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Competing Interests: AC is supported by the National Institute for Health and Care Research (NIHR) Oxford Cognitive Health Clinical Research Facility, by an NIHR Research Professorship (grant RP-2017-08-ST2-006), by the NIHR Oxford and Thames Valley Applied Research Collaboration, by the NIHR Oxford Health Biomedical Research Centre (grant NIHR203316), and by the Wellcome Trust. AC has also received research, educational, and consultancy fees from the Italian Network for Paediatric Trials, the CARIPLO Foundation, Lundbeck, and Angelini Pharma. AC is the Chief Investigator of one trial about seltorexant in adolescent depression, sponsored by Janssen. The views expressed here are those of the authors and not necessarily those of the UK National Health Service, the NIHR, or the UK Department of Health. GS reports research grants paid to her institution by the Swiss National Science Foundation, the European Commission, and the Wellcome Trust. AA declares no competing interests.

Background: There is evidence that antipsychotic drugs differ in their effect on the cognitive symptoms of schizophrenia. So far, there is no comprehensive systematic review available that would enable providers and patients to make informed choices regarding this important aspect of treatment. With a large number of substances available, conventional pairwise meta-analyses will not be sufficient to inform this choice. To fill this gap, we will conduct a network meta-analysis (NMA), integrating direct and indirect comparisons from randomized controlled trials (RCTs) to rank antipsychotics according to their effect on cognitive functioning., Methods: In our NMA, we will include RCTs in patients with schizophrenia or schizophrenia-like psychoses comparing one antipsychotic agent with another antipsychotic agent or placebo that measures cognitive function. We will include studies on patients of every age group, in any phase of illness (e.g., acute or stable, first episode or chronic schizophrenia, in- or outpatients) with an intervention time of at least 3 weeks. The primary outcome will be the composite score of cognitive functioning, preferentially measured with the test battery developed by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative. The secondary outcomes include the seven cognitive domains that the composite score is composed of, as well as functioning and quality of life. Study selection and data extraction will be conducted by at least two independent reviewers. We will use the Cochrane Risk of Bias tool 2 to determine the risk of bias in studies, and we will evaluate the confidence in the results using Confidence in Network Meta-Analysis (CINeMA). We will perform NMA using R (package netmeta). We will conduct subgroup and sensitivity analyses to explore the heterogeneity and assess the robustness of our findings., Discussion: This systematic review and network meta-analysis aims to inform evidence-based antipsychotic treatment choice for cognitive deficits in schizophrenia patients by analyzing existing RCTs on this subject. The results have the potential to support patients' and physicians' decision-making processes based on the latest available evidence., Systematic Review Registration: PROSPERO CRD42022312483., (© 2023. The Author(s).)

Introduction: Guidelines recommend clozapine for treatment-resistant schizophrenia. However, meta-analysis of aggregate data (AD) did not demonstrate higher efficacy of clozapine compared with other second-generation antipsychotics but found substantial heterogeneity between trials and variation between participants in treatment effects. Therefore, we will conduct an individual participant data (IPD) meta-analysis to estimate the efficacy of clozapine compared with other second-generation antipsychotics while accounting for potentially important effect modifiers., Methods and Analysis: In a systematic review, two reviewers will independently search Cochrane Schizophrenia Group's trial register (without restrictions in date, language or state of publication) and related reviews. We will include randomised controlled trials (RCTs) in participants with treatment-resistant schizophrenia comparing clozapine with other second-generation antipsychotics for at least 6 weeks. We will apply no restrictions in age, gender, origin, ethnicity or setting, but exclude open-label studies, studies from China, experimental studies and phase II of cross-over trials. IPD will be requested from trial authors and cross-check against published results. AD will be extracted in duplicate. Risk of bias will be assessed using Cochrane's Risk of Bias 2 tool.The primary outcome will be overall symptoms of schizophrenia.We will synthesise results using random-effects meta-analysis and meta-regression methods in a 3-level Bayesian model. The model combines IPD with AD when IPD is not available for all studies, and include participant, intervention and study design characteristics as potential effect modifiers. The effect size measures will be mean difference (or standardised mean difference when different scales were used). Confidence in the evidence will be assessed using GRADE., Ethics and Dissemination: This project has been approved by the ethics commission of the Technical University of Munich (#612/21 S-NP). The results will be published open-access in a peer-review journal and a plain-language version of the results will be disseminated.If we need to