A systematic review of meta-analyses of the efficacy of oral atypical antipsychotics for the treatment of adult patients with schizophrenia

INTRODUCTION: Meta-analyses are a convenient way for clinicians and researchers to review data regarding different interventions. Meta-analyses can overcome many of the limitations of individual studies, namely the power to detect differences, and help resolve the results of inconsistent studies. AREAS COVERED: This paper is a review of meta-analyses of oral atypical antipsychotics for the treatment of schizophrenia, located through PubMed and the Cochrane Database of Systematic Reviews. A total of 91 meta-analyses were identified that included efficacy outcome data for the 10 atypical antipsychotics available in the USA (11 focused on clozapine, 17 for risperidone, 8 for olanzapine, 5 for quetiapine, 3 for ziprasidone, 10 for aripiprazole, 5 for paliperidone, 1 for iloperidone, 0 for asenapine or lurasidone, and 31 others that were classified more broadly). These include Cochrane Reviews and other similarly executed reports, as well as pooled analyses meta-tagged in PubMed as a meta-analysis. EXPERT OPINION: In general, there is heterogeneity among the atypical antipsychotics in terms of efficacy, with clozapine evidencing consistent superiority over typical antipsychotics, trailed behind by olanzapine and risperidone. Meta-analyses generally do not support efficacy differences between the other atypical antipsychotics compared with the older typical agents. Although this review is focused on efficacy, other considerations are also important, including the large tolerability differences among all the agents and the need to individualize medication choice based on past history of therapeutic response, past history of tolerability issues and the individual's personal values and preferences.     

A review of atypical antipsychotic drugs versus conventional medication in schizophrenia

Atypical antipsychotics are replacing conventional antipsychotics for the treatment of schizophrenia. They are considered to be at least as effective as conventional agents, with most producing fewer extrapyramidal symptoms. This review presents the evidence from published meta-analyses and describes differences in clinical effectiveness and tolerability between conventional and atypical antipsychotic agents. In addition, it discusses some of the more significant adverse effects including tardive dyskinesia, weight gain, diabetes and sudden death. Results from meta-analyses are conflicting, with some finding no significant advantages on measures of efficacy or tolerability for atypical antipsychotics over moderate daily doses of conventional drugs. Other results have shown that some atypical drugs have at least minor efficacy advantages over conventional comparators. Atypical antipsychotics exhibit a much reduced risk for tardive dyskinesia compared with conventional drugs. However, weight gain is more common with some atypical drugs (especially clozapine and olanzapine). Both conventional and atypical antipsychotics have been associated with diabetes, with most reports implicating both clozapine and olanzapine. Finally, atypical antipsychotics (unlike conventional drugs) have little or no effect on QT and are not associated with sudden death.     

A review of atypical antipsychotic drugs versus conventional medication in schizophrenia

Atypical antipsychotics are replacing conventional antipsychotics for the treatment of schizophrenia. They are considered to be at least as effective as conventional agents, with most producing fewer extrapyramidal symptoms. This review presents the evidence from published meta-analyses and describes differences in clinical effectiveness and tolerability between conventional and atypical antipsychotic agents. In addition, it discusses some of the more significant adverse effects including tardive dyskinesia, weight gain, diabetes and sudden death. Results from meta-analyses are conflicting, with some finding no significant advantages on measures of efficacy or tolerability for atypical antipsychotics over moderate daily doses of conventional drugs. Other results have shown that some atypical drugs have at least minor efficacy advantages over conventional comparators. Atypical antipsychotics exhibit a much reduced risk for tardive dyskinesia compared with conventional drugs. However, weight gain is more common with some atypical drugs (especially clozapine and olanzapine). Both conventional and atypical antipsychotics have been associated with diabetes, with most reports implicating both clozapine and olanzapine. Finally, atypical antipsychotics (unlike conventional drugs) have little or no effect on QT and are not associated with sudden death.     

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

Importance of the field: 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).

Areas covered in this review: 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.

What the reader will gain: 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.

Take home message: 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.     

