalised patients in French public institutions and specialised centres, and the French authorities recognise that the management of schizophrenia is a major public health concern. The Haute Autorité de Santé (HAS) and most of the evidence-based guidelines for the maintenance treatment of schizophrenia recommend long-acting injectable (LAI) antipsychotics to be used predominantly in the prevention of relapse for non-compliant patients; however, in clinical practice, the use of LAIs remains low. This analysis aimed to estimate and to compare the cost-effectiveness of the most common antipsychotic strategies in France in the management of schizophrenia. A Markov model was developed to simulate the progression of a cohort of patients with schizophrenia through four health states (stable treated, stable non-treated, relapse and death) and considered up to three lines of treatment to account for changes in treatment management. Antipsychotics including aripiprazole LAI (ALAI), olanzapine LAI (OLAI), paliperidone LAI (PLAI), risperidone LAI (RLAI), haloperidol decanoate (HD) and oral olanzapine (OO) were compared in terms of costs and clinical outcomes. Thus, costs, quality-adjusted life-years (QALYs) and number of relapses were assessed over five years based on three-month cycles from a French health insurance perspective with a discount rate of 4 %. Patients were considered to be stabilised after clinical decompensation and would enter the model at an initiation phase, followed by a prevention of relapse phase if successful. Data (e.g. relapse or discontinuation rates) for the initiation phase came from randomised clinical trials, whereas relapse rates in the prevention phase were derived from hospitalisation risks based on French real-life data in order to capture adherence effects. Safety and utility data were derived from international publications. Additionally costs were retrieved from French health insurance databases and publications. Robustness of results was assessed through deterministic and probabilistic sensitivity analyses. First and second generations of LAIs were found to have similar costs over five years; i.e. approximately € 55,000, except for PLAI which was associated with a discounted cost of € 50,880. Oral antipsychotics were found to be less costly (i.e. OO cost € 50,379 after five years) but associated with a lower number of QALYs gained and relapse avoided. PLAI and RLAI were associated with the greatest number of QALYs gained; i.e. PLAI dominated ALAI, OLAI and HD and was associated with an incremental costs-effectiveness ratio (ICER) of € 2411 per QALY gained versus OO. Finally, PLAI and OLAI were associated with the lowest number of relapses; i.e. PLAI dominated RLAI, ALAI and HLAI and was associated with an ICER of € 1782 per avoided relapse compared to OO. OO and HD were found to have led to the highest number of relapses. This analysis, to the best of our knowledge, is the first of its kind to assess the cost-effectiveness of antipsychotics based on French observational data. PLAI was associated with the highest probability of being the optimal treatment from the French health insurance perspective. Copyright © 2016. Published by Elsevier Masson SAS.
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... release (long-acting) injection is used to treat schizophrenia (a mental illness that causes disturbed or unusual ... do not already have diabetes. If you have schizophrenia, you are more likely to develop diabetes than ...
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Long-acting antiviral agents for HIV treatment
Margolis, David A.; Boffito, Marta
2015-01-01
Purpose of review Long-acting antiretroviral (ARV) agents are currently under development for the treatment of chronic HIV infection. This review focuses on data recently produced on injectable ARVs for patients living with HIV/AIDS and on the patients’ perspectives on the use of these agents. Recent findings Crystalline nanoparticle formulations of the nonnucleoside reverse transcriptase inhibitor rilpivirine (TMC278) and of the HIV-1 integrase strand transfer inhibitor cabotegravir (GSK1265744) have progressed into phase II clinical trials as injectable maintenance therapy for patients living with HIV/AIDS with an undetectable viral load. Summary Phase II studies evaluating the coadministration of rilpivirine and cabotegravir intramuscularly to HIV-infected individuals with an undetectable viral load are currently underway. Rilpivirine and cabotegravir are characterized by different mechanisms of action against HIV and a favorable drug interaction profile, providing a rationale for coadministration. The high potency and low daily dosing requirements of oral cabotegravir and rilpivirine facilitate long-acting formulation development. Intramuscular dosing is preceded by an oral lead-in phase to assess safety and tolerability in individual participants. In addition to assessing the safety of injectable therapies in ongoing studies, it will be important to evaluate whether differences in drug adherence between injectable and oral therapies lead to different virologic outcomes, including rates of virologic failure and the emergence of resistance. Long-acting formulations may be associated with challenges, such as the management of adverse effects with persistent drug concentrations and the risk of virologic resistance, as drug concentrations decline following discontinuation. PMID:26049949
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Harrow, Martin; Jobe, Thomas H; Faull, Robert N; Yang, Jie
2017-10-01
To assess the long-term effectiveness of antipsychotic medications in facilitating work functioning in patients with schizophrenia we conducted longitudinal multifollowup research on 139 initially psychotic patients. The 70 patients with schizophrenia and 69 initially psychotic mood disordered control patients were followed up 6 times over 20 years. We compared the influence on work functioning of patients with schizophrenia continuously prescribed antipsychotics with patients with schizophrenia not prescribed antipsychotics, using statistical controls for inter-subject differences. While antipsychotics reduce or eliminate flagrant psychosis for most patients with schizophrenia at acute hospitalizations, four years later and continually until the 20 year followups, patients with schizophrenia not prescribed antipsychotics had significantly better work functioning. The work performance of the patients who were continuously prescribed antipsychotics was at a low rate and did not improve over time. Multiple other factors also interfere with work functioning. The data suggest that some patients with schizophrenia not prescribed antipsychotics for prolonged periods can function relatively well. Multiple other factors are associated with poor post-hospital work performance. The longitudinal data raise questions about prolonged treatment of schizophrenia with antipsychotic medications. Copyright © 2017 Elsevier B.V. All rights reserved.
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Ludwin, Brian M; Meeks, Suzanne
2018-05-03
This study examined the validity of a psychological model for understanding nursing home providers' treatment choices when managing challenging dementia-related behaviors. Ninety-nine nurses from 26 long-term care facilities responded to a case study with their intentions to initiate an antipsychotic or psychosocial intervention and completed self-report measures of their attitudes, descriptive norms, self-efficacy, and outcome expectancies. The multi-level modeling results demonstrated that nurses with more positive outcome expectancies for the effect of an antipsychotic on resident behavior, and those with more positive attitudes towards antipsychotics, had greater intentions to initiate an antipsychotic. Intentions to initiate a psychosocial intervention were greater when nurses perceived a lower prevalence of antipsychotics and in facilities with nurses who collectively had higher self-efficacy to implement such interventions. The findings offer partial support for the proposed model and possible intervention targets to improve psychosocial intervention use and antipsychotic prescribing. Published by Elsevier Inc.
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Wils, Regitze Sølling; Gotfredsen, Ditte Resendal; Hjorthøj, Carsten; Austin, Stephen F; Albert, Nikolai; Secher, Rikke Gry; Thorup, Anne Amalie Elgaard; Mors, Ole; Nordentoft, Merete
2017-04-01
Several national guidelines recommend continuous use of antipsychotic medication after a psychotic episode in order to minimize the risk of relapse. However some studies have identified a subgroup of patients who obtain remission of psychotic symptoms while not being on antipsychotic medication for a period of time. This study investigated the long-term outcome and characteristics of patients in remission of psychotic symptoms with no use of antipsychotic medication at the 10-year follow-up. The study was a cohort study including 496 patients diagnosed with schizophrenia spectrum disorders (ICD 10: F20 and F22-29). Patients were included in the Danish OPUS Trial and followed up 10years after inclusion, where patient data was collected on socio-demographic factors, psychopathology, level of functioning and medication. 61% of the patients from the original cohort attended the 10-year follow up and 30% of these had remission of psychotic symptoms at the time of the 10-year follow up with no current use of antipsychotic medication. This outcome was associated with female gender, high GAF-F score, participation in the labour market and absence of substance abuse. Our results describe a subgroup of patients who obtained remission while not being on antipsychotic medication at the 10-year follow-up. The finding calls for further investigation on a more individualized approach to long-term treatment with antipsychotic medication. Copyright © 2016 Elsevier B.V. All rights reserved.
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Aripiprazole in schizophrenia and schizoaffective disorder: A review.
Stip, Emmanuel; Tourjman, Valérie
2010-01-01
During the past decade, there has been some progress in the pharmacotherapy of schizophrenia and schizoaffective disorder. Current evidence supports the use of various second-generation, or atypical, antipsychotic medications, although few of these agents have been associated with long-term efficacy and tolerability. Aripiprazole is an atypical antipsychotic that has been found to improve positive and negative symptoms of schizophrenia with a favorable adverse-effect profile. This article reviews the efficacy and tolerability of aripiprazole in the context of recommended management strategies for schizophrenia and schizoaffective disorder, and in comparison with first-generation and other second-generation antipsychotics. A search of MEDLINE (1999-May 2009) was conducted for reports of short- and long-term clinical studies of atypical antipsychotics (including aripiprazole) and meta-analyses of randomized controlled trials comparing first- and second-generation antipsychotics (including aripiprazole) in the treatment of schizophrenia or schizoaffective disorder. The search terms were schizophrenia; schizoaffective disorder; pharmacogenetics; adverse effects; tardive dyskinesia AND atypical antipsychotics; aripiprazole; aripiprazole, schizophrenia, AND double-blind studies; and atypical antipsychotics AND adverse effects. The reference lists of identified articles were reviewed for additional relevant publications. Only full study publications were included. Based on the clinical evidence, including data from short-term (4-8 weeks) and long-term (26-52 weeks) randomized, double-blind clinical trials, aripiprazole has been associated with improvements in positive, negative, cognitive, and affective symptoms of schizophrenia and schizoaffective disorder. It has been associated with long-term (up to 52 weeks) symptom control in schizophrenia, as well as with efficacy in treatment-resistant schizophrenia. Common adverse effects associated with aripiprazole were nausea, insomnia, and agitation. These effects were usually transient. The evidence suggests that aripiprazole is unlikely to be associated with clinically significant weight gain or dyslipidemia, increased prolactin levels, or prolongation of the QTc interval. Compared with placebo, aripiprazole has been reported to have a relatively low potential for inducing metabolic syndrome. Based on the evidence reviewed, aripiprazole monotherapy appears to be effective and well tolerated in treating the positive, negative, and cognitive symptoms of schizophrenia and schizoaffective disorder. It was associated with a low risk for the common adverse effects of antipsychotic therapy, including metabolic and endocrine alterations. 2010 Excerpta Medica Inc. All rights reserved.
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Corticosteroid injection for the treatment of carpal tunnel syndrome
O'Gradaigh, D; Merry, P
2000-01-01
OBJECTIVE—To compare low and high dose, and short and long acting corticosteroids in the treatment of carpal tunnel syndrome. METHODS—A randomised, controlled, single blind trial with electromyographic and subjective outcome measures. RESULTS—25 mg hydrocortisone is as effective as higher doses or long acting triamcinolone at a six week and six month follow up. CONCLUSION—As low dose steroid is as effective, and potentially less toxic, this should be the recommended dose for injection of carpal tunnel syndrome. PMID:11053073
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Conventional versus novel antipsychotics: changing concepts and clinical implications.
Remington, G; Chong, S A
1999-01-01
Novel antipsychotics represent a significant advance in the treatment of schizophrenia after many years of few developments. The conventional antipsychotics are potent D2 antagonists, but fail to achieve a response in about 30% of cases. They are also associated with a high rate of extrapyramidal side effects. The greater and broader spectrum of efficacy combined with the reduced short- and long-term side effects of the new drugs such as quetiapine, risperidone, olanzapine and ziprasidone, contribute to a fresh optimism for the pharmacotherapy of schizophrenia. These novel agents are now driving further advances in schizophrenia research through a growing understanding of their pharmacological and clinical profiles. Clozapine, the first novel antipsychotic, has relatively low activity at D2 receptors, a high affinity for D4 receptors and a greater 5-HT2 (serotonin) than D2 antagonism. Hence, clozapine and other novel antipsychotics can be classified as such by this latter characteristic. However, some of these drugs have D2 occupancy greater than 60% (the clinical response threshold), while others have a lower D2 occupancy. The novel antipsychotics according have also been classified according to their activity on different neurotransmitter systems. While more effective, novel antipsychotics are not a panacea; they have limitations and side effects. In clinical practice, the American Psychiatric Association recommends either a conventional or novel antipsychotic for initial treatment of schizophrenia, whereas Canadian guidelines recommend novel agents. These agents should also be considered for treatment of refractory schizophrenia. Patients whose schizophrenia does not respond to one of these agents may respond to another. Future research should involve longer clinical trials, given the long periods needed to establish efficacy, and should address many remaining questions about the novel agents. PMID:10586534
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Stock, Kathryn J; Amuah, Joseph E; Lapane, Kate L; Hogan, David B; Maxwell, Colleen J
2017-01-01
Potentially inappropriate antipsychotic use in long-term care (LTC) facilities has been the focus of significant policy and clinical attention over the past 20 years. However, most initiatives aimed at reducing the use of these medications have overlooked assisted living (AL) settings. We sought to compare the prevalence of antipsychotic use (including potentially inappropriate use) among older AL and LTC residents and to explore the resident and facility-level factors associated with use in these two populations. We performed cross-sectional analyses of 1089 residents (mean age 85 years; 77% female) from 59 AL facilities and 1000 residents (mean age 85 years; 66% female) from 54 LTC facilities, in Alberta, Canada. Research nurses completed comprehensive resident assessments at baseline (2006-2007). Facility-level factors were assessed using standardized administrator interviews. Generalized linear models were used to estimate odds ratios for associations, accounting for clustering by facility. Over a quarter of residents in AL (26.4%) and LTC (31.8%) were using antipsychotics (p = 0.006). Prevalence of potentially inappropriate use was similar in AL and LTC (23.4 vs. 26.8%, p = 0.09). However, among users, the proportion of antipsychotic use deemed potentially inappropriate was significantly higher in AL than LTC (AL: 231/287 = 80.5%; LTC: 224/318 = 70.4%; p = 0.004). In both settings, comparable findings regarding associations between resident characteristics (including dementia, psychiatric disorders, frailty, behavioral symptoms, and antidepressant use) and antipsychotic use were observed. Few facility characteristics were associated with overall antipsychotic use, but having a pharmacist on staff (AL), or an affiliated physician (LTC) was associated with a lower likelihood of potentially inappropriate antipsychotic use. Our findings illustrate the importance of including AL settings in clinical and policy initiatives aimed at reducing inappropriate antipsychotic use among older vulnerable residents.
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Antipsychotic-like activity of Noni (Morinda citrifolia Linn.) in mice
2012-01-01
Background Noni fruit is widely consumed in tropical regions of Indonesia to the Hawaiian Islands. The noni plant has a long history of use as a medicinal plant to treat a wide variety of ailments including CNS disorders. The present investigation was designed to evaluate the antipsychotic effect of noni fruits (Morinda citrifolia Linn.) using mouse models of apomorphine-induced climbing behaviour and methamphetamine-induced stereotypy (licking, biting, gnawing and sniffing). Methods In acute study, the methanolic extract of Morinda citrifolia (MMC) at different doses 1, 3, 5, 10 g/kg was administered orally one hour prior to apomorphine (5 mg/kg, i.p) and methamphetamine ( 5 mg/kg, i.p) injection respectively in Swiss albino mice. In chronic studies, (TAHITIAN NONI® Juice, TNJ) was made available freely in daily drinking water at 30, 50 and 100% v/v for 7 days; 30 and 50% v/v for 21 days respectively. On the test day, an equivalent average daily divided dose of TNJ was administered by oral gavage one hour prior to apomorphine treatment. Immediately after apomorphine/ methamphetamine administration, the animals were placed in the cylindrical metal cages and observed for climbing behaviour/ stereotypy and climbing time. Results The acute treatment of MMC (1, 3, 5, 10 g/kg, p.o) significantly decreased the apomorphine-induced cage climbing behaviour and climbing time in mice in a dose dependent manner. The MMC also significantly inhibited methamphetamine-induced stereotypy behaviour and climbing time in mice dose-dependently. The 7 and 21 days treatment of TNJ in drinking water at 50 and 100%v/v significantly alleviated the apomorphine-induced climbing behaviour and climbing time in mice. Conclusions The present study results demonstrated the antidopaminergic effect of Morinda citrifolia Linn. in mice, suggesting that noni has antipsychotic-like activity which can be utilized in the treatment of psychiatric disorders. However further studies are warranted to identify the active principles responsible for the antipsychotic activity of noni. PMID:23082808
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Antipsychotic-like activity of noni (Morinda citrifolia Linn.) in mice.
Pandy, Vijayapandi; Narasingam, Megala; Mohamed, Zahurin
2012-10-19
Noni fruit is widely consumed in tropical regions of Indonesia to the Hawaiian Islands. The noni plant has a long history of use as a medicinal plant to treat a wide variety of ailments including CNS disorders. The present investigation was designed to evaluate the antipsychotic effect of noni fruits (Morinda citrifolia Linn.) using mouse models of apomorphine-induced climbing behaviour and methamphetamine-induced stereotypy (licking, biting, gnawing and sniffing). In acute study, the methanolic extract of Morinda citrifolia (MMC) at different doses 1, 3, 5, 10 g/kg was administered orally one hour prior to apomorphine (5 mg/kg, i.p) and methamphetamine (5 mg/kg, i.p) injection respectively in Swiss albino mice. In chronic studies, (TAHITIAN NONI® Juice, TNJ) was made available freely in daily drinking water at 30, 50 and 100% v/v for 7 days; 30 and 50% v/v for 21 days respectively. On the test day, an equivalent average daily divided dose of TNJ was administered by oral gavage one hour prior to apomorphine treatment. Immediately after apomorphine/ methamphetamine administration, the animals were placed in the cylindrical metal cages and observed for climbing behaviour/ stereotypy and climbing time. The acute treatment of MMC (1, 3, 5, 10 g/kg, p.o) significantly decreased the apomorphine-induced cage climbing behaviour and climbing time in mice in a dose dependent manner. The MMC also significantly inhibited methamphetamine-induced stereotypy behaviour and climbing time in mice dose-dependently. The 7 and 21 days treatment of TNJ in drinking water at 50 and 100%v/v significantly alleviated the apomorphine-induced climbing behaviour and climbing time in mice. The present study results demonstrated the antidopaminergic effect of Morinda citrifolia Linn. in mice, suggesting that noni has antipsychotic-like activity which can be utilized in the treatment of psychiatric disorders. However further studies are warranted to identify the active principles responsible for the antipsychotic activity of noni.
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Intraoperative floppy-iris syndrome associated with use of antipsychotic drugs.
Matsuo, Masato; Sano, Ichiya; Ikeda, Yoshifumi; Fujihara, Etsuko; Tanito, Masaki
2016-08-01
We report 3 cases of intraoperative floppy-iris syndrome (IFIS) during cataract surgery in patients without a history of selective α1-blocker use but with a long-term history of antipsychotic drug use. We reviewed previously reported cases of antipsychotic drug-associated IFIS cases. Observational case series. In case 1, bilateral IFIS developed in a 39-year-old man with chronic angle-closure glaucoma. He had used several classes of antipsychotic drugs to treat schizophrenia, including the first-generation antipsychotic drugs haloperidol and chlorpromazine, the dopamine system stabilizer aripiprazole, the dopamine serotonin antagonists olanzapine and quetiapine, and the serotonin dopamine antagonists risperidone and blonanserin for 7 years. In case 2, a 63-year-old woman with schizophrenia had used aripiprazole, quetiapine, and risperidone for more than 10 years. In case 3, a 65-year-old woman with an organic mental disorder had used haloperidol for more than 10 years. At least 5 cases of antipsychotic drug-induced IFIS have been reported in the literature. Any class of antipsychotic drugs can cause IFIS. Although antipsychotic drug-induced IFIS can be mild, surgeons should be alert to the possibility of IFIS when they treat patients with current and past use of antipsychotic drugs. Copyright © 2016 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.
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Mgbako, Ofole; Park, Su Hyun; Mayer, Kenneth H; Schneider, John A; Goedel, William C; Hambrick, H Rhodes; Duncan, Dustin T
2018-04-10
Pre-exposure prophylaxis (PrEP) is an important biomedical human immunodeficiency virus (HIV) prevention tool gaining more popularity among Parisian men who have sex with men (MSM) who engage in transactional sex. This study examines the knowledge of, and willingness to use, different modalities of PrEP among this subgroup. Broadcast advertisements were placed on a geosocial-networking smartphone application with a link to a Web-based survey during three 24-hour periods in October 2016. Modified Poisson regression models were used to assess the association between engagement in transactional sex and preferences for each of these PrEP modalities. A total of 444 respondents were included. About 14% reported engagement in transactional sex. In all, 90% of MSM who engaged in transactional sex were knowledgeable of daily oral PrEP, while 13.3% were knowledgeable about long-acting injectable PrEP or penile or rectal microbicides. They were more likely to be aware of long-acting injectable PrEP (aRR = 2.52, 95% CI = 1.16 to 5.47) and willing to use daily oral PrEP (aRR = 1.48; 95% CI = 1.11 to 1.98) or long-acting injectable PrEP (aRR = 1.40; 95% CI = 1.09 to 1.81) than MSM who had not engaged in transactional sex. Long-acting injectable PrEP may be an important HIV-prevention option for MSM who engage in transactional sex if this modality is proven effective.
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Jalenques, I; Ortega, V; Legrand, G; Auclair, C
2016-04-01
Advancing age entails specific treatment modalities for patients with schizophrenia. The choice of appropriate antipsychotic therapy (AP) and the monitoring of treatment is a major challenge. However, little is known about the real-world prescribing practices of psychiatrists for elderly schizophrenia patients. The aim of this study was to assess prescribing practices and treatment monitoring in elderly schizophrenia patients and whether socio-professional psychiatrists' characteristics are related to their practices. We contacted by mail 190 psychiatrists to take part in an observational survey of their AP prescribing practices for elderly (aged over 65) schizophrenia patients. The response rate was 44.2%, and of the psychiatrists who replied 75% were treating elderly schizophrenia patients. A second-generation AP (SGAP) was prescribed as first-line of treatment by 87.7% of the psychiatrists. The most frequently used SGAPs were risperidone and olanzapine (respectively preferred by 54.4% and 19.3% of the psychiatrists taking part). At the beginning of treatment, 91.1% of the psychiatrists prescribed a lower dose than for middle-aged patients. Of the psychiatrists taking part, 64.9% prescribed monotherapy; and among these psychiatrists, 65% cited insufficient control of the disease as the reason for their choice, while 48.7% of those who elected not to prescribe combined AP did so in order to limit the side-effects. Of the psychiatrists taking part, 54.4% prescribed long-acting injectable AP (LAAP); better therapeutic compliance and alliance was the main argument in the choice of LAAP given by the psychiatrists taking part who prescribed the drug, whereas the absence of indications and problems of tolerance were arguments against for those who did not. "Personal experience" emerged as the governing factor in the choice of AP. The AP side-effect profile was the main criterion of choice of the AP agent for 3.5% of the psychiatrists taking part, and the most frequently chosen secondary criterion (29.8%). Monitoring of treatment was partly performed according to professional recommendations: pre-treatment and post-prescription assessments of waist circumference and ophthalmological monitoring were very infrequent (8.8 to 18.5%) as were pre-treatment and early post-prescription assessments of prolactinaemia (14.8 to 20.4%); long-term cardiac monitoring was infrequent (43.9%). The psychiatrists taking part whose first-line drug was SGAP were more familiar with professional recommendations than those who prescribed first generation antipsychotic (FGA) drugs (72% as against 14.3%, P=0.006). Of the psychiatrists taking part in the study, 64.9% reported they commonly use professional recommendations. Psychiatrists who declared they commonly use professional recommendations measured pulse rate and blood pressure significantly more often over the long-term than those who did not (74.3% as against 41.2%, P=0.0315). They also measured waist circumference over the long-term significantly more often than psychiatrists who did not commonly use professional recommendations (22.9% as against 0%, P=0.0420). Psychiatrists treating more than ten of these patients yearly measured significantly more often over the long-term pulse rate and blood pressure than those treating fewer patients (80% as against 50%, P=0.0399). Over the long-term monitoring, psychiatrists with a larger number of elderly schizophrenia patients in their care also performed more often fasting blood glucose test, lipid profile and referral for cardiac consultation with ECG (respectively, 95.5% as against 70.8%, P=0.0489; 90.9% as against 58.3%, P=0.0182; 81.8% as against 29.2%, P<0.0001). The results of this survey need to be confirmed in a larger population sample. The antipsychotic prescribing practices were broadly in agreement with current recommendations except for the tolerance profile which was not the first element taken into account in the choice of the AP agent. Some clinical and paraclinical medical examinations were carried out infrequently, in particular cardiac monitoring over the long-term, which is essential in this elderly patient population. One important element to emerge from our results was that common use of professional recommendations is associated with better monitoring. Copyright © 2015 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.
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Sonego, Andreza B; Gomes, Felipe V; Del Bel, Elaine A; Guimaraes, Francisco S
2016-08-01
Cannabidiol (CBD) is a major non-psychoactive compound from Cannabis sativa plant. Given that CBD reduces psychotic symptoms without inducing extrapyramidal motor side-effects in animal models and schizophrenia patients, it has been proposed to act as an atypical antipsychotic. In addition, CBD reduced catalepsy induced by drugs with distinct pharmacological mechanisms, including the typical antipsychotic haloperidol. To further investigate this latter effect, we tested whether CBD (15-60mg/kg) would attenuate the catalepsy and c-Fos protein expression in the dorsal striatum induced by haloperidol (0.6mg/kg). We also evaluated if these effects occur through the facilitation of 5-HT1A receptor-mediated neurotransmission. For this, male Swiss mice were treated with CBD and haloperidol systemically and then subjected to the catalepsy test. Independent groups of animals were also treated with the 5-HT1A receptor antagonist WAY100635 (0.1mg/kg). As expected, haloperidol induced catalepsy throughout the experiments, an effect that was prevented by systemic CBD treatment 30min before haloperidol administration. Also, CBD, administered 2.5h after haloperidol, reversed haloperidol-induced catalepsy. Haloperidol also increased c-Fos protein expression in the dorsolateral striatum, an effect attenuated by previous CBD administration. CBD effects on catalepsy and c-Fos protein expression induced by haloperidol were blocked by the 5-HT1A receptor antagonist. We also evaluated the effects of CBD (60nmol) injection into the dorsal striatum on haloperidol-induced catalepsy. Similar to systemic administration, this treatment reduced catalepsy induced by haloperidol. Altogether, these results suggest that CBD acts in the dorsal striatum to improve haloperidol-induced catalepsy via postsynaptic 5-HT1A receptors. Copyright © 2016 Elsevier B.V. All rights reserved.
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Simon, N; Azorin, J-M
2015-04-01
Drug manufacturer seeking authorization to bring a newly medicinal compound to the market (Market Authorization Application) have to undertake various studies, each of them providing a specific report. It is however essential to know how to pool results in order to understand the behavior of the drug in all the situations likely to be encountered in clinical practice. The exploitation of these data is now carried out through pharmacometric analyzes which aim at quantifying the exposure and the response of a drug over time. These methods (named "population approach") are based on non-linear mixed effects model and therefore, on the identification of a mathematical model. A first step is to model the variations in concentrations over time by integrating the physio-pathological characteristics of the patients. At this stage, the Bayesian analysis is essential to identify and select the factors of interindividual variability. This pharmacokinetic (PK) modeling allows us to obtain the prescribed dose for each patient, but also their exposure. The second step consists in defining the relationship between exposure and effect: pharmacodynamic (PD) modeling. In psychiatry, the response can be the receptors' occupancy rate or the evolution of a clinical score (BPRS, PANSS…) over time. The final PK-PD model defines the target exposure, that is to say, the concentration values required to achieve maximum effect on the score studied without risking over-exposure. Ultimately, a Monte Carlo simulation will be conducted which will test the expected response for different doses and will facilitate a rational choice in dosage. Assessing the process behind the transition from an oral to a long-acting injectable form of an active ingredient such as aripiprazole can be done by following the same protocol. A 10- to 30-mg per day therapeutic range has thus been identified. The model incorporates all the identified factors of variability of aripiprazole (drug interactions and genetic polymorphism of the P450 2D6 cytochrome) and showed that with an injectable sustained release form, a monthly dose of 400mg would allow 90% of patients to gain exposure in the therapeutic range. In case of a drug inhibition and/or of a slow metabolizing profile, dosage adjustment is necessary. Copyright © 2015 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.
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Wei, Xiao-Lan; Han, Ying-Rui; Quan, Li-Hui; Liu, Chun-Yu; Liao, Yong-Hong
2013-05-13
The objective of this study was to prepare the nanocrystals of curcumin didecanoate (CurDD) by wet ball milling and to investigate the comparative pharmacokinetics of oily nano- and micro-suspensions after intramuscular (i.m.) administration to rats. Upon optimizing the wet ball milling parameters, CurDD nanocrystals were produced with median particle size of ~500 nm and the freeze-dried nanocrystals were readily dispersed in peanut oil to form stable nanosuspensions. Although the nanosuspension appeared to exhibit slower clearance from the injection site after i.m. injection, compared to microsuspension (~5 μm), a significantly higher maximum plasma curcumin concentration (69.0 ng/ml) was observed for the former than that for the latter (18.5 ng/ml). In addition, the nanosuspension provided significant higher plasma curcumin concentrations and brain CurDD contents for at least 15 days than the microsuspension, except for the initial times. A single i.m. injection of nanosuspension appeared to achieve reversal effect on reserpine-induced hypothermia for at least 13 days. This study demonstrates that CurDD nanosuspension may act as a long-acting i.m. injectable for sustained delivery of curcumin, potentially applicable to elicit a long-lasting antidepressant effect. Copyright © 2013 Elsevier B.V. All rights reserved.
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Naono-Nagatomo, Keiko; Naono, Hisao; Abe, Hiroshi; Takeda, Ryuichiro; Funahashi, Hideki; Uchimura, Daisuke; Ishida, Yasushi
2017-02-01
Aripiprazole (ARP) is a popular antipsychotic drug that has demonstrated ameliorative effects on hyperprolactinemia. However, no study to date has studied the utility of ARP in patients with a long history of schizophrenia and antipsychotic treatment. We therefore examined the effect of partial antipsychotic regimen replacement with ARP on hyperprolactinemia induced by chronic antipsychotic use in patients with schizophrenia. Sixteen patients with a schizophrenia diagnosis (F2) based on the International Classification of Diseases (version 10) were recruited. At months 0, 1, 3, and 6 of the study, serum prolactin, body weight, and blood glucose were measured, and QOL and psychotic symptoms were assessed using Global Assessment of Functioning scores and Clinical Global Impressions of Improvement (CGI-I) scores. Nine patients with an average age of 46.7±9.6 years and mean disease duration of 15.9±10.4 years were included in the final analysis. Serum prolactin levels significantly decreased and GAF and CGI-I scores improved significantly over the 6-month period after partial replacement with ARP. Additionally, no changes were observed in body weight or blood glucose over the 6-month period. Partial antipsychotic regimen replacement with ARP improves hyperprolactinemia, and may improve the QOL of patients with a long history of schizophrenia. Japan Medical Association, Center for clinical trials D: JMA-IIA00245. Copyright © 2016 Elsevier B.V. All rights reserved.
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Kraenzlin, M E; Wood, S M; Neufeld, M; Adrian, T E; Bloom, S R
1985-06-15
SMS 201 995 is a new long acting analogue of somatostatin. We have investigated its effect on basal and meal stimulated secretion of gut hormones and have shown that after a single s.c. injection of 50 micrograms it lowers significantly the basal plasma levels of pancreatic polypeptide, secretin, motilin, pancreatic glucagon and insulin, it also effectively suppresses the postprandial release of pancreatic polypeptide, gastrin, secretin, gastric inhibitory peptide, pancreatic glucagon and insulin. Except for the usual brief discomfort of an injection, no symptoms or untoward effects were observed.
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Shobo, Miwako; Yamada, Hiroshi; Mihara, Takuma; Kondo, Yuji; Irie, Megumi; Harada, Katsuya; Ni, Keni; Matsuoka, Nobuya; Kayama, Yukihiko
2011-01-20
Body weight gain is one of the most serious side effects associated with clinical use of antipsychotics. However, the mechanisms by which antipsychotics induce body weight gain are unknown, and no reliable animal models of antipsychotics-induced weight gain have been established. The present studies were designed to establish male rat models of weight gain induced by chronic and acute treatment with antipsychotics. Six-week chronic treatment with olanzapine (5, 7.5, and 10mg/kg/day) in male Sprague-Dawley rats fed a daily diet resembling a human macronutrient diet, significantly increased body weight gain and weight of fatty tissues. In contrast, ziprasidone (1.25, 2.5, and 5mg/kg/day) administration caused no observable adverse effects. We then investigated feeding behavior with acute antipsychotic treatment in male rats using an automated food measurement apparatus. Rats were allowed restricted access to normal laboratory chow (4h/day). With acute olanzapine (0.5, 1, and 2mg/kg, i.p.) treatment in the light phase, food intake volume and duration were significantly increased, while treatment with ziprasidone (0.3, 1, and 3mg/kg, i.p.) did not increase food intake volume or meal time duration. Findings from the present studies showed that chronic treatment with olanzapine in male rats induced body weight gain, and acute injection induced hyperphagia, suggesting that hyperphagia may be involved in the weight gain and obesity-inducing properties of chronically administered olanzapine. These animal models may provide useful experimental platforms for analysis of the mechanism of hyperphagia and evaluating the potential risk of novel antipsychotics to induce weight gain in humans. Copyright © 2010 Elsevier B.V. All rights reserved.
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Expected incidence of tardive dyskinesia associated with atypical antipsychotics.
Glazer, W M
2000-01-01
Given the problematic nature of tardive dyskinesia in persons taking conventional antipsychotics, evaluation of newer atypical antipsychotic agents should include a systematic assessment of tardive dyskinesia liability. Results of a prospective double-blind, randomized study of schizophrenic patients who participated in 3 preclinical olanzapine studies and were treated with 5 to 20 mg/day of olanzapine (N = 1192) or haloperidol (N = 522) recently indicated a significantly lower risk of development of tardive dyskinesia with olanzapine treatment than haloperidol treatment. This article discusses the known effects of atypical antipsychotic medications on tardive dyskinesia movements (both withdrawal and persistent) and the incidence rate of tardive dyskinesia among schizophrenic patients undergoing long-term treatment with olanzapine or haloperidol.
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Antipsychotic doses among community-dwelling persons with Alzheimer disease in Finland.
Taipale, Heidi; Koponen, Marjaana; Tanskanen, Antti; Tolppanen, Anna-Maija; Tiihonen, Jari; Hartikainen, Sirpa
2014-08-01
Use of antipsychotics for treatment of behavioral and psychological symptoms of dementia is frequent among persons with Alzheimer disease (AD). Doses used in long-term therapy have not been previously reported. We describe antipsychotic doses used among community-dwelling persons with AD and investigate factors associated with high-dose use. The MEDALZ-2005 (Medication use and Alzheimer disease) cohort is a nationwide sample including all persons with clinically diagnosed AD at the end of year 2005 in Finland (n = 28,093). Data including prescriptions, comorbidities, and hospital discharge diagnoses were collected from nationwide registers. Antipsychotic doses in monotherapy were investigated during 2006 to 2009. Among 8920 antipsychotic users, 4% (n = 336) used antipsychotics with high dose. Typical antipsychotics were more often used with high dose than atypical antipsychotics. High-dose use was associated with younger age (<80 years) (odds ratio [OR], 1.71; 95% confidence interval [CI], 1.36-2.15]), male sex (OR, 1.52; CI, 1.21-1.91), history of psychiatric disorder (OR, 3.25; CI, 2.54-4.15), and inversely associated with Charlson Comorbidity Index score (score 1: OR, 0.74; CI, 0.57-0.97; score ≥2: OR, 0.68; CI, 0.47-0.97). In conclusion, the majority of persons with AD used antipsychotics with low or medium dose. Typical antipsychotics were more often used with high dose than atypical antipsychotics, which indicates a need for precise dosing instructions in the treatment of behavioral and psychological symptoms of dementia. Clinicians should regularly assess dosing levels especially among men and those with history of psychiatric disorder.
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de Kuijper, G M; Hoekstra, P J
2017-10-01
People with intellectual disability (ID) frequently use antipsychotic drugs on an off-label base, often for many years. Physicians' decisions to discontinue these drugs not only depend on patient characteristics, like the presence of mental or behavioural disorders, but also on environmental factors, such as inappropriate living circumstances, and on attitudes, knowledge and beliefs of staff, clients and their representatives towards the effects of antipsychotic drug use. In this study, we therefore investigated the influence of participant and setting-related factors on decisions of physicians not to discontinue off-label prescribed antipsychotics. The study took place in living facilities of six service providers for people with ID spread over the Netherlands and staffed with support professionals, nurses, behavioural scientist and physicians and was part of an antipsychotics discontinuation trial. ID physicians had to decide whether the off-label use of antipsychotics could be discontinued. Medical and pharmaceutical records were used to establish the prevalence of antipsychotic drug use in the study population, along with duration of use and whether the use was off-label. Reasons of physicians not to discontinue the prescription of antipsychotics in those participants who used off-label antipsychotics for more than a year were collected and categorised as related to participant or setting characteristics, including lack of consent to discontinue, and staff members, participants or their legal representatives. Of the 3299 clients of the service providers, 977 used one or more antipsychotic drugs. The prevalence of antipsychotic drug use was 30%. Reasons for use were in 5% of cases, a chronic psychotic disorder classified according to Diagnostic System Mental Disorders, Fourth Edition, criteria, in 25%, present or past (suspected) non-schizophrenia-related psychotic symptoms and in 69%, challenging behaviours. Overall, physicians were willing to discontinue their prescriptions in 51% of cases, varying from 22% to 87% per service provider. The odds for decisions of physicians to discontinue off-label prescriptions varied from 0.19 to 13.95 per service provider. The variables 'a living situation with care and support' and 'challenging behaviour' were associated with a higher chance of discontinuation. The main reasons for decisions not to discontinue were concerns for symptoms of restlessness, the presence of an autism spectrum disorder, previously unsuccessful attempts to discontinue and objections against discontinuation of legal representatives. Reasons for physicians' decisions not to discontinue the off-label use of antipsychotics varied largely between the service providers. The prevalence of antipsychotic drug use for off-label indications in people with ID remains high. The results of this study indicate that there is a large variation in clinical practice of physicians regarding discontinuation of long-term antipsychotic drug prescriptions, which may be partially related to environmental factors as setting culture and attitudes of staff towards off-label antipsychotic drug use in persons with ID. © 2017 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.
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Koskinen, Hanna; Mikkola, Hennamari; Saastamoinen, Leena K; Ahola, Elina; Martikainen, Jaana E
2015-12-01
To analyze the medium- to long-term impact of generic substitution and the reference price system on the daily cost of antipsychotics in Finland. The additional impact of reference pricing over and above previously implemented generic substitution was also assessed. An interrupted time series design with a control group and segmented regression analysis was used to estimate the effect of the implementation of generic substitution and the reference price system on the daily cost of antipsychotics. The data have 69 monthly values of the average daily cost for each of the studied antipsychotics: 39 months before and 30 months after the introduction of reference pricing. For one of the studied antipsychotic, the time before the introduction of reference pricing could be further divided into time before and after the introduction of generic substitution. According to the model, 2.5 years after the implementation of reference pricing, the daily cost of the studied antipsychotics was 24.6% to 50.6% lower than it would have been if reference pricing had not been implemented. Two and a half years after the implementation of the reference price system, however, the additional impact of reference pricing over and above previously implemented generic substitution was modest, less than 1 percentage point. Although the price competition induced by reference pricing decreased the prices of antipsychotics in Finland in the short-term, the prices had a tendency to stagnate or even to turn in an upward direction in the medium- to long-term. Furthermore, the additional impact of reference pricing over and above previously implemented generic substitution remained quite modest. Copyright © 2015 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.
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Evaluation of the antipsychotic medication review process at four long-term facilities in Alberta.
Birney, Arden; Charland, Paola; Cole, Mollie; Aslam Arain, Mubashir
2016-01-01
The goal of this evaluation was to understand how four long-term care (LTC) facilities in Alberta have implemented medication reviews for the Appropriate Use of Antipsychotics (AUA) initiative. We aimed to determine how interprofessional (IP) collaboration was incorporated in the antipsychotic medication reviews and how the reviews had been sustained. Four LTC facilities in Alberta participated in this evaluation. We conducted semistructured interviews with 18 facility staff and observed one antipsychotic medication review at each facility. We analyzed data according to the following key components that we identified as relevant to the antipsychotic medication reviews: the structure of the reviews, IP interactions between the staff members, and strategies for sustaining the reviews. The duration of antipsychotic medication reviews ranged from 1 to 1.5 hours. The number of professions in attendance ranged from 3 to 9; a pharmacist led the review at two sites, while a registered nurse led the review at one site and a nurse practitioner at the remaining site. The number of residents discussed during the review ranged from 6 to 20. The process at some facilities was highly IP, demonstrating each of the six IP competencies. Other facilities conducted the review in a less IP manner due to challenges of physician involvement and staff workload, particularly of health care aides. Facilities that had an nurse practitioner on site were more efficient with the process of implementing recommendations resulting from the medication reviews. The LTC facilities were successful in implementing the medication review process and the process seemed to be sustainable. A few challenges were observed in the implementation process at two facilities. IP practice moved forward the goals of the AUA initiative to reduce the inappropriate use of antipsychotics.
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Schuster, Jean-Pierre; Raucher-Chéné, Delphine; Lemogne, Cédric; Rouillon, Frédéric; Gasquet, Isabelle; Leguay, Denis; Gierski, Fabien; Azorin, Jean-Michel; Limosin, Frédéric
2012-10-01
Although weight gain is one of the most widely studied adverse effects of second-generation antipsychotics, only relatively few studies have specifically evaluated the long-term effect of switching antipsychotic medication on body weight. We aimed to evaluate the impact of switching antipsychotics on body mass index (BMI) during a 6-month follow-up period in a large cohort of patients with schizophrenia. Data came from a 6-month prospective naturalistic survey in 6007 patients with schizophrenia. We prospectively studied the effect on BMI of initiating or switching antipsychotic medication after 6 months of treatment among 3801 patients with schizophrenia in a real-life setting. Patients who were being treated with clozapine or olanzapine at baseline were more likely to experience a decrease in BMI during the follow-up period than the patients who were being treated with a conventional antipsychotic (odds ratio, 2.25 and 1.68, respectively). Patients treated with aripiprazole and, to a lesser extent, those treated with risperidone were more likely to experience a decrease in BMI during follow-up than patients treated with conventional antipsychotics (odds ratio, 2.96 and 2.06, respectively). Our findings suggest that switching antipsychotics could be an effective strategy for reducing or preventing weight gain.
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Gordon, Michael S.; Vocci, Frank J.; Fitzgerald, Terrence T.; O'Grady, Kevin E.; O'Brien, Charles P.
2017-01-01
Background Extended-release naltrexone (XR-NTX), is an effective treatment for opioid use disorder but is rarely initiated in US prisons or with criminal justice populations. Mobile treatment for chronic diseases have been implemented in a variety of settings. Mobile treatment may provide an opportunity to expand outreach to parolees to surmount barriers to traditional clinic treatment. Methods Male and female prisoners (240) with pre-incarceration histories of opioid use disorder who are within one month of release from prison will be enrolled in this randomized clinical trial. Participants are randomized to one of two study arms: 1) [XR-NTX-OTx] One injection of long-acting naltrexone in prison, followed by 6 monthly injections post-release at a community opioid treatment program; or 2) [XR-NTX+ MMTx] One injection of long-acting naltrexone in prison followed by 6 monthly injections post-release at the patient's place of residence utilizing mobile medical treatment. The primary outcomes are: treatment adherence; opioid use; criminal activity; re-arrest; reincarceration; and HIV risk-behaviors. Results We describe the background and rationale for the study, its aims, hypotheses, and study design. Conclusions The use of long-acting injectable naltrexone may be a promising form of treatment for pre-release prisoners. Finally, as many individuals in the criminal justice system drop out of treatment, this study will assess whether treatment at their place of residence will improve adherence and positively affect treatment outcomes. PMID:28011389
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Gordon, Michael S; Vocci, Frank J; Fitzgerald, Terrence T; O'Grady, Kevin E; O'Brien, Charles P
2017-02-01
Extended-release naltrexone (XR-NTX), is an effective treatment for opioid use disorder but is rarely initiated in US prisons or with criminal justice populations. Mobile treatment for chronic diseases has been implemented in a variety of settings. Mobile treatment may provide an opportunity to expand outreach to parolees to surmount barriers to traditional clinic treatment. Male and female prisoners (240) with pre-incarceration histories of opioid use disorder who are within one month of release from prison will be enrolled in this randomized clinical trial. Participants are randomized to one of two study arms: 1) [XR-NTX-OTx] One injection of long-acting naltrexone in prison, followed by 6 monthly injections post-release at a community opioid treatment program; or 2) [XR-NTX+ MMTx] One injection of long-acting naltrexone in prison followed by 6 monthly injections post-release at the patient's place of residence utilizing mobile medical treatment. The primary outcomes are: treatment adherence; opioid use; criminal activity; re-arrest; reincarceration; and HIV risk-behaviors. We describe the background and rationale for the study, its aims, hypotheses, and study design. The use of long-acting injectable naltrexone may be a promising form of treatment for pre-release prisoners. Finally, as many individuals in the criminal justice system drop out of treatment, this study will assess whether treatment at their place of residence will improve adherence and positively affect treatment outcomes. ClinicalTrials.gov: NCT02867124. Copyright © 2016 Elsevier Inc. All rights reserved.
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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.
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Ishøy, P L; Fagerlund, B; Broberg, B V; Bak, N; Knop, F K; Glenthøj, B Y; Ebdrup, B H
2017-07-01
Schizophrenia is associated with profound cognitive and psychosocial impairments. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used for diabetes and obesity treatment, and animal studies have indicated cognitive-enhancing effects. In this investigator-initiated, double-blind, randomized, placebo-controlled trial, we tested non-metabolic effects of exenatide once-weekly (Bydureon™) in obese, antipsychotic-treated patients with schizohrenia spectrum disorder. Before and after 3 months of exenatide (N = 20) or placebo (N = 20) treatment, patients were assessed with the following: Brief Assessment of Cognition in Schizophrenia (BACS), Rey-Osterreith complex figure test (REY), Short-Form Health Survey (SF-36), Personal and Social Performance Scale (PSP) and the Positive and Negative Syndrome Scale (PANSS). We used BACS composite score as the main outcome measure. Repeated measures analysis of variance on BACS composite score showed significant effect of 'Time' (P < 0.001), no effect of 'Group' (P = 0.64) and no 'Time*Group' interaction (P = 0.77). For REY, SF-36, PSP and PANSS, only significant 'Time' effects were found. The non-significant results of this first clinical trial exploring non-metabolic effects of a long-acting GLP-1RA in patients with schizophrenia could reflect a general problem of translating cognitive-enhancing effects of GLP-1RAs from animals to humans or be explained by factors specifically related to schizophrenia spectrum patients with obesity such as antipsychotic treatment. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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Zisman-Ilani, Yaara; Shern, David; Deegan, Patricia; Kreyenbuhl, Julie; Dixon, Lisa; Drake, Robert; Torrey, William; Mishra, Manish; Gorbenko, Ksenia; Elwyn, Glyn
2018-05-22
People with psychosis struggle with decisions about their use of antipsychotics. They often want to reduce the dose or stop, while facing uncertainty regarding the effects these decisions will have on their treatment and recovery. They may also fear raising this issue with clinicians. The purpose of this study was to develop and test a shared decision making (SDM) tool to support patients and clinicians in making decisions about antipsychotics. A diverse editorial research team developed an Encounter Decision Aid (EDA) for patients and clinicians to use as part of the psychiatric consultation. The EDA was tested using 24 semistructured interviews with participants representing six stakeholder groups: patients with first-episode psychosis, patients with long-term psychosis, family members, psychiatrists, mental health counselors, and administrators. We used inductive and deductive coding of interview transcripts to identify points to revise within three domains: general impression and purpose of the EDA; suggested changes to the content, wording, and appearance; and usability and potential contribution to the psychiatric consultation. An EDA was developed in an iterative process that yielded evidence-based answers to five frequently asked questions about antipsychotic medications. Patients with long-term psychosis and mental health counselors suggested more changes and revisions than patients with first-episode psychosis and psychiatrists. Family members suggested more revisions to the answers about potential risks of stopping or adjusting antipsychotics than other respondents. The EDA was perceived as potentially useful and feasible in psychiatric routine care, especially if presented during the consultation.
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Jensen, Ralph J
2016-12-01
In the P23H rat model of retinitis pigmentosa, the dopamine D2 receptor antagonists sulpiride and eticlopride appear to improve visual responses of retinal ganglion cells (RGCs) by increasing light sensitivity of RGCs and transforming abnormal, long-latency ON-center RGCs into OFF-center cells. Antipsychotic drugs are believed to mediate their therapeutic benefits by blocking D2 receptors. This investigation was conducted to test whether haloperidol (a typical antipsychotic drug) and clozapine (an atypical antipsychotic drug) could similarly alter the light responses of RGCs in the P23H rat retina. Extracellular recordings were made from RGCs in isolated P23H rat retinas. Responses of RGCs to flashes of light were evaluated before and during bath application of a drug. Both haloperidol and clozapine increased light sensitivity of RGCs on average by ∼0.3 log unit. For those ON-center RGCs that exhibit an abnormally long-latency response to the onset of a small spot of light, both haloperidol and clozapine brought out a short-latency OFF response and markedly reduced the long-latency ON response. The selective serotonin 5-HT2A antagonist MDL 100907 had similar effects on RGCs. The effects of haloperidol on light responses of RGCs can be explained by its D2 receptor antagonism. The effects of clozapine on light responses of RGCs on the other hand may largely be due to its 5-HT2A receptor antagonism. Overall, the results suggest that antipsychotic drugs may be useful in improving vision in patients with retinitis pigmentosa.
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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.
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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.
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Dopamine and incentive learning: a framework for considering antipsychotic medication effects.
Beninger, Richard J
2006-12-01
Hyperfunction of brain dopamine (DA) systems is associated with psychosis in schizophrenia and the medications used to treat schizophrenia are DA receptor blockers. DA also plays a critical role in incentive learning produced by rewarding stimuli. Using DA as the link, these results suggest that psychosis in schizophrenia can be understood from the point of view of excessive incentive learning. Incentive learning is mediated through the non-declarative memory system and may rely on the striatum or medial prefrontal cortex depending on the task. Typical and atypical antipsychotics differentially affect expression of the immediate early gene c-fos, producing greater activity in the striatum and medial prefrontal cortex, respectively. This led to the hypothesis that performance of schizophrenic patients on tasks that depend on the striatum or medial prefrontal cortex will be differentially affected by their antipsychotic medication. Results from a number of published papers supported this dissociation. Furthermore, the effects of two atypical drugs, clozapine and olanzapine, on c-fos expression were different from another atypical, risperidone that resembles the typical antipsychotics. Similarly, in tests of incentive learning, risperidone acted like the typical antipsychotics. Thus, typical and atypical antipsychotic drugs differed in the types of cognitive performance they affected and, furthermore, members of the atypical class differed in their effects on cognition. It remains the task of researchers and clinicians to sort out the symptoms associated with the endogenous illness from possible iatrogenic symptoms resulting from the antipsychotic medications used to treat schizophrenia.
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Kose, Eiji; Uno, Kana; Hayashi, Hiroyuki
2017-01-01
Typical antipsychotics are easily expressed as adverse events such as extrapyramidal symptom (EPS). On the other hand, incidence of adverse events due to atypical antipsychotics is low. Therefore, currently, atypical antipsychotics are widely used to treat schizophrenia. However, it has been reported that there is no difference in the frequency of EPS in atypical and typical antipsychotics. This study aimed to evaluate the expression profile of EPS in atypical and typical antipsychotics treatment using the Japanese Adverse Drug Event Report (JADER) database. We analyzed reports of EPS in the JADER database and calculated the reporting odds ratio (ROR) of antipsychotics potentially associated with EPS. We applied the Weibull shape parameter to time-to-event data in the JADER database. Consequently, there was little information to distinguish between the ROR of atypical and typical antipsychotics. A significant difference related to the time of onset of EPS in both antipsychotics was not recognized. However, when comparing each drug, Paliperidone, Perospirone, Blonanserin, and Aripiprazole were relatively developed as EPS in the early stage. On the other hand, Risperidone, Clozapine, Olanzapine, and Quetiapine were developed as EPS not only at an early stage but also after long-term use. In addition, this finding was suggested from the result of the cumulative incidence of EPS in each drug and of the time-to-onset analysis using Weibull distribution. These findings may contribute to future clinical practice because we revealed the expression profile of EPS in treatment with atypical and typical antipsychotics.
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Understanding epigenetics of schizophrenia in the backdrop of its antipsychotic drug therapy.
Swathy, Babu; Banerjee, Moinak
2017-05-01
The diatheses of gene and environment interaction in schizophrenia (SCZ) are becoming increasingly evident. Genetic and epigenetic backgrounds are being considered in stratifying and addressing phenotypic variation and drug response in SCZ. But how much of these epigenetic alterations are the primary contributing factor, toward disease pathogenesis and drug response, needs further clarity. Evidence indicates that antipsychotic drugs can also alter the epigenetic homeostasis thereby inducing pharmacoepigenomic effects. We re-examine the context of epigenetics in disease pathogenesis and antipsychotic drug therapy in SCZ to understand how much of these observations act as real indicators of the disease or therapeutic response. We propose that epigenetic viewpoint in SCZ needs to be critically examined under the genetic, epigenetic and pharmacoepigenetic background.
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Tissue damage caused by the intramuscular injection of long-acting penicillin.
Schanzer, H; Jacobson, J H
1985-04-01
In order to elucidate whether tissue damage produced on occasion by intramuscular injection of long-acting penicillin is due to accidental intra-arterial injection or vasospasm, two types of experiments were carried out in rabbits. In the first set of experiments, six New Zealand White rabbits were given intra-arterial injections of 0.4 mL of a mixture containing 300,000 U of penicillin G benzathine and 300,000 units of penicillin procaine per milliliter (Bicillin C-R) into the left femoral artery and 0.4 mL of normal saline into the right femoral artery as autocontrol. In a second set of experiments, 0.4 mL of the same penicillin preparation was injected in the space surrounding the left femoral artery in five New Zealand rabbits, and 0.4 mL of normal saline was injected in a similar fashion around the right femoral artery as control. The legs of the rabbits that received the intra-arterial injection of penicillin invariably developed ischemic manifestations. None of the legs of rabbits given intra-arterial injections of normal saline had pathologic manifestations. None of the rabbits that received the periarterial penicillin preparation or normal saline developed abnormalities. These results strongly suggest that the tissue damage produced by penicillin is secondary to the intra-arterial administration of the drug.
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Strous, Rael D; Bar, Faina; Keret, Noa; Lapidus, Raya; Kosov, Nikolai; Chelben, Joseph; Kotler, Moshe
2006-01-01
Investigation of the clinical presentation and treatment of first-episode psychosis is important in order to exclude effects of age, chronic illness, long-term treatment and institutionalization. The aim of this descriptive study was to investigate the management practices of first-episode schizophrenia in a cohort of patients in Israel and to document use of the various "typical" or "atypical" antipsychotic agents. Fifty-one consecutive patients (26 M, 25 F) with first-episode psychosis were recruited for study participation and were administered either typical or atypical antipsychotic medications in a naturalistic manner. While an approximately equal number of subjects received typical and atypical medications at illness onset, a prominent shift to atypical antipsychotic treatment occurred over the study course; 18 subjects had medication class shifts: 17 from typical to atypical, and one from atypical to typical. Negative symptoms did not affect length of hospitalization, but were associated with aggression. Higher depression rates were noted in patients with long hospitalizations who received typical antipsychotic medications. Immigrants were admitted at an age approximately four years older than native-born Israelis. The prominent shift from "typical" to "atypical" antipsychotic medications may indicate sensitivity of first-episode psychotic patients to side-effects of "typical" medications and prominence of use of atypical medications in this patient subpopulation be it due to improved efficacy over time or successful marketing. Unique cultural and population characteristics may contribute to the manifestation of first-episode psychosis and suggest the importance of more effective outreach to the immigrant population in order to manage an apparent treatment delay.
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[Case report: Neuroleptic malignant syndrome and diagnostic difficulties].
Khouri, C; Planès, S; Logerot, S; Villier, C; Mallaret, M
2016-06-01
Neuroleptic malignant syndrome (NMS) is an uncommon but potentially fatal adverse effect of neuroleptic drugs. It is commonly characterized by muscular rigidity, fever, altered mental status, and autonomic dysfunction. Emerging of NMS is possible with all neuroleptics, classic and atypical. NMS occurs most often during the first week of treatment or after increasing the dosage of the neuroleptic medication. The frequency of NMS ranges from 0.07 to 2.2%. Its pathophysiology is not clearly understood but the blockade of dopamine receptors appears to be the central mechanism. Issues of NMS are those of diagnosis, treatment and reintroduction of antipsychotic treatment or not. We here present an interesting case because of its atypical clinical presentation and its slow resolution, illustrating the various problems linked to the NMS. A 55-year-old woman with a history of mental retardation and infantile psychosis is hospitalized for worsening of her psychiatric symptoms. She is treated by risperidone long-acting injection every 2weeks, escitalopram 20 mg/d and oxazepam 10 mg/d. Early December 2012, she had fever spikes treated with many antibiotics and neuroleptics were stopped, without improvement. Early January 2013, a pulmonary embolism was diagnosed, and a treatment with loxapine is introduced and her injection of risperidone is done because of the state of agitation of the patient. Two weeks later, a NMS is suspected to hyperthermia, tremor of the limbs, a slight stiffness, and neuroleptics are stopped. Dantrolene is then introduced, but after 7days of treatment the fever is still important. Other assumptions are then discussed: infection, serotonin syndrome, encephalopathy, catatonia, malignant hyperthermia. But diagnosis of NMS is finally retained because of the recurrence of symptoms after introduction of clozapine early February. In this patient, diagnosis was made more difficult by the use of long-acting neuroleptic. NMS was indeed partly rejected because of the lack of improvement despite 7 days of dantrolene treatment, but the release of risperidone lasts 7weeks after the injection. This NMS is also of atypical presentation with a minor muscular rigidity. And this case is particularly interesting because of the recurrence of NMS with clozapine, allowing to finally diagnose it. This atypical neuroleptic is not known to be a major provider of NMS but the very short period before reintroduction and possible persistence of risperidone in the body could explain the recurrence. NMS can be hard to diagnose. It is a diagnosis of exclusion, but we should keep in mind that there is great variability of its clinical presentation in order to not exclude too quickly this syndrome in a patient treated by neuroleptic. Copyright © 2016 L'Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.
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Bulking up the hippocampus in schizophrenia: a role for 5-HT1A agonists?
Frangou, Sophia
2016-07-01
The volume of the hippocampus is reduced in patients with schizophrenia, and this deficit tends to become more pronounced with chronicity. Newer antipsychotics may protect against the progressive reductions in hippocampal volume while preliminary data offer hope that specific antipsychotics may act to reverse it. 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.
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Baert, Lieven; van 't Klooster, Gerben; Dries, Willy; François, Marc; Wouters, Alfons; Basstanie, Esther; Iterbeke, Koen; Stappers, Fred; Stevens, Paul; Schueller, Laurent; Van Remoortere, Pieter; Kraus, Guenter; Wigerinck, Piet; Rosier, Jan
2009-08-01
Long-acting parenteral formulations of antiretrovirals could facilitate maintenance and prophylactic treatment in HIV. Using the poorly water- and oil-soluble non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC278 (rilpivirine) as base or hydrochloride (HCl), nanosuspensions were prepared by wet milling (Elan NanoCrystal technology) in an aqueous carrier. Laser diffraction showed that the average particles size were (1) close to the targeted size proportionality (200-400-800 nm), with increasing distributions the larger the average particle size, and (2) were stable over 6 months. Following single-dose administration, the plasma concentration profiles showed sustained release of TMC278 over 3 months in dogs and 3 weeks in mice. On comparison of intramuscular and subcutaneous injection of 5mg/kg (200 nm) in dogs, the subcutaneous route resulted in the most stable plasma levels (constant at 25 ng/mL for 20 days, after which levels declined slowly to 1-3 ng/mL at 3 months); 200 nm nanosuspensions achieved higher and less variable plasma concentration profiles than 400 and 800 nm nanosuspensions. In mice, the pharmacokinetic profiles after a single 20mg/kg dose (200 nm) were similar with two different surfactants used (poloxamer 338, or d-alpha-tocopheryl polyethylene glycol 1000 succinate). In conclusion, this study provides proof-of-concept that 200-nm sized TMC278 nanosuspensions may act as long-acting injectable.