amend this protocol, we will describe the change and give the rationale in a specific section in the resulting publication 'Changes with respect to the protocol'., Systematic Review Registration: PROSPERO (#CRD42021254986)., Competing Interests: Competing interests: In the last 3 years, SL has received honoraria as a consultant/advisor and/or for lectures from Angelini, Böhringer Ingelheim, Geodon&Richter, Janssen, Johnson&Johnson, Lundbeck, LTS Lohmann, MSD, Otsuka, Recordati, SanofiAventis, Sandoz, Sunovion, TEVA, Eisai, Rovi, Medichem and Mitsubishi., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Weight gain is among the most important side-effects of antipsychotics. It is, however, unclear whether it is associated with antipsychotic doses. We aimed to fill this gap with a dose-response meta-analysis., Methods: We searched multiple electronic databases (last update search June 2021) for all fixed-dose studies that investigated 16 second-generation antipsychotics and haloperidol in adults with acute exacerbation of schizophrenia or with negative symptoms. We estimated the dose-response curves by conducting random-effects dose-response meta-analyses. We used the restricted cubic spline to model the dose-response relationship. The primary outcome was mean weight gain in kg from baseline to endpoint, the secondary outcome was the number of patients with clinically important weight gain., Findings: Ninety-seven studies with 333 dose arms (36 326 participants) provided data for meta-analyses. Most studies were short-term with median duration of 6 weeks (range 4 to 26 weeks). In patients with acute exacerbation, amisulpride, aripiprazole, brexpiprazole, cariprazine, haloperidol, lumateperone, and lurasidone produced mild weight gain in comparison to placebo (mean difference at any dose≤1 kg), while more significant weight gain was observed by all other drugs. For most drugs, dose-response curves showed an initial dose-related increase in weight which plateaued at higher doses, while for others there was no plateau and some even had bell-shaped curves, meaning less weight gain to be associated with higher doses., Interpretation: Second-generation antipsychotics do not only differ in their propensity to produce weight gain, but also in the shapes of their dose-response curves. This information is important for dosing decisions in clinical practice., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Schizophrenia is a common, severe, and usually chronic disorder. Maintenance treatment with antipsychotic drugs can prevent relapse but also causes side-effects. We aimed to compare the efficacy and tolerability of antipsychotics as maintenance treatment for non-treatment resistant patients with schizophrenia., Methods: In this systematic review and network meta-analysis, we searched, without language restrictions, the Cochrane Schizophrenia Group's specialised register between database inception and April 27, 2020, PubMed from April 1, 2020, to Jan 15, 2021, and the lists of included studies from related systematic reviews. We included randomised controlled trials (RCTs; ≥12 weeks of follow-up) that recruited adult participants with schizophrenia or schizoaffective disorder with stable symptoms who were treated with antipsychotics (monotherapy; oral or long-acting injectable) or placebo. We excluded RCTs of participants with specific comorbidities or treatment resistance. In duplicate, two authors independently selected eligible RCTs and extracted aggregate data. The primary outcome was the number of participants who relapsed and was analysed by random-effects, Bayesian network meta-analyses. The study was registered on PROSPERO, CRD42016049022., Findings: We identified 4157 references through our search, from which 501 references on 127 RCTs of 32 antipsychotics (comprising 18 152 participants) were included. 100 studies including 16 812 participants and 30 antipsychotics contributed to our network meta-analysis of the primary outcome. All antipsychotics had risk ratios (RRs) less than 1·00 when compared with placebo for relapse prevention and almost all had 95% credible intervals (CrIs) excluding no effect. RRs ranged from 0·20 (95% CrI 0·05-0·41) for paliperidone oral to 0·65 (0·16-1·14) for cariprazine oral (moderate-to-low confidence in estimates). Generally, we interpret that there was no clear evidence for the superiority of specific antipsychotics in terms of relapse prevention because most comparisons between antipsychotics included a probability of no difference., Interpretation: As we found no clear differences between antipsychotics for relapse prevention, we conclude that the choice of antipsychotic for maintenance treatment should be guided mainly by their tolerability., Funding: The German Ministry of Education and Research and Oxford Health Biomedical Research Centre., Competing Interests: Declaration of interests In the past 3 years, SL has received honoraria as a consultant, adviser, or both, or for lectures, from Alkermes, Angelini, Eisai, Gedeon Richter, Janssen, Lundbeck, Lundbeck Institute, Merck Sharp and Dohme, Otsuka, Recordati, Rovi, Sanofi Aventis, TEVA, Medichem, and Mitsubishi. TAF reports grants from Mitsubishi-Tanabe and Shionogi, outside the submitted work; personal fees from Mitsubishi-Tanabe, MSD, SONY, and Shionogi, outside the submitted work; a patent (2018–177688) concerning smartphone cognitive behavioural therapy apps pending; and intellectual properties for the Kokoro app licensed to Mitsubishi-Tanabe. ACi has received research and consultancy fees from the Italian Network for Paediatric Trials, the CARIPLO Foundation, and Angelini Pharma, outside the submitted work. MH has received honoraria as an adviser from Recordati. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Importance: The doses of antipsychotic drugs needed for relapse prevention in schizophrenia is a debated issue., Objective: To examine dose-response findings in a meta-analysis of randomized clinical trials., Data Sources: Studies were identified through the Cochrane Schizophrenia Group's Study-Based Register of Trials (March 9, 2020), PubMed (January 1, 2021), and previous reviews. First authors and/or pharmaceutical companies were contacted for additional information., Study Selection: Two reviewers independently selected randomized clinical trials that compared fixed doses of a second-generation antipsychotic, haloperidol, or fluphenazine for relapse prevention in patients with stable schizophrenia., Data Extraction and Synthesis: Using the Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline, all parameters in duplicate were extracted and frequentist dose-response random-effects meta-analyses were conducted., Main Outcomes and Measures: Study-defined relapse (primary outcome), rehospitalization, Positive and Negative Syndrome Scale or Brief Psychiatric Rating Scale total score reduction from baseline, all-cause discontinuation, and dropouts due to adverse events., Results: Evidence from 72 dose arms from 26 studies with 4776 participants was analyzed. The efficacy-related dose-response curves had a hyperbolic shape meaning that the probability to relapse decreased rapidly with doses of up to 5-mg/d risperidone equivalent (relative relapse risk, 0.43; 95% CI, 0.31-0.57; standardized mean difference for Positive and Negative Syndrome Scale total score reduction, -0.55; 95% CI, -0.68 to -0.41), but flattened thereafter. In contrast, dropouts due to adverse events continued to increase beyond this dose (relative risk at 5 mg/d, 1.38; 95% CI, 0.87-2.55; relative risk at 15 mg/d, 2.68; 95% CI, 1.49-4.62). In a subgroup analysis of patients in remission, a plateau was reached earlier, at approximately 2.5-mg/d risperidone equivalent., Conclusions and Relevance: The findings of this meta-analysis suggest that doses higher than approximately 5-mg/d risperidone equivalent may provide limited additional benefit for relapse prevention but more adverse events. For patients in remission or who are receiving high-potency first-generation antipsychotics, doses as low as 2.5-mg/d risperidone equivalent may be sufficient. However, caution is needed at this low dose end when further decreases of dose may be accompanied by a disproportionally higher relapse risk. Moreover, the observations are averages, and factors such as slow or rapid metabolism, age, illness stage, comorbidities, and drug-drug interactions suggest that individual patients will often need higher or lower doses.

Background: Antipsychotic drugs and especially the newer compounds are known to cause metabolic side effects. However, a comprehensive comparison of the different substances regarding their propensity to cause metabolic side effects in medium- to long-term treatment of schizophrenia is lacking., Methods: We will conduct a systematic review and network meta-analysis (NMA). We will include randomized controlled trials (RCTs) in which participants received either placebo or an antipsychotic (i.e. placebo-controlled trials and head-to-head comparisons of drugs). We will include studies in individuals with schizophrenia or related disorders (such as schizophreniform or schizoaffective disorders) at any stage of the disease (acute episode; maintenance phase). We will include studies with a duration of more than 3 months (medium- to long-term treatment). The primary outcome will be the change in body weight. Secondary outcomes will be the further metabolic parameters: fastening glucose, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides. We will search for eligible studies (independent of the publication status) in Cochrane Schizophrenia Group's Study-Based Register of Trials, which is compiled by regular searches in trial registries and multiple electronic databases from their inception onwards including MEDLINE, EMBASE and PsycINFO. Additionally, we will search previously published systematic reviews and websites of pharmaceutical companies for eligible studies. At least two reviewers will independently conduct the process of study selection and data extraction. We will use the Cochrane Risk of Bias 2 tool to evaluate the risk of bias in studies. We will conduct random-effects NMA within a Bayesian framework to synthesize all evidence for each outcome. We will conduct sensitivity and subgroup analyses to assess the robustness of the findings and to explore heterogeneity. The confidence in the results will be evaluated using the Confidence in Network Meta-Analysis (CINeMA) framework., Discussion: This systematic review and network meta-analysis will provide a synthesis of the existing evidence from RCTs how antipsychotic drugs differ in terms of metabolic side effects during medium- to long-term treatment. The findings have the potential to influence the choice of antipsychotic medication made by individuals with schizophrenia and their physicians., Systematic Review Registration: PROSPERO CRD42020175414., (© 2021. The Author(s).)