Clozapine discrimination with a low training dose distinguishes atypical from typical antipsychotic drugs in rats

Rationale: Previous drug discrimination studies with clozapine have not reliably distinguished between atypical and typical antipsychotics. Objectives: The present study was conducted to determine whether low-dose clozapine drug discrimination could distinguish atypical from typical antipsychotics. Methods: Rats were trained to discriminate 1.25 mg/kg clozapine from vehicle in a two-lever drug discrimination procedure. Results: Generalization testing revealed full substitution with the atypical antipsychotics olanzapine (90.3% maximum generalization), sertindole (99.8%), and risperidone (87.1%) and partial substitution for quetiapine (seroquel, 66.4%) and the typical antipsychotics haloperidol (56.8%) and thioridazine (74.3%). Remoxipride (23.1%) and the typical antipsychotics chlorpromazine (27.9%) and fluphenazine (29.5%) did not reliably substitute for clozapine. Conclusions: In contrast to previous clozapine drug discrimination studies with higher training doses, the atypical antipsychotics olanzapine, sertindole, and risperidone reliably substituted for clozapine while typical antipsychotics did not. These results suggest that low-dose clozapine drug discrimination may be a more sensitive assay for distinguishing atypical from typical antipsychotic drugs. Received: 3 August 1999 / Final version: 9 December 1999     

Tolerability of atypical antipsychotics.

Atypical antipsychotics are expected to be better tolerated than older antipsychotics because of their lower propensity to cause certain adverse effects. All atypical drugs have been shown to cause fewer acute extrapyramidal symptoms (EPS) than a standard typical agent (usually haloperidol) and some (clozapine, sertindole and quetiapine) appear to cause these effects no more often than placebo. In the longer term, clozapine, olanzapine and (less robustly) other atypical antipsychotics are thought to cause less tardive dyskinesia than typical antipsychotics. Problems caused by hyperprolactinaemia occur less often with some atypical antipsychotics than with typical drugs although risperidone and amisulpride appear to have no advantages in this respect. Other adverse effects may occur as frequently with some atypical antipsychotics as with some typical drugs. Clozapine, risperidone and quetiapine are known to cause postural hypotension; clozapine, olanzapine and quetiapine are clearly sedative; and anticholinergic effects are commonly seen with clozapine, and, much less frequently, with olanzapine. Some adverse effects are more frequent with atypical drugs. Idiosyncratic effects seem particularly troublesome with clozapine and, to a lesser extent, sertindole, olanzapine and zotepine. Bodyweight gain is probably more problematic with atypical antipsychotics than with typical drugs. Overall tolerability, as judged by withdrawals from therapy, is not clearly proven to be better with atypical drugs, although some individual trials do indicate an advantage with atypical agents. Differences in tolerability between individual atypical antipsychotics have not been clearly shown. The tolerability profile of atypical drugs certainly benefits from a lower incidence of acute EPS effects, along with less certain or less uniform benefits in symptomatic hyperprolactinaemia or tardive dyskinesia. Other, perhaps more trivial, adverse effects militate against their good tolerability, and effects such as bodyweight gain may severely reduce tolerability. Without clear advantages in tolerability in patient groups used in trials, drug choice in regard to adverse effects should continue to be on a patient to patient basis.     

Atypical Antipsychotic Augmentation for Treatment-Resistant Depression: A Systematic Review and Network Meta-Analysis

Background:

Previous meta-analyses of atypical antipsychotics for depression were limited by few trials with direct comparisons between two treatments. We performed a network meta-analysis, which integrates direct and indirect evidence from randomized controlled trials (RCTs), to investigate the comparative efficacy and tolerability of adjunctive atypical antipsychotics for treatment-resistant depression (TRD).

Methods:

Systematic searches resulted in 18 RCTs (total n = 4422) of seven different types and different dosages of atypical antipsychotics and a placebo that were included in the review.

