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Original Investigation
March 2016

Efficacy, Acceptability, and Tolerability of Antipsychotics in Treatment-Resistant SchizophreniaA Network Meta-analysis

Author Affiliations
  • 1Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany
  • 2Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria
  • 3Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
  • 4Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
  • 5Berner Institut für Hausarztmedizin, University of Bern, Bern, Switzerland
  • 6CTU Bern (Clinical Trials Unit), Department of Clinical Research, University of Bern, Bern, Switzerland
JAMA Psychiatry. 2016;73(3):199-210. doi:10.1001/jamapsychiatry.2015.2955

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Study Selection  At least 2 independent reviewers selected published and unpublished single- and double-blind RCTs in treatment-resistant schizophrenia (any study-defined criterion) that compared any antipsychotic (at any dose and in any form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.