Background: Schizophrenia is one of the most common, burdensome, and costly psychiatric disorders in adults worldwide. Antipsychotic drugs are its treatment of choice, but there is controversy about which agent should be used. We aimed to compare and rank antipsychotics by quantifying information from randomised controlled trials., Methods: We did a network meta-analysis of placebo-controlled and head-to-head randomised controlled trials and compared 32 antipsychotics. We searched Embase, MEDLINE, PsycINFO, PubMed, BIOSIS, Cochrane Central Register of Controlled Trials (CENTRAL), WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov from database inception to Jan 8, 2019. Two authors independently selected studies and extracted data. We included randomised controlled trials in adults with acute symptoms of schizophrenia or related disorders. We excluded studies in patients with treatment resistance, first episode, predominant negative or depressive symptoms, concomitant medical illnesses, and relapse-prevention studies. Our primary outcome was change in overall symptoms measured with standardised rating scales. We also extracted data for eight efficacy and eight safety outcomes. Differences in the findings of the studies were explored in metaregressions and sensitivity analyses. Effect size measures were standardised mean differences, mean differences, or risk ratios with 95% credible intervals (CrIs). Confidence in the evidence was assessed using CINeMA (Confidence in Network Meta-Analysis). The study protocol is registered with PROSPERO, number CRD42014014919., Findings: We identified 54 417 citations and included 402 studies with data for 53 463 participants. Effect size estimates suggested all antipsychotics reduced overall symptoms more than placebo (although not statistically significant for six drugs), with standardised mean differences ranging from -0·89 (95% CrI -1·08 to -0·71) for clozapine to -0·03 (-0·59 to 0·52) for levomepromazine (40 815 participants). Standardised mean differences compared with placebo for reduction of positive symptoms (31 179 participants) varied from -0·69 (95% CrI -0·86 to -0·52) for amisulpride to -0·17 (-0·31 to -0·04) for brexpiprazole, for negative symptoms (32 015 participants) from -0·62 (-0·84 to -0·39; clozapine) to -0·10 (-0·45 to 0·25; flupentixol), for depressive symptoms (19 683 participants) from -0·90 (-1·36 to -0·44; sulpiride) to 0·04 (-0·39 to 0·47; flupentixol). Risk ratios compared with placebo for all-cause discontinuation (42 672 participants) ranged from 0·52 (0·12 to 0·95; clopenthixol) to 1·15 (0·36 to 1·47; pimozide), for sedation (30 770 participants) from 0·92 (0·17 to 2·03; pimozide) to 10·20 (4·72 to 29·41; zuclopenthixol), for use of antiparkinson medication (24 911 participants) from 0·46 (0·19 to 0·88; clozapine) to 6·14 (4·81 to 6·55; pimozide). Mean differences compared to placebo for weight gain (28 317 participants) ranged from -0·16 kg (-0·73 to 0·40; ziprasidone) to 3·21 kg (2·10 to 4·31; zotepine), for prolactin elevation (21 569 participants) from -77·05 ng/mL (-120·23 to -33·54; clozapine) to 48·51 ng/mL (43·52 to 53·51; paliperidone) and for QTc prolongation (15 467 participants) from -2·21 ms (-4·54 to 0·15; lurasidone) to 23·90 ms (20·56 to 27·33; sertindole). Conclusions for the primary outcome did not substantially change after adjusting for possible effect moderators or in sensitivity analyses (eg, when excluding placebo-controlled studies). The confidence in evidence was often low or very low., Interpretation: There are some efficacy differences between antipsychotics, but most of them are gradual rather than discrete. Differences in side-effects are more marked. These findings will aid clinicians in balancing risks versus benefits of those drugs available in their countries. They should consider the importance of each outcome, the patients' medical problems, and preferences., Funding: German Ministry of Education and Research and National Institute for Health Research., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objective: An important clinical question is how many patients with acute schizophrenia do not respond to antipsychotics despite being treated for adequate time and with an effective dose. However, up to date, the exact extent of the phenomenon remains unclear., Methods: We calculated the nonresponse and nonremission percentages using individual patient data from 16 randomized controlled trials (RCTs). Six thousand two hundred twenty-one patients were assigned to one antipsychotic (amisulpride, flupenthixol, haloperidol, olanzapine, quetiapine, risperidone, or ziprasidone) at an adequate dose; the response was assessed at 4-6 weeks. As various definitions of nonresponse have been used in the literature, we applied 4 different cut-offs covering the whole range of percent Positive and Negative Syndrome Scale (PANSS)/Brief Psychiatric Rating Scale (BPRS) reduction (≤0%, <25%, <50%, <75%).For symptomatic remission, we used the definition proposed by Andreasen without employing the time criterion., Results: The overall nonresponse for the cut-off of ≤0% PANSS/BPRS reduction was 19.8% (18.8%-20.8%); for the cut-off of <25% reduction it was 43% (41.7%-44.3%); for the cut-off of <50% reduction it was 66.5% (65.3%-67.8%); and for the cut-off of <75% reduction it was 87% (86%-87.9%). The overall percentage of no symptomatic remission was 66.9% (65.7%-68.1%). Earlier onset of illness, lower baseline severity and the antipsychotic used were significantly associated with higher nonresponse percentages., Conclusions: Nonresponse and nonremission percentages were notably high. Nevertheless, the patients in our analysis could represent a negative selection since they came from short-term RCTs and could have been treated before study inclusion; thus, further response may not have been observed. Observational studies on this important question are needed., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: A recent meta-regression had shown that the degree of placebo response, which has increased over the decades, is the major predictor of drug-placebo differences in antipsychotic drug trials in acutely ill patients with schizophrenia. Drug response, however, had remained stable. In the current meta-regression we explored the factors that are associated with placebo-response., Method: We searched multiple electronic databases, ClinicalTrials.gov and the FDA website for randomized, placebo-controlled, antipsychotic drug trials in patients with acute exacerbations of schizophrenia. The outcome was the degree of placebo response measured by the BPRS or PANSS change from baseline to endpoint. 