Results:

All standard-dose atypical antipsychotics were significantly more efficacious than placebo in the efficacy (standardized mean differences [SMDs] ranged from -0.27 to -0.43). There were no significant differences between these drugs. Low-dose atypical antipsychotics were not significantly more efficacious than the placebo. In terms of tolerability, all standard-dose atypical antipsychotics, apart from risperidone, had significantly more side-effect discontinuations than placebo (odds ratios [ORs] ranged from 2.72 to 6.40). In terms of acceptability, only quetiapine (mean 250–350mg daily) had significantly more all-cause discontinuation than placebo (OR = 1.89). In terms of quality of life/functioning, standard-dose risperidone and standard-dose aripiprazole were more beneficial than placebo (SMD = -0.38; SMD = -0.26, respectively), and standard-dose risperidone was superior to quetiapine (mean 250–350mg daily).

Conclusions:

All standard-dose atypical antipsychotics for the adjunctive treatment of TRD are efficacious in reducing depressive symptoms. Risperidone and aripiprazole also showed benefits in improving the quality of life of patients. Atypical antipsychotics should be prescribed with caution due to abundant evidence of side effects.     

Current therapy issues and unmet clinical needs in the treatment of schizophrenia: a review of the new generation antipsychotics

This review discusses the atypical antipsychotics, focusing on the possibility of symptom reduction with a minimum of side-effects. A selective review of clinically relevant reports, studies and meta-analyses is presented. The results from clinical trials suggest that atypical agents improve negative and affective symptoms, and cognitive functioning more than typical antipsychotics, but that the pattern of effects on these domains, as well as on suicidality, appears to differ. In clinical trials, the newer drugs generally have less extrapyramidal side-effects (EPS) than typical antipsychotics. However, amisulpride, risperidone, olanzapine and ziprasidone still show evidence of a dose-related increase in EPS, whereas clozapine, quetiapine, sertindole and aripiprazole do not. Weight gain, increased blood lipids/cholesterol, and insulin resistance/type 2 diabetes are emerging as significant treatment-associated concerns, particularly for clozapine and olanzapine. Sedation has been reported for all the newer compounds except sertindole. The considerable variation in benefit/risk profiles of the atypical compounds can help the clinician to select the most appropriate treatment for individual patients.     

Probabilistic classification and gambling in patients with schizophrenia receiving medication: comparison of risperidone, olanzapine, clozapine and typical antipsychotics

Rationale

We have previously shown that patients with schizophrenia treated with typical antipsychotics were impaired on the weather prediction probabilistic classification learning (PCL) task that relies on striatal function, and that similar patients treated with atypical antipsychotics were impaired on the Iowa gambling task (IGT) that depends on medial prefrontocortical function.

Objectives

We tested the hypothesis that test performance of patients treated with risperidone will be more similar to those treated with typical rather than atypical antipsychotics.

Results

Groups of schizophrenia patients treated with risperidone, olanzapine, clozapine or typical antipsychotics did not differ on the Positive and Negative Syndrome Scale or the Mini Mental State Exam (MMSE) but scored lower than controls on the MMSE. For the PCL task, patients treated with clozapine improved over trials while those treated with typical antipsychotics, olanzapine, or risperidone did not. For the IGT, patients treated with typical antipsychotics or risperidone improved over trials while those treated with clozapine or olanzapine did not.

Conclusions

Results generally supported the hypothesis that patients treated with risperidone perform more like those treated with typical antipsychotics than those treated with other atypical antipsychotics.     

Adverse effects of atypical antipsychotics : differential risk and clinical implications