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Wood, S M; Kraenzlin, M E; Adrian, T E; Bloom, S R
1985-01-01
Seven patients with gut and pancreatic endocrine tumours have been treated with a long acting somatostatin analogue (SMS 201-995), given as a twice daily subcutaneous injection. This produced dramatic improvement in their endocrine related symptoms, in association with a fall in circulating tumour peptides. One of these patients has now been treated for seven months with this analogue which has controlled his previously life threatening diarrhoea caused by a malignant VIP secreting tumour. He gives his own injections twice daily, and has returned to a full and active life. This is a promising agent both for acute treatment of peptide hypersecretion, and for the long term management of some patients who are unresponsive to other available therapy. PMID:2860052
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Wood, S M; Kraenzlin, M E; Adrian, T E; Bloom, S R
1985-05-01
Seven patients with gut and pancreatic endocrine tumours have been treated with a long acting somatostatin analogue (SMS 201-995), given as a twice daily subcutaneous injection. This produced dramatic improvement in their endocrine related symptoms, in association with a fall in circulating tumour peptides. One of these patients has now been treated for seven months with this analogue which has controlled his previously life threatening diarrhoea caused by a malignant VIP secreting tumour. He gives his own injections twice daily, and has returned to a full and active life. This is a promising agent both for acute treatment of peptide hypersecretion, and for the long term management of some patients who are unresponsive to other available therapy.
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Neale, Joanne; Tompkins, Charlotte N E; McDonald, Rebecca; Strang, John
2018-05-25
Long-acting opioid pharmacotherapy (OPT) is presumed to offer benefits over more conventional OPT formulations. This paper analyzes the views and experiences of people who use or have used heroin in order to explore two novel systems for delivering long-acting OPT: implants and depot injections. New materialism theorizing is used to interpret and frame the findings. Qualitative data were generated via seven focus groups conducted during 2017 in London, UK. Participants (n = 44; 28 men and 16 women; ages 33-66 years) had all received OPT. Focus group discussions covered real and potential OPT delivery systems. All participant data relating to implants and depot injections were coded using MAXQDA software and analysed inductively via Iterative Categorisation. Participants discussed implants and depot injections in terms of interacting physical, psychological and social factors: dose stability; OPT administration; stopping treatment; co-presence of an antagonist; breaking rituals and habits; reduced choice and control; feeling normal; information needs; getting on with everyday life; and social interaction. Participants identified both benefits and concerns, and variable needs and preferences, with respect to each delivery system. Implants and depot injections are not 'fixed' medications that can be administered to people to achieve pre-determined treatment aims. Rather, they are complex 'assemblages' with uncertain outcomes. Furthermore, they are themselves part of wider interactive 'assemblages'. Drug developers and treatment providers need to understand this complexity in order to target long-acting OPT at people most likely to benefit from it, and to reduce any unintended negative consequences. Copyright © 2018 Elsevier B.V. All rights reserved.
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Cognitive and psychomotor effects of risperidone in schizophrenia and schizoaffective disorder.
Houthoofd, Sofie A M K; Morrens, Manuel; Sabbe, Bernard G C
2008-09-01
The aim of this review was to discuss data from double-blind, randomized controlled trials (RCTs) that have investigated the effects of oral and long-acting injectable risperidone on cognitive and psychomotor functioning in patients with schizophrenia or schizoaffective disorder. PubMed/MEDLINE and the Institute of Scientific Information Web of Science database were searched for relevant English-language double-blind RCTs published between March 2000 and July 2008, using the terms schizophrenia, schizoaffective disorder, cognition, risperidone, psychomotor, processing speed, attention, vigilance, working memory, verbal learning, visual learning, reasoning, problem solving, social cognition, MATRICS, and long-acting. Relevant studies included patients with schizophrenia or schizoaffective disorder. Cognitive domains were delineated at the Consensus Conferences of the National Institute of Mental Health-Measurement And Treatment Research to Improve Cognition in Schizophrenia (NIMH-MATRICS). The tests employed to assess each domain and psychomotor functioning, and the within-group and between-group comparisons of risperidone with haloperidol and other atypical antipsychotics, are presented. The results of individual tests were included when they were individually presented and interpretable for either drug; outcomes that were presented as cluster scores or factor structures were excluded. A total of 12 articles were included in this review. Results suggested that the use of oral risperidone appeared to be associated with within-group improvements on the cognitive domains of processing speed, attention/vigilance, verbal and visual learning and memory, and reasoning and problem solving in patients with schizophrenia or schizoaffective disorder. Risperidone and haloperidol seemed to generate similar beneficial effects (on the domains of processing speed, attention/vigilance, [verbal and nonverbal] working memory, and visual learning and memory, as well as psychomotor functioning), although the results for verbal fluency, verbal learning and memory, and reasoning and problem solving were not unanimous, and no comparative data on social cognition were available. Similar cognitive effects were found with risperidone, olanzapine, and quetiapine on the domains of verbal working memory and reasoning and problem solving, as well as verbal fluency. More research is needed on the domains in which study results were contradictory. For olanzapine versus risperidone, these were verbal and visual learning and memory and psychomotor functioning. No comparative data for olanzapine and risperidone were available for the social cognition domain. For quetiapine versus risperidone, the domains in which no unanimity was found were processing speed, attention/vigilance, nonverbal working memory, and verbal learning and memory. The limited available reports on risperidone versus clozapine suggest that: risperidone was associated with improved, and clozapine with worsened, performance on the nonverbal working memory domain; risperidone improved and clozapine did not improve reasoning and problem-solving performance; clozapine improved, and risperidone did not improve, social cognition performance. Use of long-acting injectable risperidone seemed to be associated with improved performance in the domains of attention/vigilance, verbal learning and memory, and reasoning and problem solving, as well as psychomotor functioning. The results for the nonverbal working memory domain were indeterminate, and no clear improvement was seen in the social cognition domain. The domains of processing speed, verbal working memory, and visual learning and memory, as well as verbal fluency, were not assessed. The results of this review of within-group comparisons of oral risperidone suggest that the agent appeared to be associated with improved functioning in the cognitive domains of processing speed, attention/vigilance, verbal and visual learning and memory, and reasoning and problem solving in patients with schizophrenia or schizoaffective disorder. Long-acting injectable risperidone seemed to be associated with improved functioning in the domains of attention/vigilance, verbal learning and memory, and reasoning and problem solving, as well as psychomotor functioning, in patients with schizophrenia or schizoaffective disorder.
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Heusler, Peter; Newman-Tancredi, Adrian; Loock, Timothé; Cussac, Didier
2008-02-26
Antipsychotic drugs act preferentially via dopamine D(2) receptor blockade, but interaction with serotonin 5-HT(1A) receptors has attracted interest as additional target for antipsychotic treatment. As receptor internalisation is considered crucial for drug action, we tested the propensity of antipsychotics to internalise human (h)D(2S) receptors and h5-HT(1A) receptors. Agonist-induced internalisation of hemaglutinin (HA)-tagged hD(2S) and HA-h5-HT(1A) receptors expressed in HEK293 cells was increased by coexpression of G-protein coupled receptor kinase 2 and beta-arrestin2. At the HA-hD(2S) receptor, dopamine, quinpirole and bromocriptine behaved as full agonists, while S(-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine [(-)-3PPP] and sarizotan were partial agonists. The typical antipsychotic, haloperidol, and the atypical compounds, olanzapine, nemonapride, ziprasidone and clozapine did not internalise HA-hD(2S) receptors, whereas aripiprazole potently internalised these receptors (>50% relative efficacy). Among antipsychotics with combined D(2)/5-HT(1A) properties, bifeprunox and (3-exo)-8-benzoyl-N-[[(2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl]methyl]-8-azabicyclo-[3.2.1]octane-3-methanamine (SSR181507) partially internalised HA-hD(2S) receptors, piperazine, 1-(2,3-dihydro-1,4-benzodioxin-5-yl)-4-[[5-(4-fluorophenyl)-3-pyridinyl]methyl (SLV313) and N-[(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)ethyl]-3-(cyclopent-1-enyl)-benzylamine (F15063) were inactive. At the HA-h5-HT(1A) receptor, serotonin, (+)-8-hydroxy-2-(di-n-propylamino)tetralin [(+)-8-OH-DPAT] and sarizotan were full agonists, buspirone acted as partial agonist. (-)-Pindolol showed little activity and no internalising properties were manifested for the 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide (WAY100635). Most antipsychotics induced HA-h5-HT(1A) receptor internalisation, with an efficacy rank order: nemonapride>F15063>SSR181507>bifeprunox approximately SLV313 approximately ziprasidone>aripiprazole and potencies: SLV313>SSR181507 approximately F15063>bifeprunox approximately nemonapride approximately aripiprazole>ziprasidone. Interestingly, the internalisation induced by clozapine was only minimal, whereas aripirazole and bifeprunox were more potent for internalisation than for G-protein activation. These different profiles of antipsychotics for receptor internalisation may help to evaluate their potential therapeutic impact in the treatment of schizophrenia.
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Medication and aggressiveness in real-world schizophrenia. Results from the FACE-SZ dataset.
Fond, G; Boyer, L; Favez, M; Brunel, L; Aouizerate, B; Berna, F; Capdevielle, D; Chereau, I; Dorey, J M; Dubertret, C; Dubreucq; Faget, C; Gabayet, F; Laouamri, H; Lancon, C; Le Strat, Y; Misdrahi, D; Rey, R; Passerieux, C; Schandrin, A; Schurhoff, F; Tronche, A M; Urbach, M; Vidalhet, P; Llorca, P M; Pelissolo, A
2016-02-01
The primary objective of this study was to determine if second-generation antipsychotic (SGA) administration was associated with lower aggressiveness scores compared to first-generation (FGA) in schizophrenia (SZ). The secondary objective was to determine if antidepressants, mood stabilizers, and benzodiazepines administration were respectively associated with lower aggressiveness scores compared to patients who were not administered these medications. Three hundred thirty-one patients with schizophrenia (N = 255) or schizoaffective disorder (N = 76) (mean age = 32.5 years, 75.5 % male gender) were systematically included in the network of FondaMental Expert Center for Schizophrenia and assessed with the structured clinical interview for DSM-IV Axis I disorders and validated scales for psychotic symptomatology, insight, and compliance. Aggressiveness was measured by the Buss-Perry Aggression Questionnaire (BPAQ) score. Ongoing psychotropic treatment was recorded. Patients who received SGA had lower BPAQ scores than patients who did not (p = 0.01). More specifically, these patients had lower physical and verbal aggression scores. On the contrary, patients who received benzodiazepines had higher BPAQ scores than patients who did not (p = 0.04). No significant difference was found between BPAQ scores of patients respectively being administered mood stabilizers (including valproate), antidepressant, and the patients who were not. These results were found independently of socio-demographical variables, psychotic symptomatology, insight, compliance into treatment, daily-administered antipsychotic dose, the way of antipsychotic administration (oral vs long acting), current alcohol disorder, and daily cannabis consumption. The results of the present study are in favor of the choice of SGA in SZ patients with aggressiveness, but these results need further investigation in longitudinal studies. Given the potent side effects of benzodiazepines (especially dependency and cognitive impairment) and the results of the present study, their long-term prescription is not recommended in patients with schizophrenia and aggressive behavior.
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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.
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Epidemiology, Prevention, and Assessment of Tardive Dyskinesia and Advances in Treatment.
Correll, Christoph U; Kane, John M; Citrome, Leslie L
Tardive dyskinesia (TD) is a disorder characterized by involuntary movements, typically of the orofacial muscles and also of the extremities and other muscle groups. The condition is associated with exposure to dopamine receptor blocking agents, including antipsychotics. Because the indications and off-label uses for these agents have expanded over the last 2 decades, a larger number of patients are receiving antipsychotic medications than in the past. While evidence suggests that patients being treated with second-generation antipsychotics have less risk for developing TD than those treated with first-generation antipsychotics, the decreased risk is not as great as was originally expected. In addition, patients with chronic psychiatric conditions often require long-term use of antipsychotics, putting them at risk for TD. This article addresses the prevalence, risk factors, and prevention of TD; assessment strategies including diagnostic criteria and rating scales; and evidence for TD treatments, including 2 newly approved medications: deutetrabenazine and valbenazine. . © Copyright 2017 Physicians Postgraduate Press, Inc.
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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.
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Aripiprazole: the evidence of its therapeutic impact in schizophrenia
Winlow, William; Profit, Louise; Chrisp, Paul
2006-01-01
Introduction: An ideal antipsychotic would rapidly stabilize acute psychotic symptoms and maintain the patient, without relapse, for prolonged periods in the absence of extrapyramidal, endocrine, diabetic, or cardiovascular side effects, and without weight gain. The dopamine partial agonist aripiprazole is compared with this ideal and with conventional antipsychotics, such as haloperidol, and with atypical antipsychotics. Aims: To review the evidence for the clinical impact of aripiprazole in the treatment of patients with schizophrenia. Evidence review: There is clear evidence that aripiprazole is as effective as haloperidol in reducing the positive and negative symptoms of schizophrenia and schizoaffective disorder. In patients with schizophrenia, aripiprazole has been shown to stabilize acute psychotic symptoms, prevent relapse in stabilized patients, and maintain patients with schizophrenia following acute relapse. Furthermore, in common with other atypical antipsychotics, aripiprazole appears to be associated with a lower incidence of side effects than typical antipsychotics and may reduce discontinuation of drug therapy. Evidence also suggests that aripiprazole may be associated with a lower incidence of extrapyramidal symptoms than conventional antipsychotics, but further long-term studies concerning tardive dyskinesia are required. Studies on the cost effectiveness of aripiprazole, as well as the quality of life and general functioning of patients taking the drug are still required, although there is some evidence of improved quality of life. Further evidence comparing aripiprazole with other atypical antipsychotics would be welcome. Clinical value: In conclusion, aripiprazole is an atypical antipsychotic suitable for first-line use in patients with schizophrenia. Its clinical value in relation to other atypical antipsychotics remains to be elucidated. PMID:22496680
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Tao, Xuguang Grant; Lavin, Robert A; Yuspeh, Larry; Weaver, Virginia M; Bernacki, Edward J
2015-02-01
To study the relationship between the use of psychotropic and opioid medications with workers' compensation disability and costs. The study population included lost time claimants injured between 1999 and 2002 followed to closing in December 31, 2009. Controlling for age, sex, marital status, attorney involvement, and spinal surgeries, multivariate logistic regression revealed that odds ratios (95% confidence interval) of claim costs ≥$100,000 compared with claimants who were never prescribed opioids were 4.3 for short-acting opioids only; 8.6 for any use of long-acting opioids; 2.8 for any use of hypnotics; 2.6 for any use of antipsychotics; 1.6 for any use of anti-anxiety agents; and 2.9 for any use of antidepressants. The use of psychotropic and opioid medications was associated with high workers' compensation costs and prolonged disability.
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Klewe, Ib V.; Nielsen, Søren M.; Tarpø, Louise; Urizar, Eneko; Dipace, Concetta; Javitch, Jonathan A.; Gether, Ulrik; Egebjerg, Jan; Christensen, Kenneth V.
2013-01-01
Drugs acting at dopamine D2-like receptors play a pivotal role in the treatment of both schizophrenia and Parkinson’s disease. Recent studies have demonstrated a role for G-protein independent D2 receptor signaling pathways acting through β-arrestin. In this study we describe the establishment of a Bioluminescence Resonance Energy Transfer (BRET) assay for measuring dopamine induced recruitment of human β-arrestin2 to the human dopamine D2 receptor. Dopamine, as well as the dopamine receptor agonists pramipexole and quinpirole, acted as full agonists in the assay as reflected by their ability to elicit marked concentration dependent increases in the BRET signal signifying β-arrestin2 recruitment to the D2 receptor. As expected from their effect on G-protein coupling and cAMP levels mediated through the D2 receptor RNPA, pergolide, apomorphine, ropinirole, bromocriptine, 3PPP, terguride, aripiprazole, SNPA all acted as partial agonists with decreasing efficacy in the BRET assay. In contrast, a wide selection of typical and atypical anti-psychotics was incapable of stimulating β-arrestin2 recruitment to the D2 receptor. Moreover, we observed that haloperidol, sertindole, olanzapine, clozapine and ziprasidone all fully inhibited the dopamine induced β-arrestin2 recruitment to D2 receptor (short variant) in a concentration dependent manner. We conclude that most anti-psychotics are incapable of stimulating β-arrestin2 recruitment to the dopamine D2 receptor, in accordance with their antagonistic properties at the level of G-protein coupling. PMID:18455202
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Treatment of Bipolar Disorder in a Lifetime Perspective: Is Lithium Still the Best Choice?
Sani, Gabriele; Perugi, Giulio; Tondo, Leonardo
2017-08-01
Lithium preparations have been successfully used to treat bipolar disorder (BD), and remain the best established long-term treatment for the disorder. In fact, lithium is a cornerstone of treatment to minimize the risk of recurrences and improve inter-episodic symptomatology. We reviewed the available evidence for the use of lithium in the treatment of BD, including its efficacy, limitations, and potential benefits also in consideration of the different formulations available. We also overviewed salient comparative aspects regarding the long-term alternative use of anticonvulsants, antidepressants, and antipsychotics in BD patients. The available evidence indicates that BD patients should be treated primarily with lithium, combined in some cases with antipsychotics especially in acute treatments, and sometimes, because of intolerance or inefficacy of lithium, with anticonvulsants. The use of adjunctive antidepressants should be limited to episodes of breakthrough depression. Lithium should be offered to the majority of BD patients as initial treatment especially when suicide ideation or behavior is present with adequate information about its long-term benefits and its potential side effects. Many patients can tolerate lithium without concomitant use of antidepressants, which may worsen the course of the illness or antipsychotics, which may cause severe long-term side effects.
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Rajoli, Rajith KR; Back, David J; Rannard, Steve; Meyers, Caren Freel; Flexner, Charles; Owen, Andrew; Siccardi, Marco
2014-01-01
Background and Objectives Antiretrovirals (ARVs) are currently used for the treatment and prevention of HIV infection. Poor adherence and low tolerability of some existing oral formulations can hinder their efficacy. Long-acting (LA) injectable nanoformulations could help address these complications by simplifying ARV administration. The aim of this study is to inform the optimisation of intramuscular LA formulations for eight ARVs through physiologically-based pharmacokinetic (PBPK) modelling. Methods A whole-body PBPK model was constructed using mathematical descriptions of molecular, physiological and anatomical processes defining pharmacokinetics. These models were validated against available clinical data and subsequently used to predict the pharmacokinetics of injectable LA formulations Results The predictions suggest that monthly intramuscular injections are possible for dolutegravir, efavirenz, emtricitabine, raltegravir, rilpivirine and tenofovir provided that technological challenges to control release rate can be addressed. Conclusions These data may help inform the target product profiles for LA ARV reformulation strategies. PMID:25523214
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ERIC Educational Resources Information Center
Fodstad, Jill C.; Bamburg, Jay W.; Matson, Johnny L.; Mahan, Sara; Hess, Julie A.; Neal, Daniene; Holloway, Jodie
2010-01-01
Atypical antipsychotic medications are commonly used in large-scale residential care facilities for adults with developmental disabilities. While the benefits of this class of psychotropics are noted, debate exists whether the side effect profile of these medications outweigh their therapeutic benefit, especially in those who use them long-term.…
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Maust, Donovan T; Kim, H Myra; Chiang, Claire; Kales, Helen C
2018-03-17
The Centers for Medicare & Medicaid Services' National Partnership to Improve Dementia Care in Nursing Homes (hereafter referred to as the partnership) was established to improve the quality of care for patients with dementia, measured by the rate of antipsychotic prescribing. To determine the association of the partnership with trends in prescribing of antipsychotic and other psychotropic medication among older adults in long-term care. This interrupted time-series analysis of a 20% Medicare sample from January 1, 2009, to December 31, 2014, was conducted among 637 426 fee-for-service Medicare beneficiaries in long-term care with Part D coverage. Data analysis was conducted from May 1, 2017, to January 9, 2018. Quarterly prevalence of use of antipsychotic and nonantipsychotic psychotropic medications (antidepressants, mood stabilizers [eg, valproic acid and carbamazepine], benzodiazepines, and other anxiolytics or sedative-hypnotics). Among the 637 426 individuals in the study (446 538 women and 190 888 men; mean [SD] age at entering nursing home, 79.3 [12.1] years), psychotropic use was declining before initiation of the partnership with the exception of mood stabilizers. In the first quarter of 2009, a total of 31 056 of 145 841 patients (21.3%) were prescribed antipsychotics, which declined at a quarterly rate of -0.53% (95% CI, -0.63% to -0.44%; P < .001) until the start of the partnership. At that point, the quarterly rate of decline decreased to -0.29% (95% CI, -0.39% to -0.20%; P < .001), a postpartnership slowing of 0.24% per quarter (95% CI, 0.09%-0.39%; P = .003). The use of mood stabilizers was growing before initiation of the partnership and then accelerated after initiation of the partnership (rate, 0.22%; 95% CI, 0.18%-0.25%; P < .001; rate change, 0.14%; 95% CI, 0.10%-0.18%; P < .001), reaching 71 492 of 355 716 patients (20.1%) by the final quarter of 2014. Antidepressants were the most commonly prescribed medication overall: in the beginning of 2009, a total of 75 841 of 145 841 patients (52.0%) were prescribed antidepressants. As with antipsychotics, antidepressant use declined both before and after initiation of the partnership, but the decrease slowed (rate change, 0.34%; 95% CI, 0.18%-0.50%; P < .001). Findings were similar when limited to patients with dementia. Prescribing of psychotropic medications to patients in long-term care has declined, although the partnership did not accelerate this decrease. However, the use of mood stabilizers, possibly as a substitute for antipsychotics, increased and accelerated after initiation of the partnership in both long-term care residents overall and in those with dementia. Measuring use of antipsychotics alone may be an inadequate proxy for quality of care and may have contributed to a shift in prescribing to alternative medications with a poorer risk-benefit balance.
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Carnahan, Ryan M; Letuchy, Elena M
2018-01-01
Nursing home quality measures include the proportion of residents who receive antipsychotics. Residents with bipolar disorder are included even though antipsychotics are FDA-approved for this indication. We evaluated how including residents with bipolar disorder impacted the antipsychotic use quality measure for long-stay residents. We evaluated the agreement of minimum data set (MDS) bipolar disorder diagnoses with Medicare data, whether dementia was diagnosed before bipolar disorder, and how less-specific bipolar disorder diagnoses impacted findings. Cross-sectional study. Nursing homes in Iowa. 21,955 long-stay nursing home residents in the first quarter of 2014. We identified antipsychotic use and bipolar disorder using MDS data. We compared MDS bipolar disorder diagnoses with Chronic Conditions Warehouse (CCW) "ever" bipolar disorder indicators, and prior year claims. We compared CCW condition onset dates to identify bipolar disorder diagnosed after dementia. The mean (SD) proportion receiving antipsychotics was 19.6% (11.1%) with bipolar disorder and 18.3% (10.8%) without. The positive predictive value (PPV) of MDS bipolar disorder diagnoses was 80.2% versus CCW lifetime indicators, and 74.6% versus claims. PPV decreased by 27.1% when "bipolar disorder, unspecified" and "other bipolar disorders" diagnoses were excluded. Nearly three-quarters of residents with bipolar disorder had dementia. Over half of those with dementia had dementia first per CCW records. This proportion was lower among those with more specific bipolar disorder diagnoses or MDS bipolar disorder indicators. Bipolar disorder in nursing home residents is often first diagnosed after dementia using nonspecific diagnoses. This practice deserves further evaluation. Copyright © 2017 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.
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Olivares, Jose Manuel; Thirunavukarasu, Manickam; Kulkarni, Jayashri; Zhang, Hong Yan; Zhang, Mingyuan; Zhang, Fan
2013-01-01
Nonadherence is a well-known problem among schizophrenia patients, among whom relapse is fivefold more likely, adversely affecting health, employment, and social functioning. The Spanish Adherencia Terapéutica en la Esquizofrenia (ADHES) survey was developed to determine the scope and causes of medication nonadherence in schizophrenia. The 20-question ADHES survey was distributed to 19,370 psychiatrists in 13 Asia-Pacific countries in January-April 2012, to ascertain psychiatrists' perceptions of antipsychotic medication adherence levels among their schizophrenia patients, reasons for partial/nonadherence, their preferred methods of assessing adherence, and strategies to improve adherence. Responses are reported as mean and range across countries. Four thousand, six hundred sixty one psychiatrists (24% of recipients) completed the survey (highest contributors: People's Republic of China, 1854; India, 1616). Psychiatrists perceived that 56% (range, 30%-71%) of schizophrenia patients were non- or partially adherent to medication. Patients discontinue medication primarily due to lack of insight into their condition (mean, 37%; 1%-65%) and because patients consider medication unnecessary when feeling better (mean, 27%; 15%-68%). Over half of psychiatrists (mean, 55%; 42%-99%) assess medication adherence at every visit, almost exclusively (81%) by asking their patients, versus quantitative measures. One in three psychiatrists expressed their preference to switch to or add a long-acting antipsychotic to improve adherence (15%-82%). The substantial prevalence of partial/nonadherence to medication demonstrates that more proactive management of patients with schizophrenia is needed to improve adherence and thereby treatment outcomes. Registration of this study was not required.
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Repurposing psychiatric drugs as anti-cancer agents.
Huang, Jing; Zhao, Danwei; Liu, Zhixiong; Liu, Fangkun
2018-04-10
Cancer is a major public health problem and one of the leading contributors to the global disease burden. The high cost of development of new drugs and the increasingly severe burden of cancer globally have led to increased interest in the search and development of novel, affordable anti-neoplastic medications. Antipsychotic drugs have a long history of clinical use and tolerable safety; they have been used as good targets for drug repurposing. Being used for various psychiatric diseases for decades, antipsychotic drugs are now reported to have potent anti-cancer properties against a wide variety of malignancies in addition to their antipsychotic effects. In this review, an overview of repurposing various psychiatric drugs for cancer treatment is presented, and the putative mechanisms for the anti-neoplastic actions of these antipsychotic drugs are reviewed. Copyright © 2018 Elsevier B.V. All rights reserved.
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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.
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Behavioral Weight Loss Treatment in Antipsychotic Treated Youth.
Nicol, Ginger E; Kolko, Rachel P; Mills, Monica; Gunnarsdottir, Thrudur; Yingling, Michael D; Schweiger, Julia A; Lenze, Eric J; Newcomer, John W; Wilfley, Denise
2016-05-01
Antipsychotic-treated youth have increased risk for the development of obesity and type 2 diabetes. Behavioral weight loss treatments show promise in reducing obesity and diabetes risk in antipsychotic treated adults, but have received no study in antipsychotic treated youth. We describe a rationale for behavioral weight loss interventions in high-weight antipsychotic treated youth, and report behavioral, anthropomorphic, and metabolic findings from a case series of obese antipsychotic-treated adolescents participating in a short-term, family-based behavioral weight loss intervention. We adapted the Traffic Light Plan, a 16-week family-based weight loss intervention that promotes healthy energy balance using the colors of the traffic light to categorize the nutritional value of foods and intensity of physical activity, adapting a social ecological framework to address health behavior change in multiple social contexts. The intervention was administered to three obese adolescents with long-term antipsychotic medication exposure. Efficacy of the intervention was evaluated with a battery of anthropomorphic and metabolic assessments including weight, body mass index percentile, whole body adiposity, liver fat content, and fasting plasma glucose and lipids. Participants and their parents also filled out a treatment satisfaction questionnaire upon study completion. Two males and 1 female (all aged 14 years) participated. All 3 participants attended all 16 sessions, and experienced beneficial changes in adiposity, fasting lipids and liver fat content associated with weight stabilization or weight loss. Adolescents and their parents all reported a high level of satisfaction with the treatment. Family-based behavioral weight loss treatment can be feasibly delivered and is acceptable to antipsychotic-treated youth and their families. Randomized controlled trials are needed to fully evaluate the effectiveness and acceptability of behavioral weight loss interventions in antipsychotic treated youth and their families.
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Antipsychotics and dementia in Canada: a retrospective cross-sectional study of four health sectors.
Rios, Sebastian; Perlman, Christopher M; Costa, Andrew; Heckman, George; Hirdes, John P; Mitchell, Lori
2017-10-23
Antipsychotic medications are not recommended for the management of symptoms of dementia, particularly among persons with no behavioral or psychological symptoms. We examine patterns of antipsychotic medication use among persons with dementia across health sectors in Canada, with a focus on factors related to use among those without behavioral or psychotic symptoms. Using a retrospective cross-sectional design, this study examines antipsychotic use among adults aged 65 or older with dementia in home care (HC), complex continuing care (CCC), long-term care (LTC), and among alternate level care patients in acute hospitals (ALC). Using clinical data from January 1, 2009 to December 31, 2014, the prevalence of antipsychotic medication use was estimated by the presence of behavioral and psychotic symptoms. Logistic regression was used to identify sector specific factors associated with antipsychotic use in the absence of behavioral and psychotic symptoms. The total prevalence of antipsychotic use among older adults with dementia was 26% in HC, 54% in ALC, 41% in CCC, and 48% in LTC. This prevalence ranged from 38% (HC) to 73% (ALC) for those with both behavioral and psychotic symptoms and from 15% (HC) to 31% (ALC) among those with no symptoms. The regression models identified a number of variables were related to antipsychotic use in the absence of behavior or psychotic symptoms, such as bipolar disorder (OR = 6.63 in CCC; OR = 5.52 in LTC), anxious complaints (OR = 1.54 in LTC to 2.01 in CCC), and wandering (OR = 1.83 in ALC). Potentially inappropriate use of antipsychotic medications is prevalent among older adults with dementia across health sectors. The variations in prevalence observed from community to facility based care suggests that system issues may exist in appropriately managing persons with dementia.
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Dennis, Michael; Shine, Laura; John, Ann; Marchant, Amanda; McGregor, Joanna; Lyons, Ronan A; Brophy, Sinead
2017-06-01
Over recent years there has been growing evidence of increased risk of mortality associated with antipsychotic use in older people with dementia. Although this concern combined with limited evidence of efficacy has informed guidelines restricting antipsychotic prescription in this population, the use of antipsycotics remains common. Many published studies only report short-term outcomes, are restricted to examining mortality and stroke risk or have other limitations. The aim of this study was to assess adverse outcomes associated with the use of antipsychotics in older people living with dementia in Wales (UK). This was a retrospective study of a population-based dementia cohort using the Welsh Secure Anonymised Information Linkage databank. The prior event rate ratio (PERR) was used to estimate the influence of exposure to antipsychotic medication on acute cardiac events, venous thromboembolism, stroke and hip fracture, and adjusted Cox proportional hazard models were used to compare all-cause mortality. A total of 10,339 people aged ≥65 years were identified with newly diagnosed dementia. After excluding those who did not meet the inclusion criteria, 9674 people remained in the main cohort of whom 3735 were exposed to antipsychotic medication. An increased risk of a venous thromboembolic episode [PERR 1.95, 95% confidence interval (CI) 1.83-2.0], stroke (PERR 1.41, 95% CI 1.4-1.46) and hip fracture (PERR 1.62, 95% CI 1.59-1.65) was associated with antipsychotic use. However, there was no long-term increased mortality in people exposed to antipsychotics (adjusted hazard ratio 1.06, 95% CI 0.99-1.13). The increase in adverse medical events supports guidelines restricting antipsychotic use in this population.
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Đorđević, Sanela M; Santrač, Anja; Cekić, Nebojša D; Marković, Bojan D; Divović, Branka; Ilić, Tanja M; Savić, Miroslav M; Savić, Snežana D
2017-11-30
This work aimed to deepen the lately acquired knowledge about parenteral nanoemulsions as carriers for brain delivery of risperidone, a poorly water-soluble antipsychotic drug, through establishing the prospective relationship between their physicochemical, pharmacokinetic, biodistribution, and behavioral performances. For this purpose, two optimized risperidone-loaded nanoemulsions, stabilized by lecithin or lecithin/polysorbate 80 mixture, and costabilized by sodium oleate, were produced by high-pressure homogenization. The characterization revealed the favorable droplet size, narrow size distribution, high surface charge, with proven stability to autoclaving and long-term stability for at least one year at 25±2°C. Pharmacokinetic and tissue distribution results demonstrated improved plasma, liver, and brain pharmacokinetic parameters, resulting in 1.2-1.5-fold increased relative bioavailability, 1.1-1.8-fold decreased liver distribution, and about 1.3-fold improved brain uptake of risperidone active moiety following intraperitoneal administration of nanoemulsions relative to solution in rats. In behavioral study, investigated nanoemulsions showed pronounced reduction in basal and, more pertinently, amphetamine-induced locomotor activity in rats, with an early onset of antipsychotic action, and this effect lasted at least 90min after drug injection. Together, these findings corroborate the applicability of parenteral nanoemulsions as carriers for enhanced brain delivery of risperidone, further suggesting their promise in acute psychosis treatment or other emergency situations. Copyright © 2017 Elsevier B.V. All rights reserved.
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Neuropathic Pain Following Poly-L-Lactic Acid (Sculptra) Injection.
Vrcek, Ivan; El-Sawy, Tarek; Chou, Eva; Allen, Theresa; Nakra, Tanuj
Injectable fillers have become a prevalent means of facial rejuvenation and volume expansion. While typically well tolerated, serious complications have been reported. The authors present a case in which an otherwise healthy female with a history of multiple filler injections including poly-L-lactic acid, developed 3 weeks of neuropathic pain in the left temporal fossa following injection. To the best of the authors knowledge, neuropathic pain has not been reported as a complication following poly-L-lactic acid injection. The patient was treated with an injection of steroid and long-acting anesthetic with resolution of symptoms.
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Risperidone (depot) for schizophrenia.
Sampson, Stephanie; Hosalli, Prakash; Furtado, Vivek A; Davis, John M
2016-04-14
Risperidone is the first new generation antipsychotic drug made available in a long-acting injection formulation. To examine the effects of depot risperidone for treatment of schizophrenia or related psychoses in comparison with placebo, no treatment or other antipsychotic medication.To critically appraise and summarise current evidence on the resource use, cost and cost-effectiveness of risperidone (depot) for schizophrenia. We searched the Cochrane Schizophrenia Group's Register (December 2002, 2012, and October 28, 2015). We also checked the references of all included studies, and contacted industry and authors of included studies. Randomised clinical trials comparing depot risperidone with other treatments for people with schizophrenia and/or schizophrenia-like psychoses. Two review authors independently selected trials, assessed trial quality and extracted data. For dichotomous data, we calculated the risk ratio (RR), with 95% confidence interval (CI). For continuous data, we calculated mean differences (MD). We assessed risk of bias for included studies and created 'Summary of findings' tables using GRADE. Twelve studies, with a total of 5723 participants were randomised to the following comparison treatments: Risperidone depot versus placebo Outcomes of relapse and improvement in mental state were neither measured or reported. In terms of other primary outcomes, more people receiving placebo left the study early by 12 weeks (1 RCT, n=400, RR 0.74 95% CI 0.63 to 0.88, very low quality evidence), experienced severe adverse events in short term (1 RCT, n=400, RR 0.59 95% CI 0.38 to 0.93, very low quality evidence). There was however, no difference in levels of weight gain between groups (1 RCT, n=400, RR 2.11 95% CI 0.48 to 9.18, very low quality evidence). Risperidone depot versus general oral antipsychotics The outcome of improvement in mental state was not presented due to high levels of attrition, nor were levels of severe adverse events explicitly reported. Most primary outcomes of interest showed no difference between treatment groups. However, more people receiving depot risperidone experienced nervous system disorders (long-term:1 RCT, n=369, RR 1.34 95% CI 1.13 to 1.58, very-low quality evidence). Risperidone depot versus oral risperidoneData for relapse and severe adverse events were not reported. All outcomes of interest were rated as moderate quality evidence. Main results showed no differences between treatment groups with equivocal data for change in mental state, numbers leaving the study early, any extrapyramidal symptoms, weight increase and prolactin-related adverse events. Risperidone depot versus oral quetiapine Relapse rates and improvement in mental state were not reported. Fewer people receiving risperidone depot left the study early (long-term: 1 RCT, n=666, RR 0.84 95% CI 0.74 to 0.95, moderate quality evidence). Experience of serious adverse events was similar between groups (low quality evidence), but more people receiving depot risperidone experienced EPS (1 RCT, n=666, RR 1.83 95% CI 1.07 to 3.15, low quality evidence), had greater weight gain (1 RCT, n=666, RR 1.25 95% CI 0.25 to 2.25, low quality evidence) and more prolactin-related adverse events (1 RCT, n=666, RR 3.07 95% CI 1.13 to 8.36, very low quality evidence). Risperidone depot versus oral aripiprazoleRelapse rates, mental state using PANSS, leaving the study early, serious adverse events and weight increase were similar between groups. However more people receiving depot risperidone experienced prolactin-related adverse events compared to those receiving oral aripiprazole (2 RCTs, n=729, RR 9.91 95% CI 2.78 to 35.29, very low quality of evidence). Risperidone depot versus oral olanzapineRelapse rates were not reported in any of the included studies for this comparison. Improvement in mental state using PANSS and instances of severe adverse events were similar between groups. More people receiving depot risperidone left the study early than those receiving oral olanzapine (1 RCT, n=618, RR 1.32 95% CI 1.10 to 1.58, low quality evidence) with those receiving risperidone depot also experiencing more extrapyramidal symptoms (1 RCT, n=547, RR 1.67 95% CI 1.19 to 2.36, low quality evidence). However, more people receiving oral olanzapine experienced weight increase (1 RCT, n=547, RR 0.56 95% CI 0.42 to 0.75, low quality evidence). Risperidone depot versus atypical depot antipsychotics (specifically paliperidone palmitate)Relapse rates were not reported and rates of response using PANSS, weight increase, prolactin-related adverse events and glucose-related adverse events were similar between groups. Fewer people left the study early due to lack of efficacy from the risperidone depot group (long term: 1 RCT, n=749, RR 0.60 95% CI 0.45 to 0.81, low quality evidence), but more people receiving depot risperidone required use of EPS-medication (2 RCTs, n=1666, RR 1.46 95% CI 1.18 to 1.8, moderate quality evidence). Risperidone depot versus typical depot antipsychoticsOutcomes of relapse, severe adverse events or movement disorders were not reported. Outcomes relating to improvement in mental state demonstrated no difference between groups (low quality evidence). However, more people receiving depot risperidone compared to other typical depots left the study early (long-term:1 RCT, n=62, RR 3.05 95% CI 1.12 to 8.31, low quality evidence). Depot risperidone may be more acceptable than placebo injection but it is hard to know if it is any more effective in controlling the symptoms of schizophrenia. The active drug, especially higher doses, may be associated with more movement disorders than placebo. People already stabilised on oral risperidone may continue to maintain benefit if treated with depot risperidone and avoid the need to take tablets, at least in the short term. In people who are happy to take oral medication the depot risperidone is approximately equal to oral risperidone. It is possible that the depot formulation, however, can bring a second-generation antipsychotic to people who do not reliably adhere to treatment. People with schizophrenia who have difficulty adhering to treatment, however, are unlikely to volunteer for a clinical trial. Such people may gain benefit from the depot risperidone with no increased risk of extrapyramidal side effects.
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Bruins Slot, Liesbeth A; Palmier, Christiane; Tardif, Stéphanie; Cussac, Didier
2007-08-01
The effects of new generation antipsychotic drugs (APDs) targeting dopamine D(2) and serotonin 5-HT(1A) receptors were compared with typical and atypical APDs on phosphorylation of extracellular signal-regulated kinase 1/2 (ERK 1/2) and measures of G protein activation in CHO cell lines stably expressing the human dopamine D(3) receptor. The preferential dopamine D(3) agonists (+)-7-OH-DPAT and PD128907, like dopamine and quinelorane, efficaciously stimulated ERK 1/2 phosphorylation at dopamine D(3) receptors. In contrast, in [(35)S]GTPgammaS binding experiments, (+)-7-OH-DPAT exhibited partial agonist properties, while PD128907 and quinelorane maintained full agonist properties. The preferential dopamine D(3) ligand BP 897 and the antidyskinetic sarizotan partially activated ERK 1/2 phosphorylation while exerting no agonist activity on GTPgammaS binding, suggesting signal amplification at the MAP kinase level. Antipsychotics differed in their ability to inhibit both agonist-stimulated GTPgammaS binding and ERK 1/2 phosphorylation, but all typical and atypical compounds tested acted as dopamine D(3) receptor antagonists with the exception of n-desmethylclozapine, the active metabolite of clozapine, which partially activated dopamine D(3) receptor-mediated ERK 1/2 phosphorylation. Among the new generation dopamine D(2)/serotonin 5-HT(1A) antipsychotics, only F 15063 and SLV313 acted as pure dopamine D(3) receptor antagonists, bifeprunox was highly efficacious whereas SSR181507 and aripiprazole showed marked partial agonist properties for ERK 1/2 phosphorylation. In contrast, in the GTPgammaS binding study, aripiprazole was devoid of agonist properties and bifeprunox, and to an even lesser extent SSR181507, only weakly stimulated GTPgammaS binding. In summary, these findings underline the differences of dopamine D(3) properties of new generation antipsychotics which may need to be considered in understanding their diverse therapeutic actions.
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VMAT2 Inhibitors and the Path to Ingrezza (Valbenazine).
Harriott, Nicole D; Williams, John P; Smith, Evan B; Bozigian, Haig P; Grigoriadis, Dimitri E
2018-01-01
The dopaminergic system plays a key role in the central nervous system, regulating executive function, arousal, reward, and motor control. Dysregulation of this critical monoaminergic system has been associated with diseases of the central nervous system including schizophrenia, Parkinson's disease, and disorders such as attention deficit hyperactivity disorders and addiction. Drugs that modify the dopaminergic system by modulating the activity of dopamine have been successful in demonstrating clinical efficacy by providing treatments for these diseases. Specifically, antipsychotics, both typical and atypical, while acting on a number of monoaminergic systems in the brain, primarily target the dopamine system via inhibition of postsynaptic dopamine receptors. The vesicular monoamine transporter 2 (VMAT2) is an integral presynaptic protein that regulates the packaging and subsequent release of dopamine and other monoamines from neuronal vesicles into the synapse. Despite acting on opposing sides of the synapse, both antipsychotics and VMAT2 inhibitors act to decrease the activity of central dopaminergic systems. Tardive dyskinesia is a disorder characterized by involuntary repetitive movements and thought to be a result of a hyperdopaminergic state precipitated by the use of antipsychotics. Valbenazine (NBI-98854), a novel compound that selectively inhibits VMAT2 through an active metabolite, has been developed for the treatment of tardive dyskinesia and is the first drug approved for the treatment of this disorder. This chapter describes the process leading to the discovery of valbenazine, its pharmacological characteristics, along with preclinical and clinical evidence of its efficacy. © 2018 Elsevier B.V. All rights reserved.
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Rauly-Lestienne, Isabelle; Boutet-Robinet, Elisa; Ailhaud, Marie-Christine; Newman-Tancredi, Adrian; Cussac, Didier
2007-10-01
5-HT(7) receptors are present in thalamus and limbic structures, and a possible role of these receptors in the pathology of schizophrenia has been evoked. In this study, we examined binding affinity and agonist/antagonist/inverse agonist properties at these receptors of a large series of antipsychotics, i.e., typical, atypical, and third generation compounds preferentially targeting D(2) and 5-HT(1A) sites. Adenylyl cyclase (AC) activity was measured in HEK293 cells stably expressing the human (h) 5-HT(7a) receptor isoform. 5-HT and 5-CT increased cyclic adenosine monophosphate level by about 20-fold whereas (+)-8-OH-DPAT, the antidyskinetic agent sarizotan, and the novel antipsychotic compound bifeprunox exhibited partial agonist properties at h5-HT(7a) receptors stimulating AC. Other compounds antagonized 5-HT-induced AC activity with pK (B) values which correlated with their pK (i) as determined by competition binding vs [(3)H]5-CT. The selective 5-HT(7) receptor ligand, SB269970, was the most potent antagonist. For antipsychotic compounds, the following rank order of antagonism potency (pK (B)) was ziprasidone > tiospirone > SSR181507 > or = clozapine > or = olanzapine > SLV-314 > SLV-313 > or = aripiprazole > or = chlorpromazine > nemonapride > haloperidol. Interestingly, pretreatment of HEK293-h5-HT(7a) cells with forskolin enhanced basal AC activity and revealed inverse agonist properties for both typical and atypical antipsychotics as well as for aripiprazole. In contrast, other novel antipsychotics exhibited diverse 5-HT(7a) properties; SLV-313 and SLV-314 behaved as quasi-neutral antagonists, SSR181507 acted as an inverse agonist, and bifeprunox as a partial agonist, as mentioned above. In conclusion, the differential properties of third generation antipsychotics at 5-HT(7) receptors may influence their antipsychotic profile.
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Cáceda, Ricardo; Kinkead, Becky; Owens, Michael J; Nemeroff, Charles B
2005-12-14
Dopamine receptor agonist and NMDA receptor antagonist activation of the mesolimbic dopamine system increases locomotion and disrupts prepulse inhibition of the acoustic startle response (PPI), paradigms frequently used to study both the pharmacology of antipsychotic drugs and drugs of abuse. In rats, virally mediated overexpression of the neurotensin 1 (NT1) receptor in the nucleus accumbens antagonized d-amphetamine- and dizocilpine-induced PPI disruption, hyperlocomotion, and D-amphetamine-induced rearing. The NT receptor antagonist SR 142948A [2-[[5-(2,6-dimethoxyphenyl)-1-(4-N-(3-dimethylaminopropyl)-N-methylcarbamoyl)-2-isopropylphenyl)-1H-pyrazole-3-carbonyl]amino] adamantane-2-carboxylic acid, hydrochloride] blocked inhibition of dizocilpine-induced hyperlocomotion mediated by overexpression of the NT1 receptor. Together, these results suggest that increased nucleus accumbens NT neurotransmission, via the NT1 receptor, can decrease the effects of activation of the mesolimbic dopamine system and disruption of the glutamatergic input from limbic cortices, resembling the action of the atypical antipsychotic drug clozapine. In contrast to clozapine, virally mediated overexpression of the NT1 receptor in the nucleus accumbens had prolonged protective effects (up to 4 weeks after viral injection) without perturbing baseline PPI and locomotor behaviors. These data further confirm the NT1 receptor as the receptor mediating the antistimulant- and antipsychotic-like properties of NT and provide rationale for the development of NT1 receptor agonists as novel antipsychotic drugs. In addition, the NT1 receptor vector might be a valuable tool for understanding the mechanism of action of antipsychotic drugs and drugs of abuse and may have potential therapeutic applications.
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Brain structural changes associated with chronicity and antipsychotic treatment in schizophrenia.
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.
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Takeuchi, Hiroyoshi; Kantor, Navot; Sanches, Marcos; Fervaha, Gagan; Agid, Ofer; Remington, Gary
2017-09-01
Background As definitions of relapse differ substantially between studies, in investigations involving data aggregation, total scores on clinical rating scales provide a more generalisable outcome. Aims To compare total symptom trajectories for antipsychotic versus placebo treatment over a 1-year period of maintenance treatment in schizophrenia. Method Randomised controlled trials with antipsychotic and placebo treatment arms in patients with stable schizophrenia that reported Positive and Negative Syndrome Scale and Brief Psychiatric Rating Scale total scores at more than one time point were included. Meta-regression analyses were employed using a mixed model. Results A total of 11 studies involving 2826 patients were included. Meta-regression analyses revealed significant interactions between group and time ( PS <0.0001); both standardised total scores and per cent score changes remained almost unchanged in patients continuing antipsychotic treatment, whereas symptoms continuously worsened over time in those switching to placebo treatment. Conclusions When considering long-term antipsychotic treatment of schizophrenia, clinicians must balance symptomatic and functional outcomes. © The Royal College of Psychiatrists 2017.
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Antipsychotic induced weight gain in schizophrenia:mechanisms and management.
Rege, Sanil
2008-05-01
The aim of the present paper was to describe the mechanisms and management of antipsychotic-induced weight gain in schizophrenia patients. A comprehensive literature review of all available articles on the mechanisms and management of antipsychotic-induced weight gain was done by searching databases PsychINFO and PubMed. A summary of the available guidelines for monitoring of antipsychotic-induced weight gain and metabolic syndrome is also provided. There has been a substantial increase in the number of studies investigating the mechanisms and management of antipsychotic-induced weight gain after 2002. These include advances in the understanding of pharmacogenomics of weight gain and several randomized controlled trials (RCTs) evaluating pharmacological and psychological treatments to promote weight loss. The most effective strategy for prevention of weight gain is the choice of antipsychotic medication with low weight gain potential. In individuals with established weight gain and metabolic issues, switching to an antipsychotic agent with lower weight gain potential and/or lifestyle modifications with physical activity are most effective in promoting weight loss. Pharmacological agents such as orlistat and sibutramine are effective in general obesity but have not been sufficiently evaluated in antipsychotic-induced weight gain. The case to prescribe routine pharmacological treatment to promote weight loss is weak. Long-term, pragmatic studies are required to inform clinical practice. Weight gain in schizophrenia is associated with significant physical and psychological morbidity. Achieving an optimal trade-off between effectiveness and side-effects of antipsychotic agents, although difficult, is achievable. This should be based on three main principles: (i) a shared decision-making model between the patient, clinician and carer(s) when choosing an antipsychotic; (ii) a commitment to baseline and follow-up monitoring with explicit identification of the responsible individual or team; and (iii) the adoption of clear structured protocols for clinicians to follow in case of clinically significant weight gain and metabolic issues, which should incorporate greater collaboration between various health professionals from psychiatric and medical specialist services.
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One-day treatment for lobar pneumonia
Sutton, D. R.; Wicks, A. C. B.; Davidson, Lindsay
1970-01-01
An investigation was undertaken to discover whether a single intramuscular dose of long-acting (or mixed long-acting and crystalline) penicillin or a single day's therapy with oral penicillin was satisfactory treatment for lobar pneumonia. These treatments were compared with standard hospital oral and injection therapies. All the experimental treatment regimes were found to be satisfactory. They provide justification for treating lobar pneumonia on an out-patient basis in order to save hospital admissions. PMID:4392585
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Girardi, Paolo; Del Casale, Antonio; Rapinesi, Chiara; Kotzalidis, Georgios D; Splendori, Francesca; Verzura, Claudio; Trovini, Giada; Sorice, Serena; Carrus, Dario; Mancinelli, Iginia; Comparelli, Anna; De Filippis, Sergio; Francomano, Antonio; Ballerini, Andrea; Marcellusi, Andrea; Mennini, Francesco S; Ducci, Giuseppe; Sani, Gabriele; Pompili, Maurizio; Brugnoli, Roberto
2018-05-01
Long-acting injectable (LAI) antipsychotics can improve medication adherence and reduce hospitalisation rates compared with oral treatments. Paliperidone palmitate (PAL) and aripiprazole monohydrate (ARI) LAI treatments were associated with improvements in global functioning in patients with schizophrenia. The objective of this study was to assess the predictive factors of better overall functioning in patients with chronic schizophrenia and schizoaffective disorder treated with PAL and ARI. Enrolled were 143 (97 males, 46 females, mean age 38.24 years, SD = 12.65) patients with a diagnosis of schizophrenia or schizoaffective disorder, whom we allocated in two groups (PAL and ARI treatments). We assessed global functioning, amount of oral medications, adherence to oral treatment, and number of hospitalisations before LAI introduction and at assessment time point. Longer treatment time with LAIs (p < .001), lower number of oral drugs (p < .001), and hospitalisations (p = .002) before LAI introduction, and shorter duration of illness (p = .038) predicted better Global Assessment of Functioning scores in the whole sample (R 2 = 0.337). Early administration and longer duration of ARI or PAL treatments could play a significant role in improving global functioning of patients with schizophrenia and schizoaffective disorder. Better improvement in functioning could be achieved with ARI in young individuals with recent illness onset and PAL in patients at risk for recurrent hospitalisations. Copyright © 2018 John Wiley & Sons, Ltd.
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Marty, Rémi; Roze, Stéphane; Kurth, Hannah
2012-01-01
Long-acting somatostatin receptor ligands (SRL) with product-specific formulation and means of administration are injected periodically in patients with acromegaly and neuroendocrine tumors. A simple decision-tree model aimed at comparing cost savings with ready-to-use Somatuline Autogel(®) (lanreotide) and Sandostatin LAR(®) (octreotide) for the UK, France, and Germany. The drivers of cost savings studied were the reduction of time to administer as well as a reduced baseline risk of clogging during product administration reported for Somatuline Autogel(®). The decision-tree model assumed two settings for SRL administration, ie, by either hospital-based or community-based nurses. In the case of clogging, the first dose was assumed to be lost and a second injection performed. Successful injection depended on the probability of clogging. Direct medical costs were included. A set of scenarios were run, varying the cost drivers, such as the baseline risk of clogging, SRL administration time, and percentage of patients injected during a hospital stay. Costs per successful injection were less for Somatuline Autogel(®)/Depot, ranging from Euros (EUR) 13-45, EUR 52-108, and EUR 127-151, respectively, for France, Germany, and the UK. The prices for both long-acting SRL were the same in France, and cost savings came to 100% from differences other than drug prices. For Germany and the UK, the proportion of savings due to less clogging and shorter administration time was estimated to be around 32% and 20%, respectively. Based on low and high country-specific patient cohort size estimations of individuals eligible for SRL treatment among the patient population with acromegaly and neuroendocrine tumors, annual savings were estimated to be up to EUR 2,000,000 for France, EUR 6,000,000 for Germany, and EUR 7,000,000 for the UK. This model suggests that increasing usage of the Somatuline device for injection of SRL might lead to substantial savings for health care providers across Europe.
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McGowan, Ian; Dezzutti, Charlene S; Siegel, Aaron; Engstrom, Jarret; Nikiforov, Alexiy; Duffill, Kathryn; Shetler, Cory; Richardson-Harman, Nicola; Abebe, Kaleab; Back, David; Else, Laura; Egan, Deidre; Khoo, Saye; Egan, James E; Stall, Ronald; Williams, Peter E; Rehman, Khaleel K; Adler, Amy; Brand, Rhonda M; Chen, Beatrice; Achilles, Sharon; Cranston, Ross D
2016-12-01
Long-acting injectable antiretroviral agents are being developed for HIV-1 prevention. The MWRI-01 study was done to characterise the safety, acceptability, and pharmacokinetic and pharmacodynamic profile of long-acting rilpivirine. We did a phase 1 open-label study at the University of Pittsburgh. We enrolled healthy individuals (aged 18-45 years) who were seronegative for HIV-1. Participants were assigned alternately one intramuscular dose of either 1200 mg or 600 mg long-acting rilpivirine, beginning with the 1200 mg dose. We obtained plasma specimens, genital and rectal fluids, and tissue samples (rectal, cervical, and vaginal) before and after exposure to long-acting rilpivirine for assessment of pharmacokinetics and ex-vivo biopsy challenge with HIV-1. Our primary objective was to characterise product safety, and the analysis included all enrolled participants. This trial is registered with ClinicalTrials.gov, number NCT01656018. 36 participants were enrolled into the study, of whom 24 were women and 12 men. 12 women and six men received each dose. 204 adverse events were reported among the 36 participants, of which 200 (98%) were grade 1-2. The most common adverse event was injection site reaction. All grade 3 and 4 adverse events were deemed not related to rilpivirine. Geometric mean (90% CI) concentrations in plasma of rilpivirine at day 28 post dose were 53 ng/mL (38-67) in women and 43 ng/mL (23-63) in men for the 1200 mg dose and 28 ng/mL (19-37) in women and 17 ng/mL (9-24) in men for the 600 mg dose. The tissue-to-plasma ratio for rilpivirine in rectal tissue was about two-fold higher than in vaginal and cervical tissue (1·10-1·53 vs 0·61-0·72 and 0·50-0·71, respectively). Exposure to long-acting rilpivirine suppressed viral replication significantly in rectal tissue (p<0·0001), and this suppression persisted for up to 4 months. By contrast, no viral suppression was seen in cervical or vaginal tissue. Ongoing research will characterise longer term safety and acceptability of multiple injections and help ascertain whether long-acting rilpivirine should advance to assessment of efficacy in preventing HIV-1 infection. Bill & Melinda Gates Foundation. Copyright © 2016 Elsevier Ltd. All rights reserved.
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Achalia, Rashmin M; Chaturvedi, Santosh K; Desai, Geetha; Rao, Girish N; Prakash, Om
2014-06-01
Tardive dyskinesia (TD) is one of the most distressing side effects of antipsychotic treatment. As prevalence studies of TD in Asian population are scarce, a cross-sectional study was performed to assess the frequency of TD in Indian patients with schizophrenia and risk factors of TD. Cross-sectional study of 160 Indian patients fulfilling the DSM-IV TR criteria for schizophrenia and who received antipsychotics for at least one year, were examined with two validated scales for TD. Logistic regression analyses were used to examine the relationship between TD and clinical risk factors. The frequency of probable TD in the total sample was 26.4%. The logistic regression yielded significant odds ratios between TD and age, intermittent treatment, and total cumulative antipsychotic dose. The difference of TD between SGA and FGA disappeared after adjusting for important co-variables in regression analysis. Indian patients with schizophrenia and long-term antipsychotic treatment have a high risk of TD, and TD is associated with older age, intermittent antipsychotic treatment, and a high total cumulative antipsychotic dose. Our study findings suggest that there is no significant difference between SGAs with regards to the risk of causing TD as compared to FGAs. Copyright © 2014 Elsevier B.V. All rights reserved.
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Chumo, R S; Irvin, A D; Morzaria, S P; Katende, J; Purnell, R E
1989-03-04
Two field trials were carried out in successive years at the Ngong Veterinary Farm, Kenya, in which young cattle, previously unexposed to tick-borne diseases, were introduced into an area with endemic East Coast fever while protected by a series of injections of a long-acting oxytetracycline. In 1984, 12 animals which received injections of 20 mg/kg of the drug on days 0, 7, 14 and 21 after introduction, together with 12 untreated controls, were exposed without tick control until clinical disease occurred. All 12 control animals contracted East Coast fever by day 24 and 10 of them died. Five of the 12 injected animals had detectable parasites, and one of them required antitheilerial treatment. In 1985, four groups of 10 calves were introduced. One group received injections of 20 mg/kg of oxytetracycline on days 7 and 14, one group received injections on days 7, 14 and 21, and a third group received injections on days 7, 12 and 17; the fourth group (controls) had no treatment until clinical disease occurred. By day 35 all the control animals had contracted the disease and one had died despite antitheilerial treatment. Three injections of oxytetracycline suppressed the disease so that mild reactions occurred in only four animals in each group, but two injections failed to prevent severe reactions in two animals and mild reactions in four others.(ABSTRACT TRUNCATED AT 250 WORDS)
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Vázquez-Bourgon, Javier; Pérez-Iglesias, Rocío; Ortiz-García de la Foz, Víctor; Suárez Pinilla, Paula; Díaz Martínez, Álvaro; Crespo-Facorro, Benedicto
2018-01-01
The use of second-generation antipsychotics (SGA) has been associated with metabolic changes. However, there are differences in the metabolic profile between SGAs. We have previously observed that ziprasidone had a more benign early metabolic profile compared to aripiprazole and quetiapine. However, a long-term follow-up is preferred to detect clinically relevant impairment in metabolic parameters. We aimed to compare the effect of aripiprazole, ziprasidone, and quetiapine on metabolic measures in first-episode non-affective psychosis patients after 1 year of treatment. One hundred and sixty-five drug-naïve patients, suffering from a first episode of non-affective psychosis, were randomly assigned to receive quetiapine, ziprasidone, or aripiprazole. Weight and glycemic/lipid parameters were recorded at baseline and after 1 year of treatment. After 1 year of antipsychotic treatment, we found significant increments in weight, BMI, total cholesterol, LDL-cholesterol, triglycerides, and the triglyceride/HDL index in the sample as a whole. These changes produced a significant rise in the percentage of patients with obesity, hypercholesterolemia, and hypertriglyceridemia. However, when comparing the differential effect of each antipsychotic medication, we found no significant differences in any of the metabolic parameters between antipsychotics groups after 1 year of treatment. We concluded that the antipsychotics studied present similar metabolic profiles. However, the primary exposure to SGAs during the first year of psychosis was associated with significant increases in weight and metabolic parameters, leading to increments in obesity, hypertriglyceridemia, and hypercholesterolemia.