26 patient-, design-, and drug-related potential predictors of placebo response were analyzed by univariable and multivariable meta-regressions., Results: 167 double-blind randomized controlled trials with 28,102 participants were included. The mean PANSS change from baseline was 6.25 (95% CI 4.64,7.85). More recent publication year, larger study sample size, more study sites, use of the PANSS rather than the BPRS scale to measure response, shorter wash-out phases, shorter study duration, lower mean age and shorter duration of illness were associated with larger placebo response in univariable analyses. In a multivariable analysis only the number of study participants and mean participant age had an impact on placebo response., Conclusions: The degree of placebo response is moderated by a number of design and patient-related factors. These explanatory variables of placebo response are only in part identical with those that moderated drug-placebo differences., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Acutely occurring, life-threatening side-effects of antipsychotic drugs might contribute to the reduced life expectancy observed in patients with severe mental disorders. We aimed to assess this hypothesis by doing a systematic review and meta-analysis of deaths occurring in placebo-controlled trials of antipsychotic drugs., Methods: For this systematic review and meta-analysis, we included randomised controlled trials comparing second-generation antipsychotics with placebo across several diagnostic categories. We searched MEDLINE, EMBASE, Cochrane CENTRAL, BIOSIS, PsycINFO, PubMed, ClinicalTrials.gov, and WHO ICTRP from inception (the last search was done on Jan 21, 2017), and contacted pharmaceutical companies and regulatory authorities for further eligible trials. We examined mortality from any cause (the primary outcome) and mortality from natural causes, suicide, and other non-natural causes. We synthesised the results with odds ratios (ORs) in a common-effects meta-analysis. We investigated the effects of age, diagnostic category, sex, study duration, antipsychotic drug used, drug dose, and polypharmacy in subgroup and meta-regression analyses. This study is registered with PROSPERO, number CRD42016033930., Findings: We identified 596 randomised controlled trials published between 1978 and 2017, comprising 108 747 participants. 352 studies (comprising 84 988 participants) with mortality data available constituted the main dataset for our meta-analysis. 207 (0·4%) deaths were reported in 53 804 patients on an antipsychotic drug and 99 (0·3%) deaths in 31 184 patients on placebo. 300 (85%) of 352 trials were 13 weeks (3 months) or shorter in duration (median 6 weeks; IQR 4-10). We found no evidence of a difference between antipsychotic drugs and placebo in mortality by any cause (OR 1·19; 95% CI 0·93-1·53), from natural causes (1·29; 0·85-1·94), from suicide (1·15; 0·47-2·81), and from other non-natural causes (1·55; 0·66-3·63). Most subgroup and meta-regression analyses did not indicate any important effect moderators. The exceptions were increased mortality in patients with dementia (OR 1·56; 95% CI 1·10-2·21), in elderly patients (1·38; 1·01-1·89), in aripiprazole-treated patients (2·20; 1·00-4·86), and in studies with a higher proportion of women (regression coefficient 0·025; 95% credible interval 0·010-0·040). However, the effects in elderly patients, aripiprazole-treated patients, and women were mainly based on the included dementia trials. For patients with schizophrenia there was no evidence of an increased mortality risk (OR 0·69; 95% CI 0·35-1·35)., Interpretation: Overall, and for the main indication of schizophrenia, there is no evidence from randomised trials that antipsychotic drugs increase mortality. However, vulnerable populations (particularly patients with dementia) might be at increased risk. This meta-analysis could only address acute treatment effects leading to death in the short-term, and not long-term effects of antipsychotic drugs on mortality., Funding: German Ministry of Education and Research., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: Antipsychotic drug efficacy may have decreased over recent decades. The authors present a meta-analysis of all placebo-controlled trials in patients with acute exacerbations of schizophrenia, and they investigate which trial characteristics have changed over the years and which are moderators of drug-placebo efficacy differences., Method: The search included multiple electronic databases. The outcomes were overall efficacy (primary outcome); responder and dropout rates; positive, negative, and depressive symptoms; quality of life; functioning; and major side effects. Potential moderators of efficacy were analyzed by meta-regression., Results: The analysis included 167 double-blind randomized controlled trials with 28,102 mainly chronic participants. The standardized mean difference (SMD) for overall efficacy was 0.47 (95% credible interval 0.42, 0.51), but accounting for small-trial effects and publication bias reduced the SMD to 0.38. At least a "minimal" response occurred in 51% of the antipsychotic group versus 30% in the placebo group, and 23% versus 14% had a "good" response. Positive symptoms (SMD 0.45) improved more than negative symptoms (SMD 0.35) and depression (SMD 0.27). Quality of life (SMD 0.35) and functioning (SMD 0.34) improved even in the short term. Antipsychotics differed substantially in side effects. Of the response predictors analyzed, 16 trial characteristics changed over the decades. However, in a multivariable meta-regression, only industry sponsorship and increasing placebo response were significant moderators of effect sizes. Drug response remained stable over time., Conclusions: Approximately twice as many patients improved with antipsychotics as with placebo, but only a minority experienced a good response. Effect sizes were reduced by industry sponsorship and increasing placebo response, not decreasing drug response. Drug development may benefit from smaller samples but better-selected patients.