Antipsychotic drugs can be of great benefit in a range of psychiatric disorders, including schizophrenia and bipolar disorder, but all are associated with a wide range of potential adverse effects. These can impair quality of life, cause stigma, lead to poor adherence with medication, cause physical morbidity and, in extreme cases, be fatal. A comprehensive overview of tolerability requires a review of all available data, including randomised controlled trials (RCTs), observational studies and postmarketing surveillance studies. Assessing the relative tolerability of atypical antipsychotics is hampered by the paucity of RCTs that compare these drugs head-to-head, and limited and inconsistent reporting of adverse effect data that makes cross-study comparisons difficult.Despite methodological problems in assessment and interpretation of tolerability data, important differences exist between the atypical antipsychotics in the relative risk of acute extrapyramidal symptoms (highest risk: higher doses of risperidone), hyperglycaemia and dyslipidaemia (highest risk: clozapine and olanzapine), hyperprolactinaemia (highest risk: amisulpride and risperidone), prolongation of heart rate-corrected QT interval (QTc) [highest risk: ziprasidone and sertindole] and weight gain (highest risk: clozapine and olanzapine). Sedation, antimuscarinic symptoms, postural hypotension, agranulocytosis and seizures are more common with clozapine than with other atypical antipsychotics. The variation in their tolerability suggests that it is misleading to regard the atypical antipsychotics as a uniform drug class, and also means that the term 'atypical antipsychotic' has only limited usefulness. Differences between the atypical agents in terms of efficacy and pharmacodynamic profiles also support this view. As tolerability differs between specific conventional and atypical drugs, we conclude that broad statements comparing the relative risk of specific adverse effects between 'atypical' and 'conventional' antipsychotics are largely meaningless; rather, comparisons should be made between specific atypical and specific conventional drugs. Adverse effects are usually dose dependent and can be influenced by patient characteristics, including age and gender. These confounding factors should be considered in clinical practice and in the interpretation of research data. Selection of an antipsychotic should be on an individual patient basis. Patients should be involved in prescribing decisions and this should involve discussion about adverse effects.     

Time to all-cause treatment discontinuation of olanzapine compared to other antipsychotics in the treatment of schizophrenia: A systematic review and meta-analysis

Objective: This comprehensive review and meta-analysis compared the effectiveness of olanzapine and other antipsychotics in schizophrenia treatment, defining effectiveness as time to all-cause medication discontinuation (primary) and as all-cause treatment discontinuation rates. This study examined randomized clinical trials (RCTs) and observational non-interventional studies. Experimental procedures: Schizophrenia studies that compared olanzapine with individual first- (FGAs) and/or second-generation antipsychotics (SGAs) were included in the meta-analyses. Hazard ratios (HR), risk ratios (RR), and their associated 95% confidence intervals were extracted for RCTs and observational studies. Sensitivity analyses assessed the impact of sources of funding, dose of olanzapine, and allocation concealment method on final results. Results: There were 60 RCTs (N=33,360) and 27 observational studies (N=202,591) included. On time to all-cause medication discontinuation, olanzapine was significantly better than aripiprazole, quetiapine, risperidone, ziprasidone and perphenazine for RCTs and better than amisulpride, risperidone, haloperidol, and perphenazine for observational studies. There were no significant differences between olanzapine and clozapine in RCTs or observational studies. All-cause discontinuation rates in RCTs were significantly lower for olanzapine compared to all comparators except amisulpride and clozapine. In observational studies, olanzapine was less effective than clozapine. Industry-sponsored studies favored olanzapine when compared to haloperidol and perphenazine; higher dose of olanzapine favored quetiapine and perphenazine when compared to olanzapine; method of allocation concealment did not generally affect the results. Conclusion: Using a global measure of medication effectiveness (time to all-cause medication discontinuation), olanzapine appears to be more effective – in both RCTs and observational studies – than most SGAs and FGAs, except for clozapine.     

Medication patterns and costs associated with olanzapine and other atypical antipsychotics in the treatment of bipolar disorder

ABSTRACT

Objective: Atypical antipsychotics are playing an increasing role in the treatment of bipolar disorder. The objective of this study was to assess the medication treatment patterns and costs associated with different atypical antipsychotics.

Methods: PharMetrics Integrated Database for medical and pharmacy claims was used to assess medication patterns and healthcare costs associated with atypical antipsychotics in the treatment of bipolar disorder. Patients who initiated on olanzapine, risperidone, quetiapine or ziprasidone as monotherapy or in combination with other bipolar medications between 01/2003 and 01/2004 were followed for 1 year. Pair-wise group comparisons were made between olanzapine and other atypical antipsychotics using Wilcoxon without adjustment, log linear regression model with adjustment, and propensity score-adjusted bootstrapping methods.