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Aripiprazole-Induced Hypoprolactinemia in an Adult Male with First-Episode Psychosis.
Propst, Alanna J; Jarvis, G Eric; Margolese, Howard C
2016-01-01
Aripiprazole is an atypical antipsychotic that acts as a partial agonist at dopamine D2 receptors. Compared to other atypical antipsychotics, aripiprazole has less metabolic side effects and is less likely to increase prolactin. Moreover, it has been shown to have a unique prolactin lowering effect. While aripiprazole has been associated with subnormal prolactin levels in children, no documented cases of hypoprolactinemia in adults exist thus far. Here we report a case of aripiprazole-induced hypoprolactinemia in an adult male with first-episode psychosis, and the possible effects of abnormally low prolactin are discussed.
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Grisolia, G A; Danti, D A; Santoro, S; Panozzo, G; Bonini, G; Pampaloni, A
1983-11-01
In many cases deep second degree and third degree burns cause severe scarring. The authors have reported here their experience of the treatment of hypertrophic scarring from burns carried out on 44 children with intralesional injections of a long-acting cortico-steroid (Triamcinolone hexacetonide) using the jet spray technique.
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One-year follow-up study of psychotic patients treated with blonanserin: a case series.
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.
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Egerton, Alice; Brugger, Stefan; Raffin, Marie; Barker, Gareth J; Lythgoe, David J; McGuire, Philip K; Stone, James M
2012-01-01
Many patients with schizophrenia show a limited symptomatic response to treatment with dopaminergic antipsychotics. This may reflect the additional involvement of non-dopaminergic neurochemical dysfunction in the pathophysiology of the disorder. We tested the hypothesis that brain glutamate levels would differ between patients with first-episode psychosis who were symptomatic compared with those with minimal symptoms following antipsychotic treatment. Proton magnetic resonance spectroscopy (1H-MRS) spectra were acquired at 3 Tesla in the anterior cingulate cortex and left thalamus in 15 patients with first-episode psychosis in symptomatic remission, and 17 patients with first-episode psychosis who were still symptomatic following at least one course of antipsychotic treatment. Metabolite levels were estimated in ratio to creatine (Cr) using LCModel. Levels of glutamate/Cr in the anterior cingulate cortex were significantly higher in patients who were still symptomatic than in those in remission (T(30)=3.02; P=0.005). Across the entire sample, higher levels of glutamate/Cr in the anterior cingulate cortex were associated with a greater severity of negative symptoms (r=0.42; P=0.017) and a lower level of global functioning (r=−0.47; P=0.007). These findings suggest that clinical status following antipsychotic treatment in schizophrenia is linked to glutamate dysfunction. Treatment with compounds acting on the glutamatergic system might therefore be beneficial in patients who respond poorly to dopaminergic antipsychotics. PMID:22763619
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Olivares, Jose Manuel; Thirunavukarasu, Manickam; Kulkarni, Jayashri; Zhang, Hong Yan; Zhang, Mingyuan; Zhang, Fan
2013-01-01
Background Nonadherence is a well-known problem among schizophrenia patients, among whom relapse is fivefold more likely, adversely affecting health, employment, and social functioning. The Spanish Adherencia Terapéutica en la Esquizofrenia (ADHES) survey was developed to determine the scope and causes of medication nonadherence in schizophrenia. Methods The 20-question ADHES survey was distributed to 19,370 psychiatrists in 13 Asia–Pacific countries in January–April 2012, to ascertain psychiatrists’ perceptions of antipsychotic medication adherence levels among their schizophrenia patients, reasons for partial/nonadherence, their preferred methods of assessing adherence, and strategies to improve adherence. Responses are reported as mean and range across countries. Results Four thousand, six hundred sixty one psychiatrists (24% of recipients) completed the survey (highest contributors: People’s Republic of China, 1854; India, 1616). Psychiatrists perceived that 56% (range, 30%–71%) of schizophrenia patients were non- or partially adherent to medication. Patients discontinue medication primarily due to lack of insight into their condition (mean, 37%; 1%–65%) and because patients consider medication unnecessary when feeling better (mean, 27%; 15%–68%). Over half of psychiatrists (mean, 55%; 42%–99%) assess medication adherence at every visit, almost exclusively (81%) by asking their patients, versus quantitative measures. One in three psychiatrists expressed their preference to switch to or add a long-acting antipsychotic to improve adherence (15%–82%). Conclusions The substantial prevalence of partial/nonadherence to medication demonstrates that more proactive management of patients with schizophrenia is needed to improve adherence and thereby treatment outcomes. Registration Registration of this study was not required. PMID:23976858
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Novel antipsychotics: issues and controversies. Typicality of atypical antipsychotics.
Stip, E
2000-01-01
The typicality of atypical antipsychotic drugs remains debatable. Preclinical studies and findings from randomized, controlled and open trials of clozapine, olanzapine, risperidone, quetiapine, sertindole, ziprasidone and a substituted benzamide were examined. A MEDLINE search was conducted using key words, including "extrapyramidal side effects," "cognition," "schizophrenia" and the generic drug names. Over 140 articles from peer-reviewed journals were reviewed, some of which were based on a meta-analysis. New-generation neuroleptic agents were found to have greater efficacy on the negative symptoms of schizophrenia and to cause fewer unwanted extrapyramidal side effects (EPS) than the traditional antipsychotic drugs. On one hand, atypical neuroleptic agents could be strictly defined as any neuroleptic agent with antipsychotic effects at a dosage that does not cause extrapyramidal side effects. Thus, clozapine is regarded as the "standard" atypical antipsychotic drug. On the other hand, typicality is about dimension rather than category, and we suggest the use of the term "spectrum of atypicality." For example, an emphasis is placed on quetiapine to illustrate where a new compound fits in this spectrum. Although dose-related, atypicality may be more a question of prescription attitude than of a specific characteristic of a compound. The degree to which a new compound is clinically superior to another atypical antipsychotic drug, in terms of improving positive, negative or affective symptoms, cognitive function and long-term outcome, will require further a priori hypotheses based on conceptual frameworks that are clinically meaningful. In addition, the results from industry-sponsored trials should be more comparable to those obtained from investigator-leading trials. Finally, the patient characteristics that define a patient's response to a specific antipsychotic drug are unknown. PMID:10740987
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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
2014-01-01
Introduction 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. Methods and analysis 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. Ethics and dissemination 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. Trial registration 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. PMID:24401727
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Ishøy, Pelle L; Knop, Filip K; Broberg, Brian V; Bak, Nikolaj; Andersen, Ulrik B; Jørgensen, Niklas R; Holst, Jens J; Glenthøj, Birte Y; Ebdrup, Bjørn H
2017-02-01
Schizophrenia is associated with cardiovascular co-morbidity and a reduced life-expectancy of up to 20 years. Antipsychotics are dopamine D 2 receptor antagonists and are the standard of medical care in schizophrenia, but the drugs are associated with severe metabolic side effects such as obesity and diabetes. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are registered for treatment of both obesity and type 2 diabetes. We investigated metabolic effects of the GLP-1RA, exenatide once-weekly, in non-diabetic, antipsychotic-treated, obese patients with schizophrenia. Antipsychotic-treated, obese, non-diabetic, schizophrenia spectrum patients were randomized to double-blinded adjunctive treatment with once-weekly subcutaneous exenatide (n = 23) or placebo (n = 22) injections for 3 months. The primary outcome was loss of body weight after treatment and repeated measures analysis of variance was used as statistical analysis. Between March 2013 and June 2015, 40 patients completed the trial. At baseline, mean body weight was 118.3 ± 16.0 kg in the exenatide group and 111.7 ± 18.0 kg in the placebo group, with no group differences ( P = .23). The exenatide and placebo groups experienced significant ( P = .004), however similar ( P = .98), weight losses of 2.24 ± 3.3 and 2.23 ± 4.4 kg, respectively, after 3 months of treatment. Treatment with exenatide once-weekly did not promote weight loss in obese, antipsychotic-treated patients with schizophrenia compared to placebo. Our results could suggest that the body weight-lowering effect of GLP-1RAs involves dopaminergic signaling, but blockade of other receptor systems may also play a role. Nevertheless, anti-obesity regimens effective in the general population may not be readily implemented in antipsychotic-treated patients with schizophrenia. © 2016 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.
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Kishi, Taro; Hirota, Tomoya; Matsunaga, Shinji; Iwata, Nakao
2016-07-01
We performed an updated meta-analysis of antipsychotic treatment in patients with delirium, based on a previous meta-analysis published in 2007. Included in this study were randomised, placebo-controlled or usual care (UC) controlled trials of antipsychotics in adult patients with delirium. Our primary outcome measure was response rate at the study end point. The secondary outcome measures included improvement of severity of delirium, Clinical Global Impression-Severity Scale (CGI-S), time to response (TTR), discontinuation rate and individual adverse effects. The risk ratio (RR), the number-needed-to-treat/harm (NNT/NNH), 95% CIs and standardised mean difference (SMD), were calculated. We identified 15 studies (mean duration: 9.8 days) for the systematic review (total n=949, amisulpride=20, aripiprazole=8, chlorpromazine=13, haloperidol=316, intramuscular olanzapine or haloperidol injection=62, olanzapine=144, placebo=75, quetiapine=125, risperidone=124, UC=30 and ziprasidone=32), 4 of which were conference abstracts and unpublished. When pooled as a group, antipsychotics were superior to placebo/UC in terms of response rate (RR=0.22, NNT=2), delirium severity scales scores (SMD=-1.27), CGI-S scores (SMD=-1.57) and TTR (SMD=-1.22). The pooled antipsychotic group was associated with a higher incidence of dry mouth (RR=13.0, NNH=5) and sedation (RR=4.59, NNH=5) compared with placebo/UC. Pooled second-generation antipsychotics (SGAs) were associated with shorter TTR (SMD=-0.27) and a lower incidence of extrapyramidal symptoms (RR=0.31, NNH=7) compared with haloperidol. Our results suggested that SGAs have a benefit for the treatment of delirium with regard to efficacy and safety compared with haloperidol. However, further study using larger samples is required. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
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Lehmann, Eldon D.; Tarín, Cristina; Bondia, Jorge; Teufel, Edgar; Deutsch, Tibor
2007-01-01
Introduction AIDA v4 is an interactive educational diabetes simulator that has been made available, for over a decade, without charge via the Internet. The software is currently freely accessible at http://www.2aida.org. This report sets out a collaborative development plan to enhance the program with a new model of subcutaneous insulin absorption, which permits the simulation of rapidly acting and very long-acting insulin analogues, as well as insulin injection doses larger than 40 units. Methods A novel, generic, physiological subcutaneous insulin absorption model is overviewed and a methodology is proposed by which this can be substituted in place of the previously adopted insulin absorption model utilized within AIDA v4.3a. Apart from this substitution it is proposed to retain the existing model of the glucoregulatory system currently used in AIDA v4.3a. Results Initial simulation results based on bench testing of this approach using MATLAB are presented for the exogenous insulin flow profile (Iex) following subcutaneous injections of a rapidly acting insulin analogue, a short-acting (regular) insulin preparation, intermediate-acting insulins (both Semilente and neutral protamine Hagedorn types), and a very long-acting insulin analogue. Discussion It is proposed to implement this collaborative development plan—first by bench testing the approach in MATLAB and then by integrating the generic subcutaneous insulin absorption Iex model into the AIDA simulator in Pascal. The aim is to provide enhanced functionality and educational simulations of regimens utilizing novel insulin analogues, as well as injections larger than 40 units of insulin. PMID:19885100
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Movement Disorders Induced by the "Atypical" Antipsychotic Aripiprazole.
Selfani, Karim; Soland, Valérie L; Chouinard, Sylvain; Huot, Philippe
2017-01-01
Aripiprazole is an antipsychotic that acts as a partial agonist at dopamine D2 receptors. Because of its partial agonist activity, it was believed that aripiprazole would be less susceptible than typical antipsychotics to induce extrapyramidal side effects. However, a few case-reports and case-series detailing aripiprazole-induced movement disorders have been published, suggesting that aripiprazole-induced movement disorders may arise. Here, we seek to report further cases of aripiprazole-induced movement disorders to raise the awareness of clinicians on this adverse effect. Patients referred to the André-Barbeau Movement Disorder clinic treated with aripiprazole were enrolled in this study. Their charts were retrospectively reviewed and data regarding past psychiatric history, past antipsychotic medication, duration of aripiprazole treatment, daily dose of aripiprazole administered, and resulting movement disorders were collected. We report 14 cases of parkinsonism, tardive dyskinesia and akathisia induced by aripiprazole. Some of these, mostly the parkinsonian phenotype, abated spontaneously following drug discontinuation, whereas others, mostly related to tardive phenomena, persisted after aripiprazole was discontinued, and required treatment. This case-series adds to the existing literature that suggests that movement disorders may arise following treatment with aripiprazole. Clinicians should be aware of this potential side effect when prescribing aripiprazole to patients.
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Long-lasting ovulation inhibition with a new injectable progestagen ORG-2154.
Coutinho, E M; De Souza, J C; Barbosa, I C; Dourado Silva, V
1982-06-01
A new long-acting injectable progestagen was tested in 15 women who volunteered for the study. The occurrence of ovulation was assumed by the elevation of progesterone levels above 2ng/ml following a pre-ovulatory estradiol peak. Following a 200mg injection, ovulation was inhibited in all 15 women for five to ten months. In four subjects the interval between the injection and the first progesterone peak was five months. For eight, the interval was six to eight months. In the other three women, ovulation occurred more than eight months following injection. Bleeding episodes, similar to menstruation, occurred in most patients. Bleeding intervals lasting longer than 45 days occurred in nine subjects but more prolonged amenorrhea lasting longer than 60 days was reported by only five subjects. Blood chemistry which included blood cell counts, cholesterol, glucose, alkaline phosphatase, transaminases, urea nitrogen and creatinine remained within normal limits throughout the treatment.
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Use of physical restraints and antipsychotic medications in nursing homes: a cross-national study
Feng, Zhanlian; Hirdes, John P.; Smith, Trevor F.; Finne-Soveri, Harriet; Chi, Iris; Pasquier, Jean-Noel Du; Gilgen, Ruedi; Ikegami, Naoki; Mor, Vincent
2013-01-01
SUMMARY Objectives This study compares inter- and intra-country differences in the prevalence of physical restraints and antipsychotic medications in nursing homes, and examines aggregated resident conditions and organizational characteristics correlated with these treatments. Methods Population-based, cross-sectional data were collected using a standardized Resident Assessment Instrument (RAI) from 14,504 long-term care facilities providing nursing home level services in five countries participating in the interRAI consortium, including Canada, Finland, Hong Kong (Special Administrative Region, China), Switzerland, and the United States. Facility-level prevalence rates of physical restraints and antipsychotic use were examined both between and within the study countries. Results The prevalence of physical restraint use varied more than five-fold across the study countries, from an average 6% in Switzerland, 9% in the US, 20% in Hong Kong, 28% in Finland, and over 31% in Canada. The prevalence of antipsychotic use ranged from 11% in Hong Kong, between 26–27% in Canada and the US, 34% in Switzerland, and nearly 38% in Finland. Within each country, substantial variations existed across facilities in both physical restraint and antipsychotic use rates. In all countries, neither facility case mix nor organizational characteristics were particularly predictive of the prevalence of either treatment. Conclusions There exists large, unexplained variability in the prevalence of physical restraint and antipsychotic use in nursing home facilities both between and within countries. Since restraints and antipsychotics are associated with adverse outcomes, it is important to understand the idiosyncratic factors specific to each country that contribute to variation in use rates. PMID:19280680
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Use of physical restraints and antipsychotic medications in nursing homes: a cross-national study.
Feng, Zhanlian; Hirdes, John P; Smith, Trevor F; Finne-Soveri, Harriet; Chi, Iris; Du Pasquier, Jean-Noel; Gilgen, Ruedi; Ikegami, Naoki; Mor, Vincent
2009-10-01
This study compares inter- and intra-country differences in the prevalence of physical restraints and antipsychotic medications in nursing homes, and examines aggregated resident conditions and organizational characteristics correlated with these treatments. Population-based, cross-sectional data were collected using a standardized Resident Assessment Instrument (RAI) from 14,504 long-term care facilities providing nursing home level services in five countries participating in the interRAI consortium, including Canada, Finland, Hong Kong (Special Administrative Region, China), Switzerland, and the United States. Facility-level prevalence rates of physical restraints and antipsychotic use were examined both between and within the study countries. The prevalence of physical restraint use varied more than five-fold across the study countries, from an average 6% in Switzerland, 9% in the US, 20% in Hong Kong, 28% in Finland, and over 31% in Canada. The prevalence of antipsychotic use ranged from 11% in Hong Kong, between 26-27% in Canada and the US, 34% in Switzerland, and nearly 38% in Finland. Within each country, substantial variations existed across facilities in both physical restraint and antipsychotic use rates. In all countries, neither facility case mix nor organizational characteristics were particularly predictive of the prevalence of either treatment. There exists large, unexplained variability in the prevalence of physical restraint and antipsychotic use in nursing home facilities both between and within countries. Since restraints and antipsychotics are associated with adverse outcomes, it is important to understand the idiosyncratic factors specific to each country that contribute to variation in use rates. Copyright (c) 2009 John Wiley & Sons, Ltd.
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Behavioral therapy for weight loss in patients with schizophrenia.
Ganguli, Rohan
2007-01-01
Compared with the general population, individuals with schizophrenia demonstrate an increased prevalence of obesity. While most antipsychotics are associated with weight gain, certain second-generation antipsychotics (SGAs) appear to be especially problematic. Weight gain and obesity are highly distressing to these patients, can reduce treatment adherence, and may increase the relative risk of serious medical conditions and all-cause premature mortality. The selection of an antipsychotic on the basis of its effectiveness and relative side effect profile is recognized as an important initial consideration in the treatment of schizophrenia. However, less is known regarding the efficacy of dietary, pharmacologic, and behavioral therapy in reducing antipsychotic-related weight gain and obesity. Behavioral therapy, in particular, is understudied, and there are relatively few controlled trials of its effectiveness in reducing SGA-induced weight gain. Although weight loss resulting from behavioral therapy has been observed mostly as a result of effective short-term interventions, controlled behavioral studies do exist to suggest that weight can be controlled long term. In addition, a small pilot study in patients with schizophrenia or schizoaffective disorder recently demonstrated that behavioral therapy that utilizes stepped interventions, involving body weight self-monitoring, diet, and exercise, can prevent weight gain in patients initiating treatment with SGAs. Additional studies of behavioral therapy for long-term weight control in patients with schizophrenia and other forms of severe mental illness are warranted.
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2013-01-01
Background It is desirable to establish evidence for the selection of antipsychotics from the viewpoint of recovery of social activity in individual patient with schizophrenia receiving medication. From this perspective, awareness of the importance of studies about drug effectiveness on treatment discontinuation rate, remission rate, and improvement in QOL has grown recently. In Western countries, numerous reports are available in effectiveness studies, which are related to olanzapine and risperidone primarily, whereas evidence for other second-generation antipsychotics (SGAs) is poor. In Japan, no effectiveness study has been reported: thus, it is desirable to collect data that will serve as evidence for selection of the 3 SGAs approved after olanzapine. Methods The present study was a long-term effectiveness study under healthcare setting in Japan. It was designed as an open-label, multicenter, randomized, comparative study involving 104-week oral treatment with 1 of the 3 drugs (aripiprazole, blonanserin, and paliperidone) in patients with schizophrenia aged 20 years or over who required antipsychotic medication or switching of the current medication to others for reasons such as lack of efficacy and intolerability. The primary endpoint is treatment discontinuation rate for any causes. The secondary endpoints include remission rate, improvement of social activity, alleviation, aggravation or recurrence of psychiatric symptoms, and safety. The target number of subjects was set at 300. Discussion Because this study is expected to yield evidence regarding the selection of antipsychotics for facilitating the recovery of social activity in patients with schizophrenia, it is considered highly valuable to perform this effectiveness study under ordinary healthcare setting in Japan. Trial registration UMIN Clinical Trials Registry 000007942 PMID:24090047
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Gentile, Salvatore; Fusco, Maria Luigia
2017-06-01
The proportion of pregnancies exposed to either second-generation antipsychotics (SGAs) or first-generation antipsychotics (FGAs) varies between 0.3%-2% of all pregnancies, but, until now, little is known about the potential neurobehavioral teratogenicity of antipsychotics. Assessing this safety facet is the aim of this article. PubMed, Scopus, and Google Scholar were searched for eligible articles. PubMed (1954 to May 2016) was searched using several medical subject headings, variously combined. PubMed search results were also limited using the search filter for human studies published in English. Scopus and Google Scholar searches were filtered for article title (antipsychotics/neuroleptics, pregnancy). After excluding duplicates, 9,250 articles were identified and 29 met the following inclusion criteria: only articles that provided original/primary data on neurodevelopmental outcome in human offspring older than 4 months of age, independently of the study design, were selected for review. Indeed, some relevant neurodevelopmental milestones are achieved at this time. Length of study and neurodevelopmental assessment methodology did not influence the study selection. Unfortunately, published data on neurodevelopmental teratogenicity of SGAs mainly derive from case reports and small case-series studies. Even findings emerging from case-control and prospective/retrospective studies are of limited clinical relevance because of their small sample sizes. Limited data are also available on FGAs. Hence, we have to conclude that the long-term neurodevelopmental outcomes for children exposed in utero remain unclear. Low to very low quality evidence of retrieved data makes impossible to confirm or exclude potential long-lasting untoward effects on infant neurocognitive development associate with antenatal exposure to either SGAs or FGAs.
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[Atypical antipsychotics and sexual dysfunction: five case-reports associated with risperidone].
Haefliger, T; Bonsack, C
2006-01-01
Sexual and reproductive function side effects of atypical antipsychotics are frequent, often underestimated and badly tolerated. They contribute to the 50% rate of non-compliance reported for treated patients. Prevalence of sexual dysfunction associated with atypical antipsychotic treatment is high, varying from 18 to 96%. Atypical antipsychotics aren't, as a group, much better than typical antipsychotics, and among them, risperidone seems to induce more and quetiapine less sexual dysfunction. Most atypicals are non-selective, and have actions on multiple central and peripheral receptors. Among these, dopaminergic blockade could have a direct - altering motivation (desire) and reward (orgasm) - and an indirect negative influence on sexuality. Actually, the secondary hyperprolactinemia induced by some antipsychotics (typical antipsychotics, risperidone and amisulpiride), is dose-dependent, more pronounced for female patients, and may have a detrimental effect on sexual function. It also may result in hypogonadism, particularly for female patients. The long-term consequences of this secondary hypogonadism are subject to debate but potentially severe. Furthermore, the blocking and/or modulating actions of atypical antipsychotics on adrenaline, serotonine, histamine or acetyl-choline receptors all have the potential to contribute to secondary sexual problems. The pharmacological profile of risperidone, characterized by a strong affinity for D2 and alpha1 receptors, correlates with his tendency to significantly elevate prolactin levels and to produce ejaculatory disturbances. FIVE CASE-REPORTS: We describe five case-reports of sexual or hormonal disturbances associated with risperidone treatment: two cases of ejaculatory disturbance, one case of galactorrhea and two cases of amenorrhea. Alberto and David are two young male schizophrenic patients, treated with risperidone, and complaining of a total absence of ejaculation despite a preserved orgasm. Many recent case-reports describe the occurrence of retrograde ejaculation associated with risperidone but the exact prevalence is unknown. Retrograde ejaculation is thought to be related to the strong adrenolytic activity of risperidone. Alberto refused his medication because the ejaculatory dysfunction was unbearable for him. A switch to haloperidol depot was eventually well tolerated, without any sexual complaints. His case emphasizes the importance of sexual function for self-esteem and how this may amplify the intolerance to side-effects. David is on depot-risperidone in a setting of a legally forced treatment. Though he - reluctantly - accepts his medication, this side effect exacerbates his pre-existing delusions, strongly focused on sexual themes. His case illustrates how intolerance to sexual side-effects may be amplified by nature of delusions. Mireille is a 58 year old psychotic female patient, whose 2 mg risperidone treatment produced a unilateral galactorrhea. This sign became problematic because potentially visible at a time when Mireille started an activity in a sheltered occupation in town. Lowering dosage of antipsychotic allowed disappearance of the problem. Subjective responses to galactorrhea have been reported to be highly individual. Apart being a potentially visible side-effect, it may be misinterpreted as evidence of pregnancy or of a tumoral process. The cases of Ermina and Denise illustrate two contrasted situations in terms of subjective tolerability of reproductive function side-effects. Both were pre-menopausal patients with hyperprolactinemia secondary to risperidone treatment, resulting in amenorrhea. This was unbearable for Ermina. A switch to olanzapine allowed, one month later, the menses to resume. For Denise, on the other hand, the amenorrhea was a positive event, freeing her of unpleasant menses. Amenorrhea occurs in about 30% of pre-menopausal women treated with risperidone. It is a consequence of hyperprolactinemia, which, although often silent, is not devoid of potential negative consequences (ie increased risk of osteoporosis or neoplasia, worsening of psychopathology) (34). When hyperprolactinemia is symptomatic, lowering of the dose of the antipsychotic, or switching to a prolactin-sparing agent (olanzapine, quetiapine, aripiprazole and clozapine) is recommended. Before this, women with amenorrhea secondary to antipsychotic-induced hyperprolactinemia should be advised that menses may resume. Especially after long-standing amenorrhea they may assume being menopaused, hence may believe birth control measures are no longer required. The prevalence of antipsychotic-induced sexual and reproductive function side-effects is high. Clinicians should be aware of them, because they are often badly tolerated, are associated with a low satisfaction and may therefore result in low adherence with treatment. This implies for the clinician to overtly discuss with the patient of his sexuality and the potential negative impact of antipsychotic treatment on it. The recognition of these problems allows the searching together for a solution. The described cases indicate that solving the problem is often possible, provided that individual preferences and subjective impact are taken in account. Antipsychotic treatment is often prescribed for very long periods. A better knowledge of - and attention to - the associated side effects, particularly on the sexual and reproductive functions, is necessary in order to reduce some potentially negative long-term effects and to improve the adherence to treatment of our patients.
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Blonanserin-induced Mood Alteration in Schizophrenia and Schizoaffective Disorder: Two Cases.
Min, Aran; Kim, Daeho
2013-12-01
We report two outpatients, one with schizophrenia and one with schizoaffective disorder, who developed manic or hypomanic episodes following the initiation of blonanserin during the course of treatment. Blonanserin is a novel antipsychotic that acts as a 5-HT and D2 receptor antagonist. Both patients developed hypomanic episodes within 2 weeks of receiving a small dose (6-8 mg) of blonanserin, and one patient later developed full-blown mania; both episodes ended within 1 month of discontinuing blonanserin. The mood alteration observed in these cases suggests a possible antidepressant effect of blonanserin; thus, clinicians should monitor mood changes when administering this antipsychotic.
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Blonanserin-induced Mood Alteration in Schizophrenia and Schizoaffective Disorder: Two Cases
Min, Aran
2013-01-01
We report two outpatients, one with schizophrenia and one with schizoaffective disorder, who developed manic or hypomanic episodes following the initiation of blonanserin during the course of treatment. Blonanserin is a novel antipsychotic that acts as a 5-HT and D2 receptor antagonist. Both patients developed hypomanic episodes within 2 weeks of receiving a small dose (6-8 mg) of blonanserin, and one patient later developed full-blown mania; both episodes ended within 1 month of discontinuing blonanserin. The mood alteration observed in these cases suggests a possible antidepressant effect of blonanserin; thus, clinicians should monitor mood changes when administering this antipsychotic. PMID:24465254
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Citrome, Leslie
2016-01-01
Aripiprazole monohydrate (AM) and aripiprazole lauroxil (AL) are two different long-acting injectable formulations of aripiprazole. AM 400 mg administered once monthly demonstrated efficacy in an acute, double-blind, placebo-controlled, randomized clinical trial, as well as in a double-blind, placebo-controlled, randomized-withdrawal maintenance study, and in two non-inferiority maintenance studies. AL is a prodrug of aripiprazole and available in 441 mg, 662 mg or 882 mg strengths. AL 441 mg and 882 mg administered once monthly demonstrated efficacy in an acute, double-blind, placebo-controlled, randomized clinical trial. The pharmacokinetic profile of AL also led to approval of dosing intervals of every 6 weeks for the 882 mg dose. The overall tolerability profiles of both products are consistent with what is known about oral aripiprazole.
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Long-Acting Phospholipid Gel of Exenatide for Long-Term Therapy of Type II Diabetes.
Hu, Mei; Zhang, Yu; Xiang, Nanxi; Zhong, Ying; Gong, Tao; Zhang, Zhi-Rong; Fu, Yao
2016-06-01
This study aimed to develop a sustained-release formulation of exenatide (EXT) for the long-term therapeutic efficacy in the treatment of type II diabetes. In this study, we present an injectable phospholipid gel by mixing biocompatible phospholipid S100, medium chain triglyceride (MCT) with 85% (w/w) ethanol. A systemic pre-formulation study has been carried out to improve the stability of EXT during formulation fabrication. With the optimized formulation, the pharmacokinetic profiles in rats were studied and two diabetic animal models were employed to evaluate the therapeutic effect of EXT phospholipid gel via a single subcutaneous injection versus repeated injections of normal saline and EXT solution. With optimized formulation, sustained release of exenatide in vivo for over three consecutive weeks was observed after one single subcutaneous injection. Moreover, the pharmacodynamic study in two diabetic models justified that the gel formulation displayed a comparable hypoglycemic effect and controlled blood glucose level compared with exenatide solution treated group. EXT-loaded phospholipid gel represents a promising controlled release system for long-term therapy of type II diabetes.
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Blonanserin extensively occupies rat dopamine D3 receptors at antipsychotic dose range.
Baba, Satoko; Enomoto, Takeshi; Horisawa, Tomoko; Hashimoto, Takashi; Ono, Michiko
2015-03-01
Antagonism of the dopamine D3 receptor has been hypothesized to be beneficial for schizophrenia cognitive deficits, negative symptoms and extrapyramidal symptoms. However, recent animal and human studies have shown that most antipsychotics do not occupy D3 receptors in vivo, despite their considerable binding affinity for this receptor in vitro. In the present study, we investigated the D3 receptor binding of blonanserin, a dopamine D2/D3 and serotonin 5-HT2A receptors antagonist, in vitro and in vivo. Blonanserin showed the most potent binding affinity for human D3 receptors among the tested atypical antipsychotics (risperidone, olanzapine and aripiprazole). Our GTPγS-binding assay demonstrated that blonanserin acts as a potent full antagonist for human D3 receptors. All test-drugs exhibited antipsychotic-like efficacy in methamphetamine-induced hyperactivity in rats. Treatment with blonanserin at its effective dose blocked the binding of [(3)H]-(+)-PHNO, a D2/D3 receptor radiotracer, both in the D2 receptor-rich region (striatum) and the D3 receptor-rich region (cerebellum lobes 9 and 10). On the other hand, the occupancies of other test-drugs for D3 receptors were relatively low. In conclusion, we have shown that blonanserin, but not other tested antipsychotics, extensively occupies D3 receptors in vivo in rats. Copyright © 2015 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. All rights reserved.
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Amato, Davide; Heinsbroek, Jasper; Kalivas, Peter W
2018-01-01
Abstract Background Nearly half of all individuals diagnosed with schizophrenia abuse addictive substances such as cocaine. Currently, the neurobiological mechanisms in patients with schizophrenia that lead to cocaine abuse are unknown. A possible explanation for the co-morbidity between schizophrenia and addiction is that the rewarding properties of cocaine reverse the diminished motivational drive caused by chronic antipsychotic regimen. Moreover, chronic antipsychotic treatment can sensitize and amplify cocaine rewarding effects and exacerbate psychoses. Methods The rewarding properties of cocaine are attributed to the differential effects of dopamine on D1 and D2 receptor-expressing medium spiny neurons (MSNs) in the nucleus accumbens (NAc). Using in vivo Ca2+ miniature microscopic imaging, we characterize the role of D1 and D2 MSN in mono- and a cross- sensitization paradigms. D1- and D2-Cre mice were injected with a Cre dependent calcium indicator (gCaMP6f) and implanted with a gradient index (GRIN) lens above the nucleus accumbens and calcium activity was recorded using a head mounted miniature microscope. Cocaine sensitization was measured after a classic repeated cocaine regiment and antipsychotic and psychostimulant cross-sensitization was measured by a single cocaine injection after chronic pre-treatment with haloperidol. Results We found that both D1-MSN and D2-MSN populations are modulated by initial cocaine experience and further modulated during the expression of cocaine sensitization. A subpopulation of D1-MSN displayed initial activation, but reduced activity during the expression of sensitization. By contrast, the majority of D2-MSNs were suppressed by initial cocaine experience, but became active during the expression of sensitization. Furthermore, activity of D1- and D2-MSNs bidirectionally related with the observed behavioral responses to cocaine. Cross-sensitization following haloperidol treatment led to increased behavioral responses to psychostimulants. Current experiments are set out to investigate the neuronal responses of D1 and D2-MSN during cross sensitization between haloperidol and cocaine. Discussion Cocaine sensitization leads to differential neuronal responses in D1- and D2-MSN and these responses are differentially correlated with the magnitude of the sensitized behavioral response. These results reveal important new insights in the neurobiological processes in the nucleus accumbens that underlie psychostimulant sensitization and provide an important new model for studying the pharmacology of antipsychotic effects on striatal function and its potential role in increasing the susceptibility of schizophrenic patients to developing drug addiction.
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Ballard, Clive; Isaacson, Stuart; Mills, Roger; Williams, Hilde; Corbett, Anne; Coate, Bruce; Pahwa, Rajesh; Rascol, Olivier; Burn, David J
2015-10-01
To establish the mortality risk and adverse events associated with the use of atypical antipsychotic medications in people with Parkinson disease psychosis (PDP) in a clinically defined trial cohort. Post hoc analysis of data from a multicenter, open-label extension study of pimavanserin comparing people taking and not taking current antipsychotics. Primary and secondary care medical centers in the United States, Canada, Europe, and India. A total of 459 people with PDP enrolled in the extension study. Participants were between ages 30 and 80 years, and had an established diagnosis of idiopathic Parkinson disease and moderate to severe psychosis. Participants were categorized into 2 groups: those receiving concomitant antipsychotic medications ("concurrent APD") and those who did not take antipsychotic medications at any time during the study ("no APD"). Participants were receiving 40 mg pimavanserin daily in addition to concurrent antipsychotics and Parkinson disease medications. Safety assessments at 2 weeks; 1, 3, 6, 9, and 12 months; and every 6 months thereafter, including evaluation of adverse events (AEs), vital signs, weight, physical examinations, 12-lead electrocardiograms, clinical laboratory tests (serum chemistry, hematology, and urinalysis), and the Unified Parkinson's Disease Rating Scale Parts II and III (UPDRS-II+III, activities of daily living and motor impairment, respectively). Differences between participants taking and not taking current antipsychotics were evaluated using incidence rate ratios (IRRs) with 95% confidence intervals (CIs). There was significant increase in the mortality rate for participants taking concurrent antipsychotics compared with the group not taking antipsychotic medications (IRR 4.20, 95% CI 2.13-7.96). Participants who received a concurrent antipsychotic were also significantly more likely to experience overall a serious AE (IRR 2.95, 95% CI 2.02-4.24), any antipsychotic-related event (IRR 1.66, 95% CI 1.18-2.29), cognition-related events (IRR 2.70, 95% CI 1.19-5.58), infections (IRR 1.97, 95% CI 1.17-3.16), and edema (IRR 2.61, 95% CI 1.09-5.59). The risk of falls, stroke, sedation, orthostatic hypotension, and thromboembolic events was also increased in these individuals but this was not significant. This study highlights a significant risk of mortality, and severe AEs in patients with Parkinson disease receiving atypical antipsychotics. This is similar to or greater than the risks seen in people with Alzheimer disease, although with a less clear-cut risk of stroke and a longer delay to increased mortality. Copyright © 2015 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.
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Evaluation of the painful athletic hip: imaging options and imaging-guided injections.
Jacobson, Jon A; Bedi, Asheesh; Sekiya, Jon K; Blankenbaker, Donna G
2012-09-01
This article reviews diagnostic imaging tests and injections that provide important information for clinical management of patients with sports-related hip pain. In the evaluation of sports-related hip symptoms, MR arthrography is often used to evaluate intraarticular pathology of the hip. The addition of short- and long-acting anesthetic agents with the MR arthrography injection adds additional information that can distinguish between symptomatic and asymptomatic imaging findings. Osseous abnormalities can be characterized with radiography, MRI, or CT. Ultrasound is important in the assessment of iliopsoas abnormalities, including tendon snapping, and to guide diagnostic anesthetic injection.
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Hepburn, Kirsten; Brzozowska, Malgorzata Monika
2016-08-09
The atypical antipsychotic agent clozapine, although an effective treatment for schizophrenia, is linked with metabolic adverse effects. We report a case of diabetic ketoacidosis and very severe hypertriglyceridaemia associated with clozapine use, in a patient with type 2 diabetes mellitus, who was successfully treated with continuous insulin infusion and fluids. As clozapine proved to be the most efficacious in controlling the patient's psychotic symptoms, the patient has been continued on clozapine despite its known metabolic side effects. Importantly the patient has achieved satisfactory long-term lipid and glycaemic control. The current recommendations related to the metabolic care for patients treated with atypical antipsychotic agents as well as the mechanisms behind abnormal glucose and lipid regulation with clozapine therapy are discussed. 2016 BMJ Publishing Group Ltd.
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Antipsychotic medication for early episode schizophrenia
Bola, John; Kao, Dennis; Soydan, Haluk; Adams, Clive E
2014-01-01
Background Long-term treatment with antipsychotic medications in early episode schizophrenia spectrum disorders is common, but both short and long-term effects on the illness are unclear. There have been numerous suggestions that people with early episodes of schizophrenia appear to respond differently than those with multiple prior episodes. The number of episodes may moderate response to drug treatment. Objectives To assess the effects of antipsychotic medication treatment on people with early episode schizophrenia spectrum disorders. Search methods We searched the Cochrane Schizophrenia Group register (July 2007) as well as references of included studies. We contacted authors of studies for further data. Selection criteria Studies with a majority of first and second episode schizophrenia spectrum disorders comparing initial antipsychotic medication treatment with placebo, milieu, or psychosocial treatment. Data collection and analysis Working independently, we critically appraised records from 681 studies, of which five studies met inclusion criteria. We calculated risk ratios (RR) and their 95% confidence intervals (CI) where possible. For continuous data, we calculated mean difference (MD). We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. Main results Five studies (combined total n=998) met inclusion criteria. Four studies (n=724) provided leaving the study early data and results suggested that individuals treated with a typical antipsychotic medication are less likely to leave the study early than those treated with placebo (Chlorpromazine: 3 RCTs n=353, RR 0.4 CI 0.3 to 0.5, NNT 3.2, Fluphenaxine: 1 RCT n=240, RR 0.5 CI 0.3 to 0.8, NNT 5; Thioridazine: 1 RCT n=236, RR 0.44 CI 0.3 to 0.7, NNT 4.3, Trifulperazine: 1 RCT n=94, RR 0.96 CI 0.3 to 3.6). Two studies contributed data to assessment of adverse effects and present a general pattern of more frequent side effects among individuals treated with typical antipsychotic medications compared to placebo. One trial suggested a higher rehospitalisation rate for those receiving chlorpromazine compared to placebo (n=80, RR 2.29 CI 1.3 to 4.0, NNH 2.9). However, a higher attrition in the placebo group is likely to have introduced a survivor bias into this comparison, as this difference becomes non-significant in a sensitivity analysis on intent-to-treat participants (n=127, RR 1.69 CI 0.9 to 3.0). One study contributes data to a comparison of trifluoperazine to psychotherapy on long-term health in favour of the trifluoperazine group (n=92, MD 5.8 CI 1.6 to 0.0); however, data from this study are also likely to contain biases due to selection and attrition. One other study contributes data to a comparison of typical antipsychotic medication to psychosocial treatment on six-week outcome measures of global psychopathology (n=89, MD 0.01 CI −0.6 to 0.6) and global improvement (n=89, MD −0.03 CI −0.5 to 0.4), indicating no between-group differences. On the whole, there is very little useable data in the few studies meeting inclusion criteria. Authors’ conclusions With only a few studies meeting inclusion criteria, and with limited useable data in these studies, it is not possible to arrive at definitive conclusions. The preliminary pattern of evidence suggests that people with early episode schizophrenia treated with typical antipsychotic medications are less likely to leave the study early, but more likely to experience medication-related side effects. Data are too sparse to assess the effects of antipsychotic medication on outcomes in early episode schizophrenia. PMID:21678355
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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.
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van ′t Klooster, Gerben; Hoeben, Eva; Borghys, Herman; Looszova, Adriana; Bouche, Marie-Paule; van Velsen, Frans; Baert, Lieven
2010-01-01
The next-generation human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse transcriptase inhibitor rilpivirine (TMC278) was administered in rats and dogs as single intramuscular (IM) or subcutaneous (SC) injections, formulated as a 200-nm nanosuspension. The plasma pharmacokinetics, injection site concentrations, disposition to lymphoid tissues, and tolerability were evaluated in support of its potential use as a once-monthly antiretroviral agent in humans. Rilpivirine plasma concentration-time profiles showed sustained and dose-proportional release over 2 months in rats and over 6 months in dogs. The absolute bioavailability approached 100%, indicating a complete release from the depot, in spite of rilpivirine concentrations still being high at the injection site(s) 3 months after administration in dogs. For both species, IM administration was associated with higher initial peak plasma concentrations and a more rapid washout than SC administration, which resulted in a stable plasma-concentration profile over at least 6 weeks in dogs. The rilpivirine concentrations in the lymph nodes draining the IM injection site exceeded the plasma concentrations by over 100-fold 1 month after administration, while the concentrations in the lymphoid tissues decreased to 3- to 6-fold the plasma concentrations beyond 3 months. These observations suggest uptake of nanoparticles by macrophages, which generates secondary depots in these lymph nodes. Both SC and IM injections were generally well tolerated and safe, with observations of a transient inflammatory response at the injection site. The findings support clinical investigations of rilpivirine nanosuspension as a long-acting formulation to improve adherence during antiretroviral therapy and for preexposure prophylaxis. PMID:20160045
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Pont, Lisa G; Raban, Magda Z; Jorgensen, Mikaela L; Georgiou, Andrew; Westbrook, Johanna I
2018-06-08
The aim of this study was to use routinely collected electronic medicines administration (eMAR) data in residential aged care (RAC) to investigate the quality use of medicines. A cross-sectional analysis of eMAR data. 71 RAC facilities in New South Wales and the Australian Capital Territory, Australia. Permanent residents living in a participating facility on 1 October 2015. None. Variation in polypharmacy (≥5 medications), hyper-polypharmacy (≥10 medications) and antipsychotic use across facilities was examined using funnel plot analysis. The study dataset included 4775 long-term residents. The mean resident age was 85.3 years and 70.6% of residents were female. The median facility size was 60 residents and 74.3% were in metropolitan locations. 84.3% of residents had polypharmacy, 41.2% hyper-polypharmacy and 21.0% were using an antipsychotic. The extent of polypharmacy (69.75-100% of residents), hyper-polypharmacy (38.81-76.19%) and use of antipsychotic medicines (0-75.6%) varied considerably across the 71 facilities. Using eMAR data we found substantial variation in polypharmacy, hyper-polypharmacy and antipsychotic medicine use across 71 RAC facilities. Further investigation into the policies and practices of facilities performing above or below expected levels is warranted to understand variation and drive quality improvement.
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Kass, Philip H; Spangler, William L; Hendrick, Mattie J; McGill, Lawrence D; Esplin, D Glen; Lester, Sally; Slater, Margaret; Meyer, E Kathryn; Boucher, Faith; Peters, Erika M; Gobar, Glenna G; Htoo, Thurein; Decile, Kendra
2003-11-01
To determine whether particular vaccine brands, other injectable medications, customary vaccination practices, or various host factors were associated with the formation of vaccine-associated sarcomas in cats. Prospective multicenter case-control study. Cats in the United States and Canada with soft tissue sarcomas or basal cell tumors. Veterinarians submitting biopsy specimens from cats with a confirmed diagnosis of soft tissue sarcoma or basal cell tumor were contacted for patient medical history. Time window statistical analyses were used in conjunction with various assumptions about case definitions. No single vaccine brand or manufacturer within antigen class was found to be associated with sarcoma formation. Factors related to vaccine administration were also not associated with sarcoma development, with the possible exception of vaccine temperature prior to injection. Two injectable medications (long-acting penicillin and methyl prednisolone acetate) were administered to case cats more frequently than to control cats. Findings do not support the hypotheses that specific brands or types of vaccine within antigen class, vaccine practices such as reuse of syringes, concomitant viral infection, history of trauma, or residence either increase or decrease the risk of vaccine-associated sarcoma formation in cats. There was evidence to suggest that certain long-acting injectable medications may also be associated with sarcoma formation.
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Aripiprazole long-acting injection: promising but more evidence needed.
Keks, Nicholas A; Hope, Judy; Culhane, Christine
2016-08-01
Aripiprazole long acting injection (ALAI) is now available, and this paper aims to assist clinicians in deciding when to use ALAI. Aripiprazole is a partial dopamine agonist with low sedation, relatively favourable metabolic profile and a tendency to lower, rather than raise, prolactin. Available for over a decade, aripiprazole has been increasingly recognised by many clinicians as a useful option in the treatment of psychoses. ALAI is a suspension of crystalline aripiprazole in water which takes 5-7 days to reach steady state after an initial intramuscular injection. Monthly injections achieve steady state in four months. Studies have demonstrated that ALAI is effective in aripiprazole-responsive patients. ALAI was generally well tolerated, but more prone to cause extrapyramidal side-effects than the oral form. ALAI has not been compared with other depots. Although the recommended starting dose is 400 mg, it is likely that there will be significant inter-individual dose variation. Dose optimisation in each patient will be necessary for best effectiveness and tolerability. ALAI is currently appropriate for aripiprazole-responsive patients who need a depot, but clinicians are likely to try ALAI in patients who have been on other depots, particularly in whom weight gain and hyperprolactinaemia have been problematic. © The Royal Australian and New Zealand College of Psychiatrists 2016.
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Efficacy of Periarticular Injection With a Long-Acting Local Analgesic in Joint Arthroplasty.
Barrington, John W
2015-10-01
Attention to patient satisfaction is critical in today's health care environment-satisfaction surveys inform the development of hospital performance standards and can influence an institution's rankings and reimbursement. The effectiveness of postoperative pain management can affect clinical outcomes and also influence the patient's perception of the overall surgical experience. Ample clinical- trial data now exist that demonstrate the benefits of periarticular injections as part of a multimodal regimen in patients undergoing joint arthroplasty. One option that surgeons now use widely is bupivacaine liposome injectable suspension (EXPAREL®, Pacira Pharmaceuticals, Inc), a long-acting local analgesic that the orthopedic surgeon can administer intraoperatively. The US Food and Drug Administration has approved liposomal bupivacaine for injection into the surgical site to produce postsurgical analgesia. The safety and efficacy of liposomal bupivacaine has been demonstrated in clinical studies in multiple types of surgical procedure, including double-blind, randomized, controlled clinical trials that involved over 1300 patients. In a case-control study comparing clinical and economic parameters before and after the introduction of liposomal bupivacaine as a component of the multimodal perioperative pain regimen for total joint arthroplasty, liposomal bupivacaine provided improved overall pain scores, an increase in patients reporting a pain score of 0, increased patient satisfaction, decreased length of stay, and a decrease in overall costs.
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Modifying the risk of atypical antipsychotics in the treatment of juvenile-onset schizophrenia.
Townsend, Lisa; Findling, Robert L
2010-02-01
This review summarizes the evidence for use of typical and atypical antipsychotic medications for the treatment of juvenile-onset schizophrenia. We highlight the risks and benefits of antipsychotic agents for youth with this disorder, paying special attention to weight gain and metabolic effects, an area of specific concern within child and adolescent psychiatry. We describe the seriousness of juvenile-onset schizophrenia and its impact on long-term functioning, noting that pharmacological treatment remains the standard of care for this disorder. We focus on weight gain and metabolic effects associated with atypical agents and review strategies to modify risks associated with these agents. We summarize strategies for attenuating the risk of weight gain for youth on atypical antipsychotics, including what is known about nutritional counseling and exercise programs as well as pharmacotherapy with adjunctive weight loss agents. Given the negative consequences associated with untreated schizophrenia, it appears that the most effective way to improve the risk:benefit ratio in the treatment of adolescents with schizophrenia is to reduce the risks associated with pharmacological treatment.
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Efficacy and safety of novel antipsychotics: a critical review.
Balestrieri, Matteo; Vampini, Claudio; Bellantuono, Cesario
2000-10-01
Efficacy and safety of novel antipsychotic (AP) drugs (amisulpride, olanzapine, quetiapine, ziprasidone and zotepine) have been reviewed. Data on their antipsychotic efficacy and side effects profile have been evaluated only on the basis of controlled trials so far published. Overall, all these drugs have shown an antipsychotic efficacy on positive symptoms of schizophrenia similar to that of the conventional AP drugs. On negative symptoms, all novel AP drugs, except quetiapine and ziprasidone, demonstrated a better efficacy than haloperidol. Long-term efficacy of these AP drugs in the maintenance treatment of schizophrenia needs to be explored by further, better-designed, epidemiological studies. The safety profile shows that the novel AP drugs are generally well-tolerated and induce significantly less acute extrapyramidal side effects in comparison with haloperidol. Some methodological flaws in the experimental design of the clinical trials analysed are discussed. Although these novel AP drugs have potential clinical advantages, a number of relevant questions still remain to be addressed, in order to establish the impact of these drugs in the overall treatment of schizophrenia. Copyright 2000 John Wiley & Sons, Ltd.
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[Antipsychotic-drug-induced hyperprolactinemia: physiopathology, clinical features and guidance].
Besnard, I; Auclair, V; Callery, G; Gabriel-Bordenave, C; Roberge, C
2014-02-01
Hyperprolactinemia is a frequent but neglected adverse effect observed in patients treated with antipsychotic-drugs. In this review, we summarize its physiopathogenetic mechanism, its clinical manifestations in men and women, and the way to manage it. Prolactin is a hormone secreted by lactotroph cells in the anterior pituitary. Its synthesis and release are under the control of peptides, steroids and neurotransmitters. The main inhibitory regulation is made by dopamine, which binds dopamine receptors D2 on the membrane of lactotroph cells. Antipsychotic-drugs block these receptors and thus remove the inhibitory effect of dopamine on prolactin secretion. All antipsychotic-drugs block D2 receptors and all can induce hyperprolactinemia. Nonetheless, it seems that the faster the antipsychotic-drug dissociates from D2 receptors, the lesser the increase of prolactin in the plasma. Another way to explain hyperprolactinemia is the ability of antipsychotic-drugs to cross the blood-brain barrier. The role of their metabolites should also be considered. For these reasons, one can distinguish prolactin-raising (conventional neuroleptics, amisulpride, risperidone) and prolactin-sparing (clozapine, aripiprazole, olanzapine) antipsychotics. An English study showed that 18% of men and 47% of women treated with antipsychotics for severe mental illness had a prolactin level above the normal range. Hyperprolactinemia is in fact more frequent in women than in men. Sometimes it is asymptomatic, but the higher the prolactin level is, the more patients have clinical manifestations. Some symptoms are due to the hypogonadism caused by prolactin, which disturbs hypothalamic-pituitary axis function, and others are due to direct effects on target tissues. Consequently, patients can suffer from sexual dysfunction, infertility, amenorrhea, gynecomastia or galactorrhoea. Data suggest that these symptoms are common, but patients don't mention them spontaneously and clinicians underestimate their prevalence. In the long-term, hypogonadism involves a premature bone loss in men and women. Klibanski and colleagues showed that this loss is significant only in women with hyperprolactinemia associated with amenorrhea. That suggests that prolactin is not directly responsible for this clinical feature. Nevertheless, prolactin seems to be involved in the development of breast cancer, but its role is unclear for prostate cancer. Our review promotes a check-up before beginning a treatment with antipsychotic agents. First, a baseline prolactin level should be measured. It should also include the research on previous treatment with antipsychotic-drugs and the assessment of adverse effects suggestive of hyperprolactinemia. Questioning should finally look for any contra-indication to antipsychotics. Monitoring during antipsychotic treatment has been studied by a group of international experts in psychiatry, medicine, toxicology and pharmacy who made a critical review of clinical guidance on hyperprolactinemia. Experts notify that it is important to check whether patients have any sexual dysfunction, such as loss of libido or menstrual irregularity, and galactorrhoea. Prolactin level should also be controlled after three months of stable dose treatment, or if any clinical feature of hyperprolactinemia appears. If a patient prescribed antipsychotic-drugs has a confirmed prolactin level above the normal range, it is necessary to exclude other causes of hyperprolactinemia. If antipsychotics are really involved, the management should be adapted with the prolactin level and the patient him/herself. To summarize, clinicians can decrease the dose of the antipsychotic or switch to a prolactin-sparing drug. Oral contraceptives can be added whether to prevent pregnancy or to prevent bone loss and osteoporosis. Finally, experts recommend reserving dopamine agonists to treat antipsychotic-induced hyperprolactinemia in very exceptional circumstances as it can worsen the mental illness. Copyright © 2013. Published by Elsevier Masson SAS.
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Atypical antipsychotic properties of AD-6048, a primary metabolite of blonanserin.
Tatara, Ayaka; Shimizu, Saki; Masui, Atsushi; Tamura, Miyuki; Minamimoto, Shoko; Mizuguchi, Yuto; Ochiai, Midori; Mizobe, Yusuke; Ohno, Yukihiro
2015-11-01
Blonanserin is a new atypical antipsychotic drug that shows high affinities to dopamine D2 and 5-HT2 receptors; however, the mechanisms underlying its atypicality are not fully understood. In this study, we evaluated the antipsychotic properties of AD-6048, a primary metabolite of blonanserin, to determine if it contributes to the atypicality of blonanserin. Subcutaneous administration of AD-6048 (0.3-1mg/kg) significantly inhibited apomorphine (APO)-induced climbing behavior with an ED50 value of 0.200mg/kg, the potency being 1/3-1/5 times that of haloperidol (HAL). AD-6048 did not cause extrapyramidal side effects (EPS) even at high doses (up to 10mg/kg, s.c.), whereas HAL at doses of 0.1-3mg/kg (s.c.) significantly induced bradykinesia and catalepsy in a dose-dependent manner. Thus, the therapeutic index (potency ratios of anti-APO action to that of EPS induction) of AD-6048 was much higher than that of haloperidol, illustrating that AD-6048 per se possesses atypical antipsychotic properties. In addition, immunohistochemical analysis of Fos protein expression revealed that both AD-6048 and HAL significantly increased Fos expression in the shell part of the nucleus accumbens and the striatum. However, in contrast to HAL which preferentially enhanced striatal Fos expression, AD-6048 showed a preferential action to the nucleus accumbens. These results indicate that AD-6048 acts as an atypical antipsychotic, which seems to at least partly contribute to the atypicality of blonanserin. Copyright © 2015 Elsevier Inc. All rights reserved.
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Crilly, James Patrick; Jennings, Amy; Sargison, Neil
2015-09-15
Much of the current information on the effects of long-acting anthelmintics on nematode populations derives either from research farms or mathematical models. A survey was performed with the aim of establishing how moxidectin is currently being used on sheep farms in the south-east of Scotland. A study was undertaken on a subsection of the surveyed farms to examine the effects of long-acting moxidectin treatments in both spring and autumn on faecal nematode egg output. The survey showed that whole flock treatments of injectable 2% moxidectin were used to control sheep scab on 21% of farms. Injectable 2% moxidectin and oral moxidectin were used to control the periparturient rise in faecal nematode egg shedding by ewes on 13% and 55% of farms respectively. The effects of injectable 2% moxidectin treatment on faecal nematode egg shedding post-treatment in both the autumn and spring were investigated by faecal nematode egg counts at the time of treatment and at 2-weekly interval thereafter on eight and six farms in the autumn and spring, respectively. Faecal egg shedding recommenced at 8 weeks (autumn) and 4 weeks (spring) post-treatment. Counts increased to a peak and then declined. The mean (95% confidence interval) peak counts post-treatment were 2.8 (0.6, 5.1), 3.6 (1.7, 5.5) and 53.5 (25.1, 82.0) eggs per gram (EPG) for autumn-treated ewes, autumn-treated lambs and spring-treated ewes respectively. The spring treated sheep showed a statistically significantly earlier return to faecal egg shedding (p=0.0125, p=0.0342) compared to both other groups, statistically significantly higher peak in egg counts than the autumn treated sheep (p<0.001) and a statistically significantly longer period of positive egg counts (p=0.0148). There was no statistically significant difference in the timing of the peak FECs between autumn and spring (p=0.211). The FECs of all groups of sheep treated with an injectable long-acting formulation of moxidectin became positive earlier than would be expected from the period of persistence given on the datasheet, but post-treatment FECs were very low compared to pre-treatment counts. Copyright © 2015 Elsevier B.V. All rights reserved.
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Long-term thermal effects on injectivity evolution during CO 2 storage
DOE Office of Scientific and Technical Information (OSTI.GOV)
Vilarrasa, Victor; Rinaldi, Antonio P.; Rutqvist, Jonny
Carbon dioxide (CO 2 ) is likely to reach the bottom of injection wells at a colder temperature than that of the storage formation, causing cooling of the rock. This cooling, together with overpressure, tends to open up fractures, which may enhance injectivity. Here, we investigate cooling effects on injectivity enhancement by modeling the In Salah CO 2 storage site and a theoretical, long-term injection case. We use stress-dependent permeability functions that predict an increase in permeability as the effective stress acting normal to fractures decreases. Normal effective stress can decrease either due to overpressure or cooling. We calibrate ourmore » In Salah model, which includes a fracture zone perpendicular to the well, obtaining a good fitting with the injection pressure measured at KB-502 and the rapid CO 2 breakthrough that occurred at the observation well KB-5 located 2 km away from the injection well. CO 2 preferentially advances through the fracture zone, which becomes two orders of magnitude more permeable than the rest of the reservoir. Nevertheless, the effect of cooling on the long-term injectivity enhancement is limited in pressure dominated storage sites, like at In Salah, because most of the permeability enhancement is due to overpressure. But, thermal effects enhance injectivity in cooling dominated storage sites, which may decrease the injection pressure by 20%, saving a significant amount of compression energy all over the duration of storage projects. Overall, our simulation results show that cooling has the potential to enhance injectivity in fractured reservoirs.« less
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Long-term thermal effects on injectivity evolution during CO 2 storage
Vilarrasa, Victor; Rinaldi, Antonio P.; Rutqvist, Jonny
2017-08-22
Carbon dioxide (CO 2 ) is likely to reach the bottom of injection wells at a colder temperature than that of the storage formation, causing cooling of the rock. This cooling, together with overpressure, tends to open up fractures, which may enhance injectivity. Here, we investigate cooling effects on injectivity enhancement by modeling the In Salah CO 2 storage site and a theoretical, long-term injection case. We use stress-dependent permeability functions that predict an increase in permeability as the effective stress acting normal to fractures decreases. Normal effective stress can decrease either due to overpressure or cooling. We calibrate ourmore » In Salah model, which includes a fracture zone perpendicular to the well, obtaining a good fitting with the injection pressure measured at KB-502 and the rapid CO 2 breakthrough that occurred at the observation well KB-5 located 2 km away from the injection well. CO 2 preferentially advances through the fracture zone, which becomes two orders of magnitude more permeable than the rest of the reservoir. Nevertheless, the effect of cooling on the long-term injectivity enhancement is limited in pressure dominated storage sites, like at In Salah, because most of the permeability enhancement is due to overpressure. But, thermal effects enhance injectivity in cooling dominated storage sites, which may decrease the injection pressure by 20%, saving a significant amount of compression energy all over the duration of storage projects. Overall, our simulation results show that cooling has the potential to enhance injectivity in fractured reservoirs.« less
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Treatment of anorexia nervosa with long-term risperidone in an outpatient setting: case study.