Importance: In treatment-resistant schizophrenia, clozapine is considered the standard treatment. However, clozapine use has restrictions owing to its many adverse effects. Moreover, an increasing number of randomized clinical trials (RCTs) of other antipsychotics have been published., Objective: To integrate all the randomized evidence from the available antipsychotics used for treatment-resistant schizophrenia by performing a network meta-analysis., Data Sources: MEDLINE, EMBASE, Biosis, PsycINFO, PubMed, Cochrane Central Register of Controlled Trials, World Health Organization International Trial Registry, and clinicaltrials.gov were searched up to June 30, 2014., Study Selection: At least 2 independent reviewers selected published and unpublished single- and double-blind RCTs in treatment-resistant schizophrenia (any study-defined criterion) that compared any antipsychotic (at any dose and in any form of administration) with another antipsychotic or placebo., Data Extraction and Synthesis: At least 2 independent reviewers extracted all data into standard forms and assessed the quality of all included trials with the Cochrane Collaboration's risk-of-bias tool. Data were pooled using a random-effects model in a Bayesian setting., Main Outcomes and Measures: The primary outcome was efficacy as measured by overall change in symptoms of schizophrenia. Secondary outcomes included change in positive and negative symptoms of schizophrenia, categorical response to treatment, dropouts for any reason and for inefficacy of treatment, and important adverse events., Results: Forty blinded RCTs with 5172 unique participants (71.5% men; mean [SD] age, 38.8 [3.7] years) were included in the analysis. Few significant differences were found in all outcomes. In the primary outcome (reported as standardized mean difference; 95% credible interval), olanzapine was more effective than quetiapine (-0.29; -0.56 to -0.02), haloperidol (-0. 29; -0.44 to -0.13), and sertindole (-0.46; -0.80 to -0.06); clozapine was more effective than haloperidol (-0.22; -0.38 to -0.07) and sertindole (-0.40; -0.74 to -0.04); and risperidone was more effective than sertindole (-0.32; -0.63 to -0.01). A pattern of superiority for olanzapine, clozapine, and risperidone was seen in other efficacy outcomes, but results were not consistent and effect sizes were usually small. In addition, relatively few RCTs were available for antipsychotics other than clozapine, haloperidol, olanzapine, and risperidone. The most surprising finding was that clozapine was not significantly better than most other drugs., Conclusions and Relevance: Insufficient evidence exists on which antipsychotic is more efficacious for patients with treatment-resistant schizophrenia, and blinded RCTs-in contrast to unblinded, randomized effectiveness studies-provide little evidence of the superiority of clozapine compared with other second-generation antipsychotics. Future clozapine studies with high doses and patients with extremely treatment-refractory schizophrenia might be most promising to change the current evidence.

Objectives: Publication bias (PB) may seriously compromise inferences from meta-analyses. The aim of this article was to assess the potential effect of small-study effects and PB on the recently estimated relative effectiveness and ranking of pharmacological treatments for schizophrenia., Study Design and Setting: We used a recently published network of 167 trials involving 36,871 patients and comparing the effectiveness of 15 antipsychotics and placebo. We used novel visual and statistical methods to explore if smaller trials are associated with larger treatment effects and a selection model to explore if the probability of trial publication is associated with the magnitude of effect. We conducted a network meta-analysis of the published evidence as our primary analysis and used a sensitivity analysis considering low, moderate, and severe selection bias (that corresponds to the number of unpublished trials) with an aim to evaluate robustness of point estimates and ranking. We explored whether placebo-controlled and head-to-head trials are associated with different levels of PB., Results: We found that small placebo-controlled trials exaggerated slightly the efficacy of antipsychotics, and PB was not unlikely in the evidence based on placebo-controlled trials; however, ranking of antipsychotics remained robust., Conclusion: The total evidence comprises many head-to-head trials that do not appear to be prone to small-study effects or PB, and indirect evidence appears to "wash out" some of the biases in the placebo-controlled trials., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Missing outcome data is a major threat in meta-analytical studies of schizophrenia. Most clinical trials in psychiatry report only continuous outcome measures and express the effect of an intervention as a difference of means. However, these results are difficult to interpret for clinicians. Converting continuous data to binary response rates is one possible solution to the problem. Based on means and standard deviations for a continuous outcome, we examined the performance of an imputation method to define a dichotomous outcome using original individual patients' data from 16 randomized trials (6276 participants) comparing antipsychotic drugs in schizophrenia. We concluded that the imputed values re-captured in a reasonable degree the observed values providing a simple and practical alternative methodological choice for imputation of missing binary data in schizophrenia trials; nevertheless, the imputation method tended to introduce biases, especially for extreme risks and large treatment differences., (© 2013.)