Results: Among 1516 patients with bipolar disorder, olanzapine (n = 507, 51%) was significantly (?p < 0.01) more likely to be initiated as the mono-bipolar medication than risperidone (n = 424, 40%), quetiapine (n = 463, 36%) or ziprasidone (n = 122, 25%). Post-initiation, olanzapine was used as the mono-bipolar medication for significantly (?p < 0.01) more days (73.4) than risperidone (52.9), quetiapine (56.2) and ziprasidone (36.6). Annual healthcare costs incurred by patients with bipolar disorder varied from $14?216 for risperidone, $15?208 for olanzapine, $18?087 for quetiapine to $18?729 for ziprasidone treatments. No statistically significant differences in the annual healthcare costs were observed between olanzapine and risperidone treatments. Statistically significant differences between olanzapine and quetiapine were observed in two of the three models compared (?p < 0.01, Wilcoxon; p = 0.024, log linear; p = 0.390, propensity score-adjusted bootstrapping) and between olanzapine and ziprasidone in one of the three models (?p < 0.01, Wilcoxon; p = 0.068, log linear; p = 0.394, propensity score-adjusted bootstrapping).

Limitations: Those arising from the data source and nature of retrospective assessments. Potential bias may also exist due to the presence of confounding factors and unobserved conditions and characteristics. As such, results of this study need to be considered in the context of its limitations and generalizability should be reserved to similar patient populations.

Conclusions: Antipsychotic medication use patterns were statistically significantly different among atypical antipsychotics in the usual treatment of bipolar disorder. Olanzapine appears to be more likely used as a mono-bipolar medication compared with risperidone, quetiapine, and ziprasidone. The annual healthcare costs associated with the treatment of bipolar disorder by olanzapine and risperidone were similar, and the costs of these treatments were lower than with quetiapine or ziprasidone.     

Augmentation strategies in partial responder and/or treatment-resistant schizophrenia patients treated with clozapine

Introduction: Although clozapine (CLZ) is considered the best evidence-based therapeutic option for treatment of resistant schizophrenia patients, a significant proportion of CLZ-treated patients show a partial or inadequate response to treatment, leading to increased healthcare cost and poor quality of life for affected individuals.

Areas covered: This paper comprises a review of main research in CLZ augmentation strategies for treatment-refractory schizophrenia, with a focus on research conducted between 1990 and 2014. Databases that were searched include: PubMed, CINAHL, EMBASE PsychINFO, AgeLine and Cochrane Database of Systematic Reviews. Primary search terms were ‘clozapine augmentation’, ‘clozapine and add-on’ and ‘treatment-resistant schizophrenia’, with cross reference to specific agents covered in this article. We reviewed the available evidence on CLZ augmentation with antipsychotics, antidepressants, mood stabilizers and other agents.

Expert opinion: Many drugs have been evaluated as CLZ add-on therapies without demonstrating convincing efficacy in treating refractory schizophrenia symptoms. More research is needed to better define outcomes in schizophrenia, the topic of treatment-resistance and more well-designed trials are required to establish true efficacy and safety of CLZ augmentation strategies.     

Pregnancy exposure to second-generation antipsychotics and the risk of gestational diabetes

Introduction: Assessment of the metabolic safety of second-generation antipsychotics (SGAs) is mandatory in pregnant women, where the occurrence of metabolic complications and, especially, gestational diabetes mellitus (GDM) may severely impact on pregnancy and fetal outcomes.

Areas covered: The aim of this article is to review published data reporting the occurrence of GDM during SGA treatment, and to establish whether or not this iatrogenic complication is a relevant concern in clinical practice. Medical literature information published in any language since 1996 was identified using MEDLINE/PubMed, EMBASE, Scopus, and The Cochrane Library. All articles reporting metabolic complications in pregnancies exposed to single, specific SGAs were acquired, without methodological or language limitations.