Kracke, Elsa J; Tosh, Aneesh K
2014-01-01
There are currently few studies focusing on the efficacy of long-term atypical antipsychotics to treat anorexia nervosa in the pediatric population. This case report follows the treatment of a 17 year-old female with anorexia nervosa over her four-year undergraduate career. After two years of multidisciplinary treatment, low-dose risperidone was initiated due to persistence of her disease. She expressed decreased rigidity around meal times, her weight improved and she had resumption of menses. She was compliant with treatment through graduation and maintained her weight gain. Atypical antipsychotics are a treatment option in the management of anorexia nervosa. Risperidone has not been studied as frequently as olanzapine for eating disorders. Risperidone was chosen for its more favorable side effect profile and decreased cost to the patient. Previous studies on anorexia nervosa treatment have occurred during inpatient treatment and have limited follow-up due to patients' refusal to initiate or maintain medication compliance. This case presents 17 months of outpatient data. The efficacy of risperidone therapy was evaluated with frequent weight checks, subjective decrease in rigidity, serial complete metabolic panels, and restoration of menses. In this case report, an adolescent female treated with low-dose risperidone had decreased rigid thinking, weight gain and resolution of secondary amenorrhea without medication side effects. Therefore, the atypical antipsychotic risperidone may be an effective long-term outpatient treatment option for patients with anorexia nervosa.
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Manual or automated measuring of antipsychotics' chemical oxygen demand.
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.
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Spreen, William; Ford, Susan L; Chen, Shuguang; Wilfret, David; Margolis, David; Gould, Elizabeth; Piscitelli, Stephen
2014-12-15
GSK1265744 (744) is an HIV-1 integrase inhibitor in clinical development as a long-acting (LA) injectable formulation. This study evaluated plasma and tissue pharmacokinetics after single-dose administration of 744 LA administered by intramuscular (IM) or subcutaneous injections. This was a phase I, open-label, 9-cohort, parallel study of 744 in healthy subjects. 744 was administered as a 200 mg/mL nanosuspension at doses of 100-800 mg IM and 100-400 mg subcutaneous. Eight (6 active and 2 placebo) male and female subjects participated in each of the first 7 cohorts. All 8 subjects, 4 males and 4 females, received active 744 LA in cohorts 8 and 9 and underwent rectal and cervicovaginal tissue sampling, respectively. Plasma pharmacokinetic sampling was performed for a minimum of 12 weeks or until 744 concentrations were ≤0.1 μg/mL. Rectal and cervicovaginal tissue biopsies were performed at weeks 2 and 8 (cohort 8) and weeks 4 and 12 (cohort 9). 744 LA was generally safe and well tolerated after single injections. A majority of subjects reported injection site reactions, all graded as mild in intensity. Plasma concentration-time profiles were prolonged with measureable concentrations up to 52 weeks after dosing. 744 LA 800 mg IM achieved mean concentrations above protein adjusted-IC90 for approximately 16 weeks. Rectal and cervicovaginal tissue concentrations ranged from <8% to 28% of corresponding plasma concentrations. These data suggest 744 LA injection has potential application as a monthly or less frequent HIV treatment or prevention agent.
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Patient compliance with drug therapy in schizophrenia. Economic and clinical issues.
Lindström, E; Bingefors, K
2000-08-01
The effectiveness of drug treatment in clinical practice is considerably lower than the efficacy shown in controlled studies. The lower effectiveness in practice presumably leads to lower cost effectiveness of drug treatment in real-life situations compared with that demonstrated by studies based on results from controlled trials. Improved cost effectiveness in routine clinical practice would be a significant advantage in the treatment of schizophrenia, one of the most costly diseases in society. The aetiology of schizophrenia is unknown, and there is no cure. The main aims of therapy with antipsychotic medication include the effective relief of symptoms without the introduction of adverse effects or serious adverse events, improved quality of life, cost effectiveness and a positive long term outcome. The older classical antipsychotic drugs do not always meet these requirements because of their well-known limitations, such as a lack of response in a subgroup of individuals with schizophrenia and intolerable adverse effects. There has long been a need for new antipsychotics that can ameliorate more symptoms and have no or few adverse effects. Some of the recently introduced antipsychotics have been shown to be more effective in certain clinical situations and to have a more favourable adverse effect profile than the classical antipsychotics. A major factor contributing to the lower effectiveness of drug treatment is noncompliance, which may be very high in schizophrenia. There are several factors influencing compliance, including drug type and formulation, patient, disease status, physician, health care system, community care and family. There have been very few studies of compliance improvement strategies in schizophrenia or, indeed, in medicine in general. Current methods are relatively complex and there are differing opinions on their effectiveness. There are several ways to increase compliance in schizophrenia--the evidence is strongest for psychoeducative methods, changing to a new drug or using a depot formulation. However, considerably more research is needed in the field of compliance strategies.
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Repeated aripiprazole administration attenuates cocaine seeking in a rat model of relapse.
Feltenstein, Matthew W; Do, Phong H; See, Ronald E
2009-12-01
Aripiprazole (Abilify) is an atypical antipsychotic drug characterized by partial agonist activity at dopamine (DA) D(2)/D(3) receptors and a low side-effect profile. While we previously demonstrated that acute aripiprazole blocked the reinstatement of cocaine seeking in an animal model of relapse, clinical treatment of relapse prevention necessitates testing the effects of aripiprazole following prolonged abstinence, as well as after repeated administration during withdrawal from cocaine. We assessed the effects of repeated aripiprazole treatment on cocaine seeking after abstinence and during conditioned cue-induced and cocaine-primed reinstatement in rats. Rats self-administered intravenous cocaine paired with a light + tone stimulus for 10-14 days, followed by 2 weeks of abstinence. Following post-abstinence relapse testing, lever responding was allowed to extinguish, with subsequent reinstatement testing occurring either in the presence of the conditioned stimulus, or after a cocaine-priming injection (10 mg/kg, intraperitoneal (IP)). Following 3 or 7 days of pretreatment, rats received an injection of aripiprazole (0.25, 0.5, and 1.0 mg/kg, IP) or vehicle prior to post-abstinence relapse and reinstatement testing. Vehicle-pretreated animals showed robust cocaine seeking during relapse and reinstatement testing, an effect that was significantly attenuated by aripiprazole pretreatment, although no lasting effects were found in the absence of acute injection. These findings support the possibility that repeated aripiprazole may be an effective therapeutic agent for the prevention of relapse in abstinent cocaine users. Based on its antipsychotic profile, aripiprazole may be particularly useful for individuals diagnosed with comorbid psychoses, such as schizophrenia or bipolar disorder.
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Long-acting rilpivirine for HIV prevention.
Jackson, Akil; McGowan, Ian
2015-07-01
Long-acting injectable antiretroviral (ARV) formulations are being developed for the treatment and prevention of HIV infection. The purpose of this review is to summarize recent preclinical and clinical data on TMC278 (rilpivirine), a nonnucleoside reverse transcriptase inhibitor (NNRTI), that is being developed for both a treatment and prevention indication. Long-acting rilpivirine has demonstrated efficacy in preventing HIV acquisition in a humanized mouse model and has been found to be well tolerated and acceptable in several Phase I clinical trials. Pharmacokinetic data from Phase I studies suggest that 1200 mg of long-acting rilpivirine administered every 8 weeks would be associated with plasma and tissue levels of rilpivirine anticipated to be necessary for preventing HIV infection. This regimen is being evaluated in the HPTN-076 Phase II expanded safety study that will enroll women in South Africa, Zimbabwe, and the USA. The HPTN-076 study requires a 4-week run in with oral rilpivirine (25 mg capsules) before receiving 1200 mg of rilpivirine. It is not yet certain whether oral dosing will remain a prerequisite in future trials or post licensure. Long-acting rilpivirine shows promise as a candidate agent for HIV prevention. Preclinical efficacy has been demonstrated in a murine model. Phase I studies have shown good safety and efficacy, but breakthrough infection and resistance have been documented with lower doses of long-acting rilpivirine. Phase II development for a prevention indication is ongoing.
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Long acting systemic HIV pre-exposure prophylaxis: an examination of the field.
Lykins, William R; Luecke, Ellen; Johengen, Daniel; van der Straten, Ariane; Desai, Tejal A
2017-12-01
Oral pre-exposure prophylaxis for the prevention of HIV-1 transmission (HIV PrEP) has been widely successful as demonstrated by a number of clinical trials. However, studies have also demonstrated the need for patients to tightly adhere to oral dosing regimens in order to maintain protective plasma and tissue concentrations. This is especially true for women, who experience less forgiveness from dose skipping than men in clinical trials of HIV PrEP. There is increasing interest in long-acting (LA), user-independent forms of HIV PrEP that could overcome this adherence challenge. These technologies have taken multiple forms including LA injectables and implantables. Phase III efficacy trials are ongoing for a LA injectable candidate for HIV PrEP. This review will focus on the design considerations for both LA injectable and implantable platforms for HIV PrEP. Additionally, we have summarized the existing LA technologies currently in clinical and pre-clinical studies for HIV PrEP as well as other technologies that have been applied to HIV PrEP and contraceptives. Our discussion will focus on the potential application of these technologies in low resource areas, and their use in global women's health.
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Rational Use of Second-Generation Antipsychotics for the Treatment of ICU Delirium.
Mo, Yoonsun; Yam, Felix K
2017-02-01
Delirium, described as an acute neuropsychiatric syndrome, occurs commonly in critically ill patients and leads to many negative outcomes including increased mortality and long-term cognitive deficits. Despite the lack of clinical data supporting the use of antipsychotics for the management of intensive care unit (ICU) delirium, pharmacological interventions are often needed to control acutely agitated patients. Given that the most current guidelines do not advocate the use of haloperidol for either the prevention or treatment of ICU delirium due to a lack of evidence, second-generation antipsychotics (SGAs) have been commonly used as alternatives to haloperidol for ICU patients with delirium. Nonetheless, the evidence supporting the use of SGAs to treat ICU delirium remains limited. This review is designed to assess the available clinical evidence and highlights the different neuropharmacological and safety properties of SGAs in order to guide the rational use of SGAs for the treatment of ICU delirium.
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Rosenberg, David R.; Brooks, Beth Ann; Roberts, Mary W.; Diwadkar, Vaibhav A.
2012-01-01
Objective: There is general consensus that second-generation antipsychotics are at least as effective as and more tolerable than first-generation antipsychotics. We address questions of safety and tolerability in both the short-term and long-term use of these medications by reviewing the existing literature in youth and adults. Data Sources: A MEDLINE search was conducted via PubMed using the following keywords (in various combinations): typical antipsychotics, atypical antipsychotics, children, adolescents, side effects, weight gain, diabetes, metformin, metabolic syndrome, and CATIE. Only English-language articles published from 2000–2010 were included. The bibliographies of papers identified through MEDLINE searches were also reviewed. Results: Six adult studies were analyzed in detail. A summary of the data suggests that there may be a lower association of weight gain and diabetes with ziprasidone, aripiprazole, and haloperidol, while olanzapine, clozapine, quetiapine, and risperidone appear to be more highly associated. There may be less difference than originally thought concerning frequency of extrapyramidal side effects among these medications. All of these antipsychotics, including perphenazine, are similarly efficacious in treating psychosis, with the exception of clozapine, which demonstrates significantly more effectiveness. Although the studies on youth tend to be small (few subjects with large age ranges of 4 to 19 years) and short term in comparison to the adult studies, the data reviewed from 5 studies suggest that, in youth, olanzapine may be associated with the greatest weight gain, extrapyramidal side effects and metabolic changes are quite prevalent, and the antipsychotics studied seem to be similarly effective. Conclusions: Considering effectiveness, safety, and tolerability, this literature review suggests that in adults there may be a lower association of weight gain and diabetes with ziprasidone, aripiprazole, and haloperidol as compared with olanzapine, clozapine, quetiapine, and risperidone. Youth may be particularly sensitive to weight gain, especially with olanzapine, as well as extrapyramidal side effects and metabolic changes. The literature suggests similar effectiveness among the antipsychotics, perhaps with the exception of clozapine having greater effectiveness, at least in adults. PMID:23106030
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Sheehan, Rory; Horsfall, Laura; Strydom, André; Osborn, David; Walters, Kate; Hassiotis, Angela
2017-08-03
To measure the incidence of movement side effects of antipsychotic drugs in adults with intellectual disability and compare rates with adults without intellectual disability. Cohort study using data from The Health Improvement Network. UK primary care. Adults with intellectual disability prescribed antipsychotic drugs matched to a control group of adults without intellectual disability prescribed antipsychotic drugs. New records of movement side effect including acute dystonias, akathisia, parkinsonism, tardive dyskinaesia and neuroleptic malignant syndrome. 9013 adults with intellectual disability and a control cohort of 34 242 adults without intellectual disability together contributed 148 709 person-years data. The overall incidence of recorded movement side effects was 275 per 10 000 person-years (95% CI 256 to 296) in the intellectual disability group and 248 per 10 000 person-years (95% CI 237 to 260) in the control group. The incidence of any recorded movement side effect was significantly greater in people with intellectual disability compared with those without (incidence rate ratio 1.30, 95% CI 1.18 to 1.42, p<0.001, after adjustment for potential confounders), with parkinsonism and akathisia showing the greatest difference between the groups. Neuroleptic malignant syndrome, although occurring infrequently, was three times more common in people with intellectual disability-prescribed antipsychotic drugs (incidence rate ratio 3.03, 95% CI 1.26 to 7.30, p=0.013). Differences in rates of movement side effects between the groups were not due to differences in the proportions prescribed first and second-generation antipsychotic drugs. This study provides evidence to substantiate the long-held assumption that people with intellectual disability are more susceptible to movement side effects of antipsychotic drugs. Assessment for movement side effects should be integral to antipsychotic drug monitoring in people with intellectual disability. Regular medication review is essential to ensure optimal prescribing in this group. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
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Significant Effect of Valproate Augmentation Therapy in Patients With Schizophrenia
Tseng, Ping-Tao; Chen, Yen-Wen; Chung, Weilun; Tu, Kun-Yu; Wang, Hung-Yu; Wu, Ching-Kuan; Lin, Pao-Yen
2016-01-01
Abstract Valproate is an anticonvulsant, which is also widely used for treating psychiatric disorders. Some clinical trials have demonstrated benefits of valproate augmentation therapy in schizophrenia. Previous meta-analysis showed inconsistent findings because of limited literature at that time. The aim of this study is to update the newer published data by conducting a meta-analysis of clinical efficacy of valproate augmentation therapy in patients with schizophrenia or schizoaffective disorder. Data sources include electronic research through platform of PubMed. Study eligibility criteria, participants, and interventions were as follows: the inclusion criteria included articles discussing comparisons of the treatment effect in schizophrenic patients treated with antipsychotic augmented with valproate and antipsychotics with/without placebo; articles on clinical trials in humans. The exclusion criteria were case reports or series and nonclinical trials. We compared the effect between antipsychotic treatment with valproate augmentation and antipsychotic monotherapy. Data from clinical trials were pooled by random-effects model, and possible confounding variables were examined through meta-regression and subgroup analysis. Data from 11 articles including 889 patients were included into current meta-analysis. We found patients treated with antipsychotics with valproate augmentation showed significantly more improvement in total psychopathology than those treated with antipsychotics only (P = 0.02). Results from open trials, but not from randomized controlled trials (P = 0.20), showed significant improvement (P = 0.01). In addition, the significance only persisted in the studies conducted with a shorter treatment duration (P < 0.001) rather than longer treatment duration (P = 0.23). There is no difference in the dropout rate between valproate augmentation and antipsychotic treatment only (P = 0.14). We could not perform a detailed meta-analysis for every category of antipsychotics, long-term effect, and safety profiles of valproate augmentation therapy in maintenance treatment, safety in pregnant patients, and subtype of schizophrenia. Our meta-analysis highlights the significantly better treatment effect with valproate augmentation therapy in patients with schizophrenia or schizoaffective disorder, and provides important evidence for supporting the practice of valproate augmentation therapy in these patients. PMID:26825886
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Blasi, Giuseppe; Selvaggi, Pierluigi; Fazio, Leonardo; Antonucci, Linda Antonella; Taurisano, Paolo; Masellis, Rita; Romano, Raffaella; Mancini, Marina; Zhang, Fengyu; Caforio, Grazia; Popolizio, Teresa; Apud, Jose; Weinberger, Daniel R; Bertolino, Alessandro
2015-01-01
Dopamine D2 and serotonin 5-HT2A receptors contribute to modulate prefrontal cortical physiology and response to treatment with antipsychotics in schizophrenia. Similarly, functional variation in the genes encoding these receptors is also associated with these phenotypes. In particular, the DRD2 rs1076560 T allele predicts a lower ratio of expression of D2 short/long isoforms, suboptimal working memory processing, and better response to antipsychotic treatment compared with the G allele. Furthermore, the HTR2A T allele is associated with lower 5-HT2A expression, impaired working memory processing, and poorer response to antipsychotics compared with the C allele. Here, we investigated in healthy subjects whether these functional polymorphisms have a combined effect on prefrontal cortical physiology and related cognitive behavior linked to schizophrenia as well as on response to treatment with second-generation antipsychotics in patients with schizophrenia. In a total sample of 620 healthy subjects, we found that subjects with the rs1076560 T and rs6314 T alleles have greater fMRI prefrontal activity during working memory. Similar results were obtained within the attentional domain. Also, the concomitant presence of the rs1076560 T/rs6314 T alleles also predicted lower behavioral accuracy during working memory. Moreover, we found that rs1076560 T carrier/rs6314 CC individuals had better responses to antipsychotic treatment in two independent samples of patients with schizophrenia (n=63 and n=54, respectively), consistent with the previously reported separate effects of these genotypes. These results indicate that DRD2 and HTR2A genetic variants together modulate physiological prefrontal efficiency during working memory and also modulate the response to antipsychotics. Therefore, these results suggest that further exploration is needed to better understand the clinical consequences of these genotype–phenotype relationships. PMID:25563748
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Blasi, Giuseppe; Selvaggi, Pierluigi; Fazio, Leonardo; Antonucci, Linda Antonella; Taurisano, Paolo; Masellis, Rita; Romano, Raffaella; Mancini, Marina; Zhang, Fengyu; Caforio, Grazia; Popolizio, Teresa; Apud, Jose; Weinberger, Daniel R; Bertolino, Alessandro
2015-06-01
Dopamine D2 and serotonin 5-HT2A receptors contribute to modulate prefrontal cortical physiology and response to treatment with antipsychotics in schizophrenia. Similarly, functional variation in the genes encoding these receptors is also associated with these phenotypes. In particular, the DRD2 rs1076560 T allele predicts a lower ratio of expression of D2 short/long isoforms, suboptimal working memory processing, and better response to antipsychotic treatment compared with the G allele. Furthermore, the HTR2A T allele is associated with lower 5-HT2A expression, impaired working memory processing, and poorer response to antipsychotics compared with the C allele. Here, we investigated in healthy subjects whether these functional polymorphisms have a combined effect on prefrontal cortical physiology and related cognitive behavior linked to schizophrenia as well as on response to treatment with second-generation antipsychotics in patients with schizophrenia. In a total sample of 620 healthy subjects, we found that subjects with the rs1076560 T and rs6314 T alleles have greater fMRI prefrontal activity during working memory. Similar results were obtained within the attentional domain. Also, the concomitant presence of the rs1076560 T/rs6314 T alleles also predicted lower behavioral accuracy during working memory. Moreover, we found that rs1076560 T carrier/rs6314 CC individuals had better responses to antipsychotic treatment in two independent samples of patients with schizophrenia (n=63 and n=54, respectively), consistent with the previously reported separate effects of these genotypes. These results indicate that DRD2 and HTR2A genetic variants together modulate physiological prefrontal efficiency during working memory and also modulate the response to antipsychotics. Therefore, these results suggest that further exploration is needed to better understand the clinical consequences of these genotype-phenotype relationships.
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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.
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Hard, Marjie L; Mills, Richard J; Sadler, Brian M; Wehr, Angela Y; Weiden, Peter J; von Moltke, Lisa
2017-07-01
Aripiprazole lauroxil (AL) is a long-acting injectable medication approved for the treatment of schizophrenia. Current AL regimens are 441 mg, 662 mg, and 882 mg administered monthly (every 4 weeks [q4wk]), or 882 mg administered every 6 weeks (q6wk). We examined the feasibility of a 2-month (every 8 weeks [q8wk]) dosing interval of AL in a phase I open-label pharmacokinetic study investigating AL 1064 mg administered q8wk for 24 weeks, followed by 20 weeks of safety and pharmacokinetic measurements (ClinicalTrials.gov ID: NCT02320032). Second, a population pharmacokinetic model (referred to as the 2MPopPK model) was generated using data collected from the present trial, as well as data obtained from earlier studies. The phase I study included patients with schizophrenia or schizoaffective disorder maintained on an oral antipsychotic (n = 140) who were assigned to one of three groups: AL 441 mg q4wk, AL 882 mg q6wk, or AL 1064 mg q8wk, with a total of seven, five, or four injections administered, respectively. No oral aripiprazole lead-in supplementation was administered and patients continued on maintenance oral antipsychotics. Pharmacokinetic samples were collected at various time points during the 24-week study period and the 20-week follow-up period. Plasma concentrations obtained from the phase I study were analyzed using non-compartmental methods. Additionally, the data were combined with data collected from prior studies to develop the 2MPopPK model. Following the final injection of AL in the phase I study, maximum aripiprazole concentrations were achieved 24.4-35.2 days after the last dose and persisted for the duration of the study. The mean C avg,ss values were 125.8 ng/ml, 131.1 ng/ml, and 140.7 ng/ml for the 441 mg q4wk, 882 mg q6wk, and 1064 mg q8wk doses, respectively. The mean elimination half-life of aripiprazole following the last dose was 53.9 days for the 1064 mg dose, 55.1 days for the 882 mg dose, and 57.2 days for the 441 mg dose. The 2MPopPK dataset included 14,524 aripiprazole concentrations from 700 patients with schizophrenia. The duration of absorption of aripiprazole was estimated as 43 days (95% confidence interval [CI] 42-45 days), which was preceded by a 3.2-day lag time (95% CI 3.0-3.5 days) for a total duration of input into the systemic circulation of 46 days following intramuscular administration of AL. Multiple-dose simulations showed that the 1064 mg q8wk regimen provides aripiprazole concentrations within the concentration range associated with 441 mg and 882 mg q4wk doses previously demonstrated to be efficacious in a phase III study. These data from the phase I study and the 2MPopPK model support the suitability of using the AL 1064 mg dose as a 2-month (q8wk) dose interval option for the treatment of schizophrenia.
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Darville, Nicolas; van Heerden, Marjolein; Erkens, Tim; De Jonghe, Sandra; Vynckier, An; De Meulder, Marc; Vermeulen, An; Sterkens, Patrick; Annaert, Pieter; Van den Mooter, Guy
2016-02-01
Long-acting injectable (LAI) drug suspensions consist of drug nano-/microcrystals suspended in an aqueous vehicle and enable prolonged therapeutic drug exposure up to several months. The examination of injection site reactions (ISRs) to the intramuscular (IM) injection of LAI suspensions is relevant not only from a safety perspective but also for the understanding of the pharmacokinetics. The aim of this study was to perform a multilevel temporal characterization of the local and lymphatic histopathological/immunological alterations triggered by the IM injection of an LAI paliperidone palmitate suspension and an analog polystyrene suspension in rats and identify critical time points and parameters with regard to the host response. The ISRs showed a moderate to marked chronic granulomatous inflammation, which was mediated by multiple cyto-/chemokines, including interleukin-1β, monocyte Chemoattractant Protein-1, and vascular endothelial growth factor. Lymphatic uptake and lymph node retention of nano-/microparticles were observed, but the contribution to the drug absorption was negligible. A simple image analysis procedure and empirical model were proposed for the accurate evaluation of the depot geometry, cell infiltration, and vascularization. This study was designed as a reference for the evaluation and comparison of future LAIs and to support the mechanistic modeling of the formulation-physiology interplay regulating the drug absorption from LAIs. © The Author(s) 2015.
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Illicit narcotic injection masquerading as acute pulmonary embolism.
Klochan, Shelley A; Taleb, Mohammed; Hoover, Matthew J; Mauro, Vincent F; Anandan, Vasuki; Willey, James; Cooper, Christopher J
2013-04-01
A 23-year-old male presented from a nursing home with hypotension, tachycardia, diaphoresis and electrocardiographic evidence of right ventricular strain that was confirmed by echocardiography. His differential diagnosis included sepsis and pulmonary embolism. A high-resolution computed tomography scan demonstrated no pulmonary emboli but did demonstrate multiple bilateral pulmonary nodules. Upon questioning he admitted to injecting a long-acting narcotic that had been manually macerated, dissolved in saline, and injected through an indwelling intravenous line. Lung biopsy findings were consistent with cellulose-induced perivascular granulomatosis. Cellulose granulomatosis can be seen in patients who inject medications designed for oral use and should be considered in patients who present with acute pulmonary hypertension.
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Guest, Paul C.; Iwata, Keiko; Kato, Takahiro A.; Steiner, Johann; Schmitt, Andrea; Turck, Christoph W.; Martins-de-Souza, Daniel
2015-01-01
Schizophrenia is a debilitating mental disorder, affecting more than 30 million people worldwide. As a multifactorial disease, the underlying causes of schizophrenia require analysis by multiplex methods such as proteomics to allow identification of whole protein networks. Previous post-mortem proteomic studies on brain tissues from schizophrenia patients have demonstrated changes in activation of glycolytic and energy metabolism pathways. However, it is not known whether these changes occur in neurons or in glial cells. To address this question, we treated neuronal, astrocyte, and oligodendrocyte cell lines with the NMDA receptor antagonist MK-801 and measured the levels of six glycolytic enzymes by Western blot analysis. MK-801 acts on the glutamatergic system and has been proposed as a pharmacological means of modeling schizophrenia. Treatment with MK-801 resulted in significant changes in the levels of glycolytic enzymes in all cell types. Most of the differences were found in oligodendrocytes, which had altered levels of hexokinase 1 (HK1), enolase 2 (ENO2), phosphoglycerate kinase (PGK), and phosphoglycerate mutase 1 after acute MK-801 treatment (8 h), and HK1, ENO2, PGK, and triosephosphate isomerase (TPI) following long term treatment (72 h). Addition of the antipsychotic clozapine to the cultures resulted in counter-regulatory effects to the MK-801 treatment by normalizing the levels of ENO2 and PGK in both the acute and long term cultures. In astrocytes, MK-801 affected only aldolase C (ALDOC) under both acute conditions and HK1 and ALDOC following long term treatment, and TPI was the only enzyme affected under long term conditions in the neuronal cells. In conclusion, MK-801 affects glycolysis in oligodendrocytes to a larger extent than neuronal cells and this may be modulated by antipsychotic treatment. Although cell culture studies do not necessarily reflect the in vivo pathophysiology and drug effects within the brain, these results suggest that neurons, astrocytes, and oligodendrocytes are affected differently in schizophrenia. Employing in vitro models using neurotransmitter agonists and antagonists may provide new insights about the pathophysiology of schizophrenia which could lead to a novel system for drug discovery. PMID:26029051
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Valbenazine for the treatment of tardive dyskinesia.
Seeberger, Lauren C; Hauser, Robert A
2017-08-01
Tardive dyskinesia (TD) is a hyperkinetic movement disorder that may result from treatment with antipsychotics or other dopamine receptor blocking agents. Underlying pathophysiology is incompletely understood but since the 1970s dopamine depleting agents have been used to reduce involuntary movements. The search for safe, effective treatments for TD is ongoing. Valbenazine, a novel VMAT2 inhibitor, has recently been FDA approved for treatment of TD. Areas covered: An overview of TD, unmet medical needs and current treatment guidelines are presented. The background, chemistry and clinical development of valbenazine to treat TD is detailed. A competitive market is developing as the treatment gap is identified and potential therapies are discussed in context of a broader market overview. Expert opinion: Antipsychotic use is growing among adults and children in the U.S. Consequently, prevalence of TD is expected to rise. Cessation of antipsychotics is often not possible as the psychiatric condition may deteriorate. Increasing doses of an antipsychotic to suppress involuntary movements is not sustainable long term as underlying TD worsens and movements typically recur. There were no FDA approved treatments for TD. The approval of valbenazine to treat TD is a critical step in addressing this gap in neurologic care.
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Remington, Gary; Seeman, Philip; Feingold, Alan; Mann, Steve; Shammi, Chekkera; Kapur, Shitij
2011-08-01
In the treatment of schizophrenia, all currently available oral antipsychotics are administered at least once daily, with strict adherence strongly encouraged to minimize risk of relapse. Based on a better understanding of the brain kinetics of antipsychotics, we have proposed a variation of this approach, "extended" dosing, which allows for intermittent but regular dosing. We carried out a randomized, double-blind, placebo-controlled trial evaluating 35 individuals with DSM-IV-defined schizophrenia who had been stabilized on antipsychotic therapy. Over a 6-month interval, 18 subjects received their medication as usual (daily), while 17 received their antipsychotic therapy every second day (extended). Outcome measures included clinical scales to assess symptoms (Brief Psychiatric Rating Scale [the primary outcome measure], Calgary Depression Scale), illness severity (Clinical Global Impressions-Severity of Illness scale), and relapse (ie, rehospitalization) rates. Side effects were also assessed, including movement disorders (Barnes Akathisia Scale, Simpson-Angus Scale, Abnormal Involuntary Movement Scale) and weight. The study was conducted from February 2003 to July 2007. Individuals in the extended dosing group were not at greater risk of symptom exacerbation, relapse, or rehospitalization; indeed, more rehospitalizations occurred in those receiving regular dosing. At the same time, though, there was no indication that side effects were significantly reduced in the extended dosing group. These results challenge the long-standing dogma that oral antipsychotics must be administered daily in stabilized patients with schizophrenia. Further studies with larger samples are needed to replicate these findings, as well as to elucidate whether postulated clinical advantages can be established and determined to outweigh potential risks. clinicaltrials.gov Identifier: NCT00431574. © Copyright 2011 Physicians Postgraduate Press, Inc.
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2014-01-01
Background To evaluate the determinants of intensive insulin regimens (ITs) in patients with type 1 diabetes (T1D). Methods This multicenter study was conducted between December 2008 and December 2010 in 28 public clinics in 20 Brazilian cities. Data were obtained from 3,591 patients (56.0% female, 57.1% Caucasian). Insulin regimens were classified as follows: group 1, conventional therapy (CT) (intermediate human insulin, one to two injections daily); group 2 (three or more insulin injections of intermediate plus regular human insulin); group 3 (three or more insulin injections of intermediate human insulin plus short-acting insulin analogues); group 4, basal-bolus (one or two insulin injections of long-acting plus short-acting insulin analogues or regular insulin); and group 5, basal-bolus with continuous subcutaneous insulin infusion (CSII). Groups 2 to 5 were considered IT groups. Results We obtained complete data from 2,961 patients. Combined intermediate plus regular human insulin was the most used therapeutic regimen. CSII was used by 37 (1.2%) patients and IT by 2,669 (90.2%) patients. More patients on IT performed self-monitoring of blood glucose and were treated at the tertiary care level compared to CT patients (p < 0.001). The majority of patients from all groups had HbA1c levels above the target. Overweight or obesity was not associated with insulin regimen. Logistic regression analysis showed that economic status, age, ethnicity, and level of care were associated with IT (p < 0.001). Conclusions Given the prevalence of intensive treatment for T1D in Brazil, more effective therapeutic strategies are needed for long term-health benefits. PMID:24920963
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Claims-based proxies of patient instability among commercially insured adults with schizophrenia
Ruetsch, Charles; Un, Hyong; Waters, Heidi C
2018-01-01
Objective Schizophrenia (Sz) patients are among the highest utilizers of hospital-based services. Prevention of relapse is in part a treatment goal in order to reduce hospital admissions. However, predicting relapse is a challenge, particularly for payers and disease management firms with only access to claims data. Understandably, such organizations have had little success predicting relapse. A tool that allows payers to identify patients at elevated risk of relapse could facilitate targeted interventions prior to relapse and avoid rehospitalization. In this study, a series of proxy measures of patient instability, calculated from claims data were examined for their utility in identifying Sz patients at elevated risk of relapse. Methods Aetna claims were used to assess the relationship between instability of Sz patients and valence and magnitude of antipsychotic (AP) medication change during a 2-year period. Six proxies of instability including hospital admissions, emergency department visits, medication utilization patterns, and use of outpatient services were identified. Results were replicated using claims data from Truven MarketScan®. Results Patients who switched AP ingredient had the highest overall instability at the point of switch and the second steepest decline in instability following switch. Those who changed to a long-acting injectable AP showed the second highest level of instability and the steepest decrease in instability following the change. Patients augmented with a second AP showed the smallest increase in instability, up to the switch. Results were directionally consistent between the two data sets. Conclusion Using claims-based proxy measures to estimate instability may provide a viable method to better understand Sz patient markers of change in disease severity. Also, such proxies could be used to identify those individuals with the greatest need for treatment modification preventing relapse, improving patient outcomes, and reducing the burden of illness. PMID:29765242
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Younis, M N; Nadeem N el-M; Salem, H I; Hamed, A F; Ahmed, A; el-Masry, G; Hamza, A
1987-07-01
This study was carried out in 4 adjacent villages in Lower Eghypt with a combined population of 24,000. A team of social workers and physicians worked together to introduce the injectable contraceptive depomedroxyprogesterone acetate as a post-partum long-acting contraceptive to the community leaders and the villagers at several meetings and individual home visits. Post-partum women who agreed to use the drug were defined as acceptors (591) and those who did not were defined as rejectors (715). The incidence of polygamy was higher among the rejectors, and rejectors' husbands had more children from their other wives. Acceptors had more previous pregnancies and children of both sexes than rejectors. The interval between the last 2 pregnancies was shorter among the rejectors. A greater % of acceptors had previously used another contraceptive. The commonest reasons for rejection were desire for further pregnancy (69%), health problems (11%), and desire for another method of contraception (8%). Religious factors figured in only 3% of cases.
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Early Exposure to Haloperidol or Olanzapine Induces Long-Term Alterations of Dendritic Form
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
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Lorget, Florence; Parenteau, Audrey; Carrier, Michel; Lambert, Daniel; Gueorguieva, Ana; Schuetz, Chris; Bantseev, Vlad; Thackaberry, Evan
2016-09-06
Many long-acting delivery strategies for ocular indications rely on pH- and/or temperature-driven release of the therapeutic agent and degradation of the drug carrier. Yet, these physiological parameters are poorly characterized in ocular animal models. These strategies aim at reducing the frequency of dosing, which is of particular interest for the treatment of chronic disorders affecting the posterior segment of the eye, such as macular degeneration that warrants monthly or every other month intravitreal injections. We used anesthetized white New Zealand rabbits, Yucatan mini pigs, and cynomolgus monkeys to characterize pH and temperature in several vitreous locations and the central aqueous location. We also established post mortem pH changes in the vitreous. Our data showed regional and species differences, which need to be factored into strategies for developing biodegradable long-acting delivery systems.
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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.
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San, L; Estrada, G; Oudovenko, N; Vieta, E
2017-04-04
The management of acute agitation manifesting in patients with schizophrenia or bipolar disorder requires swift pharmacological intervention to provide rapid symptomatic relief and prevent escalation to aggression and violence. Antipsychotic medications are widely used in this setting and the availability of an inhaled formulation with deep lung absorption of the antipsychotic loxapine has the potential to deliver a faster onset of therapeutic effect than the available intramuscular formulations of antipsychotics. The efficacy of inhaled loxapine and the alternative antipsychotic aripiprazole delivered via intramuscular (IM) injection will be compared in the Phase IIIb PLACID study. Adults (18-65 years) with a confirmed diagnosis of schizophrenia or bipolar I disorder presenting with acute agitation will be randomly assigned to open-label treatment in a 1:1 ratio. Clinical evaluation will be conducted by raters blinded to treatment assignment. The primary efficacy endpoint is time to response (defined as a Clinical Global Impression of Improvement [CGI-I] score of 1 [very much improved] or 2 [much improved]). Secondary endpoints will include the percentage of responders at different time points after dosing; the proportion of patients who receive 1 or 2 doses of study drug; time to second dose; time to rescue medication; satisfaction with study drug (evaluated using Item 14 of the Treatment Satisfaction Questionnaire for Medication); and safety and tolerability. Approximately 360 patients will be recruited with an interim analysis conducted once 180 patients have completed the study to decide whether to stop for futility or continue with or without an increase in the sample size up to additional 288 patients. The PLACID trial will assess the efficacy and safety of inhaled loxapine with deep lung absorption compared with the IM antipsychotic, aripiprazole, in acutely agitated patients with schizophrenia or bipolar disorder. In the event that the median time to response of inhaled loxapine is significantly shorter than that of the intramuscular aripiprazole, the PLACID study has the potential to support the inhaled antipsychotic therapy as the standard of care in this setting. The study protocol was registered with the European Clinical Trials Database on the 31 October 2014 (EudraCT number 2014-000456-29 ).
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Haloperidol versus second-generation antipsychotics in the long-term treatment of schizophrenia.
Buoli, Massimiliano; Kahn, René S; Serati, Marta; Altamura, A Carlo; Cahn, Wiepke
2016-07-01
The purpose of the study was to compare antipsychotic monotherapies in terms of time to discontinuation in a sample of schizophrenia patients followed-up for 36 months. Two hundred and twenty schizophrenia patients, treated with antipsychotic monotherapy and followed-up in psychiatric outpatient clinics of Universities of Milan and Utrecht were included in the study. A survival analysis (Kaplan-Meier) of the 36-month follow-up period was performed to compare the single treatment groups. End-point was considered as discontinuation of treatment for recurrence, side effects or non-compliance. Patients treated with haloperidol discontinued more than the other groups (Breslow: risperidone p < 0.001, olanzapine p < 0.001, quetiapine p = 0.002, clozapine p < 0.001, aripiprazole p = 0.002). Lack of efficacy (recurrence) was a more frequent reason for discontinuation in the haloperidol group than in the olanzapine group (p < 0.05). Extrapyramidal side effects (EPS) were more frequent in the haloperidol group than with olanzapine (p < 0.05). The olanzapine group presented more frequently weight gain than the other groups, without reaching statistical significance. Patients treated with atypical antipsychotics appear to continue pharmacotherapy longer than patients treated with haloperidol. In addition, atypical antipsychotics seem to be more protective against recurrences than haloperidol. However, these results should be cautiously interpreted in the light of potential confounder factors such as duration of illness. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.
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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.
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Das, Chandan; Mendez, Guillermo; Jagasia, Sonal; Labbate, Lawrence A
2012-08-01
Weight gain in schizophrenia, particularly secondary to second-generation antipsychotic (SGA) use, is a common adverse effect and often is associated with significant physical and psychological morbidity. We performed a critical literature review of all controlled clinical trials for pharmacologic and/or behavioral management of SGA-induced weight gain in schizophrenia patients by searching PubMed and Google Scholar. A meta-analysis was performed to estimate and compare weight changes for various medications and behavioral interventions. Sample sizes generally were small. Clinical trials were 6 weeks to 1 year, and weight loss was modest with any treatment. Although several adjunctive pharmacologic treatments showed no weight loss, sibutramine, metformin, and topiramate showed some benefit. Amantadine and orlistat were somewhat less effective and had lower rates of tolerability. Among the behavioral therapies, nutritional counseling combined with exercise showed the most benefit. Behavioral therapies, although modest, showed the most consistent benefits compared with controls. Scheduled pharmacologic treatment to prevent weight gain or promote weight loss in schizophrenia patients on SGA therapy is limited based on current studies. Switching antipsychotic agents has not been established as a long-term solution. Additional long-term studies are required to influence clinical practice.
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Gordon, Stephen E; Dufour, Alyssa B; Monti, Sara M; Mattison, Melissa L P; Catic, Angela G; Thomas, Cindy P; Lipsitz, Lewis A
2016-06-01
US nursing homes care for increasing numbers of residents with dementia and associated behavioral problems. They often lack access to specialized clinical expertise relevant to managing these problems. Project ECHO-AGE provides this expertise through videoconference sessions between frontline nursing home staff and clinical experts at an academic medical center. We hypothesized that ECHO-AGE would result in less use of physical and chemical restraints and other quality improvements in participating facilities. A 2:1 matched-cohort study comparing quality of care outcomes between ECHO-AGE facilities and matched controls for the period July 2012 to December 2013. Eleven nursing homes in Massachusetts and Maine. Nursing home staff and a hospital-based team of geriatrician, geropsychiatrist, and neurologist discussed anonymized residents with dementia. Biweekly online video case discussions and brief didactic sessions focused on the management of dementia and behavior disorders. The primary outcome variables were percentage of residents receiving antipsychotic medications and the percentage of residents who were physically restrained. Secondary outcomes included 9 other quality of care metrics from MDS 3.0. Residents in ECHO-AGE facilities were 75% less likely to be physically restrained compared with residents in control facilities over the 18-month intervention period (OR = 0.25, P = .05). Residents in ECHO-AGE facilities were 17% less likely to be prescribed antipsychotic medication compared with residents in control facilities (OR = 0.83, P = .07). Other outcomes were not significantly different. Preliminary evidence suggests that participation in Project ECHO-AGE reduces rates of physical restraint use and may reduce rates of antipsychotic use among long-term nursing home residents. Copyright © 2016 AMDA – The Society for Post-Acute and Long-Term Care Medicine. All rights reserved.
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Biological activity studies of the novel glucagon-like peptide-1 derivative HJ07.
Han, Jing; Sun, Li-Dan; Qian, Hai; Huang, Wen-Long
2014-08-01
To identify the glucose lowering ability and chronic treatment effects of a novel coumarin-glucagon-like peptide-1 (GLP-1) conjugate HJ07. A receptor activation experiment was performed in HEK 293 cells and the glucose lowering ability was evaluated with hypoglycemic duration and glucose stabilizing tests. Chronic treatment was performed by daily injection of exendin-4, saline, and HJ07. Body weight and HbA1c were measured every week, and an intraperitoneal glucose tolerance test was performed before treatment and after treatment. HJ07 showed well-preserved receptor activation efficacy. The hypoglycemic duration test showed that HJ07 possessed a long-acting, glucose-lowering effect and the glucose stabilizing test showed that the antihyperglycemic activity of HJ07 was still evident at a predetermined time (12 h) prior to the glucose challenge (0 h). The long time glucose-lowering effect of HJ07 was better than native GLP-1 and exendin-4. Furthermore, once daily injection of HJ07 to db/db mice achieved long-term beneficial effects on HbA1c lowering and glucose tolerance. The biological activity results of HJ07 suggest that HJ07 is a potential long-acting agent for the treatment of type 2 diabetes. Copyright © 2014 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.
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Wykes, T; Evans, J; Paton, C; Barnes, T R E; Taylor, D; Bentall, R; Dalton, B; Ruffell, T; Rose, D; Vitoratou, S
2017-10-01
Capturing service users' perspectives can highlight additional and different concerns to those of clinicians, but there are no up to date, self-report psychometrically sound measures of side effects of antipsychotic medications. Aim To develop a psychometrically sound measure to identify antipsychotic side effects important to service users, the Maudsley Side Effects (MSE) measure. An initial item bank was subjected to a Delphi exercise (n = 9) with psychiatrists and pharmacists, followed by service user focus groups and expert panels (n = 15) to determine item relevance and language. Feasibility and comprehensive psychometric properties were established in two samples (N43 and N50). We investigated whether we could predict the three most important side effects for individuals from their frequency, severity and life impact. MSE is a 53-item measure with good reliability and validity. Poorer mental and physical health, but not psychotic symptoms, was related to side-effect burden. Seventy-nine percent of items were chosen as one of the three most important effects. Severity, impact and distress only predicted 'putting on weight' which was more distressing, more severe and had more life impact in those for whom it was most important. MSE is a self-report questionnaire that identifies reliably the side-effect burden as experienced by patients. Identifying key side effects important to patients can act as a starting point for joint decision making on the type and the dose of medication.
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Chen, Yin; Xu, Xiangqing; Liu, Xin; Yu, Minquan; Liu, Bi-Feng; Zhang, Guisen
2012-01-01
It is important to develop novel antipsychotics that can effectively treat schizophrenia with minor side-effects. The aim of our work is to develop novel antipsychotics that act on dopamine D(2) and D(3), serotonin 5-HT(1A) and 5-HT(2A) receptors with low affinity for the serotonin 5-HT(2C) and H(1) receptors, which can effectively cure positive symptoms, negative symptoms and cognitive impairment without the weight gain side-effect. A series of 2-substituted-5-thiopropylpiperazine (piperidine) -1,3,4-oxadiazoles derivatives have been synthesized and the target compounds were evaluated for binding affinities to D(2), 5-HT(1A) and 5-HT(2A) receptors. Preliminary results indicated that compounds 14, 16 and 22 exhibited high affinities to D(2), 5-HT(1A) and 5-HT(2A) receptors among these compounds. Further binding tests showed that compound 22 had high affinity for D(3) receptor, and low affinity for serotonin 5-HT(2C) and H(1) receptors. In addition, compound 22 inhibited apomorphine-induced climbing behavior and MK-801-induced hyperactivity with no extrapyramidal symptoms liability in mice. Moreover, compound 22 exhibited acceptable pharmacokinetic properties. Compound 22 showed an atypical antipsychotic activity without liability for extrapyramidal symptoms. We anticipate compound 22 to be useful for developing a novel class of drug for the treatment of schizophrenia.
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Łukasik-Głębocka, Magdalena; Sommerfeld, Karina; Teżyk, Artur; Panieński, Paweł; Żaba, Czesław; Zielińska-Psuja, Barbara
2015-09-01
The post-injection olanzapine delirium/sedation syndrome (PDSS) was observed in a 60-year-old Caucasian, schizophrenic, non-smoker and underweight [body mass index (BMI), 18.2 kg/m(2) ] women after the fourth intramuscular injection of 405 mg olanzapine pamoate. Clinical symptoms of PDSS were similar to those of acute oral olanzapine intoxication. The patient received supportive treatment and recovered fully. High olanzapine concentrations in serum, with maximum level of 698 ng/mL, were confirmed by liquid chromatography with tandem mass spectrometry (LC-MS/MS). The authors wonder whether a low BMI and advanced age may predispose patients to PDSS occurrence. © 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).
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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.
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Patel, Harilal; Patel, Prakash; Modi, Nirav; Patel, Pinakin; Wagh, Yogesh; George, Alex; Desai, Nirmal; Srinivas, Nuggehally R
2018-05-08
Development of prodrug of 9-hydroxyrisperidone (paliperidone) long-acting intramuscular injection has enabled delivery over four-week time period with improved compliance. The key aim of this work was to establish a reliable preclinical model which may potentially serve as a screening tool for judging the pharmacokinetics of paliperidone formulation(s) prior to human clinical work. Sparse sampling composite study was used in rats, (Wistar/Sprague-Dawley (SD; n = 10)) and a serial blood sampling study design was used in rabbits (n = 4). Animals received intramuscular injection of paliperidone palmitate in the thigh muscle at dose of 16 (rats) and 4.5 mg/kg (rabbits). Samples were drawn in rats (retro-orbital sinus) and rabbits (central ear artery) and were analysed for paliperidone using liquid chromatography-mass spectrometry/ mass spectrometry (LC-MS/MS) assay. The plasma data was subjected to pharmacokinetic analysis. Following intramuscular injection of depot formulation in Wistar/SD rats and rabbits, absorption of paliperidone was slow and gradual with median value of time to reach maximum concentration (T max ) occurring on day 7. The exposures (i.e. area under the curve (AUC; 0-28) days) were 18,597, 21,865 and 18,120 ng.h/mL, in Wistar, SD and rabbits, respectively. The clearance was slow and supported long half-life (8-10 days). Either one of the two models can serve as a research tool for establishing pharmacokinetics of paliperidone formulation(s).
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Lynch, Peter; Riedel, Aylin Altan; Samant, Navendu; Fan, Ying; Peoples, Tim; Levinson, Jenifer; Lee, Scott W
2010-12-01
This study was a real-world, retrospective evaluation of the clinical effectiveness of switching to continuous subcutaneous insulin infusion (CSII) among managed care enrollees with type 2 diabetes for whom multiple daily injections (MDI) had presumably failed. Administrative claims with integrated A1C values from a large and geographically diverse health plan were analyzed. Statistically significant A1C reductions (from the baseline period to follow-up period, mean follow-up 17 months) were achieved with CSII. Among subjects using a long-acting and rapid-acting insulin regimen at baseline, A1C decreased to mean follow-up A1C by 0.8% and to minimum follow-up A1C by 1.2% (p<0.001). The proportion of subjects at target (A1C<7%) increased significantly from baseline to follow-up (8.4-22.9% [using mean A1C] and 32.8% [using minimum A1C]; both p<0.001). The rate of severe hypoglycemic events was similar from baseline to follow-up. CSII was associated with significant reductions in A1C without an increase in hypoglycemic events in insulin-taking people with type 2 diabetes, including subjects previously using a long-acting and rapid-acting insulin regimen. Copyright © 2010 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.
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[Wellness-activities to prevent metabolic syndrome among patients with schizophrenia].
Brönner, Monika; Betz, Christine; Christ, Sarah; Froböse, Teresa; Pitschel-Walz, Gabi; Bäuml, Josef
2010-01-01
Weight gain and metabolic disturbances are growing side effects of a modern antipsychotic therapy. Different programs were developed to reduce them. This article gives an overview of existing and evaluated programs. A literature research was made through PubMed. Relevant reviews and intervention studies were identified. Studies with the main outcome variable of weight reductions are numerous, even randomised controlled trials. Short-term weight loss under antipsychotic treatment is possible, but there is still a lack of long-term studies. Life style interventions, which include e. g. physical exercise, are not that common. Also, interventions such as wellness-activities, which contribute by means of adequate motivation strategies to an enhancement of the general well-being, are still missing. Present results turned out to be positive. Further programs which exceed weight management are required. There is necessity for more studies with consistent outcome variables and methods, especially long-term programs. Georg Thieme Verlag KG Stuttgart, New York.
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Tinkler, A. E.; Hedges, A. J.; Shannon, R.
1965-01-01
In view of evidence suggesting that 1.2 mega-units of ”all-purpose” penicillin (300 000 IU potassium penicillin G, 300 000 IU procaine penicillin G and 600 000 IU benzathine penicillin) did not maintain treponemicidal serum concentrations during the week following injection—which if true, might necessitate a reappraisal of prophylactic and treatment schedules in wide use against syphilis—daily assays were performed to determine the penicillinaemia levels in ambulant adult males for one week following intramuscular injection with this dosage of two ”all-purpose” products (168 assays in all, 24 each day). Statistical evaluation of the results showed that the mean daily serum concentrations were, in fact, treponemicidal during the whole week after injection. The means of groups of 24 assays fell within narrow daily ranges on each of the seven post-injection days, suggesting that the long-acting component (benzathine penicillin) gives reliable and predictable daily levels in a high proportion of cases. This is in contrast to those penicillins which rely for their long-acting property on the oily gel in which they are suspended. On the other hand, the extremes of penicillinaemia for any individual in a large group were shown to cover a very wide range, demonstrating that a particular patient's failure to respond to standard treatment or prophylaxis can be due to factors quite unrelated to the quality or specificity of the product or to the sensitivity of the organism causing disease. PMID:5294592
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Predicting Pharmacokinetic Stability by Multiple Oral Administration of Atypical Antipsychotics
Aoki, Kazuo; Sakiyama, Yojiro; Ohnishi, Takashi; Sugita, Makoto
2013-01-01
Lower fluctuation, i.e., lower peak-to-trough plasma-concentration variation at steady-state pharmacokinetics, has several advantages for the treatment of schizophrenia with antipsychotics. The reduction of peak concentration can decrease the risk of dose-dependent side effects, such as extrapyramidal symptom and somnolence, and by contrast the increase in trough concentration can decrease the incidence of lack of efficacy due to subtherapeutic drug concentration. Using a one-compartment simulation technique with pharmacokinetic parameters of each atypical antipsychotic collected from package inserts, the fluctuation index was calculated. Among the antipsychotics, the indices varied from 0.018 to 1.9, depending on dosing regimens, formulations and several pharmacokinetic properties. The order of simulated fluctuation index is active-moiety aripiprazole (b.i.d.)
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Huhtaniska, Sanna; Jääskeläinen, Erika; Heikka, Tuomas; Moilanen, Jani S; Lehtiniemi, Heli; Tohka, Jussi; Manjón, José V; Coupé, Pierrick; Björnholm, Lassi; Koponen, Hannu; Veijola, Juha; Isohanni, Matti; Kiviniemi, Vesa; Murray, Graham K; Miettunen, Jouko
2017-08-30
High doses of antipsychotics have been associated with loss in cortical and total gray matter in schizophrenia. However, previous imaging studies have not taken benzodiazepine use into account, in spite of evidence suggesting adverse effects such as cognitive impairment and increased mortality. In this Northern Finland Birth Cohort 1966 study, 69 controls and 38 individuals with schizophrenia underwent brain MRI at the ages of 34 and 43 years. At baseline, the average illness duration was over 10 years. Brain structures were delineated using an automated volumetry system, volBrain, and medication data on cumulative antipsychotic and benzodiazepine doses were collected using medical records and interviews. We used linear regression with intracranial volume and sex as covariates; illness severity was also taken into account. Though both medication doses associated to volumetric changes in subcortical structures, after adjusting for each other and the average PANSS total score, higher scan-interval antipsychotic dose associated only to volume increase in lateral ventricles and higher benzodiazepine dose associated with volume decrease in the caudate nucleus. To our knowledge, there are no previous studies reporting associations between benzodiazepine dose and brain structural changes. Further studies should focus on how these observations correspond to cognition and functioning. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.
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Reprint of: Clinical management of tardive dyskinesia: Five steps to success.
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.
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Clinical management of tardive dyskinesia: Five steps to success.
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.
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Contraceptive discontinuation and pregnancy postabortion in Nepal: a longitudinal cohort study.
Puri, Mahesh; Henderson, Jillian T; Harper, Cynthia C; Blum, Maya; Joshi, Deepak; Rocca, Corinne H
2015-04-01
To examine postabortion contraceptive discontinuation and pregnancy in Nepal, where abortion was decriminalized in 2002. We conducted an observational cohort study of 654 women obtaining abortions from four public and nongovernmental facilities in 2011. Patients completed questionnaires at their abortion visit and 6 and 12 months later. We used Cox proportional hazards models to assess contraceptive discontinuation and pregnancy by method initiated postabortion and other sociodemographic and reproductive factors. Among the 78% (508/654) of women who initiated a modern contraceptive method within 3 months postabortion, the 1-year contraceptive discontinuation rate was 62 per 100 person-years. Discontinuation was far lower among the 5% of women using long-acting reversible methods (21/100 person-years) than among those using condoms (74/100 person-years), pills (61/100 person-years) and the injectable [64/100 person-years; adjusted hazard ratio (aHR)=0.32 (0.15-0.68)]. Unmarried women and those not living with their husband experienced higher contraceptive discontinuation [aHR=2.16 (1.47-3.17)]. The 1-year pregnancy rate for all women was 9/100 person-years. Pregnancy was highest among those who initiated no modern method postabortion (13/100 person-years) and condoms (12/100 person-years), and pregnancy was lowest among users of long-acting reversible methods (3/100 person-years). The poorest women were at increased pregnancy risk [aHR=2.31 (1.32-4.10)]. Women using intrauterine devices and implants experienced greatly reduced contraceptive discontinuation and pregnancy within a year postabortion, although initiation of these long-acting methods was low. Increased availability of long-acting methods in Nepal and similar settings may help to prevent unwanted pregnancy and attendant maternal mortality and morbidities. Initiation of modern contraception was high postabortion; however, 1-year discontinuation was high for the condom, pill and injectable, the methods most commonly used. Rates for intrauterine devices and implants were low. Results support efforts to facilitate patient knowledge and access to the full range of contraceptives, including long-acting reversible methods. Copyright © 2015 Elsevier Inc. All rights reserved.
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Montgomery, William; Liu, Li; Stensland, Michael D; Xue, Hai Bo; Treuer, Tamas; Ascher-Svanum, Haya
2013-01-01
Background This article describes the personal, societal, and economic burden attributable to schizophrenia in the People’s Republic of China and highlights the potential for effective outpatient treatment to reduce this burden given recent changes in the Chinese health care system. The importance of effective antipsychotic therapy in reducing the burden of schizophrenia is also examined. Methods Published research on the burden, disability, management, and economic costs of schizophrenia in the People’s Republic of China was examined in the context of the larger body of global research. Research written in English or Chinese and published before June 2012 was identified using PubMed, CNKI, and Wanfang Med database searches. The contribution of effective antipsychotic therapy in reducing the risk for relapse and hospitalization and improving patients’ functioning is described. Results Schizophrenia imposes a substantial burden on Chinese society, with indirect costs accounting for the majority of the total cost. Functional impairment is high, leading to lost wages and work impairment. In the People’s Republic of China, schizophrenia is the most common diagnosis among hospitalized psychiatric patients. Ongoing changes in the Chinese health care system may reduce some barriers to effective relapse prevention in schizophrenia and potentially reduce hospitalizations. The use of antipsychotics for acute episodes and maintenance treatment has been shown to decrease symptom severity and reduce the risk for relapse and hospitalization. However, discontinuing antipsychotic medication appears common and is a strong predictor of relapse. Cost-effectiveness research in the People’s Republic of China is needed to examine the potential gains from improved outpatient antipsychotic treatment. Conclusion Schizophrenia is a very costly mental illness in terms of personal, economic, and societal burden, both in the People’s Republic of China and globally. When treated effectively, patients tend to persist longer with antipsychotic treatment, have fewer costly relapses, and have improved functioning. Further research examining the long-term effects of reducing barriers to effective treatments on the societal burden of schizophrenia in the People’s Republic of China is needed. PMID:23983478
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Issy, Ana Carolina; Ferreira, Frederico R.; Viveros, Maria-Paz; Del Bel, Elaine A.; Guimarães, Francisco S.
2015-01-01
Background: Preclinical and clinical data suggest that cannabidiol (CBD), a major non-psychotomimetic compound from Cannabis sativa, induces antipsychotic-like effects. However, the antipsychotic properties of repeated CBD treatment have been poorly investigated. Behavioral changes induced by repeated treatment with glutamate N-methyl-D-aspartate receptor (NMDAR) antagonists have been proposed as an animal model of schizophrenia-like signs. In the present study, we evaluated if repeated treatment with CBD would attenuate the behavioral and molecular modifications induced by chronic administration of one of these antagonists, MK-801. Methods: Male C57BL/6J mice received daily i.p. injections of MK-801 (0.1, 0.5, or 1mg/kg) for 14, 21, or 28 days. Twenty-four hours after the last injection, animals were submitted to the prepulse inhibition (PPI) test. After that, we investigated if repeated treatment with CBD (15, 30, and 60mg/kg) would attenuate the PPI impairment induced by chronic treatment with MK-801 (1mg/kg; 28 days). CBD treatment began on the 6th day after the start of MK-801 administration and continued until the end of the treatment. Immediately after the PPI, the mice brains were removed and processed to evaluate the molecular changes. We measured changes in FosB/ΔFosB and parvalbumin (PV) expression, a marker of neuronal activity and a calcium-binding protein expressed in a subclass of GABAergic interneurons, respectively. Changes in mRNA expression of the NMDAR GluN1 subunit gene (GRN1) were also evaluated. CBD effects were compared to those induced by the atypical antipsychotic clozapine. Results: MK-801 administration at the dose of 1mg/kg for 28 days impaired PPI responses. Chronic treatment with CBD (30 and 60mg/kg) attenuated PPI impairment. MK-801 treatment increased FosB/ΔFosB expression and decreased PV expression in the medial prefrontal cortex. A decreased mRNA level of GRN1 in the hippocampus was also observed. All the molecular changes were attenuated by CBD. CBD by itself did not induce any effect. Moreover, CBD effects were similar to those induced by repeated clozapine treatment. Conclusions: These results indicate that repeated treatment with CBD, similar to clozapine, reverses the psychotomimetic-like effects and attenuates molecular changes observed after chronic administration of an NMDAR antagonist. These data support the view that CBD may have antipsychotic properties. PMID:25618402
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Gomes, Felipe V; Issy, Ana Carolina; Ferreira, Frederico R; Viveros, Maria-Paz; Del Bel, Elaine A; Guimarães, Francisco S
2014-10-31
Preclinical and clinical data suggest that cannabidiol (CBD), a major non-psychotomimetic compound from Cannabis sativa, induces antipsychotic-like effects. However, the antipsychotic properties of repeated CBD treatment have been poorly investigated. Behavioral changes induced by repeated treatment with glutamate N-methyl-D-aspartate receptor (NMDAR) antagonists have been proposed as an animal model of schizophrenia-like signs. In the present study, we evaluated if repeated treatment with CBD would attenuate the behavioral and molecular modifications induced by chronic administration of one of these antagonists, MK-801. Male C57BL/6J mice received daily i.p. injections of MK-801 (0.1, 0.5, or 1mg/kg) for 14, 21, or 28 days. Twenty-four hours after the last injection, animals were submitted to the prepulse inhibition (PPI) test. After that, we investigated if repeated treatment with CBD (15, 30, and 60mg/kg) would attenuate the PPI impairment induced by chronic treatment with MK-801 (1mg/kg; 28 days). CBD treatment began on the 6th day after the start of MK-801 administration and continued until the end of the treatment. Immediately after the PPI, the mice brains were removed and processed to evaluate the molecular changes. We measured changes in FosB/ΔFosB and parvalbumin (PV) expression, a marker of neuronal activity and a calcium-binding protein expressed in a subclass of GABAergic interneurons, respectively. Changes in mRNA expression of the NMDAR GluN1 subunit gene (GRN1) were also evaluated. CBD effects were compared to those induced by the atypical antipsychotic clozapine. MK-801 administration at the dose of 1mg/kg for 28 days impaired PPI responses. Chronic treatment with CBD (30 and 60mg/kg) attenuated PPI impairment. MK-801 treatment increased FosB/ΔFosB expression and decreased PV expression in the medial prefrontal cortex. A decreased mRNA level of GRN1 in the hippocampus was also observed. All the molecular changes were attenuated by CBD. CBD by itself did not induce any effect. Moreover, CBD effects were similar to those induced by repeated clozapine treatment. These results indicate that repeated treatment with CBD, similar to clozapine, reverses the psychotomimetic-like effects and attenuates molecular changes observed after chronic administration of an NMDAR antagonist. These data support the view that CBD may have antipsychotic properties. © The Author 2015. Published by Oxford University Press on behalf of CINP.