Background: The question of which antipsychotic drug should be preferred for the treatment of schizophrenia is controversial, and conventional pairwise meta-analyses cannot provide a hierarchy based on the randomised evidence. We aimed to integrate the available evidence to create hierarchies of the comparative efficacy, risk of all-cause discontinuation, and major side-effects of antipsychotic drugs., Methods: We did a Bayesian-framework, multiple-treatments meta-analysis (which uses both direct and indirect comparisons) of randomised controlled trials to compare 15 antipsychotic drugs and placebo in the acute treatment of schizophrenia. We searched the Cochrane Schizophrenia Group's specialised register, Medline, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for reports published up to Sept 1, 2012. Search results were supplemented by reports from the US Food and Drug Administration website and by data requested from pharmaceutical companies. Blinded, randomised controlled trials of patients with schizophrenia or related disorders were eligible. We excluded trials done in patients with predominant negative symptoms, concomitant medical illness, or treatment resistance, and those done in stable patients. Data for seven outcomes were independently extracted by two reviewers. The primary outcome was efficacy, as measured by mean overall change in symptoms. We also examined all-cause discontinuation, weight gain, extrapyramidal side-effects, prolactin increase, QTc prolongation, and sedation., Findings: We identified 212 suitable trials, with data for 43 049 participants. All drugs were significantly more effective than placebo. The standardised mean differences with 95% credible intervals were: clozapine 0·88, 0·73-1·03; amisulpride 0·66, 0·53-0·78; olanzapine 0·59, 0·53-0·65; risperidone 0·56, 0·50-0·63; paliperidone 0·50, 0·39-0·60; zotepine 0·49, 0·31-0·66; haloperidol 0·45, 0·39-0·51; quetiapine 0·44, 0·35-0·52; aripiprazole 0·43, 0·34-0·52; sertindole 0·39, 0·26-0·52; ziprasidone 0·39, 0·30-0·49; chlorpromazine 0·38, 0·23-0·54; asenapine 0·38, 0·25-0·51; lurasidone 0·33, 0·21-0·45; and iloperidone 0·33, 0·22-0·43. Odds ratios compared with placebo for all-cause discontinuation ranged from 0·43 for the best drug (amisulpride) to 0·80 for the worst drug (haloperidol); for extrapyramidal side-effects 0·30 (clozapine) to 4·76 (haloperidol); and for sedation 1·42 (amisulpride) to 8·82 (clozapine). Standardised mean differences compared with placebo for weight gain varied from -0·09 for the best drug (haloperidol) to -0·74 for the worst drug (olanzapine), for prolactin increase 0·22 (aripiprazole) to -1·30 (paliperidone), and for QTc prolongation 0·10 (lurasidone) to -0·90 (sertindole). Efficacy outcomes did not change substantially after removal of placebo or haloperidol groups, or when dose, percentage of withdrawals, extent of blinding, pharmaceutical industry sponsorship, study duration, chronicity, and year of publication were accounted for in meta-regressions and sensitivity analyses., Interpretation: Antipsychotics differed substantially in side-effects, and small but robust differences were seen in efficacy. Our findings challenge the straightforward classification of antipsychotics into first-generation and second-generation groupings. Rather, hierarchies in the different domains should help clinicians to adapt the choice of antipsychotic drug to the needs of individual patients. These findings should be considered by mental health policy makers and in the revision of clinical practice guidelines., Funding: None., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Unlabelled: Patient dropout is common in mental health trials. It is important to understand why patients drop out from trials, so that measures can be taken to minimize its occurrence. This research sought to identify trial characteristics that have an impact on premature discontinuation in antipsychotic trials for schizophrenia., Methods: Poisson regression analysis was applied with dropout rate per patient-week as the dependent variable and trial characteristics as independent variables. Multinomial logistic regression analysis was performed to examine whether the same characteristics predict whether patients drop out without providing any outcome data and whether they drop out with sufficient early data for a 'last observation carried forward' analysis to be performed., Results: trials with adequate allocation concealment, double blinding, placebo as control, higher precision, larger trial size, at least three treatment arms, recent publication, conduct in the United States and enrollment of inpatients were all associated with higher dropout rates. Similar factors were associated with whether a patient was more likely to be evaluated at least once, or be excluded entirely from the analysis. However, blinding status did not predict the former type of dropout, and allocation concealment, higher precision and larger sample size, number of arms, recent publication and recruiting inpatient did not predict the latter type of dropout., Conclusions: high dropout rates in antipsychotic trials can be associated with various characteristics, and appears to be particularly associated with use of placebo and study size., (© 2013 Elsevier B.V. and ECNP. All rights reserved.)