Expert opinion: Among studies assessing the metabolic safety of specific SGAs, we have 18 cases of GDM overall: 5 cases involve clozapine (CLO), 9 olanzapine (OLA) - the SGA agent that shows the highest number of reported cases of pregnancy exposure - and 2 each for quetiapine and risperidone. Four of these cases, 2 involving CLO and 2 OLA, were complicated by serious fetal and/or neonatal consequences. Such reports of SGA-associated GDM, together with preliminary data coming from retrospective and prospective studies, may represent signals of a potential safety issue.     

Section Review—Central & Peripheral Nervous Systems: Pre-Clinical Pharmacology of New Atypical Antipsychotics in Late Stage Development

The high incidence of motor-disturbing side-effects associated with ‘typical’ neuroleptic medication has led to the search for safer, ‘atypical’ antipsychotics. Clozapine, the most noted atypical antipsy-chotic, has proven efficacy in the treatment of schizophrenia, and induces fewer motor disturbances. Nevertheless, clozapine is associated with other, severe side-effects. Hence, new atypical antipsychotics, retaining the efficacy and profile of clozapine but without the concomitant adverse reactions, are needed. This article reviews new atypical antipsychotics, focusing especially upon those in late stage development, including SEROQUEL (ZENECA Pharmaceuticals), olanzapine (Eli Lilly), ORG 5222 (Organon), risperidone (Janssen Pharmaceutica), sertindole (Lundbeck), and ziprasidone (Pfizer).     

Cost-effectiveness of atypical antipsychotics for the management of schizophrenia in the UK

ABSTRACT

Objective: To evaluate the cost-effectiveness of atypical antipsychotic treatment sequences for the management of stable schizophrenia in the UK.

Research design and methods: A Markov model was developed to assess the cost per quality-adjusted life year (QALY) gained from 12 alternative treatment sequences each containing two of four atypical antipsychotics (aripiprazole, olanzapine, quetiapine and risperidone), followed by clozapine. The main model parameters were populated with data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study and a recent trial comparing aripiprazole with olanzapine. Patients enter the model with stable schizophrenia and may relapse, discontinue or continue and experience adverse events (AEs), or develop diabetes. Population mortality was adjusted for schizophrenia and diabetes. Utility decrements applied to stable schizophrenia, relapse, diabetes and treatment-related AEs were taken from a direct UK utility elicitation study. Resource use and unit costs were taken from published sources. A time horizon of 10 years was adopted. Results are based on 10,000 probabilistic iterations of the model.

Results: Aripiprazole followed by risperidone produced the greatest number of QALYs, an additional 0.03 compared with risperidone followed by olanzapine, at an incremental cost of £257 (incremental cost/QALY: £9,440). Aripiprazole followed by risperidone had the greatest probability among evaluated sequences of being cost-effective at a threshold of >£10,000/QALY. All other strategies were dominated by at least one of these strategies. The impact of lower pricing for risperidone (based on generic availability) did not impact results.

Conclusions: Modelling the cost-effectiveness of different treatment sequences for stable schizophrenia is appropriate given that patients rarely remain on one treatment for long periods. The treatment sequence aripiprazole followed by risperidone was the most cost-effective option for patients with stable schizophrenia in the UK.     

Therapeutic drug monitoring of antipsychotics

Therapeutic drug monitoring of conventional and atypical antipsychotics offers numerous clinical advantages to the clinician. These include cost savings, decreased risk of toxicity, and improved compliance. Among these drugs, studies of haloperidol, olanzapine, and clozapine have provided the most compelling data to justify therapeutic drug monitoring. Among atypical antipsychotics, although data document the utility of routine monitoring of clozapine and olanzapine blood levels, there are no similar data available for either risperidone or quetiapine. Additionally, the utility of therapeutic drug monitoring is enhanced by the availability of prospective dosing schemes for haloperidol, olanzapine, and clozapine.     