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Bokser, L; Zalatnai, A; Schally, A V
1989-03-01
Female mice were injected, every 30 days for 5 months, with a long-acting formulation of microcapsules liberating 2.5 micrograms D-Trp-6-LHRH/day. The control group was injected with vehicle only. At 30 days after the last injection mice were killed, ovaries, uteri and adrenals were weighed and fixed in formalin for histological studies. LH and oestradiol concentrations were measured by RIA. In the D-Trp-6-LHRH-treated group, the weights of the ovaries and uterus (P less than 0.01 and P less than 0.05, respectively), and LH and oestradiol values (P less than 0.02 and P less than 0.01, respectively) were reduced compared to controls. Histologically, the ovaries contained a large number of degenerated, atretic follicles, and corpora lutea had almost completely disappeared. These results indicate, contrary to the prevailing opinion, that mice are sensitive to inhibitory effects of LHRH agonists and that a suppression of the pituitary-gonadal axis can be obtained with long-term administration of D-Trp-6-LHRH microcapsules.
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Bolze, Florian; Bast, Andrea; Mocek, Sabine; Morath, Volker; Yuan, Detian; Rink, Nadine; Schlapschy, Martin; Zimmermann, Anika; Heikenwalder, Mathias; Skerra, Arne; Klingenspor, Martin
2016-09-01
Recombinant leptin offers a viable treatment for lipodystrophy (LD) syndromes. However, due to its short plasma half-life, leptin replacement therapy requires at least daily subcutaneous (s.c.) injections. Here, we optimised this treatment strategy in LD mice by using a novel leptin version with extended plasma half-life using PASylation technology. A long-acting leptin version was prepared by genetic fusion with a 600 residue polypeptide made of Pro, Ala and Ser (PASylation), which enlarges the hydrodynamic volume and, thus, retards renal filtration, allowing less frequent injection. LD was induced in C57BL/6J mice by feeding a diet supplemented with conjugated linoleic acid (CLA). Chronic and acute effects of leptin treatment were assessed by evaluating plasma insulin levels, insulin tolerance, histological liver sections, energy expenditure, energy intake and body composition. In a cohort of female mice, 4 nmol PAS-leptin (applied via four s.c. injections every 3 days) successfully alleviated the CLA-induced LD phenotype, which was characterised by hyperinsulinaemia, insulin intolerance and hepatosteatosis. The same injection regimen had no measurable effect when unmodified recombinant leptin was administered at an equivalent dose. In a cohort of LD males, a single s.c. injection of PAS-leptin did not affect energy expenditure but inhibited food intake and promoted a shift in fuel selection towards preferential fat oxidation, which mechanistically substantiates the metabolic improvements. The excellent pharmacological properties render PASylated leptin an agent of choice for refining both animal studies and therapeutic strategies in the context of LD syndromes and beyond.
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Azoospermia in rabbits following an intravas injection of Vasalgel ™.
Waller, Donald; Bolick, David; Lissner, Elaine; Premanandan, Christopher; Gamerman, Gary
2016-01-01
Vasectomy is currently the only long-acting contraceptive option available for men, despite increasing demand and potentially significant positive impacts on human health of additional male contraceptive options. Vasalgel ™ is a high molecular weight hydrogel polymer being developed as a non-hormonal long-acting reversible male contraceptive. Vasalgel consists of styrene-alt-maleic acid dissolved in dimethyl sulfoxide, which is distinct from styrene-alt-maleic anhydride materials previously studied. The goal of the study was to determine the contraceptive efficacy of two test articles with different levels of styrene maleic acid (100 %, and 80 % acid/20 % anhydride). The test articles were injected bilaterally in the vasa deferentia of mature male rabbits. Post-implantation analyses of semen parameters were completed over a 12 month period and compared to baseline measures of sperm concentration, motility and forward progression. Both test articles were effective in blocking the passage of spermatozoa through the vasa deferentia in the 12 subjects completing the study. A significant decrease in sperm concentration occurred following implantation of the test material, with no measurable sperm concentration except for a few samples in one animal that were markedly oligospermic. Vasalgel produced a rapid onset of azoospermia, with no sperm in semen samples collected as early as 29-36 days post-implantation, and was durable over a 12 month period. This study indicated that Vasalgel is an effective non-hormonal long-acting male contraceptive in a rabbit model.
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Wang, Lexi; Wang, Aiping; Zhao, Xiaolei; Liu, Ximing; Wang, Dan; Sun, Fengying; Li, Youxin
2012-05-10
Two kinds of in situ forming implants (ISFIs) of atypical antipsychotics, risperidone and its 9-hydroxy active metabolite, paliperidone, using poly(lactide-co-glycolide)(PLGA) as carrier, were investigated. Significant difference was observed in the solution-gel transition mechanism of the two systems: homogeneous system of N-methyl-2-pyrrolidone (NMP) ISFI, in which drug was dissolved, and heterogeneous system of dimethyl sulfoxide (DMSO) ISFI, in which drug was dispersed. Fast solvent extractions were found in both systems, but in comparison with the high drug release rate from homogeneous system of drug/polymer/NMP, a fast solvent extraction from the heterogeneous system of drug/polymer/DMSO was not accompanied by a high drug release rate but a rapid solidification of the implant, which resulted in a high drug retention, well-controlled initial burst and slow release of the drug. In vivo study on beagle dogs showed a more than 3-week sustained release with limited initial burst. Pharmacologic evaluation on optimized paliperidone ISFIs presented a sustained-suppressing effect from 1 day to 38 day on the MK-801 induced schizophrenic behavior mice model. A long sustained-release antipsychotic ISFI of 50% drug loading and controlled burst release was achieved, which indicated a good potential in clinic application. Copyright © 2012 Elsevier B.V. All rights reserved.
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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.
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Crippa, José Alexandre; Hallak, Jaime Eduardo Cecílio; Abílio, Vanessa Costhek; de Lacerda, Acioly Luiz Tavares; Zuardi, Antonio Waldo
2015-01-01
Since most patients with schizophrenia do not respond properly to treatment, scientific effort has been driven to the development of new compounds acting on pharmacological targets beyond the dopaminergic system. Therefore, the aim is to review basic and clinical research findings from studies evaluating the effects of cannabidiol (CBD), an inhibitor of the reuptake and metabolism of anandamide and several other effects on nervous system, and sodium nitroprusside, a nitric oxide donor, on the prevention and treatment of psychosis. Animal and human research supports that CBD and sodium nitroprusside might be effective in the prevention and treatment of psychosis in general and especially in schizophrenia. The evidence available to date shows that CBD and sodium nitroprusside act in pathways associated with psychotic symptoms and that they may be important agents in the management of prodromal psychotic states and psychosis. This underscores the relevance of further research on the effects of these agents and others that mediate the activity of the cannabinoid system and of nitric oxide, as well as comparative studies of their antipsychotic effects and those of other antipsychotic drugs currently used to treat schizophrenia.
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Fuxe, Kjell; Borroto-Escuela, Dasiel O; Tarakanov, Alexander O; Romero-Fernandez, Wilber; Ferraro, Luca; Tanganelli, Sergio; Perez-Alea, Mileidys; Di Palma, Michael; Agnati, Luigi F
2014-01-01
This review is focused on the D2 heteroreceptor complexes within the ventral striatum with their receptor-receptor interactions and relevance for the treatment of schizophrenia. A "guide-and-clasp" manner for receptor-receptor interactions is proposed where "adhesive guides" may be amino acid triplet homologies, which were determined for different kinds of D2 heteroreceptor complexes. The first putative D2 heteroreceptor complex to be discovered in relation to schizophrenia was the A2A-D2 heteroreceptor complex where antagonistic A2A-D2 receptor-receptor interactions were demonstrated after A2A agonist treatment in the ventral striatum. The A2A agonist CGS 21680 with atypical antipsychotic properties may at least in part act by increasing β-arrestin2 signaling over the D2 protomer in the A2A-D2 heteroreceptor complex in the ventral striatum. The antagonistic NTS1-D2 interactions in the NTS1-D2 heteroreceptor complex in the ventral striatum are proposed as one molecular mechanism for the potential antipsychotic effects of NT. Indications were obtained that the psychotic actions of the 5-HT2AR hallucinogens LSD and DOI can involve enhancement of D2R protomer signaling via a biased agonist action at the 5-HT2A protomer in the D2-5-HT2A heteroreceptor complex in the ventral striatum. Facilitatory allosteric D2likeR-OTR interactions in heteroreceptor complexes in nucleus accumbens may have a role in social and emotional behaviors. By blocking the D2 protomers of these heteroreceptor complexes, antipsychotics can fail to reduce the negative symptoms of schizophrenia. The discovery of different types of D2 heteroreceptor complexes gives an increased understanding of molecular mechanisms involved in causing schizophrenia and new strategies for its treatment and understanding the side effects of antipsychotics. © 2014 Elsevier B.V. All rights reserved.
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Tan, Xinyi; Zhong, Yue; He, Luying; Zhang, Yuanyuan; Jing, Guanghui; Li, Song; Wang, Jing; He, Haibing; Tang, Xing
2017-05-01
Many formulation and manufacturing processes can lead to morphological and crystalline transitions in many polycrystalline drugs, changing the properties of active pharmaceutical ingredients (APIs) such as solubility and physical stability which influence their therapeutic effects and safety and so limit their usefulness. Here, we report significant changes in crystal forms and morphology, including the shape and size of particles during the manufacture of off-white aripiprazole (APZ) dry powders used for long-acting and injectable suspensions. With the optimal top-down approach, powders were prepared by recrystallizing uniform monohydrous APZ (MA) and polycrystalline anhydrous APZ (AA) form III, characterized by thermal analysis, PXRD, and FT-IR. However, powders involving MA (MAP) with a lower mean size (2.126 μm), narrower distribution (span = 1.90), and higher stability compared with AA dry powders (AAP) were found to exhibit dehydration behavior and morphological changes after completion of the preparation processes based on the results of thermal analysis. In the case of APZ powders, we wished to obtain more information to guide in the industrial production and experimental design of suspensions in the future.
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-12-30
............ NA........ RAND Schizophrenia 2: ........ Annual assessment of weight/BMI, glycemic control, lipids. 41......... NA........ RAND Schizophrenia B: ........ Proportion of schizophrenia patients with long- term utilization of antipsychotic medications. 42......... NA........ RAND Schizophrenia C...
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Antipsychotics activate the TGFβ pathway effector SMAD3
Cohen, T.; Sundaresh, S.; Levine, F.
2014-01-01
Although effective in treating an array of neurological disorders, antipsychotics are associated with deleterious metabolic side effects. Through high-throughput screening, we previously identified phenothiazine antipsychotics as modulators of the human insulin promoter. Here, we extended our initial finding to structurally diverse typical and atypical antipsychotics. We then identified the TGFβ pathway as being involved in the effect of antipsychotics on the insulin promoter, finding that antipsychotics activated SMAD3, a downstream effector of the TGFβ pathway, through a receptor distinct from the TGFβ receptor family and known neurotransmitter receptor targets of antipsychotics. Of note, antipsychotics that do not cause metabolic side effects did not activate SMAD3. In vivo relevance was demonstrated by reanalysis of gene expression data from human brains treated with antipsychotics, which showed altered expression of SMAD3 responsive genes. This work raises the possibility that antipsychotics could be designed that retain beneficial CNS activity while lacking deleterious metabolic side effects. PMID:22290122
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Tsutsumi, Chisa; Uchida, Hiroyuki; Suzuki, Takefumi; Watanabe, Koichiro; Takeuchi, Hiroyoshi; Nakajima, Shinichiro; Kimura, Yoshie; Tsutsumi, Yuichiro; Ishii, Koichi; Imasaka, Yasushi; Kapur, Shitij
2011-08-01
Most patients with schizophrenia first start with a single antipsychotic, and yet most finally end up 'switching' or using 'polypharmacy'. The objective of this study was to examine the evolution of antipsychotic switch and polypharmacy in the real-world from a longitudinal perspective. A systematic review of longitudinal antipsychotic prescriptions in 300 patients with schizophrenia (ICD-10) for up to 2 years after their first visit to one of the 4 participating psychiatric clinics in Tokyo, Japan between January, 2007 and June, 2008, was conducted. Reasons for prescription change were also examined. The evolution of switching and polypharmacy was studied, and prescribed doses were compared to suggested dose ranges by the Texas Medication Algorithm Project (TMAP). 208 patients started their antipsychotic treatment with monotherapy. 34.1% of the patients gave up monotherapy with an initial antipsychotic to move to antipsychotic switch (27.4%) and/or polypharmacy (17.8%) within 2 years. The main reason for antipsychotic switch was 'ineffectiveness'; interestingly, this happened despite the fact that the monotherapy dose was below the recommended range in 47.4% of the antipsychotic switch. In a subgroup of 100 patients who started as antipsychotic-free, 2-year prevalence rates of switching and antipsychotic polypharmacy were 27.0% and 18.0%, respectively, and polypharmacy was resorted to after a median of 1 antipsychotic had been tried for 84 days (median). These findings raise a concern that physicians may perform an antipsychotic switch without exploring the entire dose range and resort to antipsychotic polypharmacy without trying an adequate number of antipsychotics. Copyright © 2011 Elsevier B.V. All rights reserved.
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Meyer, Urs; Knuesel, Irene; Nyffeler, Myriel; Feldon, Joram
2010-03-01
Converging evidence indicates that prenatal exposure to immune challenge can induce long-term cognitive deficits relevant to schizophrenia. Such cognitive impairments may be related to deficient hippocampal neurogenesis at adult age. In the present study, we sought evidence for the possibility that chronic treatment with the reference atypical antipsychotic drug clozapine may improve prenatal infection-induced cognitive dysfunctions by stimulating adult hippocampal neurogenesis. This hypothesis was tested in a well-established mouse model of prenatal immune challenge which is based on prenatal administration of the viral mimic, polyriboinosinic-polyribocytidilic acid (PolyI:C). We found that maternal PolyI:C (5 mg/kg, i.v.) exposure on gestation day 17 led to significant spatial working memory impairment and reduced hippocampal neurogenesis in the resulting offspring at adult age. The latter effect was apparent in postmortem immunohistochemical analyses of the cell proliferation marker bromodeoxyuridine and the microtubule-associated protein doublecortin, a marker of newborn neuronal cells. Chronic (3 weeks) administration of clozapine (5 mg/kg/day, i.p.) significantly improved the prenatal PolyI:C-induced working memory deficits, while at the same time, it negatively affected working memory performance in adult offspring born to control mothers. These bidirectional cognitive effects of clozapine were not paralleled by concomitant effects on adult hippocampal neurogenesis. Our findings do not support the hypothesis that the atypical antipsychotic drug clozapine may influence cognitive functions by acting on adult neurogenesis in the hippocampus, regardless of whether the drug is administered to subjects with or without a neurodevelopmental predisposition to adult neuropathology.
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Stachnik, Joan; Gabay, Michael
2010-01-01
Autistic disorder is a largely misunderstood and difficult to treat neurodevelopmental disorder. Three core domains of functioning are affected by autistic disorder, ie, socialization, communication, and behavior. Signs of autistic disorder may be present early, but are frequently overlooked, resulting in a delay in its diagnosis and a subsequent delay in treatment. No one definitive therapy is available, and treatment consists of early educational and behavioral interventions, as well as drug therapy. Atypical antipsychotics have often been used in the treatment of autistic disorder to target irritability, aggression, and self-injurious behavior, all of which can interfere with other aspects of treatment. One atypical antipsychotic, aripiprazole, has recently been approved for treatment of irritability associated with autistic disorder. Based on the results from two randomized, controlled trials, with efficacy data from nearly 300 patients, treatment with aripiprazole was associated with reductions in irritability, global improvements in behavior, and improvements in quality of life from both the patient and caregiver perspectives. Dosage of aripiprazole ranged from 5 mg to 15 mg per day. Aripiprazole was well tolerated during clinical trials, with most adverse events considered mild or moderate. Clinically relevant weight gain occurred in about 30% of patients given aripiprazole, although when compared with other atypical antipsychotics, aripiprazole appears to have fewer metabolic effects and a lower risk of weight gain. However, pediatric patients taking any atypical antipsychotic should be carefully monitored for potential adverse events, because the long-term effects of antipsychotic therapy in this population are not well known. When used appropriately, aripiprazole has the potential to be an effective treatment for children with autistic disorder to improve irritability and aggressive behavior and improve quality of life.
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Veijola, Juha; Guo, Joyce Y.; Moilanen, Jani S.; Jääskeläinen, Erika; Miettunen, Jouko; Kyllönen, Merja; Haapea, Marianne; Huhtaniska, Sanna; Alaräisänen, Antti; Mäki, Pirjo; Kiviniemi, Vesa; Nikkinen, Juha; Starck, Tuomo; Remes, Jukka J.; Tanskanen, Päivikki; Tervonen, Osmo; Wink, Alle-Meije; Kehagia, Angie; Suckling, John; Kobayashi, Hiroyuki; Barnett, Jennifer H.; Barnes, Anna; Koponen, Hannu J.; Jones, Peter B.; Isohanni, Matti; Murray, Graham K.
2014-01-01
Studies show evidence of longitudinal brain volume decreases in schizophrenia. We studied brain volume changes and their relation to symptom severity, level of function, cognition, and antipsychotic medication in participants with schizophrenia and control participants from a general population based birth cohort sample in a relatively long follow-up period of almost a decade. All members of the Northern Finland Birth Cohort 1966 with any psychotic disorder and a random sample not having psychosis were invited for a MRI brain scan, and clinical and cognitive assessment during 1999–2001 at the age of 33–35 years. A follow-up was conducted 9 years later during 2008–2010. Brain scans at both time points were obtained from 33 participants with schizophrenia and 71 control participants. Regression models were used to examine whether brain volume changes predicted clinical and cognitive changes over time, and whether antipsychotic medication predicted brain volume changes. The mean annual whole brain volume reduction was 0.69% in schizophrenia, and 0.49% in controls (p = 0.003, adjusted for gender, educational level, alcohol use and weight gain). The brain volume reduction in schizophrenia patients was found especially in the temporal lobe and periventricular area. Symptom severity, functioning level, and decline in cognition were not associated with brain volume reduction in schizophrenia. The amount of antipsychotic medication (dose years of equivalent to 100 mg daily chlorpromazine) over the follow-up period predicted brain volume loss (p = 0.003 adjusted for symptom level, alcohol use and weight gain). In this population based sample, brain volume reduction continues in schizophrenia patients after the onset of illness, and antipsychotic medications may contribute to these reductions. PMID:25036617
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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.
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Stachnik, Joan; Gabay, Michael
2010-01-01
Autistic disorder is a largely misunderstood and difficult to treat neurodevelopmental disorder. Three core domains of functioning are affected by autistic disorder, ie, socialization, communication, and behavior. Signs of autistic disorder may be present early, but are frequently overlooked, resulting in a delay in its diagnosis and a subsequent delay in treatment. No one definitive therapy is available, and treatment consists of early educational and behavioral interventions, as well as drug therapy. Atypical antipsychotics have often been used in the treatment of autistic disorder to target irritability, aggression, and self-injurious behavior, all of which can interfere with other aspects of treatment. One atypical antipsychotic, aripiprazole, has recently been approved for treatment of irritability associated with autistic disorder. Based on the results from two randomized, controlled trials, with efficacy data from nearly 300 patients, treatment with aripiprazole was associated with reductions in irritability, global improvements in behavior, and improvements in quality of life from both the patient and caregiver perspectives. Dosage of aripiprazole ranged from 5 mg to 15 mg per day. Aripiprazole was well tolerated during clinical trials, with most adverse events considered mild or moderate. Clinically relevant weight gain occurred in about 30% of patients given aripiprazole, although when compared with other atypical antipsychotics, aripiprazole appears to have fewer metabolic effects and a lower risk of weight gain. However, pediatric patients taking any atypical antipsychotic should be carefully monitored for potential adverse events, because the long-term effects of antipsychotic therapy in this population are not well known. When used appropriately, aripiprazole has the potential to be an effective treatment for children with autistic disorder to improve irritability and aggressive behavior and improve quality of life. PMID:24600266
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Issues related to sex differences in antipsychotic treatment.
Crawford, Mitchell B; DeLisi, Lynn E
2016-05-01
The effectiveness, side-effect profiles, and numerous other characteristics of antipsychotic medications have been extensively studied. However, the majority of publications do not address the many potential sex differences in efficacy and doses of medications, as well as other sex-specific considerations. Of studies that exist, some suggest that female patients respond to lower doses of antipsychotic medications than males and that side-effect profiles vary between the sexes. However, the majority of preclinical trials use only male laboratory animals, and human clinical trials consist of too few women to analyze their response as a separate group. Although changes in hormone production occurring at multiple stages throughout a women's life (such as during pregnancy, breast feeding, menopause, and postmenopausal) are presented as too complex to deal with in clinical trials, they could instead be embraced as clinical dilemmas that require additional study and consideration. We suggest that a focus should be made to reanalyze data from existing major treatment trials of antipsychotics to determine what medications specifically provide the most efficacy for female patients and at what dose range. In addition, new prospective studies are needed to specifically address appropriate adjustments in psychopharmacologic treatment for female patients during pregnancy, and when postmenopausal. More studies of the effects of antipsychotics on male and female fetuses in utero and during breast feeding are also needed to better manage women with schizophrenia and their offspring on a long-term basis in the community. There is currently too little known about sex differences in neuropharmacology. With the new USA National Institutes of Health policy to include sex in all new proposals, the time has come to close this gap in knowledge.
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Hulshof, Tessa A; Zuidema, Sytse U; Ostelo, Raymond W J G; Luijendijk, Hendrika J
2015-10-01
Numerous observational studies have reported an increased risk of mortality for conventional antipsychotics in elderly patients, and for haloperidol in particular. Subsequently, health authorities have warned against use of conventional antipsychotics in dementia. Experimental evidence is lacking. To assess the mortality risk of conventional antipsychotics in elderly patients with a meta-analysis of trials. Original studies were identified in electronic databases, online trial registers, and hand-searched references of published reviews. Two investigators found 28 potentially eligible studies, and they selected 17 randomized placebo-controlled trials in elderly patients with dementia, delirium, or a high risk of delirium. Two investigators independently abstracted trial characteristics and deaths, and 3 investigators assessed the risk of bias. Deaths were pooled with RevMan to obtain risk differences and risk ratios. Data of 17 trials with a total of 2387 participants were available. Thirty-two deaths occurred. The pooled risk difference of 0.1% was not statistically significant (95% confidence interval (CI) -1.0%-1.2%). The risk ratio was 1.07 (95% CI 0.54-2.13). Eleven of 17 trials tested haloperidol (n = 1799). The risk difference was 0.4% (95% CI -0.9%-1.6%), the risk ratio was 1.25 (95% CI 0.59-2.65). This meta-analysis of placebo-controlled randomized trials does not show that conventional antipsychotics in general or haloperidol in particular increase the risk of mortality in elderly patients. It questions the observational findings and the warning based on these findings. Copyright © 2015 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.
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Walsh, Kieran A; Dennehy, Rebecca; Sinnott, Carol; Browne, John; Byrne, Stephen; McSharry, Jennifer; Coughlan, Eoin; Timmons, Suzanne
2017-10-01
Antipsychotic prescribing is prevalent in nursing homes for the management of behavioral and psychological symptoms of dementia (BPSD), despite the known risks and limited effectiveness. Many studies have attempted to understand this continuing phenomenon, using qualitative research methods, and have generated varied and sometimes conflicting findings. To date, the totality of this qualitative evidence has not been systematically collated and synthesized. To synthesize the findings from individual qualitative studies on decision-making and prescribing behaviors for antipsychotics in nursing home residents with dementia, with a view to informing intervention development and quality improvement in this field. A systematic review and synthesis of qualitative evidence was conducted (PROSPERO protocol registration CRD42015029141). Six electronic databases were searched systematically from inception through July 2016 and supplemented by citation, reference, and gray literature searching. Studies were included if they used qualitative methods for both data collection and analysis, and explored antipsychotic prescribing in nursing homes for the purpose of managing BPSD. The Critical Appraisal Skills Program assessment tool was used for quality appraisal. A meta-ethnography was conducted to synthesize included studies. The Confidence in the Evidence from Reviews of Qualitative research approach was used to assess the confidence in individual review findings. All stages were conducted by at least 2 independent reviewers. Of 1534 unique records identified, 18 met the inclusion criteria. Five key concepts emerged as influencing decision-making: organizational capacity; individual professional capability; communication and collaboration; attitudes; regulations and guidelines. A "line of argument" was synthesized and a conceptual model constructed, comparing this decision-making process to a dysfunctional negative feedback loop. Our synthesis indicates that when all stakeholders come together to communicate and collaborate as equal and empowered partners, this can result in a successful reduction in inappropriate antipsychotic prescribing. Antipsychotic prescribing in nursing home residents with dementia occurs in a complex environment involving the interplay of various stakeholders, the nursing home organization, and external influences. To improve the quality of antipsychotic prescribing in this cohort, a more holistic approach to BPSD management is required. Although we have found the issue of antipsychotic prescribing has been extensively explored using qualitative methods, there remains a need for research focusing on how best to change the prescribing behaviors identified. Copyright © 2017 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.
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Long-acting insulins alter milk composition and metabolism of lactating dairy cows.
Winkelman, L A; Overton, T R
2013-01-01
This study investigated the effect of 2 different types of long-acting insulin on milk production, milk composition, and metabolism in lactating dairy cows. Multiparous cows (n=30) averaging 88 d in milk were assigned to one of 3 treatments in a completely randomized design. Treatments consisted of control (C), Humulin-N (H; Eli Lilly and Company, Indianapolis, IN), and insulin glargine (L). The H and L treatments were administered twice daily at 12-h intervals via subcutaneous injection for 10d. Cows were milked twice daily, and milk composition was determined every other day. Mammary biopsies were conducted on d 11, and mammary proteins extracted from the biopsies were analyzed by Western blot for components of insulin and mammalian target of rapamycin signaling pathways. Treatment had no effect on dry matter intake or milk yield. Treatment with both forms of long-acting insulin increased milk protein content and tended to increase milk protein yield over the 10-d treatment period. Analysis of milk N fractions from samples collected on d 10 of treatment suggested that cows administered L tended to have higher yields of milk protein fractions than cows administered H. Milk fat content and yield tended to be increased for cows administered long-acting insulins. Lactose content and yields were decreased by treatment with long-acting insulins. Administration of long-acting insulins, particularly L, tended to shift milk fatty acid composition toward increased short- and medium-chain fatty acids and decreased long-chain fatty acids. Plasma concentrations of glucose and urea N were lower for cows administered long-acting insulins; interactions of treatment and sampling time were indicative of more pronounced effects of L than H on these metabolites. Concentrations of nonesterified fatty acids and insulin were increased in cows administered long-acting insulins. Decreased concentrations of urea N in both plasma and milk suggested more efficient use of N in cows administered long-acting insulins. Western blot analysis of mammary tissue collected by biopsy indicated that the ratios of phosphorylated protein kinase b (Akt) to total Akt and phosphorylated ribosomal protein S6 (rpS6) to total rpS6 were not affected by long-acting insulins. Modestly elevating insulin activity in lactating dairy cows using long-acting insulins altered milk composition and metabolism. Future research should explore mechanisms by which either insulin concentrations or insulin signaling pathways in the mammary gland can be altered to enhance milk fat and protein production. Copyright © 2013 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.
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Switching antipsychotic medications.
Weiden, P J; Aquila, R; Dalheim, L; Standard, J M
1997-01-01
Compared with conventional antipsychotics, the so-called "atypical" antipsychotics promise improved side effect profiles and better control of the symptoms of schizophrenia. Therefore, most patients currently taking conventional antipsychotics could potentially benefit from a switch to an atypical antipsychotic. Often, the key issue in deciding whether to switch is the presence of countervailing factors that mitigate against the change. This paper discusses the indications and contraindications for switching antipsychotics, plus issues that require consideration before a switch is made. Also, the advantages and disadvantages of various switching techniques are discussed, with a particular focus on the newer antipsychotic olanzapine.
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Henderson, Catherine; Knapp, Martin; Yeeles, Ksenija; Bremner, Stephen; Eldridge, Sandra; David, Anthony S.; O’Connell, Nicola; Burns, Tom; Priebe, Stefan
2015-01-01
Background Offering a modest financial incentive to people with psychosis can promote adherence to depot antipsychotic medication, but the cost-effectiveness of this approach has not been examined. Methods Economic evaluation within a pragmatic cluster-randomised controlled trial. 141 patients under the care of 73 teams (clusters) were randomised to intervention or control; 138 patients with diagnoses of schizophrenia, schizo-affective disorder or bipolar disorder participated. Intervention participants received £15 per depot injection over 12 months, additional to usual acute, mental and community primary health services. The control group received usual health services. Main outcome measures: incremental cost per 20% increase in adherence to depot antipsychotic medication; incremental cost of ‘good’ adherence (defined as taking at least 95% of the prescribed number of depot medications over the intervention period). Findings Economic and outcome data for baseline and 12-month follow-up were available for 117 participants. The adjusted difference in adherence between groups was 12.2% (73.4% control vs. 85.6% intervention); the adjusted costs difference was £598 (95% CI -£4 533, £5 730). The extra cost per patient to increase adherence to depot medications by 20% was £982 (95% CI -£8 020, £14 000). The extra cost per patient of achieving 'good' adherence was £2 950 (CI -£19 400, £27 800). Probability of cost-effectiveness exceeded 97.5% at willingness-to-pay values of £14 000 for a 20% increase in adherence and £27 800 for good adherence. Interpretation Offering a modest financial incentive to people with psychosis is cost-effective in promoting adherence to depot antipsychotic medication. Direct healthcare costs (including costs of the financial incentive) are unlikely to be increased by this intervention. Trial Registration ISRCTN.com 77769281 PMID:26448540
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Casey, Sara E; Cannon, Amy; Mushagalusa Balikubirhi, Benjamin; Muyisa, Jean-Bosco; Amsalu, Ribka; Tsolka, Maria
2017-01-01
Despite the inclusion of sexual and reproductive health (SRH) services in the minimum standards of health care in humanitarian settings, access to SRH services, and especially to contraception, is often compromised in war. Very little is known about continuation and switching of contraceptive methods in these settings. An evaluation of a contraceptive services program in North Kivu, Democratic Republic of the Congo (DRC) was conducted to measure 12-month contraceptive continuation by type of contraceptive method (short-acting or long-acting). A stratified systematic sample of women who initiated a contraceptive method 12-18 months prior to data collection was selected retrospectively from facility registers. A total of 548 women was interviewed about their contraceptive use: 304 who began a short-acting method (pills, injectables) and 244 who began a long-acting method (intra-uterine devices, implants). Key characteristics of short-acting method versus long-acting method acceptors were compared using chi-square statistics for categorical data and t-tests for continuous data. Unadjusted and adjusted Cox proportional hazard ratios were estimated to assess factors associated with discontinuation. At 12 months, 81.6% women reported using their baseline contraceptive method continuously, with more long-acting than short-acting contraceptive acceptors (86.1% versus 78.0%, p = .02) continuing contraceptive use. Use of a short-acting method (Hazard ratio (HR) 1.74 [95%CI 1.13-2.67]) and desiring a child within two years (HR 2.58 [95%CI 1.45-4.54]) were associated with discontinuation within the first 12 months of use. The vast majority (88.3%) of women reported no prior contraceptive use. This is the first study of contraceptive continuation in a humanitarian setting. The high percentages of women continuing contraceptive use found here demonstrates that women will choose to initiate and continue use of their desired contraceptive method, even in a difficult, unstable and low contraceptive prevalence setting like North Kivu.
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Azekawa, Takaharu; Ohashi, Shizuko; Itami, Akira
2011-01-01
Background Effectiveness of a drug is a key concept dependent on efficacy, safety, and tolerability. Time to discontinuation of treatment is also representative of effectiveness. We investigated differences in treatment discontinuation among newly started second-generation antipsychotics in the clinical setting. Methods Using a retrospective cohort study design, we screened all outpatients (n = 7936) who visited the Shioiri Mental Clinic between July 1, 2008 and June 30, 2010. We identified a cohort of patients (n = 703) diagnosed with schizophrenia or schizoaffective disorder and calculated the time to discontinuation of each second-generation antipsychotic. Results Of the 703 patients, 149 were newly treated with aripiprazole, 67 with blonanserin, 95 with olanzapine, 36 with quetiapine, 74 with perospirone, and 120 with risperidone. The time to discontinuation for all causes was significantly longer for aripiprazole than for blonanserin, olanzapine, and risperidone. In addition, aripiprazole tended to be continued for longer than quetiapine and perospirone, but these differences were not significant. Conclusion Aripiprazole may be considered the best available option for long-term treatment of patients with schizophrenia or schizoaffective disorder. PMID:22128254
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Azekawa, Takaharu; Ohashi, Shizuko; Itami, Akira
2011-01-01
Effectiveness of a drug is a key concept dependent on efficacy, safety, and tolerability. Time to discontinuation of treatment is also representative of effectiveness. We investigated differences in treatment discontinuation among newly started second-generation antipsychotics in the clinical setting. Using a retrospective cohort study design, we screened all outpatients (n = 7936) who visited the Shioiri Mental Clinic between July 1, 2008 and June 30, 2010. We identified a cohort of patients (n = 703) diagnosed with schizophrenia or schizoaffective disorder and calculated the time to discontinuation of each second-generation antipsychotic. Of the 703 patients, 149 were newly treated with aripiprazole, 67 with blonanserin, 95 with olanzapine, 36 with quetiapine, 74 with perospirone, and 120 with risperidone. The time to discontinuation for all causes was significantly longer for aripiprazole than for blonanserin, olanzapine, and risperidone. In addition, aripiprazole tended to be continued for longer than quetiapine and perospirone, but these differences were not significant. Aripiprazole may be considered the best available option for long-term treatment of patients with schizophrenia or schizoaffective disorder.
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Feifel, D.; Shilling, P. D.; Melendez, G.
2014-01-01
Our laboratory and others have reported that Brattleboro (BRAT) rats, a Long Evans (LE) strain with a single gene mutation, have inherent deficits in prepulse inhibition (PPI) homologous to those observed in schizophrenia patients and that these deficits are reversed by antipsychotic drugs (APDs). To further evaluate the potential predictive validity of BRAT rat PPI for APDs, we compared the effects of acute subcutaneous administration of the typical APD chlorpromazine to that of three psychotropic drugs without antipsychotic efficacy, the antidepressant imipramine, the anxiolytic diazepam and the anticonvulsant mood stabilizer valproic acid on male and female BRAT rat PPI. Male and female BRAT rats exhibited baseline (saline treatment) PPI that was not different from each other (21.1 % and 21.3 %, respectively) and low compared to those historically exhibited by LE rats (approximately 59 %). Chlorpromazine facilitated PPI in male and female BRAT rats, whereas imipramine, diazepam, and valproic acid had no significant effect on PPI. These results suggest that PPI in the BRAT rat responds specifically to drugs with APD efficacy but not psychotropic drugs of different therapeutic families. PMID:21106605
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[Augmented antipsychotic therapy with pantogam active in patients with schizophrenia].
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.
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Reeves, Gloria M; Wehring, Heidi J; Connors, Kathleen M; Bussell, Kristin; Schiffman, Jason; Medoff, Deborah R; Tsuji, Thomas; Walker, Jane; Brown, Alicia; Strobeck, Danielle; Clough, Tammy; Rush, Caitlin B; Riddle, Mark A; Love, Raymond C; Zachik, Albert; Hoagwood, Kimberly; Olin, S Serene; Stephan, Sharon; Okuzawa, Nana; Edwards, Sarah; Baquet, Claudia; dosReis, Susan
2015-12-01
The Patient Protection and Affordable Care Act focuses on improving consumer engagement and patient-centered care. This article describes the design and rationale of a study targeting family engagement in pediatric mental health services. The study is a 90-day randomized trial of a telephone-delivered Family Navigator services versus usual care for parents of Medicaid-insured youth younger than 13 years with serious mental illness. Youth are identified through a pediatric antipsychotic medication preauthorization program. Family Navigators offer peer support to empower and engage parents in their child's recovery. Outcomes include parent report of empowerment, social support, satisfaction with child mental health services, and child functioning as well as claims-based measures of psychotherapy service utilization and antipsychotic medication dosage. The focus on "family-centered" care in this study is strongly supported by the active role of consumers in study design and implementation.
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Calabrese, Joseph R; Jin, Na; Johnson, Brian; Such, Pedro; Baker, Ross A; Madera, Jessica; Hertel, Peter; Ottinger, Jocelyn; Amatniek, Joan; Kawasaki, Hiroaki
2018-06-10
The long-acting injectable antipsychotic aripiprazole once-monthly 400 mg (AOM 400) was recently approved for maintenance treatment of bipolar I disorder (BP-I). The purpose of this study was to evaluate the safety, tolerability, and efficacy of AOM 400 as long-term maintenance treatment for BP-I. This open-label multicenter study evaluated the effectiveness of AOM 400 as maintenance treatment for BP-I by assessing safety and tolerability (primary objective) and efficacy (secondary objective). The study enrolled AOM 400-naive ("de novo") patients as well as AOM 400-experienced ("rollover") patients with BP-I from a lead-in randomized, placebo-controlled clinical trial that demonstrated the efficacy of AOM 400 in the maintenance treatment of BP-I (Calabrese et al. in J Clin Psychiatry 78:324-331, 2017). Safety variables included frequency and severity of treatment-emergent adverse events (TEAEs) and TEAEs resulting in study discontinuation. Efficacy was assessed by the proportion of patients maintaining stability throughout the maintenance phase, as well as mean changes from baseline in Young Mania Rating Scale (YMRS), Montgomery-Asberg Depression Rating Scale, and Clinical Global Impressions for Bipolar Disorder-Severity of Illness Scale (CGI-BP-S) total scores. Patient acceptability and tolerability of treatment was assessed using the Patient Satisfaction with Medication Questionnaire-Modified. Of 464 patients entering the maintenance phase, 379 (82%) were de novo and 85 (18%) were rollover. TEAEs were more common in de novo than rollover patients. The overall discontinuation rate due to TEAEs was 10.3% (48/464). Improvements in YMRS and CGI-BP-S total scores were maintained during the study, and the vast majority of both de novo (87.0%) and rollover (97.6%) patients maintained stability through their last visit. Overall, the need for rescue medication during the maintenance phase was minimal (< 10% of patients). Patient satisfaction levels were high, with both de novo and rollover patients rating the side effect burden of AOM 400 as greatly improved relative to previous medications. AOM 400 was safe, effective, and well tolerated by both de novo and AOM 400-experienced patients with BP-I for long-term maintenance treatment. Trial registration ClinicalTrials.gov, NCT01710709.
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Periodic catatonia with long-term treatment: a case report.
Chen, Ruei-An; Huang, Tiao-Lai
2017-09-29
Periodic catatonia has long been a challenging diagnosis and there are no absolute guidelines for treatment when precipitating factors are also unclear. We report a schizophrenia patient with periodic catatonia with a 15-year treatment course. A possible correlation between decreased daylight exposure and periodic attacks has been observed. We describe a 49-year-old woman with periodic catatonia associated with schizophrenia with 15 years of follow-up. The patient was treated with the antipsychotics risperidone, haloperidol, loxapine and quetiapine, but catatonia still relapsed once per year during the first few years of her disease course. The treatment was consequently been switched to clozapine due to fluctuated psychotic illness, and a longer duration of remittance was achieved. Lorazepam-diazepam protocol was used for rapid relief of catatonic symptoms, and was able to significantly shorten the duration of the symptoms. In addition, we observed a possible correlation between catatonic episodes and decreased daylight exposure during the 15-year duration. Successful treatment of acute periodic catatonia was achieved with a lorazepam-diazepam protocol, and the patient remained in remission for a longer duration under clozapine treatment. Besides, the possibility of decreased daylight exposure acting as a precipitating factor was observed during our 15 years of follow-up.
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Development and characterization of a long-acting nanoformulated abacavir prodrug.
Singh, Dhirender; McMillan, JoEllyn; Hilaire, James; Gautam, Nagsen; Palandri, Diana; Alnouti, Yazen; Gendelman, Howard E; Edagwa, Benson
2016-08-01
A myristoylated abacavir (ABC) prodrug was synthesized to extend drug half-life and bioavailability. Myristoylated ABC (MABC) was made by esterifying myristic acid to the drug's 5-hydroxy-cyclopentene group. Chemical composition, antiretroviral activity, cell uptake and retention and cellular trafficking of free MABC and poloxamer nanoformulations of MABC were assessed by proton nuclear magnetic resonance and tested in human monocyte-derived macrophages. Pharmacokinetics of ABC and nanoformulated MABC were evaluated after intramuscular injection into mice. MABC antiretroviral activity in monocyte-derived macrophages was comparable to native drug. Encasement of MABC into poloxamer nanoparticles extended drug bioavailability for 2 weeks. MABC synthesis and encasement in polymeric nanoformulations improved intracellular drug accumulation and demonstrate translational potential as part of a long-acting antiretroviral regimen.
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Schweitzer, Cécile; Goldstein, Michael H; Place, Ned J; Adkins-Regan, Elizabeth
2013-01-01
In birds, early exposure to steroid hormones deposited in egg yolks is hypothesized to result in long-lasting effects on brain and behavior. However, the long-term effects of maternal androgens on the development of social behavior, and whether these could interfere with the effects of the endogenous gonadal hormones that mediate sexual differentiation, remain poorly known. To answer these questions, we enhanced yolk testosterone by injecting testosterone (T) in oil into Japanese quail (Coturnix japonica) eggs prior to incubation. Vehicle-injected (V) eggs served as controls. From age 3 weeks to 8 weeks, sexual development was measured using morphological and physiological traits, and social behavior was measured, including male-typical sexual behavior. In females, treatment with testosterone boosted growth. Males from T-injected eggs developed an affiliative preference for familiar females and differed from V-injected males in the acoustic features of their crows, whereas sexual interest (looking behavior) and copulatory behavior were not affected. These long-lasting and sex-specific yolk testosterone effects on the development of dimorphic traits, but without disrupting sexual differentiation of reproductive behavior suggest potential organizational effects of maternal testosterone, but acting through separate processes than the endocrine mechanisms previously shown to control sexual differentiation. Separate processes could reflect the action of androgens at different times or on multiple targets that are differentially sensitive to steroids or develop at different rates. Copyright © 2012 Elsevier Inc. All rights reserved.
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Lambert, M; Conus, P; Eide, P; Mass, R; Karow, A; Moritz, S; Golks, D; Naber, D
2004-11-01
(1) determine which antipsychotic side effects (SE) schizophrenic patients consider the most distressing during treatment with typical antipsychotics, (2) measure the impact of actual and past SE on patients' attitude toward antipsychotics and (3) assess the influence of both on adherence. The 213 schizophrenics, treated with conventional antipsychotics, were recruited in two psychiatric hospitals in Hamburg. Subjects were assessed about type and severity of present and past side effects and their attitude and adherence to antipsychotic treatment. The 82 (39%) patients presented present SE while 131 (61%) did not. Sexual dysfunctions (P < 0.001), extrapyramidal (P < 0.05) and psychic side effects (P < 0.05) were rated as significantly subjectively more distressing than sedation or vegetative side effects. Patients presenting with present SE compared with patients without present SE had a significantly more negative general attitude toward antipsychotics (P < 0.05), were more doubtful about their efficacy (P < 0.01) and were less likely to encourage a relative to take such a medication in case of need (P < 0.001). A regression analysis indicated that nonadherence was mainly influenced by negative general and efficacy attitudes toward antipsychotics and the experience of past or present antipsychotic side effects. All antipsychotic side effects, present or past, can have a durable negative impact on patient's attitude toward antipsychotic treatment and adherence. Non-adherence is mainly determined, among other factors, by these negative attitudes, which are partly influenced by the experience of past or present antipsychotic-induced side effects.
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Treatment of Tourette syndrome.
Kurlan, Roger M
2014-01-01
Tourette's syndrome (TS) consists of chronic motor and phonic tics and characteristically begins in childhood. The tics can be disabling and commonly associated behavioral comorbities such as attention deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD), can also cause problems in daily functioning. The underlying etiology and neurobiology of TS remain unknown although genetic factors appear to be important, cortical control of basal ganglia motor function appears to be disturbed and neurochemical abnormalities, particularly involving dopamine neurotransmission, are likely present. The treatment of TS involves appropriate education and support. Tics can be treated with habit reversal cognitive behavioral therapy, medications (most commonly alpha agonists and antipsychotics), local intramuscular injections of botulinum toxin and some severe, refractory cases have responded to deep brain stimulation surgery (DBS). It is important to appropriately diagnose and treat comorbid behavioral disorders that are disrupting function. OCD can be treated with cognitive behavioral therapy, selective serotonin reuptake inhibitors, and atypical antipsychotics. DBS has become a treatment option for patients with disabling OCD despite other therapies. ADHD is treated with appropriate classroom accommodations, behavioral therapy, alpha agonists, atomoxetine or methylphenidate-containing stimulant drugs.
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Hashimoto's Encephalopathy Presenting with Unusual Behavioural Disturbances in an Adolescent Girl
Subashini, Viswanath; Balakrishnan, Ramasamy
2017-01-01
Hashimoto's encephalopathy (HE) is a rare autoimmune disorder with neurological and neuropsychiatric manifestations and elevated titres of anti-thyroid antibodies. Here we are reporting a case of HE in a 19-year-old girl who presented with seizure-like episodes, confusion, and behavioural disturbances with catatonic symptoms such as posturing, echopraxia, echolalia, and ambivalence. Patient did not respond to antipsychotics and anticonvulsants. On further investigation, patient was found to have high serum anti-TPO antibodies of about 1261 U/mL with euthyroid status, which supported a suspicion of HE. Our consultant neurologist confirmed the diagnosis and she was started on injection of methylprednisolone 750 mg OD. Since patient started showing clinical improvement, her antipsychotic medications were tapered off. On follow-up, patient has recovered and is functioning well. Since HE is a diagnosis of exclusion, very high anti-TPO antibodies and good response to steroids supported the diagnosis of HE in this patient after excluding other etiological possibilities. This case has been reported because the clinical presentation was predominantly neurobehavioural manifestations which is uncommon with HE. PMID:28607558
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Metabolic syndrome and atypical antipsychotics: Possibility of prediction and control.
Franch Pato, Clara M; Molina Rodríguez, Vicente; Franch Valverde, Juan I
Schizophrenia and other psychotic disorders are associated with high morbidity and mortality, due to inherent health factors, genetic factors, and factors related to psychopharmacological treatment. Antipsychotics, like other drugs, have side-effects that can substantially affect the physical health of patients, with substantive differences in the side-effect profile and in the patients in which these side-effects occur. To understand and identify these risk groups could help to prevent the occurrence of the undesired effects. A prospective study, with 24 months follow-up, was conducted in order to analyse the physical health of severe mental patients under maintenance treatment with atypical antipsychotics, as well as to determine any predictive parameters at anthropometric and/or analytical level for good/bad outcome of metabolic syndrome in these patients. There were no significant changes in the physical and biochemical parameters individually analysed throughout the different visits. The baseline abdominal circumference (lambda Wilks P=.013) and baseline HDL-cholesterol levels (lambda Wilks P=.000) were the parameters that seem to be more relevant above the rest of the metabolic syndrome constituents diagnosis criteria as predictors in the long-term. In the search for predictive factors of metabolic syndrome, HDL-cholesterol and abdominal circumference at the time of inclusion were selected, as such that the worst the baseline results were, the higher probability of long-term improvement. Copyright © 2016 SEP y SEPB. Publicado por Elsevier España, S.L.U. All rights reserved.
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Feldman, Peter D; Hay, Linda K; Deberdt, Walter; Kennedy, John S; Hutchins, David S; Hay, Donald P; Hardy, Thomas A; Hoffmann, Vicki P; Hornbuckle, Kenneth; Breier, Alan
2004-01-01
The objective of this study was to investigate risk of diabetes among elderly patients during treatment with antipsychotic medications. We conducted a longitudinal, retrospective study assessing the incidence of new prescription claims for antihyperglycemic agents during antipsychotic therapy. Prescription claims from the AdvancePCS claim database were followed for 6 to 9 months. Study participants consisted of patients in the United States aged 60+ and receiving antipsychotic monotherapy. The following cohorts were studied: an elderly reference population (no antipsychotics: n = 1,836,799), those receiving haloperidol (n = 6481) or thioridazine (n = 1658); all patients receiving any conventional antipsychotic monotherapy (n = 11,546), clozapine (n = 117), olanzapine (n = 5382), quetiapine (n = 1664), and risperidone (n = 12,244), and all patients receiving any atypical antipsychotic monotherapy (n = 19,407). We used Cox proportional hazards regression to determine the risk ratio of diabetes for antipsychotic cohorts relative to the reference population. Covariates included sex and exposure duration. New antihyperglycemic prescription rates were higher in each antipsychotic cohort than in the reference population. Overall rates were no different between atypical and conventional antipsychotic cohorts. Among individual antipsychotic cohorts, rates were highest among patients treated with thioridazine (95% confidence interval [CI], 3.1- 5.7), lowest with quetiapine (95% CI, 1.3-2.9), and intermediate with haloperidol, olanzapine, and risperidone. Among atypical cohorts, only risperidone users had a significantly higher risk (95% CI, 1.05-1.60; P = 0.016) than for haloperidol. Conclusions about clozapine were hampered by the low number of patients. These data suggest that diabetes risk is elevated among elderly patients receiving antipsychotic treatment. However, causality remains to be demonstrated. As a group, the risk for atypical antipsychotic users was not significantly different than for users of conventional antipsychotics.
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Injectable controlled release depots for large molecules
Schwendeman, Steven P.; Shah, Ronak B.; Bailey, Brittany A.; Schwendeman, Anna S.
2014-01-01
Biodegradable, injectable depot formulations for long-term controlled drug release have improved therapy for a number of drug molecules and led to over a dozen highly successful pharmaceutical products. Until now, success has been limited to several small molecules and peptides, although remarkable improvements have been accomplished in some of these cases. For example, twice-a-year depot injections with leuprolide are available compared to the once-a-day injection of the solution dosage form. Injectable depots are typically prepared by encapsulation of the drug in poly(lactic-co-glycolic acid) (PLGA), a polymer that is used in children every day as a resorbable suture material, and therefore, highly biocompatible. PLGAs remain today as one of the few “real world” biodegradable synthetic biomaterials used in US FDA-approved parenteral long-acting-release (LAR) products. Despite their success, there remain critical barriers to the more widespread use of PLGA LAR products, particularly for delivery of more peptides and other large molecular drugs, namely proteins. In this review, we describe key concepts in the development of injectable PLGA controlled-release depots for peptides and proteins, and then use this information to identify key issues impeding greater widespread use of PLGA depots for this class of drugs. Finally, we examine important approaches, particularly those developed in our research laboratory, toward overcoming these barriers to advance commercial LAR development. PMID:24929039
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Antipsychotics and associated risk of out-of-hospital cardiac arrest.
Weeke, P; Jensen, A; Folke, F; Gislason, G H; Olesen, J B; Fosbøl, E L; Wissenberg, M; Lippert, F K; Christensen, E F; Nielsen, S L; Holm, E; Kanters, J K; Poulsen, H E; Køber, L; Torp-Pedersen, C
2014-10-01
Antipsychotic drugs have been associated with sudden cardiac death, but differences in the risk of out-of-hospital cardiac arrest (OHCA) associated with different antipsychotic drug classes are not clear. We identified all OHCAs in Denmark (2001-2010). The risk of OHCA associated with antipsychotic drug use was evaluated by conditional logistic regression analysis in case-time-control models. In total, 2,205 (7.6%) of 28,947 OHCA patients received treatment with an antipsychotic drug at the time of the event. Overall, treatment with any antipsychotic drug was associated with OHCA (odds ratio (OR) = 1.53, 95% confidence interval (CI): 1.23-1.89), as was use with typical antipsychotics (OR = 1.66, CI: 1.27-2.17). By contrast, overall, atypical antipsychotic drug use was not (OR = 1.29, CI: 0.90-1.85). Two individual typical antipsychotic drugs, haloperidol (OR = 2.43, CI: 1.20-4.93) and levomepromazine (OR = 2.05, CI: 1.18-3.56), were associated with OHCA, as was one atypical antipsychotic drug, quetiapine (OR = 3.64, CI: 1.59-8.30).
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Pharmacological interventions for borderline personality disorder
Stoffers, Jutta; Völlm, Birgit A; Rücker, Gerta; Timmer, Antje; Huband, Nick; Lieb, Klaus
2014-01-01
Background Drugs are widely used in borderline personality disorder (BPD) treatment, chosen because of properties known from other psychiatric disorders (“off-label use”), mostly targeting affective or impulsive symptom clusters. Objectives To assess the effects of drug treatment in BPD patients. Search methods We searched bibliographic databases according to the Cochrane Developmental, Psychosocial and Learning Problems Group strategy up to September 2009, reference lists of articles, and contacted researchers in the field. Selection criteria Randomised studies comparing drug versus placebo, or drug versus drug(s) in BPD patients. Outcomes included total BPD severity, distinct BPD symptom facets according to DSM-IV criteria, associated psychopathology not specific to BPD, attrition and adverse effects. Data collection and analysis Two authors selected trials, assessed quality and extracted data, independently. Main results Twenty-eight trials involving a total of 1742 trial participants were included. First-generation antipsychotics (flupenthixol decanoate, haloperidol, thiothixene); second-generation antipsychotics (aripirazole, olanzapine, ziprasidone), mood stabilisers (carbamazepine, valproate semisodium, lamotrigine, topiramate), antidepressants (amitriptyline, fluoxetine, fluvoxamine, phenelzine sulfate, mianserin), and dietary supplementation (omega-3 fatty acid) were tested. First-generation antipsychotics were subject to older trials, whereas recent studies focussed on second-generation antipsychotics and mood stabilisers. Data were sparse for individual comparisons, indicating marginal effects for first-generation antipsychotics and antidepressants. The findings were suggestive in supporting the use of second-generation antipsychotics, mood stabilisers, and omega-3 fatty acids, but require replication, since most effect estimates were based on single studies. The long-term use of these drugs has not been assessed. Adverse event data were scarce, except for olanzapine. There was a possible increase in self-harming behaviour, significant weight gain, sedation and changes in haemogram parameters with olanzapine. A significant decrease in body weight was observed with topiramate treatment. All drugs were well tolerated in terms of attrition. Direct drug comparisons comprised two first-generation antipsychotics (loxapine versus chlorpromazine), first-generation antipsychotic against antidepressant (haloperidol versus amitriptyline; haloperidol versus phenelzine sulfate), and second-generation antipsychotic against antidepressant (olanzapine versus fluoxetine). Data indicated better outcomes for phenelzine sulfate but no significant differences in the other comparisons, except olanzapine which showed more weight gain and sedation than fluoxetine. The only trial testing single versus combined drug treatment (olanzapine versus olanzapine plus fluoxetine; fluoxetine versus fluoxetine plus olanzapine) yielded no significant differences in outcomes. Authors’ conclusions The available evidence indicates some beneficial effects with second-generation antipsychotics, mood stabilisers, and dietary supplementation by omega-3 fatty acids. However, these are mostly based on single study effect estimates. Antidepressants are not widely supported for BPD treatment, but may be helpful in the presence of comorbid conditions. Total BPD severity was not significantly influenced by any drug. No promising results are available for the core BPD symptoms of chronic feelings of emptiness, identity disturbance and abandonment. Conclusions have to be drawn carefully in the light of several limitations of the RCT evidence that constrain applicability to everyday clinical settings (among others, patients’ characteristics and duration of interventions and observation periods). PMID:20556762
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Thibodeau, Rachel B; Ornelas, Laura C; Romero, Jordan; Memos, Nicoletta; Scheible, Matthew; Avila, Alfred; Schumacher, Abby; Navarro, April; Zimmermann, Karen; Cuenod, Bethany A; Frohardt, Russell J; Guarraci, Fay A
2013-02-01
The present study was designed to investigate the long-term effects of repeated methamphetamine (MA) exposure on sexual motivation in female rats tested after a period of drug abstinence. In Experiment 1, female subjects received three injections of MA (1.0mg/kg/day, every other day) or saline and were tested for paced mating behavior (where females could control the receipt of sexual stimulation from one male rat) 21 days after their last injection. In Experiment 2, female subjects received 12 consecutive injections of MA (1.0mg/kg/day) or saline and were tested for mate choice (where females could control the receipt of sexual stimulation from two male rats simultaneously) 6 days after their last injection. Experiment 3 was identical to Experiment 2 except that female subjects received no baseline mating test and were tested for mate choice 24h and 6 days after their last injection. Open field tests were conducted in each experiment to measure locomotor activity after repeated exposure to MA. Although repeated MA exposure increased locomotor activity, mating behavior was not facilitated after either a short (6 days) or long (21 days) period of drug abstinence. Nevertheless, sexual behavior was disrupted during the 24h acute withdrawal period. Therefore, although the present study found no evidence of cross-sensitization between female sexual behavior and MA after either a short or a long period of drug abstinence, sexual behavior in sexually naïve female rats is sensitive to the depressive state associated with acute withdrawal from MA. In conclusion, the results of the present study suggest that MA acts differently from other psychomotor stimulants, and that the effects of MA withdrawal on sexual behavior differ between male and female rats. Copyright © 2012 Elsevier Inc. All rights reserved.
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Psychosocial Acute Treatment in Early-Episode Schizophrenia Disorders
ERIC Educational Resources Information Center
Bola, John R.
2006-01-01
Objective: This article reviews evidence on the treatment of early episode schizophrenia spectrum disorders that contradicts, in some cases, the American Psychiatric Association's generic recommendation of antipsychotic medication treatment for at least a year. Method: Evidence on lack of diagnostic validity, absence of demonstrated long-term…
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Recent trends in the treatment of testosterone deficiency syndrome.
Hong, Bum Sik; Ahn, Tai Young
2007-11-01
Testosterone deficiency syndrome (TDS) is defined as a clinical and biochemical syndrome associated with advancing age and is characterized by typical symptoms and deficiency in serum testosterone levels. TDS is a result of the interaction of hypothalamo-pituitary and testicular factors. Now, treatment of TDS with testosterone is still controversial due to a lack of large, controlled clinical trials on efficacy. The risks of treatment with testosterone appear to be minimal, although long-term studies on the safety of testosterone therapy are lacking. The aim of the therapy is to establish a physiological concentration of serum testosterone in order to correct the androgen deficiency, relieve its symptoms and prevent long-term sequelae. All of the available products, despite their varying pharmacodynamic and pharmacokinetic profiles, are able to reach this goal. Newer testosterone patches seem not to cause severe skin irritation. Testosterone gels minimize the skin irritation while providing flexibility in dosing and a low discontinuation rate. Oral testosterone undecanoate (TU) is free of liver toxicity. Recent formulation of oral TU markedly increased shelf-live, a major drawback in the older preparation. Producing swings in testosterone levels rising rapidly to the supraphysiological range is not the case with the new injectable long-acting preparation of TU. To be able to rapidly react and stop treatment in cases where side-effects and contraindications are detected, the short-acting transdermal and oral delivery modes have certain advantages. However, there is no evidence that the use of an injectable long-acting TU in men with TDS has limitations in clinical application for this reason. The use of dehydroepiandrosterone is still controversial because of a lack of well designed long-term trials, although some recent studies suggest positive effects on various body systems. Only a few studies have been carried out to investigate the effect of hCG (human chorionic gonadotropin) in TDS with some positive results on various body systems.