Background: Relapse prevention with antipsychotic drugs compared with placebo in patients with schizophrenia has not been sufficiently addressed by previous systematic reviews. We aimed to assess the association between such drugs and various outcomes in patients with schizophrenia to resolve controversial issues., Methods: We searched the Cochrane Schizophrenia Group's specialised register for reports published before Nov 11, 2008; and PubMed, Embase, and ClinicalTrials.gov for those before June 8, 2011. We also contacted pharmaceutical companies and searched the reference lists of included studies and previous reviews. Randomised trials of patients with schizophrenia continued on or withdrawn from any antipsychotic drug regimen after stabilisation were eligible. Our primary outcome was relapse between 7 and 12 months. We also examined safety and various functional outcomes. We used the random effects model and verified results for the primary outcome with a fixed effects model. Heterogeneity was investigated with subgroup and meta-regression analyses., Findings: We identified 116 suitable reports from 65 trials, with data for 6493 patients. Antipsychotic drugs significantly reduced relapse rates at 1 year (drugs 27%vs placebo 64%; risk ratio [RR] 0·40, 95% CI 0·33-0·49; number needed to treat to benefit [NNTB] 3, 95% CI 2-3). Fewer patients given antipsychotic drugs than placebo were readmitted (10%vs 26%; RR 0·38, 95% CI 0·27-0·55; NNTB 5, 4-9), but less than a third of relapsed patients had to be admitted. Limited evidence suggested better quality of life (standardised mean difference -0·62, 95% CI -1·15 to -0·09) and fewer aggressive acts (2%vs 12%; RR 0·27, 95% CI 0·15-0·52; NNTB 11, 6-100) with antipsychotic drugs than with placebo. Employment data were scarce and too few deaths were reported to allow significant differences to be identified. More patients given antipsychotic drugs than placebo gained weight (10%vs 6%; RR 2·07, 95% CI 2·31-3·25), had movement disorders (16%vs 9%; 1·55, 1·25-1·93), and experienced sedation (13%vs 9%; 1·50, 1·22-1·84). Substantial heterogeneity in size of effect was recorded. In subgroup analyses, number of episodes, whether patients were in remission, abrupt or gradual withdrawal of treatment, length of stability before trial entry, first-generation or second-generation drugs, and allocation concealment method did not significantly affect relapse risk. Depot preparations reduced relapse (RR 0·31, 95% CI 0·21-0·41) more than did oral drugs (0·46, 0·37-0·57; p=0·03); depot haloperidol (RR 0·14, 95% CI 0·04-0·55) and fluphenazine (0·23, 0·14-0·39) had the greatest effects. The effects of antipsychotic drugs were greater in two unblinded trials (0·26, 0·17-0·39) than in most blinded studies (0·42, 0·35-0·51; p= 0·03). In a meta-regression, the difference between drug and placebo decreased with study length., Interpretation: Maintenance treatment with antipsychotic drugs benefits patients with schizophrenia. The advantages of these drugs must be weighed against their side-effects. Future studies should focus on outcomes of social participation and clarify the long-term morbidity and mortality of these drugs., Funding: German Ministry of Education and Research., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Conventional meta-analyses have shown inconsistent results for efficacy of pharmacological treatments for acute mania. We did a multiple-treatments meta-analysis, which accounted for both direct and indirect comparisons, to assess the effects of all antimanic drugs., Methods: We systematically reviewed 68 randomised controlled trials (16,073 participants) from Jan 1, 1980, to Nov 25, 2010, which compared any of the following pharmacological drugs at therapeutic dose range for the treatment of acute mania in adults: aripiprazole, asenapine, carbamazepine, valproate, gabapentin, haloperidol, lamotrigine, lithium, olanzapine, quetiapine, risperidone, topiramate, and ziprasidone. The main outcomes were the mean change on mania rating scales and the number of patients who dropped out of the allocated treatment at 3 weeks. Analysis was done by intention to treat., Findings: Haloperidol (standardised mean difference [SMD] -0·56 [95% CI -0·69 to -0·43]), risperidone (-0·50 [-0·63 to -0·38), olanzapine (-0·43 [-0·54 to -0·32], lithium (-0·37 [-0·63 to -0·11]), quetiapine (-0·37 [-0·51 to -0·23]), aripiprazole (-0·37 [-0·51 to -0·23]), carbamazepine (-0·36 [-0·60 to -0·11], asenapine (-0·30 [-0·53 to -0·07]), valproate (-0·20 [-0·37 to -0·04]), and ziprasidone (-0·20 [-0·37 to -0·03]) were significantly more effective than placebo, whereas gabapentin, lamotrigine, and topiramate were not. Haloperidol had the highest number of significant differences and was significantly more effective than lithium (SMD -0·19 [95% CI -0·36 to -0·01]), quetiapine (-0·19 [-0·37 to 0·01]), aripiprazole (-0·19 [-0·36 to -0·02]), carbamazepine (-0·20 [-0·36 to -0·01]), asenapine (-0·26 [-0·52 to 0·01]), valproate (-0·36 [-0·56 to -0·15]), ziprasidone -0·36 [-0·56 to -0·15]), lamotrigine (-0·48 [-0·77 to -0·19]), topiramate (-0·63 [-0·84 to -0·43]), and gabapentin (-0·88 [-1·40 to -0·36]). Risperidone and olanzapine had a very similar profile of comparative efficacy, being more effective than valproate, ziprasidone, lamotrigine, topiramate, and gabapentin. Olanzapine, risperidone, and quetiapine led to significantly fewer discontinuations than did lithium, lamotrigine, placebo, topiramate, and gabapentin., Interpretation: Overall, antipsychotic drugs were significantly more effective than mood stabilisers. Risperidone, olanzapine, and haloperidol should be considered as among the best of the available options for the treatment of manic episodes. These results should be considered in the development of clinical practice guidelines., Funding: None., (Copyright © 2011 Elsevier Ltd. All rights reserved.)