Dopamine D2 receptor blockade in vivo with the novel antipsychotics risperidone and remoxipride — an123I-IBZM single photon emission tomography (SPET) study

Risperidone and remoxipride are recently introduced atypical antipsychotics, with clinical efficacy comparable to that of classical antipsychotics but lower propensity to induce extrapyramidal side effects (EPS). It is unclear whether these properties relate to weak dopamine D₂ receptor blockade in vivo, as has been suggested for the archetypal atypical antipsychotic clozapine. We have used¹²³I-IBZM single photon emission tomography (SPET) to characterize the patterns of striatal D₂ receptor binding in vivo in DSMIII-R-diagnosed schizophrenic and schizo-affective patients treated with either risperidone (n=6) or remoxipride (n=4) but predominantly EPS free. These groups were compared to age- and BPRS- matched subjects from a previously reported D₂ receptor binding database of patients treated with clozapine (n=10) and classical antipsychotics (n=10). Patients on risperidone and remoxipride had high levels of D₂ receptor blockade, comparable to those of patients on classical antipsychotics, and significantly greater than those obtained with clozapine-treated patients (risperidone versus clozapine,P<0.005; remoxipride versus clozapine,P<0.025). These results suggest high levels of striatal D₂ receptor occupancy in association with remoxipride and risperidone treatment and argue against modest D₂ antagonism as the explanation for the low incidence of EPS associated with these drugs.     

Lack of a pharmacokinetic interaction between mirtazapine and the newer antipsychotics clozapine, risperidone and olanzapine in patients with chronic schizophrenia.

The effect of mirtazapine on steady-state plasma concentrations of the newer atypical antipsychotics clozapine, risperidone and olanzapine was investigated in 24 patients with chronic schizophrenia. In order to treat residual negative symptoms, additional mirtazapine (30 mg per day) was administered for six consecutive weeks to nine patients stabilized on clozapine therapy (200-650 mg per day), eight on risperidone (3-8 mg per day) and seven on olanzapine (10-20mg per day). There were only minimal and statistically insignificant changes in mean plasma concentrations of clozapine and its metabolite norclozapine, risperidone and its metabolite 9-hydroxyrisperidone, and olanzapine during the study period. Mirtazapine co-administration with either clozapine, risperidone or olanzapine was well tolerated. In the overall sample, a slight improvement in negative symptomatology, as assessed by the Scale for Assessment of Negative Symptoms, was observed at final evaluation (P<0.01) and six patients (two in each treatment group) were classified as responders. While double-blind, controlled studies are needed to evaluate the potential clinical benefits of mirtazapine in chronic schizophrenia, our findings indicate that mirtazapine has a negligible effect on the metabolism of clozapine, risperidone and olanzapine and can be added safely to an existing treatment with these antipsychotics.     

Adverse effects of atypical antipsychotics in the elderly: a review

Use of antipsychotic medication is very common in the elderly and often an essential therapy. However, successful treatment in the elderly requires appropriate multidimensional assessment of the patient, knowledge of possible multiple co-morbidities, and awareness of the complexities of polypharmacy, age-dependent changes in pharmacokinetics and pharmacodynamics, and drug-drug interactions in this age group. Antipsychotics are known to have a number of adverse effects. New antipsychotics, such as amisulpride, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, zotepine and aripiprazole, may interact with both dopamine and serotonin receptors. However, compared with conventional antipsychotics, they are less likely to cause extrapyramidal symptoms and are better tolerated in the elderly. At the same time, consistent differences between atypical antipsychotics have been demonstrated. Use of clozapine, for example, is limited by the risk of agranulocytosis, whereas this is not a disadvantage of olanzapine, risperidone, quetiapine and, more recently, ziprasidone, which are being widely used with good results in schizophrenia. However, use of the latter agents to treat the behavioural and psychological symptoms of dementia has been restricted because of recent observations of increased cardiovascular events in patients taking risperidone and olanzapine treatment. Nonetheless, careful review of the literature suggests that the available evidence does not support any causal relationship between use of risperidone or olanzapine and cardiovascular events. This article focuses on some of the main adverse effects commonly reported during administration of atypical antipsychotics to elderly patients. Such effects may be partly explained by age-related changes in pharmacokinetics and pharmacodynamics, and partly by the characteristics of the drugs themselves and their different receptor binding profiles.