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Blonanserin: a review of its use in the management of schizophrenia.
Deeks, Emma D; Keating, Gillian M
2010-01-01
Oral blonanserin (Lonasen) is an atypical antipsychotic agent indicated for use in patients with schizophrenia in Japan and Korea. It is effective in the treatment of patients with schizophrenia, providing short- and long-term efficacy against both the positive and negative symptoms of the disorder in several randomized and noncomparative trials. Notably, in two randomized, double-blind trials of 8 weeks' duration, blonanserin was noninferior to haloperidol or risperidone for primary endpoints, although it appeared to be better than haloperidol in improving negative symptoms. Blonanserin is generally well tolerated and appears to have an acceptable profile in terms of bodyweight gain. Potential tolerability benefits of the drug in short-term trials included fewer extrapyramidal symptoms than haloperidol and fewer reports of prolactin level increases or hyperprolactinaemia than risperidone. Nevertheless, extrapyramidal symptoms and hyperprolactinaemia were among the most common adverse reactions associated with blonanserin in noncomparative long-term studies. Further prospective and long-term comparative studies are required in order to definitively position blonanserin with respect to other antipsychotic agents. In the meantime, available clinical data suggest that blonanserin is an effective and generally well tolerated option for the short-term treatment of schizophrenia and for those requiring longer-term therapy.
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Severus, Emanuel; Bauer, Michael; Geddes, John
2018-06-13
For more than 40 years, lithium has been the gold standard in the long-term treatment of bipolar disorders. In the course of the last 15 years, other drugs have been approved in this indication and are widely used in clinical practice at the expense of lithium. New research from the last few years, however, indicates that lithium is still the first-line treatment in this indication. Against this background and lithium's proven acute antimanic efficacy, we should perhaps be using lithium more regularly (in combination with an atypical antipsychotic, if necessary) right from the start for the acute treatment of a manic episode and, once remission has been achieved and euthymia maintained during continuation treatment, to regularly taper off the atypical antipsychotic, if possible, and continue with lithium as monotherapy for prophylactic treatment. This might lead to lithium being used more consistently with the scientific evidence in the long-term treatment of bipolar disorders. It remains uncertain, however, to predict who will respond to and tolerate lithium prophylactically, and more research is needed to deliver the best possible individualized care to our patients. © Georg Thieme Verlag KG Stuttgart · New York.
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Update on GH therapy in adults.
Boguszewski, Cesar Luiz
2017-01-01
Over the last three decades, short- and long-term observational studies, clinical trials, systematic reviews, and meta-analyses have provided relevant information on the efficacy and safety of growth hormone (GH) replacement therapy in adults with GH deficiency (AGHD). The knowledge acquired during this time has been compiled into different guidelines that offer clinicians an evidence-based, practical approach for the management of AGHD. There are, however, still open questions in some key areas in which recommendations are supported by only moderate or weak evidence. In the last recent years, the development of long-acting GH preparations has created new therapeutic possibilities by decreasing injection frequency, improving adherence and thereby potentially maximizing clinical outcomes. The aims of this review are to advance our understanding on the diagnosis and treatment of AGHD and to present an update and future perspectives on the use of long-acting GH preparations.
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Insulin analogues with improved absorption characteristics.
Brange, J; Hansen, J F; Langkjaer, L; Markussen, J; Ribel, U; Sørensen, A R
1992-01-01
The insulin preparations available today are not ideal for therapy as s.c. injection does not provide a physiological insulin profile. With the aim to improve the absorption properties recombinant DNA technology has been utilized to design novel insulin molecules with changed physico-chemical characteristics and hence altered subcutaneous absorption kinetics. Soluble, long-acting human insulin analogues in which the isoelectric point has been increased from 5.4 to approx. 7 are absorbed very slowly, providing a more constant basal insulin delivery with lower day-to-day variation than present protracted preparations. In addition they have better storage stability. Rapid-acting human insulin analogues with largely reduced self-association are absorbed substantially faster from subcutaneous tissue than current regular insulin and thus are better suited for bolus injection. The absorption kinetics of these analogues have been able to explain the mechanism behind the dose effect on insulin absorption rate.
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Antipsychotics and Amotivation
Fervaha, Gagan; Takeuchi, Hiroyoshi; Lee, Jimmy; Foussias, George; Fletcher, Paul J; Agid, Ofer; Remington, Gary
2015-01-01
Antipsychotic drugs are thought to produce secondary negative symptoms, which can also exacerbate primary negative symptoms. In the present study, we examined whether motivational deficits in particular were related to antipsychotic treatment in patients with schizophrenia in a dose-dependent manner. Five hundred and twenty individuals with schizophrenia who were receiving antipsychotic monotherapy for at least 6 months and followed prospectively were included in the present study. Participants were receiving one of five antipsychotic medications (olanzapine, perphenazine, quetiapine, risperidone, or ziprasidone), and analyses were conducted for patients receiving each drug separately. Analysis of covariance models were constructed to examine the effect of antipsychotic dose on level of motivational impairment, controlling for selected demographic and clinical variables (eg, positive symptoms). Level of motivation, or deficits therein, were evaluated using a derived measure from the Quality of Life Scale, and in addition with scores derived from the Positive and Negative Syndrome Scale. Antipsychotic dose was not related to the level of amotivation for any of the medications examined. Moreover, severity of sedation was not significantly related to the degree of amotivation. One hundred and twenty-one individuals were identified as antipsychotic-free at baseline, and after 6 months of antipsychotic treatment, no change in motivation was found. Chronic treatment with antipsychotics does not necessarily impede or enhance goal-directed motivation in patients with schizophrenia. It is possible that the negative impact of antipsychotics in this regard is overstated; conversely, the present results also indicate that we must look beyond antipsychotics in our efforts to improve motivation. PMID:25567425
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Antipsychotics and amotivation.
Fervaha, Gagan; Takeuchi, Hiroyoshi; Lee, Jimmy; Foussias, George; Fletcher, Paul J; Agid, Ofer; Remington, Gary
2015-05-01
Antipsychotic drugs are thought to produce secondary negative symptoms, which can also exacerbate primary negative symptoms. In the present study, we examined whether motivational deficits in particular were related to antipsychotic treatment in patients with schizophrenia in a dose-dependent manner. Five hundred and twenty individuals with schizophrenia who were receiving antipsychotic monotherapy for at least 6 months and followed prospectively were included in the present study. Participants were receiving one of five antipsychotic medications (olanzapine, perphenazine, quetiapine, risperidone, or ziprasidone), and analyses were conducted for patients receiving each drug separately. Analysis of covariance models were constructed to examine the effect of antipsychotic dose on level of motivational impairment, controlling for selected demographic and clinical variables (eg, positive symptoms). Level of motivation, or deficits therein, were evaluated using a derived measure from the Quality of Life Scale, and in addition with scores derived from the Positive and Negative Syndrome Scale. Antipsychotic dose was not related to the level of amotivation for any of the medications examined. Moreover, severity of sedation was not significantly related to the degree of amotivation. One hundred and twenty-one individuals were identified as antipsychotic-free at baseline, and after 6 months of antipsychotic treatment, no change in motivation was found. Chronic treatment with antipsychotics does not necessarily impede or enhance goal-directed motivation in patients with schizophrenia. It is possible that the negative impact of antipsychotics in this regard is overstated; conversely, the present results also indicate that we must look beyond antipsychotics in our efforts to improve motivation.
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Sarkar, Siddharth; Gupta, Nitin
2017-01-01
Neuroleptic malignant syndrome (NMS) is a rare but potentially fatal adverse event associated with the use of antipsychotics. Although atypical antipsychotics were initially considered to carry no risk of NMS, reports have accumulated over time implicating them in NMS causation. Almost all atypical antipsychotics have been reported to be associated with NMS. The clinical profile of NMS caused by certain atypical antipsychotics such as clozapine has been reported to be considerably different from the NMS produced by typical antipsychotics, with diaphoresis encountered more commonly, and rigidity and tremor encountered less frequently. This article briefly discusses the evidence relating to the occurrence, presentation and management of NMS induced by atypical antipsychotics. PMID:28811916
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Sarkar, Siddharth; Gupta, Nitin
2017-08-01
Neuroleptic malignant syndrome (NMS) is a rare but potentially fatal adverse event associated with the use of antipsychotics. Although atypical antipsychotics were initially considered to carry no risk of NMS, reports have accumulated over time implicating them in NMS causation. Almost all atypical antipsychotics have been reported to be associated with NMS. The clinical profile of NMS caused by certain atypical antipsychotics such as clozapine has been reported to be considerably different from the NMS produced by typical antipsychotics, with diaphoresis encountered more commonly, and rigidity and tremor encountered less frequently. This article briefly discusses the evidence relating to the occurrence, presentation and management of NMS induced by atypical antipsychotics.
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Greene, George J.; Swann, Greg; Fought, Angela J.; Carballo-Diéguez, Alex; Hope, Thomas J.; Kiser, Patrick F.; Mustanski, Brian; D’Aquila, Richard T.
2016-01-01
HIV prevention method preferences were evaluated among 512 U.S. men who have sex with men (MSM; median age: 22 years). Approximately 90% consistently preferred one option across pairwise comparisons of condoms, daily oral pre-exposure prophylaxis (PrEP), and long-acting PrEP delivered via either an injectable or one of two types of PrEP implants differing in visibility. Condoms were most frequently preferred (33.8%), followed by non-visible implants (21.5%), and oral PrEP (17.0%); HIV risk was reported by more choosing implants. In a follow-up question comparing the four PrEP options only, daily oral pills and non-visible implants were most frequently preferred (35.5% and 34.3%, respectively), followed by injections (25.2%) and visible implants (4.3%). An inductive, open-coding approach determined that convenience, duration of protection, and privacy were the most commonly cited reasons for a PrEP method choice, and associated with self-report of HIV risk. Tailoring PrEP product development to privacy and other concerns important to those at highest HIV risk may improve HIV prevention. PMID:27770215
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The impact of antipsychotic polytherapy costs in the public health care in Sao Paulo, Brazil.
Razzouk, Denise; Kayo, Monica; Sousa, Aglaé; Gregorio, Guilherme; Cogo-Moreira, Hugo; Cardoso, Andrea Alves; Mari, Jair de Jesus
2015-01-01
Guidelines for the treatment of psychoses recommend antipsychotic monotherapy. However, the rate of antipsychotic polytherapy has increased over the last decade, reaching up to 60% in some settings. Studies evaluating the costs and impact of antipsychotic polytherapy in the health system are scarce. To estimate the costs of antipsychotic polytherapy and its impact on public health costs in a sample of subjects with psychotic disorders living in residential facilities in the city of Sao Paulo, Brazil. A cross-sectional study that used a bottom-up approach for collecting costs data in a public health provider's perspective. Subjects with psychosis living in 20 fully-staffed residential facilities in the city of Sao Paulo were assessed for clinical and psychosocial profile, severity of symptoms, quality of life, use of health services and pharmacological treatment. The impact of polytherapy on total direct costs was evaluated. 147 subjects were included, 134 used antipsychotics regularly and 38% were in use of antipsychotic polytherapy. There were no significant differences in clinical and psychosocial characteristics between polytherapy and monotherapy groups. Four variables explained 30% of direct costs: the number of antipsychotics, location of the residential facility, time living in the facility and use of olanzapine. The costs of antipsychotics corresponded to 94.4% of the total psychotropic costs and to 49.5% of all health services use when excluding accommodation costs. Olanzapine costs corresponded to 51% of all psychotropic costs. Antipsychotic polytherapy is a huge economic burden to public health service, despite the lack of evidence supporting this practice. Great variations on antipsychotic costs explicit the need of establishing protocols for rational antipsychotic prescriptions and consequently optimising resource allocation. Cost-effectiveness studies are necessary to estimate the best value for money among antipsychotics, especially in low and middle income countries.
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Kochi, Kenji; Sato, Izumi; Nishiyama, Chika; Tanaka-Mizuno, Sachiko; Doi, Yuko; Arai, Masaru; Fujii, Yosuke; Matsunaga, Toshiyuki; Ogawa, Yusuke; Furukawa, Toshi A; Kawakami, Koji
2017-06-01
This study aimed to assess the trends in antipsychotic prescriptions for outpatients in Japan, where a community-based approach to mental healthcare is emphasized. This descriptive epidemiological study used claims data from 1038 community pharmacies across Japan. Outpatients who were ≥18 years old and receiving their initial antipsychotic prescription during 2006-2012 were evaluated. The annual trends were reported for monotherapies, polypharmacy, antipsychotic doses, and the concurrent prescription of psychotropic medications. The 152 592 outpatients included 101 133 (66%) adults (18-64 years old) and 51 459 (34%) older adults (≥65 years old). Among the adults, second-generation antipsychotic monotherapy prescriptions increased from 49% in 2006 to 71% in 2012, first-generation antipsychotic monotherapy prescriptions decreased from 29 to 14%, and antipsychotic polypharmacy decreased from 23 to 15%, respectively. Among the older adults, second-generation antipsychotic monotherapy prescriptions increased from 64 to 82%, first-generation antipsychotic monotherapy prescriptions decreased from 29 to 12%, and antipsychotic polypharmacy decreased from 7 to 6%, respectively. During the study period, >80% of the adults and >90% of the older adults received antipsychotics at risperidone-equivalent doses of <6 mg/day. Anxiolytics/hypnotics, antidepressants, antiparkinson agents, mood stabilizers, and anti-dementia agents were concurrently prescribed with antipsychotics for 70, 33, 20, 20, and 0.3% of the adults and for 43, 16, 19, 8, and 16% of the older adults, respectively. The present study evaluated large-scale claims-based datasets and found that high-dose prescriptions and antipsychotic polypharmacy among Japanese outpatients were not as prevalent as has been previously thought. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.
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Vasankari, T; Kujala, U; Taimela, S; Törmä, A; Irjala, K; Huhtaniemi, I
1995-11-01
The purpose of this study was to delineate the possible endocrine effects of exercise-induced GH secretion. Twelve healthy adult males were studied during short (20 min) and subsequent prolonged (2 h) physical exercise and recovery period (2 h), both after injection of a long acting somatostatin analog [Sandostatin (ST); 0.1 or 0.05 mg, sc] and after a control saline injection. Additional subjects were studied during rest with similar injections of ST (0.1 mg) and saline (n = 7) or using a lower ST dose (0.01 mg; n = 6). Several venous blood samples were taken during the trials and analyzed for selected hormones, monitoring pituitary, testicular, and adrenal functions. ST injection blocked the serum GH response to short term maximal bicycle ergometer exercise, but not to the following prolonged bicycle exercise. No relationship of the exercise-associated GH increase to the concomitant endocrine responses of the adrenals and testes was observed. Unexpectedly, the higher ST doses (0.1 and 0.05 mg) increased the mean levels of serum testosterone by 18-25% in both exercise (P = 0.0017) and rest trials (P < 0.0001), respectively. ST did not affect the levels of LH, FSH, or cortisol. ST slightly increased serum sex hormone-binding globulin (3%; P = 0.021) and albumin (4%; P = 0.017) concentrations, but not that of free testosterone. Because the testosterone response to somatostatin was fast and without a simultaneous increase in LH, it was consistent with a direct testicular response. The explanation for this novel ST effect remains obscure, but it may be due to modulation of some paracrine mechanisms inhibiting testicular steroidogenesis.
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Mittapelly, Naresh; Rachumallu, Ramakrishna; Pandey, Gitu; Sharma, Shweta; Arya, Abhishek; Bhatta, Rabi Shankar; Mishra, Prabhat Ranjan
2016-04-01
In the present work, we prepared memantine-pamoic acid (MEM-PAM) salt by counter ion exchange in the aqueous phase to reduce the water solubility of MEM hydrochloride (native form) to make it suitable for long acting injection. The ratio of MEM to PAM in salt formation was optimized to maximize the loading efficiency and complexation efficiency. The 2:1 molar ratio of MEM to PAM salt form displayed nearly 95% complexation efficiency and 50% drug loading. The solubility was decreased by a ∼1250 folds. Thermo Gravimetric Analysis (TGA), Differential Scanning Calorimetry (DSC), and Powder X-ray Diffraction Analysis (PXRD) studies revealed the formation of new solid phase. Additionally, Nuclear Magnetic Resonance (NMR) spectroscopy confirmed the anhydrous nature of the salt form. Through Fourier transformation infrared spectroscopy (FT-IR) we identified the molecular interactions. Further, the microcrystals of the salt were transformed into nanocrystals (NCs) using high pressure homogenization. The particle size distribution and atomic force microscopy confirmed the monodispersed and spherical shape of the NCs. The in vitro dissolution studies were performed under sink condition in phosphate buffer saline pH 6.8. The results of MTT assay in murine fibroblast 3T3 cell line show that the NCs were less cytotoxic and more tolerable than plain MEM HCl. The in vivo performance of NCs administered as i.m. injection at three different doses in female Sprague-Dawley rats showed that the plasma levels lasted till the 24th day of the study. The pharmacokinetic parameters AUC0-∞ and Cmax increased linearly with increasing dose. Therefore, the results suggest that injectable NCs could represent a therapeutic alternative for the treatment of AD. Copyright © 2016 Elsevier B.V. All rights reserved.
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Schizophrenics for Whom Phenothiazines May Be Contraindicated or Unnecessary.
ERIC Educational Resources Information Center
Rappaport, Maurice; And Others
In this study of young male schizophrenic patients who reported they were not taking antipsychotic medication at follow-up, those treated with placebos in contrast to those treated with chlorpromazine while hospitalized showed significantly greater long term clinical improvement, less pathology at follow-up, fewer rehospitalizations and better…
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International trends in antipsychotic use: A study in 16 countries, 2005-2014.
Hálfdánarson, Óskar; Zoëga, Helga; Aagaard, Lise; Bernardo, Miquel; Brandt, Lena; Fusté, Anna Coma; Furu, Kari; Garuoliené, Kristina; Hoffmann, Falk; Huybrechts, Krista F; Kalverdijk, Luuk J; Kawakami, Koji; Kieler, Helle; Kinoshita, Takuya; Litchfield, Melisa; López, Soffy C; Machado-Alba, Jorge E; Machado-Duque, Manuel E; Mahesri, Mufaddal; Nishtala, Prasad S; Pearson, Sallie-Anne; Reutfors, Johan; Saastamoinen, Leena K; Sato, Izumi; Schuiling-Veninga, Catharina C M; Shyu, Yu-Chiau; Skurtveit, Svetlana; Verdoux, Hélène; Wang, Liang-Jen; Yahni, Corinne Zara; Bachmann, Christian J
2017-10-01
The objective of this study was to assess international trends in antipsychotic use, using a standardised methodology. A repeated cross-sectional design was applied to data extracts from the years 2005 to 2014 from 16 countries worldwide. During the study period, the overall prevalence of antipsychotic use increased in 10 of the 16 studied countries. In 2014, the overall prevalence of antipsychotic use was highest in Taiwan (78.2/1000 persons), and lowest in Colombia (3.2/1000). In children and adolescents (0-19 years), antipsychotic use ranged from 0.5/1000 (Lithuania) to 30.8/1000 (Taiwan). In adults (20-64 years), the range was 2.8/1000 (Colombia) to 78.9/1000 (publicly insured US population), and in older adults (65+ years), antipsychotic use ranged from 19.0/1000 (Colombia) to 149.0/1000 (Taiwan). Atypical antipsychotic use increased in all populations (range of atypical/typical ratio: 0.7 (Taiwan) to 6.1 (New Zealand, Australia)). Quetiapine, risperidone, and olanzapine were most frequently prescribed. Prevalence and patterns of antipsychotic use varied markedly between countries. In the majority of populations, antipsychotic utilisation and especially the use of atypical antipsychotics increased over time. The high rates of antipsychotic prescriptions in older adults and in youths in some countries merit further investigation and systematic pharmacoepidemiologic monitoring. Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.
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Knowles, Scott O; Grace, Neville D
2017-09-20
Nutritional supplementation with selenium (Se) can prevent Se deficiency in food-producing animals. Injection with slow-release formulations is a preferred method for free-range grazing sheep and cattle, and barium selenate (BaSeO 4 ) provides optimal efficacy. This chemical can become a health risk to humans if the concentrated depot of an injection site is consumed, and consequently such use is recently banned in the EU. A possible replacement is selenomethionine (SeMet), a naturally occurring form of Se supplementation hitherto only administered orally. In four animal studies we found that injection with SeMet maintained nutritionally adequate concentrations of Se in blood and tissues of lambs for at least 191 days and in blood and milk of dairy cows for at least 95 days. Stereoisomer forms L- and DL-SeMet were functionally equivalent. This is the first demonstration that injectable SeMet can deliver efficacy similar to BaSeO 4 but with less risk of undesirable residues in edible tissues.
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Hubacher, David; Spector, Hannah; Monteith, Charles; Chen, Pai-Lien; Hart, Catherine
2017-02-01
Measures of contraceptive effectiveness combine technology and user-related factors. Observational studies show higher effectiveness of long-acting reversible contraception compared with short-acting reversible contraception. Women who choose long-acting reversible contraception may differ in key ways from women who choose short-acting reversible contraception, and it may be these differences that are responsible for the high effectiveness of long-acting reversible contraception. Wider use of long-acting reversible contraception is recommended, but scientific evidence of acceptability and successful use is lacking in a population that typically opts for short-acting methods. The objective of the study was to reduce bias in measuring contraceptive effectiveness and better isolate the independent role that long-acting reversible contraception has in preventing unintended pregnancy relative to short-acting reversible contraception. We conducted a partially randomized patient preference trial and recruited women aged 18-29 years who were seeking a short-acting method (pills or injectable). Participants who agreed to randomization were assigned to 1 of 2 categories: long-acting reversible contraception or short-acting reversible contraception. Women who declined randomization but agreed to follow-up in the observational cohort chose their preferred method. Under randomization, participants chose a specific method in the category and received it for free, whereas participants in the preference cohort paid for the contraception in their usual fashion. Participants were followed up prospectively to measure primary outcomes of method continuation and unintended pregnancy at 12 months. Kaplan-Meier techniques were used to estimate method continuation probabilities. Intent-to-treat principles were applied after method initiation for comparing incidence of unintended pregnancy. We also measured acceptability in terms of level of happiness with the products. Of the 916 participants, 43% chose randomization and 57% chose the preference option. Complete loss to follow-up at 12 months was <2%. The 12-month method continuation probabilities were 63.3% (95% confidence interval, 58.9-67.3) (preference short-acting reversible contraception), 53.0% (95% confidence interval, 45.7-59.8) (randomized short-acting reversible contraception), and 77.8% (95% confidence interval, 71.0-83.2) (randomized long-acting reversible contraception) (P < .001 in the primary comparison involving randomized groups). The 12-month cumulative unintended pregnancy probabilities were 6.4% (95% confidence interval, 4.1-8.7) (preference short-acting reversible contraception), 7.7% (95% confidence interval, 3.3-12.1) (randomized short-acting reversible contraception), and 0.7% (95% confidence interval, 0.0-4.7) (randomized long-acting reversible contraception) (P = .01 when comparing randomized groups). In the secondary comparisons involving only short-acting reversible contraception users, the continuation probability was higher in the preference group compared with the randomized group (P = .04). However, the short-acting reversible contraception randomized group and short-acting reversible contraception preference group had statistically equivalent rates of unintended pregnancy (P = .77). Seventy-eight percent of randomized long-acting reversible contraception users were happy/neutral with their initial method, compared with 89% of randomized short-acting reversible contraception users (P < .05). However, among method continuers at 12 months, all groups were equally happy/neutral (>90%). Even in a typical population of women who presented to initiate or continue short-acting reversible contraception, long-acting reversible contraception proved highly acceptable. One year after initiation, women randomized to long-acting reversible contraception had high continuation rates and consequently experienced superior protection from unintended pregnancy compared with women using short-acting reversible contraception; these findings are attributable to the initial technology and not underlying factors that often bias observational estimates of effectiveness. The similarly patterned experiences of the 2 short-acting reversible contraception cohorts provide a bridge of generalizability between the randomized group and usual-care preference group. Benefits of increased voluntary uptake of long-acting reversible contraception may extend to wider populations than previously thought. Copyright © 2016 Elsevier Inc. All rights reserved.
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Brady, B M; Amory, J K; Perheentupa, A; Zitzmann, M; Hay, C J; Apter, D; Anderson, R A; Bremner, W J; Pollanen, P; Nieschlag, E; Wu, F C W; Kersemaekers, W M
2006-01-01
The combination of etonogestrel implants with injectable testosterone decanoate was investigated as a potential male contraceptive. One hundred and thirty subjects were randomly assigned to three treatment groups, all receiving two etonogestrel rods (204 mg etonogestrel) and 400 mg testosterone decanoate either every 4 weeks (group I, n = 42), or every 6 weeks (group II, n = 51) or 600 mg testosterone decanoate every 6 weeks (group III, n = 37) for a treatment period of 48 weeks. One hundred and ten men completed 48 weeks of treatment. Sperm concentrations of <1 x 10(6)/ml were achieved in 90% (group I), 82% (group II) and 89% (group III) of subjects by week 24. Suppression was slower in group II, which also demonstrated more frequent escape from gonadotrophin suppression than groups I and III. Peak testosterone concentrations remained in the normal range throughout in all groups. Mean trough testosterone concentrations were initially subphysiological but increased into the normal range during treatment. Mean haemoglobin levels increased in group I, and a non-significant increase in weight and decline in high-density lipoprotein cholesterol was observed in all groups. Fourteen subjects discontinued treatment due to adverse events. Subcutaneous etonogestrel implants in combination with injectable testosterone decanoate resulted in profound suppression of spermatogenesis that could be maintained for up to 1 year. Efficacy of suppression was less in group II, probably due to inadequate testosterone dosage. This combination has potential as a long-acting male hormonal contraceptive.
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Chamanza, Ronnie; Darville, Nicolas; van Heerden, Marjolein; De Jonghe, Sandra
2018-01-01
To investigate the effects of common nanosuspension-stabilizing excipients on the nature and temporal evolution of histopathological changes at intramuscular (i.m.) administration sites, 5 groups of 39 male rats per group received a single injection of 1 of the 5 analogous crystalline drug nanosuspensions containing 200 mg/ml of an antiviral compound with particle sizes of ±200 nm and identical vehicle compositions, except for the type of nanosuspension stabilizer. The investigated stabilizers were poloxamer 338, poloxamer 407, d-α-tocopherol polyethylene glycol 1,000-succinate (TPGS), polysorbate 80, and polysorbate 80 combined with egg phosphatidylglycerol. Histopathology and immunohistochemistry revealed progressive inflammatory changes at the i.m. administration sites and the draining lymph nodes that differed according to the time point of sacrifice and the type of stabilizer. Although the overall time course of inflammatory changes was similar across the groups, differences in the nature, severity, and timing of the inflammatory response were observed between animals injected with poloxamer- or TPGS-containing nanosuspensions and those injected with formulations containing polysorbate 80. A more severe and prolonged active inflammatory phase, the presence of multinucleate giant cells, prolonged macrophage infiltration of the formulation depot, and more persistent histiocytic infiltrates in the lymph nodes were observed in the polysorbate 80-containing nanosuspension groups. Such vehicle-mediated effects could influence the overall tolerability profile of long-acting nanosuspensions.
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Utilization and costs of antipsychotic agents: a Canadian population-based study, 1996-2006.
Alessi-Severini, Silvia; Biscontri, Robert G; Collins, David M; Kozyrskyj, Anita; Sareen, Jitender; Enns, Murray W
2008-05-01
This study evaluated the prescribing patterns and costs for antipsychotic agents in the population of the Canadian province of Manitoba over the past decade. A population-based study of antipsychotic utilization and costs was conducted on data collected from the administrative databases of the Manitoba Population Health Data Repository and the Statistics Canada census between index years 1996 and 2006 (April 1, 1995, through March 31, 2006). The total annual number of antipsychotic prescriptions dispensed in Manitoba increased by 227% between 1996 and 2006, and the prevalence of antipsychotic users increased by 62% over the same time interval. The fastest-growing segment of antipsychotic users in Manitoba appears to be young males, who increased from .16% in 1996 to .88% in 2006. The highest numbers of prescriptions were reported for schizophrenia, dementia, and conduct disorder. Annual expenditures for antipsychotics increased from $1.7 million in 1996 to $22.0 million in 2006 (expenditures are in Canadian dollars). The cost of second-generation agents reached 80% of total antipsychotic expenditures in 2006; risperidone was the most prescribed agent in all age groups of patients. The per-patient annual cost of antipsychotic pharmacotherapy increased by approximately 680% between 1996 and 2006 in Manitoba. The number of antipsychotic prescriptions and the prevalence of users of antipsychotic medications increased significantly in Manitoba over the study period, despite a steady-state population of approximately 1.2 million. Incremental costs relative to the use of antipsychotic medications can be explained by the market penetration of the second-generation agents and their expanded use in the treatment of various diagnoses.
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Antipsychotic treatment among youth in foster care.
Dosreis, Susan; Yoon, Yesel; Rubin, David M; Riddle, Mark A; Noll, Elizabeth; Rothbard, Aileen
2011-12-01
Despite national concerns over high rates of antipsychotic medication use among youth in foster care, concomitant antipsychotic use has not been examined. In this study, concomitant antipsychotic use among Medicaid-enrolled youth in foster care was compared with disabled or low-income Medicaid-enrolled youth. The sample included 16 969 youths younger than 20 years who were continuously enrolled in a Mid-Atlantic state Medicaid program and had ≥1 claim with a psychiatric diagnosis and ≥1 antipsychotic claim in 2003. Antipsychotic treatment was characterized by days of any use and concomitant use with ≥2 overlapping antipsychotics for >30 days. Medicaid program categories were foster care, disabled (Supplemental Security Income), and Temporary Assistance for Needy Families (TANF). Multicategory involvement for youths in foster care was classified as foster care/Supplemental Security Income, foster care/TANF, and foster care/adoption. We used multivariate analyses, adjusting for demographics, psychiatric comorbidities, and other psychotropic use, to assess associations between Medicaid program category and concomitant antipsychotic use. Average antipsychotic use ranged from 222 ± 110 days in foster care to only 135 ± 101 days in TANF (P < .001). Concomitant use for ≥180 days was 19% in foster care only and 24% in foster care/adoption compared with <15% in the other categories. Conduct disorder and antidepressant or mood-stabilizer use was associated with a higher likelihood of concomitant antipsychotic use (P < .0001). Additional study is needed to assess the clinical rationale, safety, and outcomes of concomitant antipsychotic use and to inform statewide policies for monitoring and oversight of antipsychotic use among youths in the foster care system.
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Forecasting Medicaid Expenditures for Antipsychotic Medications.
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.
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Development and characterization of a long-acting nanoformulated abacavir prodrug
Singh, Dhirender; McMillan, JoEllyn; Hilaire, James; Gautam, Nagsen; Palandri, Diana; Alnouti, Yazen; Gendelman, Howard E; Edagwa, Benson
2016-01-01
Aim: A myristoylated abacavir (ABC) prodrug was synthesized to extend drug half-life and bioavailability. Methods: Myristoylated ABC (MABC) was made by esterifying myristic acid to the drug's 5-hydroxy-cyclopentene group. Chemical composition, antiretroviral activity, cell uptake and retention and cellular trafficking of free MABC and poloxamer nanoformulations of MABC were assessed by proton nuclear magnetic resonance and tested in human monocyte-derived macrophages. Pharmacokinetics of ABC and nanoformulated MABC were evaluated after intramuscular injection into mice. Results: MABC antiretroviral activity in monocyte-derived macrophages was comparable to native drug. Encasement of MABC into poloxamer nanoparticles extended drug bioavailability for 2 weeks. Conclusion: MABC synthesis and encasement in polymeric nanoformulations improved intracellular drug accumulation and demonstrate translational potential as part of a long-acting antiretroviral regimen. PMID:27456759
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Extrapyramidal side effects of antipsychotic treatment: scope of problem and impact on outcome.
Tandon, Rajiv; Jibson, Michael D
2002-06-01
Previously, clinicians worked with antipsychotic drugs (conventional or typical) that almost invariably caused extrapyramidal symptoms (EPS) at clinically effective doses. This led to the false impression that all antipsychotics were the same, and that EPS were an unavoidable consequence of effective antipsychotic therapy. EPS adversely impact several aspects of antipsychotic efficacy and tolerability, thereby worsening outcome of afflicted individuals. EPS reduce beneficial effects of antipsychotic treatment on the negative, cognitive, and mood symptom domains, while increasing the risk of tardive dyskinesia and reducing compliance. By definition, the newer generation of "atypical" antipsychotic agents are significantly better than conventional agents with regard to EPS (i.e., they are clinically effective at doses at which they do not cause EPS). Pharmacologically, this difference is expressed in the greater degree of separation between respective dose response curves for antipsychotic and EPS effects observed for "atypical" in contrast to conventional agents. Clinically, this EPS advantage of atypical antipsychotics translates into several important benefits, including better negative symptom efficacy, less dysphoria, less impaired cognition, a lower risk of TD, and better overall outcome.
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Liu, Kuo-Sheng; Kao, Cheng-Hsiung; Liu, Shyun-Yeu; Sung, K C; Kuei, Chun-Hsiung; Wang, Jhi-Joung
2006-03-01
Buprenorphine is a promising new pharmacotherapy for the management of physical dependence to opioids. The aim of the study was to evaluate the duration of action of several novel depots of buprenorphine in the treatment of physical dependence to morphine in mice. Following intramuscular injection, the duration of action of several novel oil-based depots of buprenorphine base in morphine-dependent mice were evaluated. The traditional dosage form of buprenorphine hydrochloride in saline was used as control. We found that the depot of buprenorphine base in sesame oil produced a dose-related long-lasting effect. On an equimolar basis of 6 micromol kg(-1), its effect was 5.7-fold longer than that of buprenorphine hydrochloride in saline. When prepared in several other oleaginous vehicles (castor oil, cottonseed oil, peanut oil and soybean oil), buprenorphine base also produced a long-lasting effect, which was similar to buprenorphine base in sesame oil. In conclusion, buprenorphine base, when prepared in oleaginous vehicles and injected intramuscularly in mice, produced a long-lasting effect on physical dependence to morphine.
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Lombardi, Adolph V; Berend, Keith R; Mallory, Thomas H; Dodds, Kathleen L; Adams, Joanne B
2004-11-01
The purpose of this study was to determine if an intraoperative intraarticular and soft-tissue injection of local anaesthetic, epinephrine, and morphine has a beneficial effect for total knee arthroplasty. A control group of 138 patients (181 knees) received no intraoperative injection. The study group of 171 patients (197 knees) received intraoperative injection of 0.25% bupivacaine with epinephrine and morphine with 2/3 injected into the soft tissues and 1/3 injected into the joint. Patients having bilateral simultaneous procedures received a divided dose. The pain treatment protocol otherwise was identical. Pain, sedation, rescue narcotic usage, narcotic reversal and blood loss were examined. Pain levels during the immediate postoperative period, blood loss, and bleeding indices were reduced with injection. Considerably more control patients required rescue doses of narcotics. Preemptive analgesia with soft tissue and intra-articular injection of long-acting local anesthetic with epinephrine and morphine provides better pain control in the immediate postoperative period, decreases blood loss, and decreases the need for rescue narcotics and reversal agents. This simple, inexpensive method provides an effective adjunct to a multimodal approach in improving the postoperative course of primary total knee arthroplasty.
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Connelly, Jacob O; Edwards, Paul K; Mears, Simon C; Barnes, C Lowry
2015-01-01
Postoperative pain control after total knee arthroplasty is a major contributing factor to patient satisfaction, rehabilitation, and length of stay. Current clinical practice guidelines recommend a multimodal pain management protocol, including the use of regional anesthesia. Periarticular injection (PAI) has been shown to provide excellent pain relief after total knee arthroplasty. Recently, liposomal bupivacaine has been introduced as a long-acting alternative to traditional local anesthetics, such as bupivacaine or ropivacaine. Liposomal bupivacaine is a sustained-release preparation designed to provide local analgesia up to 72 hours after initial application. The efficacy of PAI relies significantly on a meticulous, systematic injection technique. This article details recommendations for solution preparation and injection during total knee arthroplasty on the basis of the experience of a high-volume orthopaedic reconstruction service.
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Psychoactive medication use in intermediate-care facility residents.
Beers, M; Avorn, J; Soumerai, S B; Everitt, D E; Sherman, D S; Salem, S
1988-11-25
Despite the large number of elderly patients in nursing homes and the intensity of medication use there, few current data are available on patterns of medication use in this setting. We studied all medication use among 850 residents of 12 representative intermediate-care facilities in Massachusetts. Data on all prescriptions and patterns of actual use were recorded for all patients during one month. On average, residents were prescribed 8.1 medications during the month (interquartile range, 7.4 to 8.8) and actually received 4.7 (range, 4.2 to 5.4) medications during this period. More than half of all residents were receiving a psychoactive medication, with 26% receiving antipsychotic medication. Twenty-eight percent of patients were receiving sedative/hypnotics during the study month, primarily on a scheduled rather than an as-needed basis. Of patients receiving a sedative/hypnotic, 26% (range, 14% to 41%) were taking diphenhydramine hydrochloride, a strongly anticholinergic hypnotic. Of those receiving one of the benzodiazepines, 30% were receiving long-acting drugs, generally not recommended for elderly patients. The typical benzodiazepine dose was equivalent to 7.3 mg per patient per day of diazepam. The most commonly used antidepressant was amitriptyline hydrochloride, the most sedating and anticholinergic antidepressant in common use. These data indicate that despite growing evidence of the risks of psychoactive drug use in elderly patients, the nursing home population studied was exposed to high levels of sedative/hypnotic and antipsychotic drug use. Suboptimal choice of medication within a given class was common, and use of standing vs as-needed orders was often not in keeping with current concepts in geriatric psychopharmacology. Additional research is needed to assess the impact of such drug therapy on cognitive and physical functioning, as well as to determine how best to improve patterns of medication use in this vulnerable population.
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Antipsychotic Treatment and Tobacco Craving in People With Schizophrenia.
Wehring, Heidi J; Heishman, Stephen J; McMahon, Robert P; Liu, Fang; Feldman, Stephanie; Raley, Heather; Weiner, Elaine; Kelly, Deanna L
2017-01-01
Nicotine dependence is high in schizophrenia, and craving is known to impact relapse during quit attempts. We compared tobacco craving in smokers with schizophrenia treated with different antipsychotics. Mean craving scores were lowest in participants receiving first-generation antipsychotics, although these differences were not statistically significant. Craving with clozapine was not lower than with other antipsychotics. Further research is needed to determine whether differences in craving exist between antipsychotic classes.
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Detecting and Managing Adverse Effects of Antipsychotic Medications: Current State of Play.
Ames, Donna; Carr-Lopez, Sian M; Gutierrez, Mary A; Pierre, Joseph M; Rosen, Jennifer A; Shakib, Susan; Yudofsky, Lynn M
2016-06-01
Antipsychotics are some of the most frequently prescribed medications not only for psychotic disorders and symptoms but also for a wide range of on-label and off-label indications. Because second-generation antipsychotics have largely replaced first-generation antipsychotics as first-line options due to their substantially decreased risk of extrapyramidal side effects, attention has shifted to other clinically concerning adverse events associated with antipsychotic therapy. The focus of this article is to update the nonextrapyramidal side effects associated with second-generation antipsychotics. Issues surrounding diagnosis and monitoring as well as clinical management are addressed. Published by Elsevier Inc.
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Barclay, Rebecca P; Penfold, Robert B; Sullivan, Donna; Boydston, Lauren; Wignall, Julia; Hilt, Robert J
2017-04-01
To learn if a quality of care Medicaid child psychiatric consultation service implemented in three different steps was linked to changes in statewide child antipsychotic utilization. Washington State child psychiatry consultation program primary data and Medicaid pharmacy division antipsychotic utilization secondary data from July 1, 2006, through December 31, 2013. Observational study in which consult program data were analyzed with a time series analysis of statewide antipsychotic utilization. All consultation program database information involving antipsychotics was compared to Medicaid pharmacy division database information involving antipsychotic utilization. Washington State's total child Medicaid antipsychotic utilization fell from 0.51 to 0.25 percent. The monthly prevalence of use fell by a mean of 0.022 per thousand per month following the initiation of elective consults (p = .004), by 0.065 following the initiation of age/dose triggered mandatory reviews (p < .001), then by another 0.022 following the initiation of two or more concurrent antipsychotic mandatory reviews (p = .001). High-dose antipsychotic use fell by 57.8 percent in children 6- to 12-year old and fell by 52.1 percent in teens. Statewide antipsychotic prescribing for Medicaid clients fell significantly at different rates following each implementation step of a multilevel consultation and best-practice education service. © Health Research and Educational Trust.
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Self-reported motivation to smoke in schizophrenia is related to antipsychotic drug treatment.
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.
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Pharmacological causes of hyperprolactinemia
Torre, Daria La; Falorni, Alberto
2007-01-01
Hyperprolactinemia is a common endocrinological disorder that may be caused by several physiological and pathological conditions. Several drugs may determine a significant increase in prolactin serum concentration that is frequently associated with symptoms. The so-called typical antipsychotics are frequently responsible for drug-related hyperprolactinemia. Risperidone is one of the atypical neuroleptics most likely to induce hyperprolactinemia, while other atypical drugs are unfrequenlty and only transiently associated with increase of prolactin levels. Women are more sensitive than men to the hyperprolactinemic effect of antipsychotics. Classical and risperidone-induced hyperprolactinemia may be revert when a gradual antipsychotic drug discontinuation is combined with olanzapine or clozapine initiation. Antidepressant drugs with serotoninergic activity, including selective serotonin reuptake inhibitors (SSRI), monoamine oxidase inhibitors (MAO-I) and some tricyclics, can cause hyperprolactinemia. A long list of other compounds may determine an increase in prolactin levels, including prokinetics, opiates, estrogens, anti-androgens, anti-hypertensive drugs, H2-receptor antagonists, anti-convulsivants and cholinomimetics. Finally, hyperprolactinemia has also been documented during conditioning and after autologous blood stem-cell transplantation and during chemotherapy, even though disturbances of prolactin seem to occur less frequently than impairments of the hypothalamus-pituitary-gonad/thyroid axis after intensive treatment and blood marrow transplantation. PMID:18473017
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Atypical Antipsychotic Drugs and the Risk of Sudden Cardiac Death
Ray, Wayne A.; Chung, Cecilia P.; Murray, Katherine T.; Hall, Kathi; Stein, C. Michael
2009-01-01
Background Users of typical antipsychotics have increased risk of serious ventricular arrhythmias and sudden cardiac death. However, less is known regarding the cardiac safety of the atypical antipsychotic drugs, which have largely replaced the older agents in clinical practice. Methods We calculated the adjusted incidence of sudden cardiac death among current users of antipsychotics in a retrospective cohort of Tennessee Medicaid enrollees. The primary analysis included 44,218 and 46,089 baseline users of single typical and atypical drugs, respectively, and 186,600 matched nonuser controls. To assess residual confounding related to antipsychotic indication, we performed a secondary analysis of antipsychotic users with no baseline diagnosis of schizophrenia or related psychoses, propensity-score matched with nonusers. Results Current users of both typical and atypical antipsychotics had greater rates of sudden cardiac death than did nonusers of any antipsychotic, with adjusted incidence-rate ratios (IRRs) of 2.00 (95% CI, 1.69–2.35) and 2.27 (1.89–2.73), respectively. Former antipsychotic users had no significantly increased risk (IRR = 1.13 [0.98–1.30]). For both classes of drugs, the risk for current users increased significantly with dose. For typical antipsychotics the IRRs increased from 1.31 (0.97–1.77) for low doses to 2.42 (1.91–3.06) for high doses (p<.001). For atypical agents the IRRs increased from 1.59 (1.03–2.46) for low doses to 2.86 (2.25–3.65) for high doses (p=.015). The IRR for atypical vs typical antipsychotics was 1.14 (.93–1.39). Similar findings were present in the propensity-score matched cohort. Conclusion Current users of both typical and atypical antipsychotics had a similar, dose-related increased risk of sudden cardiac death. PMID:19144938
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Antipsychotic Treatment Among Youth in Foster Care
Yoon, Yesel; Rubin, David M.; Riddle, Mark A.; Noll, Elizabeth; Rothbard, Aileen
2011-01-01
OBJECTIVE: Despite national concerns over high rates of antipsychotic medication use among youth in foster care, concomitant antipsychotic use has not been examined. In this study, concomitant antipsychotic use among Medicaid-enrolled youth in foster care was compared with disabled or low-income Medicaid-enrolled youth. PATIENTS AND METHODS: The sample included 16 969 youths younger than 20 years who were continuously enrolled in a Mid-Atlantic state Medicaid program and had ≥1 claim with a psychiatric diagnosis and ≥1 antipsychotic claim in 2003. Antipsychotic treatment was characterized by days of any use and concomitant use with ≥2 overlapping antipsychotics for >30 days. Medicaid program categories were foster care, disabled (Supplemental Security Income), and Temporary Assistance for Needy Families (TANF). Multicategory involvement for youths in foster care was classified as foster care/Supplemental Security Income, foster care/TANF, and foster care/adoption. We used multivariate analyses, adjusting for demographics, psychiatric comorbidities, and other psychotropic use, to assess associations between Medicaid program category and concomitant antipsychotic use. RESULTS: Average antipsychotic use ranged from 222 ± 110 days in foster care to only 135 ± 101 days in TANF (P < .001). Concomitant use for ≥180 days was 19% in foster care only and 24% in foster care/adoption compared with <15% in the other categories. Conduct disorder and antidepressant or mood-stabilizer use was associated with a higher likelihood of concomitant antipsychotic use (P < .0001). CONCLUSIONS: Additional study is needed to assess the clinical rationale, safety, and outcomes of concomitant antipsychotic use and to inform statewide policies for monitoring and oversight of antipsychotic use among youths in the foster care system. PMID:22106072
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Wu, Chi-Shin; Chang, Chia-Ming; Tsai, Yu-Ting; Huang, Ya-Wen; Tsai, Hui-Ju
2015-09-01
To investigate the association between antipsychotic treatment and risk of hip fracture in subjects with schizophrenia. Among patients with schizophrenia (ICD-9-CM code 295), 605 cases with hip fracture and 2,828 matched controls were identified from 2002 to 2011 using the National Health Insurance Research Database in Taiwan. The authors conducted a nested case-control study to investigate the association between antipsychotic treatment and risk of hip fracture in subjects with schizophrenia. The modifiable effects of age and gender were evaluated by stratified analysis. In addition, the effects of antipsychotic use, antipsychotic classes, and receptor-binding profiles of antipsychotics, individually, on hip fracture were estimated, and potential confounding factors were adjusted in subsequent analysis. Conditional logistic regressions were applied to determine the effect of antipsychotic treatment on hip fracture. Current antipsychotic use was associated with an increased risk for hip fracture (adjusted odds ratio [AOR] = 1.61; 95% CI, 1.24-2.10). Among current users, new users had a higher risk of hip fracture (AOR = 4.28; 95% CI, 1.76-10.36) than past users (AOR = 1.11; 95% CI, 0.79-1.56). In addition, a significant increased risk of hip fracture was noted in schizophrenia subjects with first-generation antipsychotic use (AOR = 1.59; 95%CI, 1.15-2.20) but not in those with second-generation antipsychotic use (AOR = 1.16; 95% CI, 0.91-1.48). These results extend previous findings and demonstrate an increased risk of hip fracture associated with antipsychotic use in schizophrenia subjects. Further investigation is needed to dissect the underlying mechanisms related to the effect of antipsychotic use on hip fracture in subjects at risk. © Copyright 2015 Physicians Postgraduate Press, Inc.
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Body weight gain induced by a newer antipsychotic agent reversed as negative symptoms improved.
Koga, M; Nakayama, K
2005-07-01
We describe a patient in whom improvement in negative symptoms contributed to early weight loss and subsequent long-term improvement in weight management. Case report. A 26-year-old woman with schizophrenia gained 7 kg over the course of 1 year after starting treatment with olanzapine. However, as negative symptoms gradually improved with treatment, she became motivated to diet and exercise regularly. She quickly lost 9 kg and subsequently maintained optimal weight (55 kg; body mass index, 24.1 kg/m(2) ). Important strategies for minimizing weight gain in patients taking antipsychotic agents include improving negative symptoms of avolition and apathy, regular monitoring of body weight and potential medical consequences of overweight and obesity, and educating the patient about the importance of diet and regular exercise.
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Synthesis of the olanzapine labeled by carbon-14.
Saadatjoo, Naghi; Javaheri, Mohsen; Saemian, Nader; Amini, Mohsen
2016-06-30
Olanzapine is one of the most widely used antipsychotic drugs, which acts as an antagonist for multiple neurotransmitter receptor sites. 2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno [2,3-b][1,5] benzodiazepine (Olanzapine) labeled with carbon-14 in the four positions has been synthesized as part of a three-step sequence from 2-amino-5-methylthiophene-3-carbonitrile-[carbonitrile-(14) C]. Copyright © 2016 John Wiley & Sons, Ltd.
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Juenke, JoEtta M; Brown, Paul I; Urry, Francis M; Johnson-Davis, Kamisha L; McMillin, Gwendolyn A
2013-08-23
Most antipsychotic drugs that are commonly prescribed in the USA are monitored by liquid and gas chromatographic methods. Method performance has been improved using ultra high pressure liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). A rapid and simple procedure for monitoring haloperidol, thiothixene, fluphenazine, and perphenazine is described here. Antipsychotic drug concentrations in serum and plasma were determined by LCMS/MS (Waters Acquity UPLC TQD). The instrument is operated with an ESI interface, in multiple reaction monitoring (MRM), and positive ion mode. The resolution of both quadrupoles was maintained at unit mass with a peak width at half height of 0.7amu. Data analysis was performed using the Waters Quanlynx software. Serum or plasma samples were thawed at room temperature and a 100μL aliquot was placed in a tube. Then 300μL of precipitating reagent (acetonitrile-methanol [50:50, volume: volume]) containing the internal standard (0.12ng/μL Imipramine-D3) was added to each tube. The samples were vortexed and centrifuged. The supernatant was transferred to an autosampler vial and 8μL was injected into the UPLC-MS/MS. Utilizing a Waters Acquity UPLC HSS T3 1.8μm, 2.1×50mm column at 25ºC, the analytes were separated using a timed, linear gradient of acetonitrile and water, each having 0.1% formic acid added. The column is eluted into the LC-MS/MS to detect imipramine D3 at transition 284.25>89.10, haloperidol at 376.18>165.06, thiothixene at 444.27>139.24, fluphenazine at 438.27>171.11, and perphenazine at 404.19>143.07. Secondary transitions for each analyte are also monitored for imipramine D3 at 284.25>193.10, haloperidol at 376.18>122.97, thiothixene at 444.27>97.93, fluphenazine at 438.27>143.08, and perphenazine at 404.19>171.11. The run-time is 1.8min per injection with baseline resolved chromatographic separation. The analytical measurement range was 0.2 to 12.0ng/mL for fluphenazine and perphenazine, and was 1 to 60.0ng/mL for haloperidol and thiothixene. Intra-assay and inter-assay imprecisions (CV) were less than 15% at two concentrations for each analyte. By utilizing a LC-MS/MS method we combined two previously established analytical assays into one, yielding a 75% time-savings on set-up, and a significantly shortened analytical run-time. These changes reduced the turn-around time for analysis and eliminated interference issues resulting in fewer injections and increased column lifetime. Copyright © 2013 Elsevier B.V. All rights reserved.
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Hong, Chen-Jee; Chen, Tzu-Ting; Bai, Ya Mei; Liou, Ying-Jay; Tsai, Shih-Jen
2012-01-01
Schizophrenic patients treated with clozapine or olanzapine often develop hypertriglyceridemia. The apolipoprotein A5 gene (APOA5), which affects VLDL production and lipolysis, has been implicated in the triglyceride (TG) metabolism. This study examined the association of common APOA5 genetic variants and TG levels in chronically institutionalized schizophrenic patients, on a stable dose of atypical antipsychotic (clozapine, olanzapine or risperidone. The TG levels in 466 schizophrenic patients treated with clozapine (n = 182), olanzapine (n = 89) or risperidone (n = 195) were measured. Patients were genotyped for the three APOA5 single nucleotide polymorphisms (SNPs) rs662799 (-1131T > C), rs651821 (3A > G) and rs2266788 (1891T > C). A gene × drug interaction with TG levels was observed. In single-marker-based analysis, the minor alleles of the two polymorphisms (-1131C and -3G) were observed to be associated with increased TGs in patients treated with risperidone, but not with clozapine or olanzapine. Haplotype analysis further revealed that carriers of the haplotype constructed with the three minor alleles had higher TG levels than those who did not carry this haplotype in patients taking risperidone (CGC((+/+)) vs. = 125.4 ± 59.1 vs. 82.2 ± 65.8, P = 0.015; CGC((-/+ )) vs. CGC((-/-)) = 113.7 ± 80.4 vs. 82.2 ± 65.8, P = 0.012). Our findings extend and add new information to the existing data regarding the association between APOA5 and TG regulation during long-term atypical antipsychotic treatment.
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Birkenhäger-Gillesse, Elizabeth G; Kollen, Boudewijn J; Achterberg, Wilco P; Boersma, Froukje; Jongman, Lydia; Zuidema, Sytse U
2018-03-01
Dementia is often accompanied by neuropsychiatric symptoms. Psychotropic drugs for the treatment of neuropsychiatric symptoms are frequently used to manage these problems, but they are of limited effectiveness and can have serious side effects. Psychosocial interventions are advocated as first line treatment and may help to reduce psychotropic drug use. To assess the effect of multidisciplinary psychosocial interventions in nursing homes on the psychotropic drug prescription rate. Literature obtained from searches in 9 electronic databases was systematically reviewed. In addition, the pooled effects of specific psychosocial interventions in homogenous subgroups were analyzed (meta-analysis). Eleven randomized controlled studies that investigated multiple psychotropic drugs interventions (psychotropic drugs in 3, antipsychotics in 9, and antidepressants in 5 studies) as well as different types of psychosocial interventions were included. We separately analyzed interventions directed at the care staff level (educational programs in 3, in-reach services or consultation in 1, cultural or process change in 6 studies) and the individual resident level in 1 study. In 7 out of 9 studies reporting on antipsychotic drug use, the physician was actively involved. Nine studies in which antipsychotic drug use was specified reported a significant decrease in prescription rate as a result of psychosocial interventions [relative risk (RR) 0.71, 95% confidence interval (CI) 0.59-0.88], whereas meta-analysis of 5 studies investigating antidepressant drug use failed to show a significant effect (RR 0.82, 95% CI 0.64-1.02). Pooled effect sizes of 6 studies investigating cultural change, showed a significant decrease in antipsychotic drug use (RR 0.65, 95% CI 0.57-0.73). Effect sizes of 2 studies on educational programs on antipsychotic use were nonsignificant (RR 1.50, 95% CI 0.49-4.64). Sensitivity analysis of 7 studies reporting on antipsychotic drug use involving prescribing physicians showed a more robust decrease (RR 0.66, 95% CI 0.54-0.80). The results of this study show that psychosocial interventions may lead to a substantial reduction of antipsychotic drug prescription, especially in studies that reported on cultural change and that involved prescribing physicians. Conspicuously, a profound lack of information was observed in many studies as to what exactly constituted the care-as-usual treatment in the control group. Copyright © 2018 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.
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The Impact of Antipsychotic Polytherapy Costs in the Public Health Care in Sao Paulo, Brazil
Razzouk, Denise; Kayo, Monica; Sousa, Aglaé; Gregorio, Guilherme; Cogo-Moreira, Hugo; Cardoso, Andrea Alves; Mari, Jair de Jesus
2015-01-01
Introduction Guidelines for the treatment of psychoses recommend antipsychotic monotherapy. However, the rate of antipsychotic polytherapy has increased over the last decade, reaching up to 60% in some settings. Studies evaluating the costs and impact of antipsychotic polytherapy in the health system are scarce. Objective To estimate the costs of antipsychotic polytherapy and its impact on public health costs in a sample of subjects with psychotic disorders living in residential facilities in the city of Sao Paulo, Brazil. Method A cross-sectional study that used a bottom-up approach for collecting costs data in a public health provider´s perspective. Subjects with psychosis living in 20 fully-staffed residential facilities in the city of Sao Paulo were assessed for clinical and psychosocial profile, severity of symptoms, quality of life, use of health services and pharmacological treatment. The impact of polytherapy on total direct costs was evaluated. Results 147 subjects were included, 134 used antipsychotics regularly and 38% were in use of antipsychotic polytherapy. There were no significant differences in clinical and psychosocial characteristics between polytherapy and monotherapy groups. Four variables explained 30% of direct costs: the number of antipsychotics, location of the residential facility, time living in the facility and use of olanzapine. The costs of antipsychotics corresponded to 94.4% of the total psychotropic costs and to 49.5% of all health services use when excluding accommodation costs. Olanzapine costs corresponded to 51% of all psychotropic costs. Conclusion Antipsychotic polytherapy is a huge economic burden to public health service, despite the lack of evidence supporting this practice. Great variations on antipsychotic costs explicit the need of establishing protocols for rational antipsychotic prescriptions and consequently optimising resource allocation. Cost-effectiveness studies are necessary to estimate the best value for money among antipsychotics, especially in low and middle income countries. PMID:25853709
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Frequency of sexual dysfunction in patients with a psychotic disorder receiving antipsychotics.
Montejo, Angel L; Majadas, Susana; Rico-Villademoros, Fernando; Llorca, Ginés; De La Gándara, Jesús; Franco, Manuel; Martín-Carrasco, Manuel; Aguera, Luis; Prieto, Nieves
2010-10-01
Although it is a troublesome side effect, information on antipsychotic-induced sexual dysfunction is limited. To evaluate the frequency of sexual dysfunction and its impact on treatment adherence in patients with a psychotic disorder treated with various antipsychotics under routine clinical conditions. Subjects included were sexually active male and female patients 18 years of age or older with a diagnosis of schizophrenia, schizophreniform disorder, schizoaffective disorder, or other psychotic disorder. This was a multicenter, cross-sectional, and naturalistic study conducted by 18 investigators. In addition to sexual functioning, we recorded demographic data, psychiatric diagnosis according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition), and medication history. Pyschotropic-Related Sexual Dysfunction Questionnaire (PRSexDQ-SalSex). All the analyses were performed in the 243 evaluable patients. Most patients were males (71%), and the most common diagnosis was schizophrenia (71%). Overall, 46% of the patients exhibited sexual dysfunction according to the assessment with the SalSex (50% of the males and 37% of the females). Only 37% of the patients with sexual dysfuntion spontaneously reported it. Among the patients exhibiting sexual dysfunction, 32% reported to have poor tolerance to the disturbance. With the exception of conventionals depot, which had a very important and greater effect on females' sexual funtioning, the severity and tolerance of sexual dysfunction were worse in males than in females regardless of the antipsychotic studied. In the univariate logistic regression analysis, using olanzapine as a reference category, risperidone (odds ratio [OR] 7.45, 95% confidence interval [CI] 3.73-14.89) and conventionals, depot (OR 4.57, 95% CI 1.72-12.13) and nondepot (OR 4.92, 95% CI 1.43-16.93), showed a significant increased risk of sexual dysfunction. Our results show that sexual dysfunction is very common in patients receiving long-term treatment with antipsychotics, and it is associated with a great impact in a substantial proportion of patients. © 2010 International Society for Sexual Medicine.
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Developing the Second Generation of Improvised Explosive Device Detector Dog
2013-04-15
improvement, we obtained a consult from Dr. Thierry Olivry, a veterinary dermatologist, who recommended further treatment for bacterial dermatitis ...cefovecin (Convenia) long-acting injectable, 8 mg/kg for two doses, plus medicated baths) but also suggested possibility of atopic dermatitis . After...presumptive diagnosis of atopic dermatitis , we started a novel protein diet trial in April (Iams kangaroo/potato), and most clinical signs were resolved
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Essentials of Endodontic Microsurgery
2010-04-01
protocol is divided into regional and local injections and are as follows: 1. The administration of a long-acting anesthetic agent such as bupivicaine (Mar...mandibular anterior teeth receive bilateral mental nerve blocks. All of these can be supplemented, as need be, with corresponding palatal or lingual...infiltrations of the same anesthetic . In studies examining the effectiveness of lidocaine versus bupivicaine, it was shown that lidocaine was faster in
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The Effects of Antipsychotic Quality Reporting on Antipsychotic and Psychoactive Medication Use.
Bowblis, John R; Lucas, Judith A; Brunt, Christopher S
2015-08-01
The objective of this study is to examine how nursing homes changed their use of antipsychotic and other psychoactive medications in response to Nursing Home Compare's initiation of publicly reporting antipsychotic use in July 2012. The study includes all state recertification surveys (n = 40,415) for facilities six quarters prior and post the initiation of public reporting. Using a difference-in-difference framework, the change in use of antipsychotics and other psychoactive medications is compared for facilities subject to public reporting and facilities not subject to reporting. The percentage of residents using antipsychotics, hypnotics, or any psychoactive medication is found to decline after public reporting. Facilities subject to reporting experienced an additional decline in antipsychotic use (-1.94 vs. -1.40 percentage points) but did not decline as much for hypnotics (-0.60 vs. -1.21 percentage points). Any psychoactive use did not vary with reporting status, and the use of antidepressants and anxiolytics did not change. Public reporting of an antipsychotic quality measure can be an effective policy tool for reducing the use of antipsychotic medications--though the effect many only exist in the short run. © Health Research and Educational Trust.
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Sinayko, V; Korovina, L
2016-01-01
The aim of the study was to investigate the influence of motivational and targeted psychoeducational programs designed for patients with paranoid schizophrenia with abdominal obesity. We observed 34 women aged 18-42 with continuous-flow type paranoid schizophrenia. All patients had a concomitant abdominal obesity, which developed secondarily after long-term administration of second generation antipsychotic medications (at least 1 year). Based on clinical-psychopathological and psychometric methods of assessment and on the analysis of Treatment Satisfaction Questionnaire we have developed modules for psychoeducational programs. Based on the results of the treatment we conclude that the application of psychoeducational programs is an effective component of complex treatment of patients with paranoid schizophrenia. Abdominal obesity should be regarded as an important and the main side effect of long-term therapy with atypical antipsychotic medications. It has a marked negative effect on subjective assessment of patients and decreases the level of their mental and social adaptation. This factor should be the basis for the formation of re-socialization and compliance-oriented actions.
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Valbenazine for Tardive Dyskinesia.
Freudenreich, Oliver; Remington, Gary
Tardive dyskinesia (TD) remains a clinical concern for any patient who receives an antipsychotic. While the overall risk of developing TD is lower with newer antipsychotics compared to older agents, a significant number of patients who require long-term treatment will develop TD. Recently, valbenazine (brand name Ingrezza) became the first drug to be approved by the FDA specifically for the treatment of TD. In this New Drug Review, we summarize the basic pharmacology and clinical trial results for valbenazine. Valbenazine is a modified metabolite of the vesicular monoamine transporter 2 (VMAT-2) inhibitor tetrabenazine, which is approved for the treatment of the hyperkinetic movement disorder, Huntington's disease. In short-term clinical trials, valbenazine at a dose of 80 mg/day improved TD, with an effect size that is clinically significant (d=0.90). The effect size for the 40-mg/day dose was lower (d=0.52). Compared to tetrabenazine, valbenazine has better clinical characteristics (i.e., once-a-day dosing, better short-term side effect profile). However, only long-term experience in routine clinical populations can delineate valbenazine's full benefits, optimal dosing, and risks not identified during short-term registration trials.
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Use of second-generation antipsychotic agents for sleep and sedation: a provider survey.
Hermes, Eric D A; Sernyak, Michael; Rosenheck, Robert
2013-04-01
Anecdotal evidence suggests that second-generation antipsychotic agents are increasingly used to treat sleep problems. This study sought to quantify the proportion of new prescriptions for second-generation antipsychotic agents started for sleep/sedation and the correlates of such use. A cross-sectional survey of provider decision making at the time second-generation antipsychotic agents were prescribed, documenting the reasons for the medication, patient demographics, psychiatric and medical diagnoses, patient health characteristics, and provider background. A single Veterans Affairs Medical Center over a 20-month period. Prescribers of second-generation antipsychotic agents. N/A. Seven hundred seven (32.2%) of 2,613 surveys indicated sleep/sedation was at least one reason for using a second-generation anti-psychotic agent, whereas for 266 (12.1%) it was the only reason. Quetiapine was most frequently prescribed overall as well as for sleep/sedation (47.0% and 73.6% respectively). Second-generation antipsychotic agent use for sleep/sedation was unrelated to sociodemographic characteristics, least likely in patients with schizophrenia or bipolar disorder, and most likely as a newly started second-generation antipsychotic agent. Sleep/sedation is a common reason given for new prescriptions of second-generation antipsychotic agents. Quetiapine is most frequently used for this purpose. A greater understanding of why providers use second-generation antipsychotic agents rather than safer and less costly alternatives for sleep problems may advance the development of interventions to reduce adverse effects.
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He, Jue; Kong, Jiming
2009-01-01
Antipsychotic drugs are divided into two groups: typical and atypical. Recent clinical studies show atypical antipsychotics have advantages over typical antipsychotics in a wide variety of neuropsychiatric conditions, in terms of greater efficacy for positive and negative symptoms, beneficial effects on cognitive functioning, and fewer extra pyramidal side effects in treating schizophrenia. As such, atypical antipsychotics may be effective in the treatment of depressive symptoms associated with psychotic and mood disorders, posttraumatic stress disorder and psychosis in Alzheimer disease. In this paper, we describe the effects and potential neurochemical mechanisms of action of atypical antipsychotics in several animal models showing memory impairments and/or non-cognitive behavioral changes. The data provide new insights into the mechanisms of action of atypical antipsychotics that may broaden their clinical applications. PMID:19372744
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Testing the effects of long-acting steroids in edema and ecchymosis after closed rhinoplasty
Gutierrez, Santiago; Wuesthoff, Carolina
2014-01-01
BACKGROUND: Steroids have proven to be of some benefit in rhinoplasty edema and ecchymosis when administered at a high and repeated dose. OBJECTIVE: To evaluate the effects of single-dose, long-acting intramuscular steroids on postoperative edema and ecchymosis after closed rhinoplasty with osteotomies compared with placebo. METHODS: A randomized, double-blinded, placebo-controlled trial was performed. Fifty-four patients were randomly assigned to two groups: 28 received a single dose of long-acting dexamethasone (mean [± SD] dose 16±4 mg) immediately before anesthetic induction; the remaining 26 received an intramuscular injection of saline solution. The same surgeon performed all surgeries, with patients under general anesthesia. Acetaminophen was the only analgesic used to control postoperative pain. High-resolution digital photographs were taken on postoperative days 1, 3, 7 and 14. Scoring was performed separately for eyelid swelling and ecchymosis by an independent observer using a graded scale (0 to 5) for edema and a scoring system (0 to 13) for ecchymosis. RESULTS: No statistically significant differences in terms of age, sex or amount of bleeding during surgery were found between the two groups. No statistically significant difference was observed in the decrease of both ecchymosis and edema between placebo and high-dose, long-acting dexamethasone. A statistically significant difference in operation time was found, favouring the steroid group. No severe complications were observed due to steroid use. DISCUSSION: Osteotomies are basically a form of (controlled) trauma, with considerable disruption of the abundant blood vessels in this facial region and, therefore, are associated with with undesirable effects. A recent meta-analysis failed to show benefits of the use of steroids after postoperative day 3. Only a trend toward reduction in edema and ecchymosis with the use of long-acting steroids compared with placebo was demonstrated in the present study. CONCLUSION: There was no benefit in administering single-dose, long-acting steroids in patients undergoing closed rhinoplasty with osteotomies. PMID:25114618
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Atypical and Typical Antipsychotics in the Schools
ERIC Educational Resources Information Center
Noggle, Chad A.; Dean, Raymond S.
2009-01-01
The use of antipsychotic medications within the school-age population is rapidly increasing. Although typical antipsychotics may be used in rare cases, this influx is largely secondary to the availability of the atypical antipsychotics. Reduction of possible adverse effects and increased efficacy represent the primary basis for the atypical…
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Caron, Guillaume; Marqueste, Tanguy; Decherchi, Patrick
2015-01-01
The aim of the present study was to investigate long term effects of motor denervation by botulinum toxin complex type A (BoNT/A) from Clostridium Botulinum, on the afferent fibers originating from the gastrocnemius muscle of rats. Animals were divided in 2 experimental groups: 1) untreated animals acting as control and 2) treated animals in which the toxin was injected in the left muscle, the latter being itself divided into 3 subgroups according to their locomotor recovery with the help of a test based on footprint measurements of walking rats: i) no recovery (B0), ii) 50% recovery (B50) and iii) full recovery (B100). Then, muscle properties, metabosensitive afferent fiber responses to potassium chloride (KCl) and lactic acid injections and Electrically-Induced Fatigue (EIF), and mechanosensitive responses to tendon vibrations were measured. At the end of the experiment, rats were killed and the toxin injected muscles were weighted. After toxin injection, we observed a complete paralysis associated to a loss of force to muscle stimulation and a significant muscle atrophy, and a return to baseline when the animals recover. The response to fatigue was only decreased in the B0 group. The responses to KCl injections were only altered in the B100 groups while responses to lactic acid were altered in the 3 injected groups. Finally, our results indicated that neurotoxin altered the biphasic pattern of response of the mechanosensitive fiber to tendon vibrations in the B0 and B50 groups. These results indicated that neurotoxin injection induces muscle afferent activity alterations that persist and even worsen when the muscle has recovered his motor activity. PMID:26485650
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Caron, Guillaume; Marqueste, Tanguy; Decherchi, Patrick
2015-01-01
The aim of the present study was to investigate long term effects of motor denervation by botulinum toxin complex type A (BoNT/A) from Clostridium Botulinum, on the afferent fibers originating from the gastrocnemius muscle of rats. Animals were divided in 2 experimental groups: 1) untreated animals acting as control and 2) treated animals in which the toxin was injected in the left muscle, the latter being itself divided into 3 subgroups according to their locomotor recovery with the help of a test based on footprint measurements of walking rats: i) no recovery (B0), ii) 50% recovery (B50) and iii) full recovery (B100). Then, muscle properties, metabosensitive afferent fiber responses to potassium chloride (KCl) and lactic acid injections and Electrically-Induced Fatigue (EIF), and mechanosensitive responses to tendon vibrations were measured. At the end of the experiment, rats were killed and the toxin injected muscles were weighted. After toxin injection, we observed a complete paralysis associated to a loss of force to muscle stimulation and a significant muscle atrophy, and a return to baseline when the animals recover. The response to fatigue was only decreased in the B0 group. The responses to KCl injections were only altered in the B100 groups while responses to lactic acid were altered in the 3 injected groups. Finally, our results indicated that neurotoxin altered the biphasic pattern of response of the mechanosensitive fiber to tendon vibrations in the B0 and B50 groups. These results indicated that neurotoxin injection induces muscle afferent activity alterations that persist and even worsen when the muscle has recovered his motor activity.
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Malla, Ashok; Mustafa, Sally; Rho, Aldanie; Abadi, Sherezad; Lepage, Martin; Joober, Ridha
2016-07-01
Aripiprazole has been associated with a low prevalence of metabolic side effects as compared to other second generation antipsychotic (SGA) medications mostly in patients with long standing illness. The purpose of the present study was to assess specifically the effectiveness and safety of aripiprazole as a first choice for antipsychotic therapy for young patients presenting with a previously untreated first episode of a psychotic disorder (FEP). Seventy-three patients presenting with a FEP and with minimal prior exposure to antipsychotic medications were recruited to be part of an open label naturalistic outcome study using aripiprazole as the first choice of antipsychotic medication. Data on positive, negative and total symptom severity including general psychopathological symptoms, level of functioning and metabolic indices were collected prospectively over a one-year period. As compared to baseline, patients treated with aripiprazole (mean dose 9.6mg) improved significantly on measures of positive (p<0.001), negative (p<0.001) and total severity-general psychopathology symptoms (p<0.001) and level of functioning (p<0.001). Seventy two percent of the participants achieved positive symptom remission and 50% achieved total remission (positive and negative) at one year of follow up. Unlike reports on patients with longer standing illness, significant weight gain (p<0.001) was observed, with 44% of participants experiencing >7% increase in body weight. FEP patients starting treatment with aripiprazole improved on symptoms and social and occupational functioning. Aripiprazole was well tolerated except for a significant weight gain. Copyright © 2016 Elsevier B.V. All rights reserved.
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Challenges and Promises of Pediatric Psychopharmacology.
Giles, Lisa L; Martini, D Richard
2016-08-01
Most prescriptions for psychotropic medications are written by primary care physicians, yet pediatricians, many of whom are teaching residents and medical students about pediatric psychopharmacology, often feel inadequately trained to treat mental health concerns. Over the past several decades, the number, size, and quality of psychopharmacologic studies in youth has greatly increased. Here we review the current evidence for efficacy and safety of each of the major pharmacologic drug classes in youth (psychostimulants, antidepressants, mood stabilizers, and antipsychotics). Psychostimulants have a robust body of literature supporting their evidence as first-line treatment for attention-deficit/hyperactivity disorder. Selective serotonin reuptake inhibitors (SSRIs) have documented efficacy for pediatric depression and multiple different anxiety disorders with childhood onset. Combining cognitive-behavioral therapy with SSRI treatment enhances treatment benefit and minimizes adverse events of medication. Mood stabilizers, including lithium and anticonvulsant medications, have a less robust strength of evidence and come with more problematic side effects. However, they are increasingly prescribed to youth, often to treat irritability, mood lability, and aggression, along with treatment of bipolar disorder. Antipsychotics have long been a mainstay of treatment for childhood-onset schizophrenia, and in recent years, the evidence base for providing antipsychotics to youth with bipolar mania and autistic disorder has grown. Most concerning with antipsychotics are the metabolic side effects, which appear even more problematic in youth than adults. By better understanding the evidence-based psychopharmacologic interventions, academic pediatricians will be able to treat patients and prepare future pediatrician to address the growing mental health care needs of youth. Copyright © 2016 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.
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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
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Differences in Nursing Home Quality Between Medicare Advantage and Traditional Medicare Patients.
Chang, Emiley; Ruder, Teague; Setodji, Claude; Saliba, Debra; Hanson, Mark; Zingmond, David S; Wenger, Neil S; Ganz, David A
2016-10-01
Medicare Advantage (MA) enrollment is steadily growing, but little is known about the quality of nursing home (NH) care provided to MA enrollees compared to enrollees in traditional fee-for-service (FFS) Medicare. To compare MA and FFS enrollees' quality of NH care. Cross-sectional. US nursing homes. 2.17 million Medicare enrollees receiving care at an NH during 2011. CMS methodology was used to calculate the 18 Nursing Home Compare quality measures as applicable for each enrollee. Among Medicare enrollees using NH in 2011, 17% were in MA plans. Most quality scores were similar between MA and FFS. After adjusting for facility, beneficiary age and gender, CMS Hierarchical Condition Category score, and geographic region, short-stay MA enrollees had statistically significantly lower rates of new or worsening pressure ulcers [relative risk (RR) = 0.76, 95% confidence interval (CI) = 0.71-0.82] and new antipsychotic use (RR = 0.82, 95% CI = 0.80-0.83) but higher rates of moderate to severe pain (RR = 1.09, 95% CI = 1.07-1.12), compared with short-stay FFS enrollees. MA long-stay enrollees had lower rates of antipsychotic use (RR = 0.94, 95% CI = 0.93-0.96) but had higher rates of incontinence (RR = 1.08, 95% CI = 1.06-1.09) and urinary catheterization (RR = 1.10, 95% CI = 1.06-1.13), compared with long-stay FFS enrollees. Overall, we found few differences in NH quality scores between MA and FFS Medicare enrollees. MA enrollment was associated with better scores for pressure ulcers and antipsychotic use but worse scores for pain control, incontinence, and urinary catheterization. Results may be limited by residual case-mix differences between MA and FFS patients or by the small number of short-stay measures reported. Copyright © 2016 AMDA - The Society for Post-Acute and Long-Term Care Medicine. All rights reserved.
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Jucker, Beat M; Alsaid, Hasan; Rambo, Mary; Lenhard, Stephen C; Hoang, Bao; Xie, Fang; Groseclose, M Reid; Castellino, Stephen; Damian, Valeriu; Bowers, Gary; Gupta, Manish
2017-12-28
Long-Acting Parenterals (LAPs) have been used in the clinic to provide sustained therapeutic drug levels at a target site, and thereby reducing the frequency of dosing required. In an effort to understand the factors associated with long-acting cabotegravir (GSK1265744 LAP) pharmacokinetic variability, the current study was designed to investigate the temporal relationship between intramuscular (IM) or subcutaneous (SC) drug depot morphology and distribution kinetics with plasma pharmacokinetics. Therefore, a multi-modal molecular imaging (MRI & MALDI IMS) approach was employed to examine the temporal GSK1265744 LAP biodistribution in rat following either IM or SC administration. Serial MRI was performed immediately post drug administration, and then at day 1 (24h post), 2, 3, 4, 7, and 14. In a separate cohort of rats, an MRI contrast agent, Feraheme® (USPIO), was administered 2days post IM drug injection in order to investigate the potential involvement of macrophages trafficking to the GSK1265744 LAP and Vehicle depot sites. The GSK1265744 LAP depot volume increased rapidly by day 2 in the IM injected rats (~3-7 fold) compared with a ~1 fold increase in the SC injected rats. In addition, the USPIO contrast agent labeled macrophages were shown to be present in the depot region of the GSK1265744 LAP injected gastrocnemius while the Vehicle injected gastrocnemius appeared to show reduced uptake. Matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS) of muscle and abdominal tissue sections identified the drug content primarily within the depot. Co-registration of the GSK1265744 ion images with immunohistochemical images established that the drug was taken up by macrophages associated with the depot. Linear regression analysis demonstrated that the drug depot characteristics including volume, surface area, and perimeter assessed by MRI at day 2 correlated with early time point plasma drug concentrations. In summary, a multimodal molecular imaging approach was used to identify the drug depot location and volumetric/physiologic changes in both IM and SC locations following GSK1265744 LAP administration. The IM depot volume increased rapidly to a maximum volume at 2days post-GSK1265744 LAP administration, while the Vehicle depot did not suggesting that the active drug substance and/or related particle was a key driver for drug depot evolution. The depot expansion was associated with an increase in macrophage infiltration and edema in and around the depot region and was correlated to plasma drug concentration at early time points (0-4days). Consequently, molecular imaging approaches may be used in patients to help understand the biodistribution of GSK1265744 LAP and its associated pharmacokinetics. Copyright © 2017 Elsevier B.V. All rights reserved.
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[Cost-effectiveness of Antipsychotics in the Maintenance Treatment of Schizophrenia in Colombia].
Quitian Reyes, Hoover; Arciniegas Barrera, Jair Alberto; Bohórquez Peñaranda, Adriana; Gómez Restrepo, Carlos
2016-01-01
Assess the cost-effectiveness of the antipsychotics for treatment of schizophrenia. A five-year Markov model was built form patients with schizophrenia on the stage of maintenance. Costs were taken from the perspective of the Colombian health care system (Sistema General de Seguridad Social en Salud). The effectiveness was measured in years of life under the same maintenance plan. The Markov model indicated clozapine as the as the most cost-effective alternative between the first line antipsychotics and haloperidol is it when comparing other antipsychotics. Clozapine it's the cost-effectiveness strategy among the first line of antipsychotics and haloperidol is it among the other antipsychotics. Strategies prioritizing the use of cost-effective antipsychotics could improve the resources allocation in the Colombian health care system. Copyright © 2014 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.
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ERIC Educational Resources Information Center
Lunsky, Yona; Elserafi, Jonny
2012-01-01
Antipsychotic medication rates are high in adults with developmental disability. This study considered rates of antipsychotic use in 743 adults with developmental disability who had experienced a psychiatric crisis. Nearly half (49%) of these adults were prescribed antipsychotics. Polypharmacy was common with 22% of those prescribed antipsychotics…
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Physical Health and Drug Safety in Individuals with Schizophrenia
Kelly, Martina; Urness, Doug; Teehan, Michael; Ismail, Zahinoor; Gardner, David
2017-01-01
Background: While antipsychotic medications are the mainstay of therapy for individuals with schizophrenia and psychotic disorders, their use is associated with adverse effects on physical health that require the attention and care of prescribers. Methods: We used the ADAPTE process to adapt existing guideline recommendations from the National Institute for Health and Care Excellence (NICE) and Scottish Intercollegiate Guidelines Network (SIGN) guidelines on the dosing of antipsychotics and antipsychotic polypharmacy, screening for adverse effects of antipsychotics, and management of metabolic and extrapyramidal side effects to the Canadian context. Results: Prescribers are encouraged to use the lowest effective dose and to avoid the routine use of multiple antipsychotics. Scheduled monitoring of body mass index, waist circumference, blood pressure, glucose, lipids, prolactin, electrocardiograms, and extrapyramidal symptoms is recommended. Lifestyle interventions are recommended to mitigate antipsychotic-induced weight gain. Prescribers should follow Canadian guidelines on the treatment of obesity, dyslipidemia, and diabetes. Recommendations on antipsychotic drug choice are made for users particularly concerned about extrapyramidal symptoms. Conclusion: Careful monitoring and attention by prescribers may mitigate adverse effects associated with antipsychotic medications. PMID:28718324
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Bingham, C; Hodge, A; Mariadass, B
2017-05-01
To determine if there was a benefit from treating ewes with a low body condition score (BCS) with long acting anthelmintic products pre-lambing and to compare the effects of two commonly used treatment options. The study was conducted on a single commercial hill country sheep and beef property in the central North Island of New Zealand. Mixed age twin-bearing ewes were preselected by the farmer as being in poor condition 4 weeks before the planned start of lambing, and were sequentially drafted into three equal groups identified with coloured ear tags. The negative control group (n=199) received no anthelmintic treatment; the other two groups received either a controlled release capsule (CRC) containing abamectin, albendazole, Se and Co (n=200) or a long-acting injection of moxidectin (n=200). All ewes were body condition scored (1-5 scale) and weighed at pre-lambing, docking (65 days after treatment) and at weaning (127 days after treatment). Faecal nematode egg counts (FEC) were carried out on 10 ewes from each group at these three times. Most lambs were matched to the ewe treatment groups at weaning, and weighed. At weaning the mean body weight of ewes treated with moxidectin was 3.2 (95% CI=2.3-4.3) kg heavier than controls, and of ewes treated with CRC was 3.6 (95% CI=2.5-4.5) kg heavier than control ewes (p<0.001). At the start of the trial only 61/599 (10.2%) ewes had a BCS≥3. At weaning, more ewes treated with CRC (140/194; 72%) or moxidectin (122/187; 65%) had a BCS≥3 than control ewes (55/179 (31%); p<0.001). In lambs that were matched with ewes from the treatment groups, the mean weight at weaning of lambs from ewes treated with moxidectin was 2.6 (95% CI=1.9-3.3) kg heavier, and from ewes treated with CRC was 2.6 (95% CI=1.9-3.4) kg heavier than lambs from control ewes (p<0.001). Treating twin-bearing ewes with low BCS pre-lambing with long acting anthelmintic treatments (moxidectin long acting injection or CRC) resulted in an increase in mean body weight of the ewes and lambs at weaning. There were no significant differences between the two pre-lambing treatments used. These results were based on a single property and thus cannot be generalised to all properties where management conditions and parasite populations may differ.
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Psychotic and Bipolar Disorders: Antipsychotic Drugs.
Holder, Sarah D; Edmunds, Alaina L; Morgan, Sherri
2017-04-01
Antipsychotic drugs block dopamine receptors and are used to manage psychosis as well as other mental illnesses that may or may not have psychotic features, such as bipolar disorders and major depressive disorder. First-generation antipsychotic drugs are more likely to cause adverse effects such as extrapyramidal symptoms and tardive dyskinesia. Adverse effects of second-generation antipsychotic drugs typically are related to metabolic abnormalities such as weight gain, abnormal blood glucose levels, and elevated lipid levels. Neuroleptic malignant syndrome is a rare but serious adverse effect of antipsychotic drugs that causes mental status changes, hyperthermia, and generalized rigidity. Timely diagnosis is essential due to a high risk of related morbidities if the syndrome remains untreated. Some adverse effects of antipsychotics can be identified and managed so that patients can continue beneficial therapy while minimizing the physiologic consequences. Patients taking antipsychotic drugs should be monitored regularly for adverse effects. Antipsychotics are also associated with potential drug interactions, the most lethal being prolongation of the QT interval, which can lead to fatal arrhythmias. Antipsychotic drugs can be used in special populations, such as pregnant women, children, and elderly patients, per recommendation from a mental health subspecialist. Written permission from the American Academy of Family Physicians is required for reproduction of this material in whole or in part in any form or medium.
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The Effects of Antipsychotic Quality Reporting on Antipsychotic and Psychoactive Medication Use
Bowblis, John R; Lucas, Judith A; Brunt, Christopher S
2015-01-01
Objective The objective of this study is to examine how nursing homes changed their use of antipsychotic and other psychoactive medications in response to Nursing Home Compare’s initiation of publicly reporting antipsychotic use in July 2012. Research Design and Subjects The study includes all state recertification surveys (n = 40,415) for facilities six quarters prior and post the initiation of public reporting. Using a difference-in-difference framework, the change in use of antipsychotics and other psychoactive medications is compared for facilities subject to public reporting and facilities not subject to reporting. Principal Findings The percentage of residents using antipsychotics, hypnotics, or any psychoactive medication is found to decline after public reporting. Facilities subject to reporting experienced an additional decline in antipsychotic use (−1.94 vs. −1.40 percentage points) but did not decline as much for hypnotics (−0.60 vs. −1.21 percentage points). Any psychoactive use did not vary with reporting status, and the use of antidepressants and anxiolytics did not change. Conclusion Public reporting of an antipsychotic quality measure can be an effective policy tool for reducing the use of antipsychotic medications—though the effect many only exist in the short run. PMID:25600861
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Antipsychotic metabolic effects: weight gain, diabetes mellitus, and lipid abnormalities.
McIntyre, R S; McCann, S M; Kennedy, S H
2001-04-01
To review published and nonpublished literature describing changes in weight, glucose homeostasis, and lipid milieu with antipsychotics. A Medline search was completed using the words weight gain, diabetes mellitus, cholesterol, triglycerides, risperidone, clozapine, olanzapine, quetiapine, ziprasidone, predictors, prolactin, obesity, and conventional antipsychotics. Publications, including original articles, review articles, letters to the editor, abstracts or posters presented at professional meetings in the last 4 years, and references from published articles, were collected. Manufacturers, including Eli Lilly Canada Inc, JanssenOrtho Inc, Pfizer Canada Inc, AstraZeneca Inc, and Novartis Pharmaceuticals, were contacted to retrieve additional medical information. The topic of antipsychotic-induced weight gain is understudied, and there are relatively few well-controlled studies. Weight gain as a side effect has been described with both conventional and atypical antipsychotics. Moreover, some atypical antipsychotics are associated with de novo diabetes mellitus and increased serum triglyceride levels. Predictors of weight gain may be age, baseline body mass index, appetite stimulation, previous antipsychotic exposure, and antipsychotic treatment duration. Significant weight gain is reported with the existing atypical antipsychotics. The weight gain described is highly distressing to patients, may reduce treatment adherence, and may increase the relative risk for diabetes mellitus and hypertriglyceridemia. Physicians employing these agents should routinely monitor weight, fasting blood glucose, and lipid profiles.
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Side effect burden of antipsychotic drugs in real life - Impact of gender and polypharmacy.
Iversen, Trude Seselie Jahr; Steen, Nils Eiel; Dieset, Ingrid; Hope, Sigrun; Mørch, Ragni; Gardsjord, Erlend Strand; Jørgensen, Kjetil Nordbø; Melle, Ingrid; Andreassen, Ole A; Molden, Espen; Jönsson, Erik G
2018-03-02
Antipsychotic-associated side effects are well known and represent a significant treatment challenge. Still, few large studies have investigated the overall side effect burden of antipsychotics in real-life settings. To describe the occurrence of side effects and perceived burden of antipsychotics in a large naturalistic sample, taking polypharmacy and patient characteristics into account. Patients (n=1087) with psychotic disorders were assessed for side effects using the Udvalg for Kliniske Undersøgelser (UKU) side effect rating scale in addition to assessment of clinical and pharmacological data. Statistical analyses were performed controlling for possible confounding factors. Use of antipsychotics showed significant associations to neurologic and sexual symptoms, sedation and weight gain, and >75% of antipsychotics-users reported side effects. More side effects were observed in patients using several antipsychotics (p=0.002), with increasing total dose (p=0.021) and with antipsychotics in combinations with other psychotropic drugs. Patients and investigators evaluated the side effect burden differently, particularly related to severity, gender and antipsychotics dose. Twice as many females described side effect burden as severe (p=0.004). Patients with psychotic disorders have a high occurrence of symptoms associated with use of antipsychotics, and polypharmacy and female gender are seemingly risk factors for reporting a severe side effect burden. Due to the cross-sectional design evaluation of causality is tentative, and these findings should be further investigated in prospective studies. Copyright © 2017 Elsevier Inc. All rights reserved.
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Woods, Scott W.; Morgenstern, Hal; Saksa, John R.; Walsh, Barbara C.; Sullivan, Michelle C.; Money, Roy; Hawkins, Keith A.; Gueorguieva, Ralitza V.; Glazer, William M.
2011-01-01
Objective Most previous studies of the incidence of tardive dyskinesia with atypical compared to conventional antipsychotics have not had tardive dyskinesia as their primary focus. The current study aimed to compare the incidence of tardive dyskinesia with atypical vs. conventional antipsychotics using methods similar to those from a previous prospective cohort study at our site in the 1980s. Method 352 initially tardive dyskinesia-free psychiatric outpatients were examined for a new diagnosis of tardive dyskinesia every 6 months for up to 4 years at a community mental health center. At baseline, subjects were receiving conventional antipsychotics only (23%), atypicals only (64%), or both (14%). Only 26 subjects had never received conventional antipsychotics. Results Compared with subjects treated with conventional antipsychotics alone since the previous visit, the adjusted tardive dyskinesia incidence rate-ratio for subjects treated with atypical antipsychotics alone was 0.68 (95% confidence interval 0.29 to 1.64). The incidence and prevalence of tardive dyskinesia was similar to previous findings at this site in the 1980s. Conclusion The incidence of tardive dyskinesia with recent exposure to atypical antipsychotics alone was more similar to that for conventional antipsychotics than in most previous studies. Despite high penetration of atypical antipsychotics into clinical practice, the incidence and prevalence of tardive dyskinesia appeared relatively unchanged since the 1980s. Clinicians should continue to monitor for tardive dyskinesia, and researchers should continue to pursue efforts to treat or prevent it. PMID:20156410
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Woods, Scott W; Morgenstern, Hal; Saksa, John R; Walsh, Barbara C; Sullivan, Michelle C; Money, Roy; Hawkins, Keith A; Gueorguieva, Ralitza V; Glazer, William M
2010-04-01
Most previous studies of the incidence of tardive dyskinesia with atypical antipsychotics compared with conventional antipsychotics have not had tardive dyskinesia as their primary focus. The current study aimed to compare the incidence of tardive dyskinesia with atypical vs conventional antipsychotics using methods similar to those from a previous prospective cohort study at our site in the 1980s. Three hundred fifty-two initially tardive dyskinesia-free psychiatric outpatients (diagnosed at baseline using the Structured Clinical Interview for DSM-IV) were examined for a new diagnosis of tardive dyskinesia (using the Abnormal Involuntary Movement Scale and Glazer-Morgenstern criteria) every 6 months for up to 4 years at a community mental health center. At baseline, subjects were receiving conventional antipsychotics only (23%), atypicals only (64%), or both (14%). Only 26 subjects had never received conventional antipsychotics. Baseline evaluations were conducted from November 2000 through May 2003. Follow-ups were conducted through February 2005. Compared with subjects treated with conventional antipsychotics alone since the previous visit, the adjusted tardive dyskinesia incidence rate-ratio for subjects treated with atypical antipsychotics alone was 0.68 (95% CI, 0.29-1.64). The incidence and prevalence of tardive dyskinesia was similar to previous findings at this site in the 1980s. The incidence of tardive dyskinesia with recent exposure to atypical antipsychotics alone was more similar to that for conventional antipsychotics than in most previous studies. Despite high penetration of atypical antipsychotics into clinical practice, the incidence and prevalence of tardive dyskinesia appeared relatively unchanged since the 1980s. Clinicians should continue to monitor for tardive dyskinesia, and researchers should continue to pursue efforts to treat or prevent it. Copyright 2010 Physicians Postgraduate Press, Inc.
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Hochman, Eldar; Krivoy, Amir; Schaffer, Ayal; Weizman, Abraham; Valevski, Avi
2016-12-01
Antipsychotic adjunctive therapy to mood stabilizers (MSs) may improve relapse prevention; however, only a few naturalistic studies, reflecting more generalizable bipolar disorder (BD) samples, support this notion. We compared the 1-year rehospitalization rates of manic patients with bipolar I disorder (BD-I) who were discharged with MS (lithium or valproate) monotherapy or with adjunctive atypical or typical antipsychotic therapy. A total of 201 patients with BD-I who were hospitalized with manic episodes between 2005 and 2013 were retrospectively followed for 1-year rehospitalization rates according to treatment at discharge: MS monotherapy, MS with atypical antipsychotics, and MS with typical antipsychotics. Additionally, time to rehospitalization during the 1-year period after discharge was compared between treatment groups. Multivariable survival analyses adjusted for covariates known to influence rehospitalization were conducted. Rehospitalization rates within 1 year were significantly lower in the MS with atypical antipsychotics group (6.3%) compared to the MS monotherapy group (24.3%, P=.008) and to the MS with typical antipsychotics group (20.6%, P=.02). Time to rehospitalization was significantly longer for the MS with atypical antipsychotics group (345.5 days) compared to the MS monotherapy group (315.1 days, P=.006) and to the MS with typical antipsychotics group (334.1 days, P=.02). The MS with atypical antipsychotics group had a significantly reduced adjusted risk of rehospitalization (hazard ratio=0.17, 95% confidence interval: 0.05-0.61, P=.007) compared to the MS monotherapy group. Atypical antipsychotic adjunctive therapy to MSs may be more effective than MS monotherapy in preventing rehospitalization during the 1-year period after a BD manic episode. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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EADSG Guidelines: Insulin Therapy in Diabetes.
Silver, Bahendeka; Ramaiya, Kaushik; Andrew, Swai Babu; Fredrick, Otieno; Bajaj, Sarita; Kalra, Sanjay; Charlotte, Bavuma M; Claudine, Karigire; Makhoba, Anthony
2018-04-01
A diagnosis of diabetes or hyperglycemia should be confirmed prior to ordering, dispensing, or administering insulin (A). Insulin is the primary treatment in all patients with type 1 diabetes mellitus (T1DM) (A). Typically, patients with T1DM will require initiation with multiple daily injections at the time of diagnosis. This is usually short-acting insulin or rapid-acting insulin analogue given 0 to 15 min before meals together with one or more daily separate injections of intermediate or long-acting insulin. Two or three premixed insulin injections per day may be used (A). The target glycated hemoglobin A1c (HbA1c) for all children with T1DM, including preschool children, is recommended to be < 7.5% (< 58 mmol/mol). The target is chosen aiming at minimizing hyperglycemia, severe hypoglycemia, hypoglycemic unawareness, and reducing the likelihood of development of long-term complications (B). For patients prone to glycemic variability, glycemic control is best evaluated by a combination of results with self-monitoring of blood glucose (SMBG) (B). Indications for exogenous insulin therapy in patients with type 2 diabetes mellitus (T2DM) include acute illness or surgery, pregnancy, glucose toxicity, contraindications to or failure to achieve goals with oral antidiabetic medications, and a need for flexible therapy (B). In T2DM patients, with regards to achieving glycemic goals, insulin is considered alone or in combination with oral agents when HbA1c is ≥ 7.5% (≥ 58 mmol/mol); and is essential for treatment in those with HbA1c ≥ 10% (≥ 86 mmol/mol), when diet, physical activity, and other antihyperglycemic agents have been optimally used (B). The preferred method of insulin initiation in T2DM is to begin by adding a long-acting (basal) insulin or once-daily premixed/co-formulation insulin or twice-daily premixed insulin, alone or in combination with glucagon-like peptide-1 receptor agonist (GLP-1 RA) or in combination with other oral antidiabetic drugs (OADs) (B). If the desired glucose targets are not met, rapid-acting or short-acting (bolus or prandial) insulin can be added at mealtime to control the expected postprandial raise in glucose. An insulin regimen should be adopted and individualized but should, to the extent possible, closely resemble a natural physiologic state and avoid, to the extent possible, wide fluctuating glucose levels (C). Blood glucose monitoring is an integral part of effective insulin therapy and should not be omitted in the patient's care plan. Fasting plasma glucose (FPG) values should be used to titrate basal insulin, whereas both FPG and postprandial glucose (PPG) values should be used to titrate mealtime insulin (B). Metformin combined with insulin is associated with decreased weight gain, lower insulin dose, and less hypoglycemia when compared with insulin alone (C). Oral medications should not be abruptly discontinued when starting insulin therapy because of the risk of rebound hyperglycemia (D). Analogue insulin is as effective as human insulin but is associated with less postprandial hyperglycemia and delayed hypoglycemia (B). The shortest needles (currently the 4-mm pen and 6-mm syringe needles) are safe, effective, and less painful and should be the first-line choice in all patient categories; intramuscular (IM) injections should be avoided, especially with long-acting insulins, because severe hypoglycemia may result; lipohypertrophy is a frequent complication of therapy that distorts insulin absorption, and therefore, injections and infusions should not be given into these lesions and correct site rotation will help prevent them (A). Many patients in East Africa reuse syringes for various reasons, including financial. This is not recommended by the manufacturer and there is an association between needle reuse and lipohypertrophy. However, patients who reuse needles should not be subjected to alarming claims of excessive morbidity from this practice (A). Health care authorities and planners should be alerted to the risks associated with syringe or pen needles 6 mm or longer in children (A).
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Regional variation in physician adoption of antipsychotics: Impact on US Medicare expenditures
Donohue, Julie M.; Normand, Sharon-Lise T.; Horvitz-Lennon, Marcela; Men, Aiju; Berndt, Ernst R.; Huskamp, Haiden A.
2016-01-01
Background Regional variation in US Medicare prescription drug spending is driven by higher prescribing of costly brand-name drugs in some regions. This variation likely arises from differences in the speed of diffusion of newly-approved medications. Second-generation antipsychotics were widely adopted for treatment of severe mental illness and for several off-label uses. Rapid diffusion of new psychiatric drugs likely increases drug spending but its relationship to non-drug spending is unclear. The impact of antipsychotic diffusion on drug and medical spending is of great interest to public payers like Medicare, which finance a majority of mental health spending in the U.S. Aims We examine the association between physician adoption of new antipsychotics and antipsychotic spending and non-drug medical spending among disabled and elderly Medicare enrollees. Methods We linked physician-level data on antipsychotic prescribing from an all-payer dataset (IMS Health's Xponent™) to patient-level data from Medicare. Our physician sample included 16,932 U.S. psychiatrists and primary care providers with ≥10 antipsychotic prescriptions per year from 1997-2011. We constructed a measure of physician adoption of 3 antipsychotics introduced during this period (quetiapine, ziprasidone and aripiprazole) by estimating a shared frailty model of the time to first prescription for each drug. We then assigned physicians to one of 306 U.S. hospital referral regions (HRRs) and measured the average propensity to adopt per region. Using 2010 data for a random sample of 1.6 million Medicare beneficiaries, we identified 138,680 antipsychotic users. A generalized linear model with gamma distribution and log link was used to estimate the effect of region-level adoption propensity on beneficiary-level antipsychotic spending and non-drug medical spending adjusting for patient demographic and socioeconomic characteristics, health status, eligibility category, and whether the antipsychotic was for an on- vs. off-label use. Results In our sample, mean patient age was 62 years, 42% were male, and 86% had low-income. Half of antipsychotic users in Medicare had an on-label indication. The weighted average propensity to adopt the three new antipsychotics varied four-fold across HRRs. For every one standard deviation increase in the propensity to adopt there was a 5% increase in antipsychotic spending after adjusting for covariates (adjusted ratio of spending = 1.05, 95% CI 1.01-1.08, p= 0.005). Physician propensity to adopt new antipsychotics was not associated with non-drug medical spending (adjusted ratio 0.96, 95% CI 0.91-1.01, p<0.117). Discussion These findings suggest wide regional variation in physicians’ propensity to adopt new antipsychotic medications. While physician adoption of new antipsychotics was positively associated with antipsychotic expenditures, it was not associated with non-drug spending. Our analysis is limited to Medicare and may not generalize to other payers. Also, claims data do not allow the measurement of health outcomes, which would be important to evaluate when calculating the value of rapid vs. slow technology adoption. Implications for Health Policies This study will provide important insight on the relationship between the speed of adoption of new antipsychotic medications and drug and non-drug medical spending for payers and policymakers seeking to maximize the value of health care expenditures. PMID:27453458
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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.
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Tolley, Elizabeth E; McKenna, Kevin; Mackenzie, Caroline; Ngabo, Fidele; Munyambanza, Emmanuel; Arcara, Jennet; Rademacher, Kate H; Lendvay, Anja
2014-05-01
Between 1995 and 2005, injectable use doubled worldwide. However, discontinuation rates remain high, partly because of side effects but also because of missed appointments for reinjection. A longer-acting injectable (LAI) may improve compliance by reducing the required number of reinjection visits, thereby reducing unintentional discontinuation. This study examined acceptability of LAI characteristics comprising the target product profile (TPP). In 2012, we conducted qualitative case studies in Kenya and Rwanda, consisting of 19 focus group discussions (FGDs) with 177 current, previous, or never users of injectables and 46 in-depth interviews (IDIs) with providers, program implementers, and policy makers. FGDs and IDIs assessed current injectable experiences; attitudes toward potential LAI products; and perceptions of TPP attributes, including ranking preferences for the most and least important characteristics. In addition, we obtained completed electronic surveys from 28 international family planning opinion leaders about the perceived need for an LAI, important product characteristics, and challenges to LAI development or introduction. Many FGD participants and interviewees spontaneously expressed strong interest in an LAI, but there was some variation in TPP preferences. The majority of participants ranked effectiveness as the most important TPP attribute. Providers were generally more concerned about side effects than potential users; some potential users suggested that side effects were related less to the product than to their own body chemistry and that side effects were acceptable as long as they did not last a long time or disrupt daily activities. Women and providers, especially in Kenya, preferred a method with a predictable return to fertility. Some participants associated amenorrhea with delayed or reduced fertility. Most women and providers preferred delivery of the LAI in a single, prepackaged, disposable injection system to facilitate injections by providers and to reduce the risk of pain or discomfort for women. While providers and policy makers ranked cost as one of the most important issues, it was among the least important issues for most potential users. Many Kenyan, but few Rwandan, participants appeared willing to pay for an LAI, with some presuming cost savings from reduced menstruation and fewer clinic visits. Some TPP preferences for an LAI have implications for product development decisions about formulation, delivery mechanism, or presentation, while others point to the need for tailored communication and counseling approaches to ensure acceptability and adherence within clinical trials and beyond.
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Kawano, Masahiko; Oshibuchi, Hidehiro; Kawano, Takaaki; Muraoka, Hiroyuki; Tsutsumi, Takahiro; Yamada, Makiko; Inada, Ken; Ishigooka, Jun
2016-06-15
Clozapine has improved efficacy relative to typical antipsychotics in schizophrenia treatment, particularly regarding emotional symptoms. However, the mechanisms underlying its therapeutic benefits remain unclear. Using a methamphetamine-sensitised rat model, we measured changes in dopamine levels in the amygdalae in response to a fear-conditioned cue, serving as a biochemical marker of emotional cognitive processing disruption in psychosis, for analysing the biochemical mechanisms associated with the clinical benefits of clozapine. We also compared how clozapine and haloperidol affected basal dopamine levels and phasic dopamine release in response to the fear-conditioned cue. Extracellular dopamine was collected from the amygdalae of freely moving rats via microdialysis and was analysed by high-performance liquid chromatography. Clozapine or haloperidol was injected during microdialysis, followed by exposure to the fear-conditioned cue. We analysed the ratio of change in dopamine levels from baseline. Haloperidol treatment increased the baseline dopamine levels in both non-sensitised and sensitised rats. Conversely, clozapine only increased the basal dopamine levels in the non-sensitised rats, but not in the sensitised rats. Although both antipsychotics attenuated phasic dopamine release in both the non-sensitised and sensitised rats, the attenuation extent was greater for clozapine than for haloperidol under both dopaminergic conditions. Our findings indicate that stabilized dopamine release in the amygdalae is a common therapeutic mechanism of antipsychotic action during emotional processing. However, the specific dopaminergic state-dependent action of clozapine on both basal dopamine levels and stress-induced dopamine release may be the underlying mechanism for its superior clinical effect on emotional cognitive processing in patients with schizophrenia. Copyright © 2016 Elsevier B.V. All rights reserved.
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People’s Republic of China Scientific Abstracts, Number 159
1976-12-14
Sciences TITLE: "Early Mesozoic Ostracods From Some Localities in Southwest China" SOURCE: Peking KU-SHENG-WU HSUEH-PAO [ACTA PAIAEONTOLOGICA SINICA] in...analysis of 202 cases treated between 1971-1974 was made. The operative procedure was described in detail. Low sacral or local perianal anesthesia...made. During operation, anal skin bridges were preserved between the dissections. After operation long acting anesthetic compound was injected on the
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Greene, George J; Swann, Greg; Fought, Angela J; Carballo-Diéguez, Alex; Hope, Thomas J; Kiser, Patrick F; Mustanski, Brian; D'Aquila, Richard T
2017-05-01
HIV prevention method preferences were evaluated among 512 U.S. men who have sex with men (MSM; median age: 22 years). Approximately 90 % consistently preferred one option across pairwise comparisons of condoms, daily oral pre-exposure prophylaxis (PrEP), and long-acting PrEP delivered via either an injectable or one of two types of PrEP implants differing in visibility. Condoms were most frequently preferred (33.8 %), followed by non-visible implants (21.5 %), and oral PrEP (17.0 %); HIV risk was reported by more choosing implants. In a follow-up question comparing the four PrEP options only, daily oral pills and non-visible implants were most frequently preferred (35.5 and 34.3 %, respectively), followed by injections (25.2 %) and visible implants (4.3 %). An inductive, open-coding approach determined that convenience, duration of protection, and privacy were the most commonly cited reasons for a PrEP method choice, and associated with self-report of HIV risk. Tailoring PrEP product development to privacy and other concerns important to those at highest HIV risk may improve HIV prevention.
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Wang, R D; Dangler, L A; Greengrass, R A
2001-12-01
Long-acting local anaesthetics are primarily used in the practice of anaesthesia, particularly in regional anaesthesia and analgesia. Ropivacaine is a new long-acting local anaesthetic that has been the focus of interest because of its increased cardiovascular safety compared with bupivacaine. Other advantages of ropivacaine over bupivacaine include a greater sensorimotor differential block and shorter elimination half-life (t(1/2)), with a lower potential for accumulation. The most important attribute of ropivacaine, however, is its increased margin of safety compared with bupivacaine when given in equal doses. Many post-marketing studies have focused on the comparisons of efficacy in blocks and toxicity profiles of bupivacaine versus ropivacaine. Recent animal toxicity studies confirm the results of original studies showing that ropivacaine has less cardiovascular toxicity than bupivacaine with respect to direct myocardial depression, success of resuscitation and arrhythmogenic potential when given in equal doses. Reduced cardiotoxicity may be a distinct characteristic of ropivacaine. A review of current literature suggests that, at clinically relevant doses, ropivacaine provides the lowest potential risk of cardiotoxicity for inadvertent intravascular injection. Studies are currently under way comparing ropivacaine with levobupivacaine, the latest addition to the group of long-acting local anaesthetics.
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Muñoz Torres, Manuel
2014-03-01
Degludec is the most recent molecule of the ultra-long-acting basal insulin analogues approved for human use. It forms soluble multihexamers which after subcutaneous injection are converted into monomers, and are thus slowly and continuously absorbed into the bloodstream. This absorption mechanism confers degludec an ultra-long and stable action profile, with no concentration peaks. This paper discusses the most recent studies in patients with type 1 and 2 diabetes mellitus, which showed degludec to be non inferior in decreasing HbA1c, ensuring optimum glycemic control similar to that achieved with insulin glargine or detemir. Degludec also had an improved safety profile, as it was associated to a significantly lower rate of nocturnal hypoglycemia in both types of diabetes and to a potentially lower overall hypoglycemia rate in type 2 DM. Degludec also opens the possibility to use more flexible regimens. Copyright © 2013 SEEN. Published by Elsevier Espana. All rights reserved.
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Atypical antipsychotic usage among Asian Americans and Pacific Islanders.
Takeshita, Junji; Goebert, Deborah; Else, Iwalani; Carlton, Barry; Matsu, Courtenay; Guerrero, Anthony
2014-09-01
Previous studies have shown significant ethnic differences in prescribing patterns of two or more antipsychotics. This study examined changes in atypical and typical antipsychotic prescriptions among Asian Americans and Pacific Islanders. Five hundred consecutive charts were reviewed for antipsychotics at the time of admission and discharge from each of two inpatient psychiatric facilities in Hawai'i. Multiple antipsychotic prescription rates were 9% at intake and 6% at discharge. For the ethnic groups studied, there were no statistically significant differences by patient ethnicity regarding antipsychotics at intake (χ(2) = 29.2, df = 21, P = .110) or discharge (χ(2) = 20.5, df = 24, P = .667). There were no significant differences in prescription and polypharmacy patterns among Asian Americans and Pacific Islanders ethnic groups in this study.
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Escobar, M A; Tehranchi, R; Karim, F A; Caliskan, U; Chowdary, P; Colberg, T; Giangrande, P; Giermasz, A; Mancuso, M E; Serban, M; Tsay, W; Mahlangu, J N
2017-01-01
Surgery in patients with haemophilia B carries a high risk of excessive bleeding and requires adequate haemostatic control until wound healing. Nonacog beta pegol, a long-acting recombinant glycoPEGylated factor IX (FIX), was used in the perioperative management of patients undergoing major surgery. To evaluate the efficacy and safety of nonacog beta pegol in patients with haemophilia B who undergo major surgery. This was an open-label, multicentre, non-controlled surgery trial aimed at assessing peri- and postoperative efficacy and safety of nonacog beta pegol in 13 previously treated patients with haemophilia B. All patients received a preoperative nonacog beta pegol bolus injection of 80 IU kg -1 . Postoperatively, the patients received fixed nonacog beta pegol doses of 40 IU kg -1 , repeated at the investigator's discretion. Safety assessments included monitoring of immunogenicity and adverse events. Intraoperative haemostatic effect was rated 'excellent' or 'good' in all 13 cases. Apart from the preoperative injection, none of the patients needed additional doses of nonacog beta pegol on the day of surgery. The median number of postoperative doses of nonacog beta pegol was 2.0 from days 1 to 6 and 1.5 from days 7 to 13. No unexpected intra- or postoperative complications were observed including deaths or thromboembolic events. No patients developed inhibitors. These results indicated that nonacog beta pegol was safe and effective in the perioperative setting, allowing major surgical interventions in patients with haemophilia B with minimal peri- and postoperative concentrate consumption and infrequent injections as reported with standard FIX products. © 2016 John Wiley & Sons Ltd.
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Cohen-Barak, Orit; Sakov, Anat; Rasamoelisolo, Michele; Bassan, Merav; Brown, Kurt; Mendzelevski, Boaz; Spiegelstein, Ofer
2015-11-01
TV-1106 (Teva Pharmaceuticals) is a genetically fused recombinant protein of human GH (hGH) and human serum albumin, in development for treatment of GH deficiency (GHD). TV-1106 is expected to have an extended duration of action compared to daily GH treatment and may enable a reduction in the frequency of injections and improve compliance and quality of life for adults and children requiring GHD therapy. To assess the safety, local tolerability, pharmacokinetics and pharmacodynamics of TV-1106 following single s.c. injections in healthy male volunteers. Subjects (n=56) were assigned to one of seven ascending dose groups (3-100 mg) and received either a single dose of TV-1106 (n=6) or placebo (n=2) by s.c. injection. Eighteen subjects reported 43 adverse effects (AEs), which were mild to moderate; no serious AEs (SAEs) occurred. In 50, 70 and 100 mg groups there were mild to moderate increases in heart rate and systolic blood pressure that significantly correlated with higher levels of IGF1. TV-1106 showed pharmacokinetic characteristics of a long-acting hGH as demonstrated by a terminal elimination half-life of 23-35 h, delayed time of peak concentration, and systemic levels seen up to 7 days after dosing. IGF1 levels increased in a dose-dependent manner, before reaching a plateau, with levels above baseline extending beyond 7 days post dose. Single administration of TV-1106 up to 100 mg was safe in healthy volunteers. Pharmacokinetics and pharmacodynamics support once-weekly administration in patients with GHD. © 2015 The authors.
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The effects of lithium and anticonvulsants on brain structure in bipolar disorder.
Germaná, C; Kempton, M J; Sarnicola, A; Christodoulou, T; Haldane, M; Hadjulis, M; Girardi, P; Tatarelli, R; Frangou, S
2010-12-01
To investigate the effect of lithium, anticonvulsants and antipsychotics on brain structure in bipolar disorder (BD). A cross-sectional structural brain magnetic resonance imaging study of 74 remitted patients with BD, aged 18-65, who were receiving long-term prophylactic treatment with lithium or anticonvulsants or antipsychotics. Global and regional grey matter, white matter, and cerebrospinal fluid volumes were compared between treatment groups. Grey matter in the subgenual anterior cingulate gyrus on the right (extending into the hypothalamus) and in the postcentral gyrus, the hippocampus/amygdale complex and the insula on the left was greater in BD patients on lithium treatment compared to all other treatment groups. Lithium treatment in BD has a significant effect on brain structure particularly in limbic/paralimbic regions associated with emotional processing. © 2010 John Wiley & Sons A/S.
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Gannon, Matthew A; Brown, Clifford J; Stevens, Rachel M; Griffith, Molly S; Marczinski, Cecile A; Bardgett, Mark E
2015-03-01
Risperidone is an antipsychotic drug that is approved for use in childhood psychiatric disorders such as autism. One concern regarding the use of this drug in pediatric populations is that it may interfere with social interactions that serve to nurture brain development. This study used rats to assess the impact of risperidone administration on maternal-offspring interactions and juvenile play fighting between cage mates. Mixed-sex litters received daily subcutaneous injections of vehicle or 1.0 or 3.0mg/kg of risperidone between postnatal days (PNDs) 14-42. Rats were weaned and housed three per cage on PND 21. In observations made between PNDs 14-17, risperidone significantly suppressed several aspects of maternal-offspring interactions at 1-hour post-injection. At 23 h post-injection, pups administered risperidone had lower activity scores and made fewer non-nursing contacts with their moms. In observations of play-fighting behavior made once a week between PNDs 22-42, risperidone profoundly decreased many forms of social interaction at 1h post-injection. At 23h post-injection, rats administered risperidone made more non-social contacts with their cage mates, but engaged in less social grooming. Risperidone administration to rats at ages analogous to early childhood through adolescence in humans produces a pattern of abnormal social interactions across the day that could impact how such interactions influence brain development. Copyright © 2015 Elsevier Inc. All rights reserved.
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Gannon, Matthew A.; Brown, Clifford J.; Stevens, Rachel M.; Griffith, Molly S.; Marczinski, Cecile A.; Bardgett, Mark E.
2015-01-01
Risperidone is an antipsychotic drug that is approved for use in childhood psychiatric disorders such as autism. One concern regarding the use of this drug in pediatric populations is that it may interfere with social interactions that serve to nurture brain development. This study used rats to assess the impact of risperidone administration on maternal-offspring interactions and juvenile play fighting between cage mates. Mixed-sex litters received daily subcutaneous injections of vehicle or 1.0 or 3.0 mg/kg of risperidone between postnatal days (PNDs) 14-42. Rats were weaned and housed three per cage on PND 21. In observations made between PNDs 14-17, risperidone significantly suppressed several aspects of maternal-offspring interactions at one-hour post-injection. At 23 hours post-injection, pups administered risperidone had lower activity scores and made fewer non-nursing contacts with their moms. In observations of play-fighting behavior made once a week between PNDs 22-42, risperidone profoundly decreased many forms of social interaction at one hour post-injection. At 23 hours post-injection, rats administered risperidone made more non-social contacts with their cage mates, but engaged in less social grooming. Risperidone administration to rats at ages analogous to early childhood through adolescence in humans produces a pattern of abnormal social interactions across the day that could impact how such interactions influence brain development. PMID:25600754
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GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK.
Beiroa, Daniel; Imbernon, Monica; Gallego, Rosalía; Senra, Ana; Herranz, Daniel; Villarroya, Francesc; Serrano, Manuel; Fernø, Johan; Salvador, Javier; Escalada, Javier; Dieguez, Carlos; Lopez, Miguel; Frühbeck, Gema; Nogueiras, Ruben
2014-10-01
GLP-1 receptor (GLP-1R) is widely located throughout the brain, but the precise molecular mechanisms mediating the actions of GLP-1 and its long-acting analogs on adipose tissue as well as the brain areas responsible for these interactions remain largely unknown. We found that central injection of a clinically used GLP-1R agonist, liraglutide, in mice stimulates brown adipose tissue (BAT) thermogenesis and adipocyte browning independent of nutrient intake. The mechanism controlling these actions is located in the hypothalamic ventromedial nucleus (VMH), and the activation of AMPK in this area is sufficient to blunt both central liraglutide-induced thermogenesis and adipocyte browning. The decreased body weight caused by the central injection of liraglutide in other hypothalamic sites was sufficiently explained by the suppression of food intake. In a longitudinal study involving obese type 2 diabetic patients treated for 1 year with GLP-1R agonists, both exenatide and liraglutide increased energy expenditure. Although the results do not exclude the possibility that extrahypothalamic areas are also modulating the effects of GLP-1R agonists, the data indicate that long-acting GLP-1R agonists influence body weight by regulating either food intake or energy expenditure through various hypothalamic sites and that these mechanisms might be clinically relevant. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
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ERIC Educational Resources Information Center
Breidenstine, Angela S.; Couvillion, Joy; Many, Cecile
2012-01-01
At the age of 4 years, Joseph came to the Orleans Parish Early Childhood Supports and Services program (ECSS) for mental health services because of serious aggression and anger. His history included physical abuse before age 2, long-term maintenance on an atypical antipsychotic medication, and other biological, psychological, and…
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ERIC Educational Resources Information Center
Sporn, Alexandra L.; Vermani, Anoop; Greenstein, Deanna K.; Bobb, Aaron J.; Spencer, Edgar P.; Clasen, Liv S.; Tossell, Julia W.; Stayer, Catherine C.; Gochman, Peter A.; Lenane, Marge C.; Rapoport, Judith L.; Gogtay, Nitin
2007-01-01
Objective: Clozapine is a unique atypical antipsychotic with superior efficacy in treatment-resistant schizophrenia. Plasma concentration of clozapine and its major metabolite N-desmethylclozapine (NDMC) as well as the ratio of NDMC to clozapine have been reported to be predictors of clozapine response. Here we evaluate these as well as other…
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MacE, Shubhra; Taylor, David
2005-01-01
Objective : In the United Kingdom (UK) the National Institute for Clinical Excellence (NICE) has recommended the use of atypical antipsychotics for the treatment of schizophrenia. As part of its guidance it discourages the concurrent use of typical and atypical antipsychotics. In previous prescribing surveys antipsychotic polypharmacy has been noted to be widespread. We sought to evaluate atypical antipsychotic prescribing after the publication of NICE guidance. Method : We invited psychiatric centres in England and Wales to participate, in March 2004, in an atypical antipsychotic prescribing survey of hospital in-patients. Results : Thirty-six in-patient units submitted data for 2012 patients. After exclusions, 1092 patients were eligible. Of these, 28.6% (312) were prescribed a typical alongside an atypical antipsychotic and 19.3% (211) were prescribed high-dose antipsychotics. Co-prescription was more prevalent in patients aged 40 years and above (32.0 vs. 25.3%; P=0.018). It was also noted that in centres employing senior pharmacists, co-prescription was more common (28.6 vs. 14.3%; P=0.03). High-dose treatment was more commonly observed in patients of a white ethnic background (20.6 vs. 13.9%; P=0.02) as well as in patients aged 40 years and above (24.4 vs. 15.0%; P<0.001). Prescription of anticholinergics was significantly more prevalent in those receiving atypical and typical combinations than atypicals alone (26.0 vs. 12.0%; P<0.001). Conclusions : Antipsychotic polypharmacy remains commonplace. Similarly the prescription of high-dose antipsychotics is also widespread.
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Antipsychotic Response Worsens With Postmenopausal Duration in Women With Schizophrenia.
González-Rodríguez, Alexandre; Catalán, Rosa; Penadés, Rafael; Ruiz Cortés, Victoria; Torra, Mercè; Seeman, Mary V; Bernardo, Miquel
2016-12-01
The loss of estrogens in the menopause may lead to increased vulnerability for psychotic relapse, poor clinical outcome, and a need for increased antipsychotic dose. However, confounders such as cumulative estrogen exposure and time since menopause have been inadequately studied. Our aim was to investigate potential variables capable of influencing antipsychotic response in a sample of postmenopausal women with schizophrenia. Sixty-four postmenopausal schizophrenic women were followed in a 12-week prospective treatment-by-clinical requirement study. Duration of reproductive years was considered an indirect measure of lifetime cumulative estrogens exposure. Psychopathological assessment included the following: Positive and Negative Syndrome Scale, Personal and Social Performance, and Clinical Global Impression-Schizophrenia Scale. Response was defined as a reduction of 30% or more of Positive and Negative Syndrome Scale total scores. Antipsychotic adherence was assessed by plasma level monitoring at 4 weeks. Regression analyses were performed to investigate the association between potential confounding factors and antipsychotic response. Forty-two participants (66%) were found to be antipsychotic responders. Time since menopause was significantly and negatively associated with overall antipsychotic response, explaining almost 42% of the variance of the model used. Smoking and cumulative estrogen exposures were associated with improvement in negative symptoms. Smoking and time since menopause were associated with improvement in excitement symptoms, and smoking was positively associated with improvement in depressive and cognitive symptoms. Time since menopause was significantly negatively associated with antipsychotic response in postmenopausal schizophrenic women, suggesting a decline in antipsychotic response after menopause. The neurobiological basis for antipsychotic response may include a role for estrogen and nicotine receptors.
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Goga, Joshana K; Depaolo, Antonio; Khushalani, Sunil; Walters, J Ken; Roca, Robert; Zisselman, Marc; Borleis, Christopher
2017-01-01
To Evaluate the Effects of Applying Lean Methodology-Improving Quality Increasing Efficiency by Eliminating Waste and Reducing Costs-An Approach To Decrease the Prescribing Frequency of Antipsychotics for The Indication of Agitation. Historically Controlled Study. Bheppard Pratt Health System is the Largest Private Provider of Psychiatric Care in Maryland With a Total Bed Capacity of 300. There Were 4 337 Patient Days From November 1 2012 to October 31 2013 on the Dementia Unit. All Patients Admitted on the Dementia Unit Were 65 Years of Age and Older with a Primary Diagnosis of Dementia. our Multidisciplinary Team Used Lean Methodology to Identify the Root Causes and Interventions Necessary to Reduce Inappropriate Antipsychotic Use. The Primary Outcome Was Rate of Inappropriately Indicating Agitation as the Rationale When Prescribing Antipsychotic Medications. There Was a 90% (P < 0.001) Reduction in Rate Of Antipsychotic Prescribing with an Indication of Agitation. The Lean Methodology Interventions Led To A 90% (P < 0.001) Reduction in the Rate of Antipsychotic Prescribing with an Indication of Agitation and a 10% Rate Reduction in Overall Antipsychotic Prescribing. Key Words: Agitation Alzheimer's Antipsychotics Behavioral and Psychological Symptoms of Dementia Centers For Medicare & Medicaid Services Dementia Root-cause Analysis. BPSD = Behavioral and Psychological Symptoms of Dementia CATIE-AD = Clinical Antipsychotic Trials of Intervention Effectiveness in Alzheimer's Disease EMR = Electronic Medical Records GAO = Government Accountability Office GNCIS = Geriatric Neuropsychiatric Clinical Indicator Scale.
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Atypical antipsychotic medications to control symptoms of delirium in children and adolescents.
Turkel, Susan Beckwitt; Jacobson, Julienne; Munzig, Elizabeth; Tavaré, C Jane
2012-04-01
Atypical antipsychotics have been documented to be effective in the management of delirium in adults, but despite considerable need, their use has been less studied in pediatric patients. A retrospective chart review was done to describe the use of atypical antipsychotics in controlling symptoms of delirium in children and adolescents. Pharmacy records at Children's Hospital Los Angeles were reviewed to identify patients to whom antipsychotic agents were dispensed over a 24-month period. Psychiatric inpatient consultations during the same 24-month period were reviewed. Patients 1-18 years old diagnosed with delirium given antipsychotics constituted the study population. Delirium Rating Scale-Revised-98 (DRS-R98) scores were retrospectively calculated, when possible, at time antipsychotic was started to confirm the initial diagnosis of delirium and evaluate symptom severity, and again when antipsychotic was stopped, to assess symptom response. Olanzapine (n=78), risperidone (n=13), and quetiapine (n=19) were used during the 2 years of the study. Mean patient age, length of treatment, and response were comparable for the three medications. For patients with two DRS-R98 scores available (n=75/110), mean DRS-R98 scores decreased significantly (p<0.001) with antipsychotic without significant adverse side effects. Although randomized placebo-controlled studies are needed, atypical antipsychotic medications appeared to be effective and safe for managing delirium symptoms in pediatric patients while underlying etiology was addressed.
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Can metabolic side effects of antipsychotics be reversed by lifestyle changes?
Bolger, Alistair; Verdolini, Norma; Agius, Mark
2014-11-01
Antipsychotics, particularly atypical antipsychotics, are known to have metabolic side effects such as; weight gain, hyperlipidaemia and insulin resistance. This is problematic as metabolic syndrome can be a precursor to many diseases, including type II diabetes and coronary heart disease. In an attempt to overcome these side-effects, lifestyle changes have been recommended in tandem with commencement of atypical antipsychotics, but is this effective at halting metabolic syndrome? There is some evidence suggesting that lifestyle changes can reduce weight gain caused by atypical antipsychotics. However, there seems to be a paucity of evidence about whether this correlates with correction of metabolic dysregulation. Moreover, there is a lack of research into the precise mechanism of metabolic syndrome as caused by atypical antipsychotics,as well as a lack of evidence into how exercise remedies this. Furthermore, there is research to suggest that the pathophysiology of psychosis may lead to metabolic dysregulation independently of treatment. Lifestyle changes should still be part of a treatment as they seem to partially reverse metabolic changes seen with atypical antipsychotics. However, more research is needed to identify weight independent mechanisms for metabolic dysregulation seen in those taking atypical antipsychotics in order to solve this pressing issue.
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Hashimoto, Takashi; Baba, Satoko; Ikeda, Hiroko; Oda, Yasunori; Hashimoto, Kenji; Shimizu, Isao
2018-07-05
Long-term treatment with antipsychotic drugs in patients with schizophrenia can lead to dopamine supersensitivity psychosis. It is reported that repeated administration of haloperidol caused dopamine supersensitivity in rats. Blonanserin is an atypical antipsychotic drug with high affinity for dopamine D 2 , D 3 and serotonin 2A receptors. In this study, we investigated whether chronic administration of blonanserin leads to dopamine supersensitivity. Following oral treatment with blonanserin (0.78 mg/kg) or haloperidol (1.1 mg/kg) twice daily for 28 days, the dopamine D 2 agonist quinpirole-induced hyperlocomotion test and a dopamine D 2 receptor binding assay were conducted. We found that haloperidol significantly enhanced both quinpirole-induced hyperlocomotion and striatal dopamine D 2 receptor density in rats. On the other hand, repeated administration of blonanserin had no effect on either locomotor activity or striatal dopamine D 2 receptor density. Further, our results show that mRNA levels of dopamine D 2 and D 3 receptors in several brain regions were unaffected by repeated administration of both agents. In addition, we examined the effect of the dopamine D 3 receptor antagonist PG-01037 on development of dopamine supersensitivity induced by chronic haloperidol treatment and showed that PG-01037 prevents the development of supersensitivity to quinpirole in chronic haloperidol-treated rats. Given the higher affinity of blonanserin at dopamine D 3 receptors than haloperidol, antagonism of blonanserin at dopamine D 3 receptors may play a role in lack of dopamine supersensitivity after chronic administration. The present findings suggest long-term treatment with antipsychotic dose of blonanserin may be unlikely to lead to dopamine supersensitivity. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.
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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.
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Mohamed, Somaia; Rosenheck, Robert A; Lin, Haiqun; Swartz, Marvin; McEvoy, Joseph; Stroup, Scott
2015-07-01
No large-scale randomized trial has compared the effect of different second-generation antipsychotic drugs and any first-generation drug on alcohol, drug and nicotine use in patients with schizophrenia. The Clinical Antipsychotic Trial of Intervention Effectiveness study randomly assigned 1432 patients formally diagnosed with schizophrenia to four second-generation antipsychotic drugs (olanzapine, risperidone quetiapine, and ziprasidone) and one first-generation antipsychotic (perphenazine) and followed them for up to 18 months. Secondary outcome data documented cigarettes smoked in the past week and alcohol and drug use severity ratings. At baseline, 61% of patients smoked, 35% used alcohol, and 23% used illicit drugs. Although there were significant effects of time showing reduction in substance use over the 18 months (all p < 0.0001), this study found no evidence that any antipsychotic was robustly superior to any other in a secondary analysis of data on substance use outcomes from a large 18-month randomized schizophrenia trial.
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Kontis, Dimitrios; Theochari, Eirini; Kleisas, Spyridon; Kalogerakou, Stamatina; Andreopoulou, Angeliki; Psaras, Rafael; Makris, Yannis; Karouzos, Charalambos; Tsaltas, Eleftheria
2010-10-01
Despite consistent recommendations for antipsychotic monotherapy, antipsychotic polypharmacy (the use of two or more antipsychotic agents) and the administration of excessive doses (higher than 1000 mgr/day of chloropromazine equivalents) is a common practice in schizophrenia. The therapeutic and adverse effects of this practice are poorly studied, in particular with regards to the cognitive symptoms of the disease. In this cross-sectional study we investigated the cognitive effects of antipsychotic polypharmacy and excessive doses in 53 patients with chronic schizophrenia using non-verbal cognitive tasks involving speed of movement, memory and executive functions. No significant difference in performance scores was found between the groups under polypharmacy and monotherapy, or the groups receiving either excessive or normal doses of antipsychotics. Since these groups did not also differ in demographic, clinical, other pharmacologic parameters, in the relative anticholinergic potency of antipsychotics, or in intelligence scores, we raise doubts about the association of polypharmacy and excessive doses with non-verbal cognitive performance in chronic schizophrenia. Copyright © 2010 Elsevier Inc. All rights reserved.
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Stewart, Michael W
2018-01-27
Vascular endothelial growth factor (VEGF) plays a pivotal role in the development of neovascularization and edema from several common chorioretinal vascular conditions. The intravitreally injected drugs (aflibercept, bevacizumab, conbercept, pegaptanib, and ranibizumab) used to treat these conditions improve the visual acuity and macular morphology in most patients. Monthly or bimonthly injections were administered in the phase III pivotal trials but physicians usually individualize therapy with pro re nata (PRN) or treat and extend regimens. Despite these lower frequency treatment regimens, frequent injections and clinic visits are still needed to produce satisfactory outcomes. Newly developed drugs and refillable reservoirs with favorable pharmacokinetic profiles may extend durations of action and require fewer office visits. However, we have learned from previous experiences that the longer durations of action seen in strategically designed phase III trials often do not translate to less frequent injections in real-life clinical practice. Unfortunately, long-acting therapies that produce soluble VEGF receptors (encapsulated cell technology and adenovirus injected DNA) have failed in phase II trials. The development of longer duration therapies remains a difficult and frustrating process, and frequent drug injections are likely to remain the standard-of-care for years to come.
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Froes Brandao, Denise; Strasser-Weippl, Kathrin; Goss, Paul E
2016-01-15
Hyperprolactinemia, defined as a sustained elevation of prolactin (PRL) levels greater than 530 mIU/L in women and greater than 424 mIU/L in men, has been implicated for a long time in breast cancer etiology and prognosis. Elevated PRL values (approximately 2-3 times higher than the reference values) are a common adverse effect of antipsychotic medications, especially with first-generation drugs, and most antipsychotics carry a standard warning regarding PRL elevations on their US product labels. These associations foster undertreatment of serious psychiatric illnesses in both otherwise healthy patients and cancer patients. This review assesses both the preclinical and clinical evidence that has led to the hypothesis of PRL's role in breast cancer risk or breast cancer progression. It is concluded that taken together, the published data are unconvincing and insufficient to deprive cancer patients in general and breast cancer patients specifically of potentially effective antipsychotic or antidepressant medications for serious psychiatric indications. We thus call on revised medication guidelines to avoid the existing undertreatment of serious psychiatric illnesses among cancer patients based on an unproven contraindication to psychiatric medications. Cancer 2016;122:184-188. © 2015 American Cancer Society. © 2015 American Cancer Society.
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Rustembegovic, Avdo; Sofic, Emin; Wichart, Ildiko
2006-01-01
Weight gain is a common adverse effect associated with the use of most typical and atypical antipsychotic. Aim of this study was to investigate serum prolactin, leptin, cholesterol, triglyceride, lipoproteins, such high density lipoprotein (HDL), and low density lipoprotein (LDL) levels in patients with Parkinson's disease (PD)-related psychosis during long-term medication with atypical antipsychotic. The study population comprised 40 patients, who were divided into 4 groups: olanzapine (n=10), risperidone (n=10), seroquel (n=10) monotherapy, a group of 10 patients receiving only antiparkinson drugs and a control group of 8 healthy persons. The patients were evaluated at baseline and at the sixth and twelfth week according to the Positive and Negative Syndrome Scale (PANSS), body mass index (BMI), and fasting serum prolactin, leptin, lipids and lipoproteins levels. Treatment of patients with olanzapine caused marked increase of serum LDL, cholesterol, triglyceride, and leptin levels (p<0,02). No changes in HDL concentrations. There was positive relationship between serum leptin, lipid levels and BMI. However, treatment of patients with seroquel did not cause changes in serum prolactin, leptin, lipids, and lipoproteins levels. Our results suggest that treatment of patients with PD-related psychosis with seroquel appears to have minimal influence on serum leptin, prolactin, lipids, lipoproteins and BMI compared with olanzapine and risperidone.
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Bushe, Chris J; Bradley, Andrew; Pendlebury, John
2010-07-01
Hyperprolactinaemia is a common adverse event reported in association with treatments used in schizophrenia and bipolar disorder. Recent data are suggestive that hyperprolactinaemia may have a range of significant short-and long-term clinical consequences. The objective of this review is to examine the causes, frequency and clinical consequences of hyperprolactinaemia in the severely mentally ill (SMI) with a focus on patients taking antipsychotic medications. A Medline search was carried out to identify relevant publications. Reference lists from previous review articles were also examined to search for additional data. Hyperprolactinaemia may be one of the most common adverse events associated with some antipsychotic medications. Precise rates with individual drugs had however until recently been poorly categorized. The relationship between hyperprolactinaemia and adverse outcomes in the SMI population appears similar to that in the general population. Adverse outcomes (such as sexual dysfunction) can occur acutely and in the longer term (bone fractures and possibly breast cancer), but the precise link between degree and length of hyperprolactinaemia and adverse outcome remains to be established. In conclusion, hyperprolactinaemia is a common treatment-emergent adverse event of some antipsychotic medications and may have clinical consequences. Physicians must balance the benefits and risks of treatment when determining appropriate therapy for individual patients.
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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
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Pagsberg, Anne Katrine; Tarp, Simon; Glintborg, Dorte; Stenstrøm, Anne Dorte; Fink-Jensen, Anders; Correll, Christoph Ulrich; Christensen, Robin
2017-03-01
To determine the comparative efficacy and safety of antipsychotics for youth with early-onset schizophrenia using network meta-analytic methods combining direct and indirect trial data. The authors systematically searched MEDLINE, the Cochrane Library, and clinicaltrials.gov and selected randomized controlled trials allocating youth with schizophrenia spectrum disorders to a (non-clozapine) antipsychotic versus placebo or another antipsychotic. Major efficacy outcomes were Positive and Negative Syndrome Scale (PANSS) total and positive symptoms. Major safety outcomes were weight, plasma triglyceride levels, extrapyramidal symptoms, akathisia, and all-cause discontinuation. Sixteen additional outcomes were analyzed. A random-effects arm-based network meta-analysis was applied, and consistency was assessed by pairwise meta-analysis. Confidence in PANSS total estimates was assessed by applying the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Twelve 6- to 12-week trials (N = 2,158; 8-19 years old; 61% boys) involving 8 antipsychotics (aripiprazole, asenapine, paliperidone, risperidone, quetiapine, olanzapine, molindone, and ziprasidone) were analyzed. PANSS total symptom change was comparable among antipsychotics (low- to moderate-quality evidence), except ziprasidone (very low- to low-quality evidence), and all antipsychotics were superior to placebo (low- to high-quality evidence), except ziprasidone and asenapine (low- to moderate-quality evidence). PANSS positive changes and additional efficacy outcomes were comparable among antipsychotics. Weight gain was primarily associated with olanzapine; extrapyramidal symptoms and akathisia were associated with molindone; and prolactin increased with risperidone, paliperidone, and olanzapine. Serious adverse events, discontinuation of treatment, sedation, insomnia, or change in triglycerides did not differ among antipsychotics. This network meta-analysis showed comparable efficacy among antipsychotics for early-onset schizophrenia, except that efficacy appeared inferior for ziprasidone and unclear for asenapine. Adverse reaction profiles varied substantially among the investigated antipsychotics and were largely consistent with prior findings in adults. Protocol registration information-Antipsychotic Treatment for Children With Schizophrenia Spectrum Disorders: Network Meta-Analysis of Randomised Trials; https://www.crd.york.ac.uk/PROSPERO/; CRD42013006676. Copyright © 2017 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.
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Afebrile Neuroleptic Malignant Syndrome associated with Fluphenazine decanoate: A case report
Assareh, Marzieh
2010-01-01
Neuroleptic Malignant Syndrome (NMS) is unusual but could be a lethal reaction associated with neuroleptic drugs. It occurs in almost 0.07-2.2% of patients under treatment with neuroleptics. There are some medical treatments that may also be helpful for its treatment, including dopamine agonists, muscle relaxants, and electroconvulsive therapy (ECT). We present this case to alert the clinicians to the potential for inducing afebrile NMS. Our case is a 41-year-old man with a history of schizophrenia showing signs and symptoms in accordance with NMS, 2 weeks after receiving one dose of 12.5 mg fluphenazine decanoate, abruptly following the 3rdsession of ECT. The patient presented with decreased level of consciousness, muscular rigidity, waxy flexibility, mutism, generalized tremor, sever diaphoresis and tachycardia which progressed during the previous 24 h. Laboratory data indicated primarily leukocytosis, an increasing level of creatinine phosphokinase and hypokalemia during the next 72h. In patients receiving antipsychotics, any feature of NMS should carefully be evaluated whether it is usual or unusual particularly in patients receiving long acting neuroleptics. PMID:22952496
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Tislerova, Barbora; Brunovsky, Martin; Horacek, Jiri; Novak, Tomas; Kopecek, Miloslav; Mohr, Pavel; Krajca, Vladimír
2008-01-01
The aim of our study was to detect changes in the distribution of electrical brain activity in schizophrenic patients who were antipsychotic naive and those who received treatment with clozapine, olanzapine or risperidone. We included 41 subjects with schizophrenia (antipsychotic naive = 11; clozapine = 8; olanzapine = 10; risperidone = 12) and 20 healthy controls. Low-resolution brain electromagnetic tomography was computed from 19-channel electroencephalography for the frequency bands delta, theta, alpha-1, alpha-2, beta-1, beta-2 and beta-3. We compared antipsychotic-naive subjects with healthy controls and medicated patients. (1) Comparing antipsychotic-naive subjects and controls we found a general increase in the slow delta and theta frequencies over the fronto-temporo-occipital cortex, particularly in the temporolimbic structures, an increase in alpha-1 and alpha-2 in the temporal cortex and an increase in beta-1 and beta-2 in the temporo-occipital and posterior limbic structures. (2) Comparing patients who received clozapine and those who were antipsychotic naive, we found an increase in delta and theta frequencies in the anterior cingulate and medial frontal cortex, and a decrease in alpha-1 and beta-2 in the occipital structures. (3) Comparing patients taking olanzapine with those who were antipsychotic naive, there was an increase in theta frequencies in the anterior cingulum, a decrease in alpha-1, beta-2 and beta-3 in the occipital cortex and posterior limbic structures, and a decrease in beta-3 in the frontotemporal cortex and anterior cingulum. (4) In patients taking risperidone, we found no significant changes from those who were antipsychotic naive. Our results in antipsychotic-naive patients are in agreement with existing functional findings. Changes in those taking clozapine and olanzapine versus those who were antipsychotic naive suggest a compensatory mechanism in the neurobiological substrate for schizophrenia. The lack of difference in risperidone patients versus antipsychotic-naive subjects may relate to risperidone's different pharmacodynamic mechanism. Copyright 2008 S. Karger AG, Basel.
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Zhang, Chen; Li, Ming
2012-02-01
Repeated administration of haloperidol (HAL) and olanzapine (OLZ) causes a progressively enhanced disruption of the conditioned avoidance response (CAR) and a progressively enhanced inhibition of phencyclidine (PCP)-induced hyperlocomotion in rats (termed antipsychotic sensitization). Both actions are thought to reflect intrinsic antipsychotic activity. The present study examined the extent to which antipsychotic-induced sensitization in one model (e.g. CAR) can be transferred or maintained in another (e.g. PCP hyperlocomotion) as a means of investigating the contextual and behavioral controls of antipsychotic sensitization. Well-trained male Sprague-Dawley rats were first repeatedly tested in the CAR or the PCP (3.2 mg/kg, subcutaneously) hyperlocomotion model under HAL or OLZ for 5 consecutive days. Then they were switched to the other model and tested for the expression of sensitization. Finally, all rats were switched back to the original model and retested for the expression of sensitization. Repeated HAL or OLZ treatment progressively disrupted avoidance responding and decreased PCP-induced hyperlocomotion, indicating a robust sensitization. When tested in a different model, rats previously treated with HAL or OLZ did not show a stronger inhibition of CAR-induced or PCP-induced hyperlocomotion than those treated with these drugs for the first time; however, they did show such an effect when tested in the original model in which they received repeated antipsychotic treatment. These findings suggest that the expression of antipsychotic sensitization is strongly influenced by the testing environment and/or selected behavioral response under certain experimental conditions. Distinct contextual cues and behavioral responses may develop an association with unconditional drug effects through a Pavlovian conditioning process. They may also serve as occasion setters to modulate the expression of sensitized responses. As antipsychotic sensitization mimics the clinical effects of antipsychotic treatment, understanding the neurobiological mechanisms of antipsychotic sensitization and its contextual control would greatly enhance our understanding of the psychological and neurochemical nature of antipsychotic treatment in the clinic.
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Zhang, Chen; Li, Ming
2011-01-01
Repeated administration of haloperidol and olanzapine causes a progressively enhanced disruption of conditioned avoidance response (CAR) and a progressively enhanced inhibition of phencyclidine (PCP)-induced hyperlocomotion in rats (termed antipsychotic sensitization). Both actions are thought to reflect intrinsic antipsychotic activity. The present study examined to the extent to which antipsychotic-induced sensitization in one model (e.g. CAR) can be transferred or maintained in another (e.g. PCP hyperlocomotion) as a means of investigating the contextual and behavioral controls of antipsychotic sensitization. Well-trained male Sprague-Dawley rats were first repeatedly tested in the CAR or PCP (3.2 mg/kg, sc) hyperlocomotion model under haloperidol or olanzapine for five consecutive days. Then they were switched to the other model and tested for the expression of sensitization. Finally, all rats were switched back to the original model and retested for the expression of sensitization. Repeated haloperidol or olanzapine treatment progressively disrupted avoidance responding and decreased PCP-induced hyperlocomotion, indicating a robust sensitization. When tested in a different model, rats previously treated with haloperidol or olanzapine did not show a stronger inhibition of CAR or PCP-induced hyperlocomotion than those treated with these drugs for the first time; however, they did show such an effect when tested in the original model in which they received repeated antipsychotic treatment. These findings suggest that the expression of antipsychotic sensitization is strongly influenced by the testing environment and/or selected behavioral response under certain experimental conditions. Distinct contextual cues and behavioral responses may enter an association with unconditional drug effects via a Pavlovian conditioning process. They may also serve as occasion-setters to modulate the expression of sensitized responses. Because antipsychotic sensitization mimics clinical effects of antipsychotic treatment, understanding the neurobiological mechanisms of antipsychotic sensitization and its contextual control would greatly enhance our understanding of the psychological and neurochemical nature of antipsychotic treatment in the clinic. PMID:22157143
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Pringsheim, Tamara; Hirsch, Lauren; Gardner, David; Gorman, Daniel A
2015-01-01
Objective: Attention-deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and conduct disorder (CD) are among the most common psychiatric diagnoses in childhood. Aggression and conduct problems are a major source of disability and a risk factor for poor long-term outcomes. Methods: We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) of antipsychotics, lithium, and anticonvulsants for aggression and conduct problems in youth with ADHD, ODD, and CD. Each medication was given an overall quality of evidence rating based on the Grading of Recommendations Assessment, Development and Evaluation approach. Results: Eleven RCTs of antipsychotics and 7 RCTs of lithium and anticonvulsants were included. There is moderate-quality evidence that risperidone has a moderate-to-large effect on conduct problems and aggression in youth with subaverage IQ and ODD, CD, or disruptive behaviour disorder not otherwise specified, with and without ADHD, and high-quality evidence that risperidone has a moderate effect on disruptive and aggressive behaviour in youth with average IQ and ODD or CD, with and without ADHD. Evidence supporting the use of haloperidol, thioridazine, quetiapine, and lithium in aggressive youth with CD is of low or very-low quality, and evidence supporting the use of divalproex in aggressive youth with ODD or CD is of low quality. There is very-low-quality evidence that carbamazepine is no different from placebo for the management of aggression in youth with CD. Conclusion: With the exception of risperidone, the evidence to support the use of antipsychotics and mood stabilizers is of low quality. PMID:25886656
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Calvó-Perxas, Laia; Turró-Garriga, Oriol; Aguirregomozcorta, Maria; Bisbe, Josep; Hernández, Erélido; López-Pousa, Secundino; Manzano, Anna; Palacios, Mónica; Pericot-Nierga, Imma; Perkal, Héctor; Ramió, Lluís; Vilalta-Franch, Joan; Garre-Olmo, Josep
2014-07-01
Psychotropic drugs are usually prescribed to deal with behavioral and psychological symptoms of dementia, especially when nonpharmacologic approaches are not available or have limited efficacy. Poor outcomes and serious adverse events of the drugs used must be addressed, and risk-benefit ratios need to be considered. The aim of this longitudinal study was to describe the evolution of dispensation of psychotropic drugs in patients with Alzheimer's disease (AD) and to identify the associated demographic and clinical variables. Longitudinal study using 698 cases with AD included in the Registry of Dementias of Girona in 2007 and 2008 and followed up during 3 years. Drugs were categorized according to the Anatomical Therapeutic Chemical classification. Binary logistic regression analyses were used to detect the variables associated with the use of antipsychotics, selective serotonin reuptake inhibitors (SSRIs), anxiolytics, and hypnotics. Of the patients, 51.2% consumed antipsychotics at least once during the three years of the study, whereas 73.3% and 58.2% consumed SSRIs and anxiolytics, respectively; 32.8% used hypnotics. Antipsychotic use was associated with a diagnosis of AD with delusions) [odds ratio (OR) = 5.7] and with increased behavior disorders (OR = 1.2). Patients with AD with depressed mood were more likely to be treated with SSRIs (OR = 3.1), while being a woman was associated with increased dispensation of anxiolytics (OR = 1.9) and SSRIs (OR = 2.2). Consumption of psychotropic drugs by the patients with AD registered in the Registry of Dementias of Girona is very high. Despite all the described adverse effects and recommendations of caution in their use, antipsychotics still are extensively used. Copyright © 2014 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.
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Impact of regulatory measures on antipsychotics drug consumption in Castilla y León, Spain.
Martín Arias, L H; Treceño Lobato, C; Pérez García, S; García Ortega, P; Sáinz Gil, M; Sanz Fadrique, R; Carvajal García-Pando, A
2016-12-01
Antipsychotics are currently used to treat different diseases; even some off-labelled conditions are treated with this medication. Consumption and cost of antipsychotic drugs sharply increased in Spain after second-generation drugs were marketed; several regulatory measures were adopted to curb this trend. The aim of this study was to examine the impact of these measures upon the use and cost of antipsychotics. Study of drug use (SDU) from 1995 to 2012. Consumption and cost data were obtained from the CONCYLIA database; this database contains the retail community pharmacies sales of medicinal products reimbursed by the National Health System in Castilla y León (Spain). Data are presented as defined daily doses per 1000 inhabitants per day (DID) and day treatment cost (DTC). First-generation antipsychotics prescriptions gradually decreased from 3.0 to 1.8 DID; meanwhile, prescriptions for second-generation antipsychotics considerably increased from 0.3 to 9.9 DID. The use of risperidone dropped after the marketing of its structural derivative paliperidone with a similar efficacy but with a substantially higher cost per day. In 2011 and thereafter, patients in Spain began to pay a part of the medications cost, but this did not decrease antipsychotics consumption. Global cost of antipsychotics only began to fall after measures were adopted to lower the price of medicines because of the economic collapse in Spain after May 2010. Several health policy measures have tried to reduce antipsychotics consumption in Spain, special ways of dispensing, marketing of generic drugs and special economic measures for patients. These measures eventually failed to avoid the increase in antipsychotics use. The cost only dropped when lowering prescription drug prices took place. Copyright © 2016 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.
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Quality use of antipsychotic medicines inresidential aged care facilities in New Zealand.
Ndukwe, Henry C; Nishtala, Prasad S; Wang, Ting; Tordoff, June M
2016-12-01
INTRODUCTION Antipsychotic medicines are used regularly or when required in residential aged care facilities to treat symptoms of dementia, but have been associated with several adverse effects. AIM The aim of this study was to examine 'quality use' of antipsychotic medicines in residential aged care facilities in New Zealand, by surveying nurse managers. METHODS A cross-sectional survey was mailed to 318 nurse managers working in a nationally representative sample of aged care facilities. A purpose-developed, pre-tested, 22-item structured questionnaire was used to explore practice related to the quality use of antipsychotic medicines. RESULTS Overall, 31.4% of nurse managers responded to the survey. They mostly (88%) had ≥ 1 year's relevant work experience and 83% of facilities provided care for those within the range of 21 to 100 residents. Respondents reported that staff education on dementia management occurred early in employment. Two-thirds of participants reported non-pharmacological interventions were commonly used for managing challenging behaviours, while less than half (45%) cited administering antipsychotic medicine. Respondents reported 'managing behavioural symptoms' (81%) as one of the main indications for antipsychotic use. Frequently identified adverse effects of antipsychotic medicines were drowsiness or sedation (64%) and falls (61%). Over 90% reported general practitioners reviewed antipsychotic use with respect to residents' target behaviour 3-monthly, and two-thirds used an assessment tool to appraise residents' behaviour. DISCUSSION Staff education on dementia management soon after employment and resident 3-monthly antipsychotic medicine reviews were positive findings. However, a wider use of behavioural assessment tools might improve the care of residents with dementia and the quality use of antipsychotic medicines.
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Starace, Fabrizio; Mungai, Francesco; Barbui, Corrado
2018-01-01
In mental healthcare, one area of major concern identified by health information systems is variability in antipsychotic prescribing. While most studies have investigated patient- and prescriber-related factors as possible reasons for such variability, no studies have investigated facility-level characteristics. The present study ascertained whether staffing level is associated with antipsychotic prescribing in community mental healthcare. A cross-sectional analysis of data extracted from the Italian national mental health information system was carried out. For each Italian region, it collects data on the availability and use of mental health facilities. The rate of individuals exposed to antipsychotic drugs was tested for evidence of association with the rate of mental health staff availability by means of univariate and multivariate analyses. In Italy there were on average nearly 60 mental health professionals per 100,000 inhabitants, with wide regional variations (range 21 to 100). The average rate of individuals prescribed antipsychotic drugs was 2.33%, with wide regional variations (1.04% to 4.01%). Univariate analysis showed that the rate of individuals prescribed antipsychotic drugs was inversely associated with the rate of mental health professionals available in Italian regions (Kendall's tau -0.438, p = 0.006), with lower rates of antipsychotic prescriptions in regions with higher rates of mental health professionals. After adjustment for possible confounders, the total availability of mental health professionals was still inversely associated with the rate of individuals exposed to antipsychotic drugs. The evidence that staffing level was inversely associated with antipsychotic prescribing indicates that any actions aimed at decreasing variability in antipsychotic prescribing need to take into account aspects related to the organization of the mental health system.
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Atypical antipsychotic use and outcomes in an urban maternal mental health service.
Hatters Friedman, Susan; Moller-Olsen, Charmian; Prakash, Chandni; North, Abigail
2016-08-01
Objective Despite many women suffering from psychosis in their childbearing years, limited data exist about the use of atypical antipsychotic agents in pregnancy. Atypical antipsychotic agents are often used to treat bipolar disorder, instead of lithium or valproate because of the known teratogenicity of those agents. As well, atypical antipsychotics are often prescribed in anxiety disorders and depression. This study sought to describe pregnancy outcomes for women prescribed atypical antipsychotics during pregnancy. Methods This retrospective review included all cases treated by Auckland Maternal Mental Health services in which atypical antipsychotic agents were utilized during pregnancy over three years. Results Over the three years, 45 pregnant women were prescribed atypical antipsychotic agents, most commonly quetiapine or olanzapine. Two-fifths (40%) were diagnosed with bipolar disorder and almost one-third (31%) with a psychotic disorder. Two-thirds (64%) were prescribed multiple psychotropic medications during their pregnancy. Instrumental delivery rates were elevated at 38%. A minority (13%) of the women developed gestational diabetes mellitus. Although 7% of infants were born premature, all were born after 35 weeks. Two major malformations were noted, similar to baseline community rates. Conclusions This naturalistic study adds to the limited literature about treatment with atypical antipsychotic agents in pregnancy, though not adequately powered to detect small differences in malformations or obstetrical outcomes. It also highlights the myriad of indications for which pregnant women are prescribed atypical antipsychotics, and the multiple other risk factors seen in this population.
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Clinical practice variations in prescribing antipsychotics for patients with schizophrenia.
Owen, Richard R; Fischer, Ellen P; Kirchner, JoAnn E; Thrush, Carol R; Williams, D Keith; Cuffel, Brian J; Elliott, Carl E; Booth, Brenda M
2003-01-01
Few studies have examined the variations among individual physicians in prescribing antipsychotics for schizophrenia. This study examined clinical practice variations in the route and dosage of antipsychotic medication prescribed for inpatients with schizophrenia by 11 different psychiatrists. The sample consisted of 130 patients with a DSM-III-R diagnosis of schizophrenia who had received inpatient care at a state hospital or Veterans Affairs medical center in the southeastern United States in 1992-1993. Mixed-effects regression models were developed to explore the influence of individual physicians and hospitals on route of antipsychotic administration (oral or depot) and daily antipsychotic dose, controlling for patient case-mix variables (age, race, sex, duration of illness, symptom severity, and substance-abuse diagnosis). The average daily antipsychotic dose was 1092 +/- 892 chlorpromazine mg equivalents. Almost half of the patients (48%) were prescribed doses above or below the range recommended by current practice guidelines. The proportion of patients prescribed depot antipsychotics was significantly different at the 2 hospitals, as was the antipsychotic dose prescribed at discharge. Individual physicians and patient characteristics were not significantly associated with prescribing practices. These data, which were obtained before clinical practice guidelines were widely disseminated, provide a benchmark against which to examine more current practice variations in antipsychotic prescribing. The results raise several questions about deviations from practice guidelines in the pharmacological treatment of schizophrenia. To adequately assess quality and inform and possibly further develop clinical practice guideline recommendations for schizophrenia, well-designed research studies conducted in routine clinical settings are needed.
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Agarwal, Sri Mahavir; Bose, Anushree; Shivakumar, Venkataram; Narayanaswamy, Janardhanan C; Chhabra, Harleen; Kalmady, Sunil V; Varambally, Shivarama; Nitsche, Michael A; Venkatasubramanian, Ganesan; Gangadhar, Bangalore N
2016-01-30
Transcranial direct current stimulation (tDCS) has generated interest as a treatment modality for schizophrenia. Dopamine, a critical pathogenetic link in schizophrenia, is also known to influence tDCS effects. We evaluated the influence of antipsychotic drug type (as defined by dopamine D2 receptor affinity) on the impact of tDCS in schizophrenia. DSM-IV-TR-diagnosed schizophrenia patients [N=36] with persistent auditory hallucinations despite adequate antipsychotic treatment were administered add-on tDCS. Patients were divided into three groups based on the antipsychotic's affinity to D2 receptors. An auditory hallucinations score (AHS) was measured using the auditory hallucinations subscale of the Psychotic Symptom Rating Scales (PSYRATS). Add-on tDCS resulted in a significant reduction inAHS. Antipsychotic drug type had a significant effect on AHS reduction. Patients treated with high affinity antipsychotics showed significantly lesser improvement compared to patients on low affinity antipsychotics or a mixture of the two. Furthermore, a significant sex-by-group interaction occurred; type of medication had an impact on tDCS effects only in women. Improvement differences could be due to the larger availability of the dopamine receptor system in patients taking antipsychotics with low D2 affinity. Sex-specific differences suggest potential estrogen-mediated effects. This study reports a first-time observation on the clinical utility of antipsychotic drug type in predicting tDCS effects in schizophrenia. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
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Rocchetti, Jill; Isingrini, Elsa; Dal Bo, Gregory; Sagheby, Sara; Menegaux, Aurore; Tronche, François; Levesque, Daniel; Moquin, Luc; Gratton, Alain; Wong, Tak Pan; Rubinstein, Marcelo; Giros, Bruno
2015-03-15
Dysfunctional mesocorticolimbic dopamine signaling has been linked to alterations in motor and reward-based functions associated with psychiatric disorders. Converging evidence from patients with psychiatric disorders and use of antipsychotics suggests that imbalance of dopamine signaling deeply alters hippocampal functions. However, given the lack of full characterization of a functional mesohippocampal pathway, the precise role of dopamine transmission in memory deficits associated with these disorders and their dedicated therapies is unknown. In particular, the positive outcome of antipsychotic treatments, commonly antagonizing D2 dopamine receptors (D2Rs), on cognitive deficits and memory impairments remains questionable. Following pharmacologic and genetic manipulation of dopamine transmission, we performed anatomic, neurochemical, electrophysiologic, and behavioral investigations to uncover the role of D2Rs in hippocampal-dependent plasticity and learning. Naïve mice (n = 4-21) were used in the different procedures. Dopamine modulated both long-term potentiation and long-term depression in the temporal hippocampus as well as spatial and recognition learning and memory in mice through D2Rs. Although genetic deletion or pharmacologic blockade of D2Rs led to the loss of long-term potentiation expression, the specific genetic removal of presynaptic D2Rs impaired long-term depression and performances on spatial memory tasks. Presynaptic D2Rs in dopamine fibers of the temporal hippocampus tightly modulate long-term depression expression and play a major role in the regulation of hippocampal learning and memory. This direct role of mesohippocampal dopamine input as uncovered here adds a new dimension to dopamine involvement in the physiology underlying deficits associated with neuropsychiatric disorders. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
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Bokser, L; Schally, A V
1988-10-01
Recently, we have developed a long-acting delivery system for our somatostatin (SS) analog RC-160 based on injectable microcapsules in poly-(D,L-lactide-coglycolide). We studied the capacity of this formulation to repeatedly block the GH secretion induced by administration of GRF-(1-29)NH2 (GRF) on different days. Male rats anesthetized with pentobarbital were injected iv with 2.5 micrograms/kg BW GRF-(1-29)NH2 or saline. Five minutes later, blood samples were taken for GH measurement, and the animals were injected im with RC-160 microcapsules at a dose calculated to release 25 micrograms/day of the analog for 7 days or with the vehicle. The GRF stimuli were repeated 48 h, 96 h, and 8 days after administration of SS analog in microcapsules. GRF administration increased GH levels at the four times tested (P less than 0.01) in the control group injected with vehicle, while RC-160 microcapsules inhibited the GH response for more than 96 h (P less than 0.01). The GH levels augmented by pentobarbital were also decreased by the RC-160 microcapsules (P less than 0.01). Animals treated with microcapsules showed smaller increases in their body weight than untreated rats (P less than 0.05). We also investigated the effect of RC-160 microcapsules on hyperprolactinemic female rats implanted with pituitary glands under the kidney capsules. High PRL levels in rats bearing pituitary grafts showed a significant decrease when measured 4 days after the administration of RC-160 microcapsules. These results demonstrate the efficacy of the long-acting delivery system of the SS analog RC-160 and suggest the possible clinical usefulness of this formulation for lowering GH and PRL levels.
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Simbar, Masoumeh; Tehrani, Fahimeh Ramezani; Hashemi, Zeinab; Zham, Hananeh; Fraser, Ian S
2007-10-01
The most common reason for discontinuation of long-acting progestogen-only contraceptives is irregular bleeding following local endometrial vascular changes. To reduce unpredictable bleeding episodes among depot medroxyprogesterone acetate (DMPA) users, the combined injectable contraceptive, Cyclofem, was offered as an alternative. However, there is a gap in our knowledge about the effects of Cyclofem on the endometrial vasculature and patterns of bleeding. This study aimed to compare the effects of Cyclofem and DMPA on endometrial vascular density, endometrial histology and pattern of bleeding. Sixty-eight healthy women with regular menstrual bleeding and seeking injectable long-acting contraceptives were recruited. Two endometrial samples (before and 3 to 6 months after initial exposure to DMPA or Cyclofem) were collected from each participant. The samples were stained using an immunohistochemical method and anti-CD34 to visualise the endometrial vasculature. Endometrial vascular density was assessed using standard techniques. Sixty-eight women were randomly assigned to Cyclofem (38 women) or DMPA (30 women). Endometrial vascular density was 149.3 +/- 6.7 (mean +/- SD)/mm(2) before injection. This significantly decreased to 132.4 +/- 12.2 after DMPA use, and from 151.9 +/- 5.8 to 131.8 +/- 12.8 vessels/mm(2) following Cyclofem use (paired t-test, p <0.05). However, there was no significant difference between endometrial vascular density during treatment with Cyclofem or DMPA. Total bleeding days in the first and second 3-month time intervals were 28 +/- 23 and 18 +/- 12 days in DMPA users and 22 +/- 14 and 16 +/- 9 days in Cyclofem users, respectively, Spotting was the most common type of bleeding experienced, and atrophic endometrium was the most common histological pattern observed in both groups. This study demonstrated that both Cyclofem and DMPA use are associated with decreased endometrial vascular density and atrophic endometrium, in addition to irregular bleeding, mainly spotting. There was no significant difference in bleeding patterns or endometrial findings observed for these two injectable contraceptives in Iranian women.
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Kiyatkin, Eugene A; Ren, Suelynn; Wakabayashi, Ken T; Baumann, Michael H; Shaham, Yavin
2016-01-01
MDMA-induced hyperthermia is highly variable, unpredictable, and greatly potentiated by the social and environmental conditions of recreational drug use. Current strategies to treat pathological MDMA-induced hyperthermia in humans are palliative and marginally effective, and there are no specific pharmacological treatments to counteract this potentially life-threatening condition. Here, we tested the efficacy of mixed adrenoceptor blockers carvedilol and labetalol, and the atypical antipsychotic clozapine, in reversing MDMA-induced brain and body hyperthermia. We injected rats with a moderate non-toxic dose of MDMA (9 mg/kg) during social interaction, and we administered potential treatment drugs after the development of robust hyperthermia (>2.5 °C), thus mimicking the clinical situation of acute MDMA intoxication. Brain temperature was our primary focus, but we also simultaneously recorded temperatures from the deep temporal muscle and skin, allowing us to determine the basic physiological mechanisms of the treatment drug action. Carvedilol was modestly effective in attenuating MDMA-induced hyperthermia by moderately inhibiting skin vasoconstriction, and labetalol was ineffective. In contrast, clozapine induced a marked and immediate reversal of MDMA-induced hyperthermia via inhibition of brain metabolic activation and blockade of skin vasoconstriction. Our findings suggest that clozapine, and related centrally acting drugs, might be highly effective for reversing MDMA-induced brain and body hyperthermia in emergency clinical situations, with possible life-saving results.
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Kiyatkin, Eugene A; Ren, Suelynn; Wakabayashi, Ken T; Baumann, Michael H; Shaham, Yavin
2016-01-01
MDMA-induced hyperthermia is highly variable, unpredictable, and greatly potentiated by the social and environmental conditions of recreational drug use. Current strategies to treat pathological MDMA-induced hyperthermia in humans are palliative and marginally effective, and there are no specific pharmacological treatments to counteract this potentially life-threatening condition. Here, we tested the efficacy of mixed adrenoceptor blockers carvedilol and labetalol, and the atypical antipsychotic clozapine, in reversing MDMA-induced brain and body hyperthermia. We injected rats with a moderate non-toxic dose of MDMA (9 mg/kg) during social interaction, and we administered potential treatment drugs after the development of robust hyperthermia (>2.5 °C), thus mimicking the clinical situation of acute MDMA intoxication. Brain temperature was our primary focus, but we also simultaneously recorded temperatures from the deep temporal muscle and skin, allowing us to determine the basic physiological mechanisms of the treatment drug action. Carvedilol was modestly effective in attenuating MDMA-induced hyperthermia by moderately inhibiting skin vasoconstriction, and labetalol was ineffective. In contrast, clozapine induced a marked and immediate reversal of MDMA-induced hyperthermia via inhibition of brain metabolic activation and blockade of skin vasoconstriction. Our findings suggest that clozapine, and related centrally acting drugs, might be highly effective for reversing MDMA-induced brain and body hyperthermia in emergency clinical situations, with possible life-saving results. PMID:26105141
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Marks, G A; Sachs, O W; Birabil, C G
2008-09-22
The brainstem reticular formation is an area important to the control of rapid eye movement (REM) sleep. The antagonist of GABA-type A (GABA(A)) receptors, bicuculline methiodide (BMI), injected into the rat nucleus pontis oralis (PnO) of the reticular formation resulted in a long-lasting increase in REM sleep. Thus, one factor controlling REM sleep appears to be the number of functional GABA(A) receptors in the PnO. The long-lasting effect produced by BMI may result from secondary influences on other neurotransmitter systems known to have long-lasting effects. To study this question, rats were surgically prepared for chronic sleep recording and additionally implanted with guide cannulas aimed at sites in the PnO. Multiple, 60 nl, unilateral injections were made either singly or in combination. GABA(A) receptor antagonists, BMI and gabazine (GBZ), produced dose-dependent increases in REM sleep with GBZ being approximately 35 times more potent than BMI. GBZ and the cholinergic agonist, carbachol, produced very similar results, both increasing REM sleep for about 8 h, mainly through increased period frequency, with little reduction in REM latency. Pre-injection of the muscarinic antagonist, atropine, completely blocked the REM sleep-increase by GBZ. GABAergic control of REM sleep in the PnO requires the cholinergic system and may be acting through presynaptic modulation of acetylcholine release.
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Summary of the comparative effectiveness review on off-label use of atypical antipsychotics.
Maher, Alicia R; Theodore, George
2012-06-01
Conventional and atypical antipsychotic medications are approved by the FDA for treatment of schizophrenia and bipolar disorder. Over many decades, the widespread use of conventional antipsychotics produced various side effects requiring additional medications, such as the atypical antipsychotics. Beginning in 2006, 9 atypical antipsychotic drugs have been approved by the FDA for indications that were previously off-label uses: aripiprazole (as augmentation for major depressive disorder [MDD] and for autism spectrum disorders), asenapine, clozapine, iloperidone, olanzapine (in combination with fluoxetine for MDD and bipolar depression), paliperidone, quetiapine (quetiapine and quetiapine XR [extended release] as monotherapy in bipolar depression and quetiapine XR as augmentation for MDD), risperidone (for autism spectrum disorders), and ziprasidone. In 2006, the Agency for Healthcare Research and Quality (AHRQ) published a systematic review on the comparative effectiveness of off-label uses of atypical antipsychotics. Since that time, numerous studies have been published evaluating these therapies in various new off-label uses; new or increased adverse effects have been observed with off-label uses; new atypical antipsychotics have been approved; and previously off-label uses have been approved for some atypical antipsychotics. Hence, AHRQ published an updated review in September 2011 that summarized the benefits and harms of atypical antipsychotics in the treatment of attention-deficit hyperactivity disorder/attention deficit disorder (ADHD), anxiety, behavioral disturbances of dementia and severe geriatric agitation, depression, eating disorders, insomnia, obsessive-compulsive disorder (OCD), personality disorder, post-traumatic stress disorder (PTSD), substance use and dependence disorders, and Tourette's syndrome. The new report also investigated topics for which data in the previous report were found to be insufficient to make conclusions, including subpopulations (i.e., race/ethnicity, gender) that would benefit most from atypical antipsychotics, appropriate dose, and time needed to see clinical improvement. The 2011 review included the following atypical antipsychotics: aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone; no clinical trials were found for off-label use of the 3 most recently FDA-approved atypical antipsychotics (asenapine, iloperidone, and paliperidone). To (a) familiarize health care professionals with the methods and findings from AHRQ's 2011 Comparative Effectiveness Review (CER) of off-label use of atypical antipsychotics, (b) encourage consideration of the clinical and managed care applications of the review findings, and (c) identify limitations and gaps in the existing research with respect to the benefits and risks of off-label use of atypical antipsychotics. Antipsychotic medications are FDA approved for the treatment of schizophrenia and bipolar disorder. Conventional antipsychotics have been widely used for decades and spurred the development of the atypical antipsychotics. Atypical antipsychotics were produced and are now being used for patients who may have experienced various side effects while using conventional antipsychotics.In 2006, an AHRQ study reviewed off-label uses of atypical antipsychotics (excluding clozapine because of its association with potentially fatal bone marrow suppression and the requirement for frequent blood tests for safety monitoring). Findings indicated that the most common off-label uses of these drugs included depression, OCD, PTSD, personality disorders, Tourette's syndrome, autism, and agitation in dementia. The reviewers concluded in 2006 that overall there was not sufficiently high strength of evidence of efficacy for any off-label use of atypical antipsychotics. There was, however, strong evidence for an increased risk of adverse events with off-label use, including significant weight gain and sedation and increased mortality among the elderly.Since the 2006 review, significant developments occurred in the use of atypical antipsychotics, including FDA approval of the atypical antipsychotics asenapine, iloperidone, and paliperidone and FDA approval of previous off-label uses: (a) quetiapine and quetiapine XR as monotherapy in bipolar depression; (b) quetiapine XR as augmentation therapy for MDD; (c) aripiprazole as augmentation therapy for MDD; (d) olanzapine/fluoxetine combination for MDD; (e) olanzapine/fluoxetine combination for bipolar depression; and (f) risperidone and aripiprazole for autism spectrum disorders. Additional studies have been published for new off-label uses, and there have been reports of new or increased adverse effects for off-label uses.Further review of previously insufficient information was warranted on subpopulations where treatment modification such as dosing may increase efficacy. The 2006 review did not have sufficient information to make conclusions regarding subpopulations (i.e., race/ethnicity, gender) that would benefit most from atypical antipsychotics, appropriate dosing, and the duration of treatment needed to see clinical improvement. The updated AHRQ report in 2011 reviewed off-label uses of atypical antipsychotic medications in anxiety, ADHD, behavioral disturbances of dementia and severe geriatric agitation, MDD, eating disorders, insomnia, OCD, PTSD, personality disorders, substance abuse, and Tourette's syndrome; autism was included in the 2006 review but is now reviewed in a separate report of the comparative effectiveness of antipsychotics for on-label uses. The significant findings in the updated review include (a) small but statistically significant benefits for olanzapine, aripiprazole, and risperidone for elderly patients with dementia; (b) quetiapine appears superior to placebo for general anxiety disorder (GAD); (c) risperidone was associated with benefits in the treatment of OCD; and (d) adverse events are common. Atypical antipsychotics were not effective in the treatment of eating disorders or personality disorder. The evidence did not support the use of atypical antipsychotics in the treatment of substance abuse, and data were inconclusive for the use of these medications for insomnia. The number needed to harm (NNH) was calculated for adverse events in elderly patients, including risk of death (NNH = 87), stroke (NNH = 53 for risperidone), extrapyramidal symptoms (NNH = 10 for olanzapine and NNH = 20 for risperidone), and urinary symptoms (NNH = 16 to 36). Adverse events in nonelderly adults included weight gain (particularly with olanzapine), fatigue, sedation, akathisia (with aripiprazole), and extrapyramidal symptoms.
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Liu, Xia; Zhang, Hong-xia; Wang, Li-ping; Fu, Wei-ping
2013-01-15
To evaluate the efficacy and adverse effects of half-dose depot long-acting triptorelin in the therapy of endometriosis. The efficacy and adverse effects of routine-dose or half-dose triptorelin in postoperative endometriosis patients were prospectively observed. A total of 186 postoperative patients with moderate or severe endometriosis received an intramuscular injection of triptorelin every 28 days for 6 times. They were randomly divided into 3 groups, i.e. half-dose group (n = 99): 1.875 mg each time; "draw-back" group (n = 52): 3.75 mg first time, then 1.875 mg each time; and routine-dose group (n = 35): 3.75 mg each time. Amenorrhea was effectively induced in all patients after the second injection. There was no significant difference in the rate of serum E2 level at Day 28 of every injection below the upper limit of "estrogen threshold (110 - 146 pmol/L)" not stimulating ectopic endometrium proliferation among half-dose group, "draw-back" group and routine-dose group (99% vs 100% and 99.0%, P > 0.05), the percentage of E2 < 37 pmol/L in E2 < 110 pmol/L in half-dose group was significantly lower than that in "draw-back" and routine-dose groups after 2-5(th) injection (69% vs 79% and 85%, P < 0.01), but there was no significant difference after first half-dose and routine-dose injection (71% vs 73%, P > 0.05). No significant difference existed in the rate of pelvic pain relief during the first returning menstruation and the recurrence rate of endometriosis within 1 year postoperation among three groups (both P > 0.05). However, the incidences of menopausal syndrome and severe menopausal syndrome in half-dose group were significantly lower than those in "draw-back" and routine-dose groups (both P < 0.01). And the incompletion rate of six-time drug for severe menopause syndrome was also significantly lower (P < 0.05) while the completion rate of six-time drug use in half-dose group was significantly higher (P < 0.05). As a postoperative adjuvant, half-dose depot triptorelin therapy is efficacious for endometriosis. It reduces menopausal syndrome and treatment cost and enhances patient compliance.
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ERIC Educational Resources Information Center
Findling, Robert L.; Johnson, Jacqueline L.; McClellan, Jon; Frazier, Jean A.; Vitiello, Benedetto; Hamer, Robert M.; Lieberman, Jeffrey A.; Ritz, Louise; McNamara, Nora K.; Lingler, Jacqui; Hlastala, Stefanie; Pierson, Leslie; Puglia, Madeline; Maloney, Ann E.; Kaufman, Emily Michael; Noyes, Nancy; Sikich, Linmarie
2010-01-01
Objective: To examine the long-term safety and efficacy of three antipsychotics in early-onset schizophrenia spectrum disorders. Method: Patients (8 to 19 years old) who had improved during an 8-week, randomized, double-blind acute trial of olanzapine, risperidone, or molindone (plus benztropine) were eligible to continue on the same medication…
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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…
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Management of schizophrenia: clinical experience with asenapine.
Cortese, Leonardo; Bressan, Rodrigo A; Castle, David J; Mosolov, Sergey N
2013-04-01
Schizophrenia is a chronic brain disorder comprising a range of clinical features, including positive and negative symptoms, cognitive dysfunction and mood symptoms (particularly depression and anxiety). The management of schizophrenia requires effective short- and long-term treatment with antipsychotic medication that is effective across these symptom domains, while being well tolerated over the long term. Asenapine is the first tetracyclic atypical antipsychotic to be licensed in the USA and several other countries outside Europe for the acute and maintenance treatment of schizophrenia in adults. It has a unique receptor-binding profile and a broad range of therapeutic effects. Since clinical trials are conducted under strict conditions in tightly defined patient populations, evidence of an agent's efficacy and tolerability under 'real-world' clinical practice conditions is also required. As in clinical trials, real-life case reports demonstrate that asenapine is effective in treating the positive symptoms of schizophrenia, both in the acute setting and for relapse prevention. It is also effective in treating negative symptoms and shows promise in the treatment of depressive symptoms associated with schizophrenia. Asenapine has a favourable tolerability profile, having a minimal impact on weight and metabolic parameters. As such, asenapine is valuable option for the treatment of schizophrenia in adults.
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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.
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Newer antipsychotics and upcoming molecules for schizophrenia.
George, Melvin; Amrutheshwar, Radhika; Rajkumar, Ravi Philip; Kattimani, Shivanand; Dkhar, Steven Aibor
2013-08-01
The management of schizophrenia has seen significant strides over the last few decades, due to the increasing availability of a number of antipsychotics. Yet, the diminished efficacy in relation to the negative and cognitive symptoms of schizophrenia, and the disturbing adverse reactions associated with the current antipsychotics, reflect the need for better molecules targeting unexplored pathways. To review the salient features of the recently approved antipsychotics; namely, iloperidone, asenapine, lurasidone and blonanserin. We discuss the advantages, limitations and place in modern pharmacotherapy of each of these drugs. In addition, we briefly highlight the new targets that are being explored. Promising strategies include modulation of the glutamatergic and GABAergic pathways, as well as cholinergic systems. Although regulatory bodies have approved only a handful of antipsychotics in recent years, the wide spectrum of targets that are being explored could eventually bring out antipsychotics with improved efficacy and acceptability, as well as the potential to revolutionize psychiatric practice.
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Wall, Kristin M; Vwalika, Bellington; Haddad, Lisa; Khu, Naw H; Vwalika, Cheswa; Kilembe, William; Chomba, Elwyn; Stephenson, Rob; Kleinbaum, David; Nizam, Azhar; Brill, Ilene; Tichacek, Amanda; Allen, Susan
2013-05-01
To evaluate the impact of family planning promotion on incident pregnancy in a combined effort to address Prongs 1 and 2 of prevention of mother-to-child transmission of HIV. We conducted a factorial randomized controlled trial of 2 video-based interventions. "Methods" and "Motivational" messages promoted long-term contraceptive use among 1060 couples with HIV in Lusaka, Zambia. Among couples not using contraception before randomization (n = 782), the video interventions had no impact on incident pregnancy. Among baseline contraceptive users, viewing the "Methods video" which focused on the intrauterine device and contraceptive implant was associated with a significantly lower pregnancy incidence [hazard ratio (HR) = 0.38; 95% confidence interval (CI): 0.19 to 0.75] relative to those viewing control and/or motivational videos. The effect was strongest in concordant positive couples (HR = 0.22; 95% CI: 0.08 to 0.58) and couples with HIV-positive women (HR = 0.23; 95% CI: 0.09 to 0.55). The "Methods video" intervention was previously shown to increase uptake of long-acting contraception and to prompt a shift from daily oral contraceptives to quarterly injectables and long-acting methods such as the intrauterine device and implant. Follow-up confirms sustained intervention impact on pregnancy incidence among baseline contraceptive users, in particular couples with HIV-positive women. Further work is needed to identify effective interventions to promote long-acting contraception among couples who have not yet adopted modern methods.