Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple treatments meta-analysis.


While all antipsychotics tested were more effective than placebo, their efficacy and side-effects differed substantially. Clozapine had highest efficacy. Haloperidol was associated with the most extrapyramidal side-effects (EPS) while clozapine was associated with less EPS than placebo. Olanzapine was associated with the most weight gain.


  • Meta-analysis of 212 randomized controlled trials to compare 15 antipsychotics and placebo in the acute treatment of schizophrenia or related disorders (schizoaffective, schizophreniform, or delusional disorder).
  • Data collected from 43,049 total participants.
  • Primary outcome: efficacy, measured by mean overall change in symptoms (Positive and Negative Syndrome Scale, or Brief Psychiatric Rating Scale).
  • Secondary outcomes: all-cause discontinuation, weight gain, use of non-prophylactic antiparkinson drugs (as a measure of EPS), prolactin increase, QTc prolongation, and sedation.
  • Focus was on acute treatment, defined as a 6-week duration, or closest data available.


  • All 15 antipsychotic drugs were significantly more effective than placebo, but many were not significantly different from each other.
  • Efficacy: Clozapine showed greatest efficacy, followed by amisulpride, olanzapine, risperidone, and paliperidone.
  • Haloperidol had highest all-cause discontinuation.
  • Weight gain: Olanzapine had greatest weight gain, followed by zotepine, and clozapine. Haloperidol, Ziprasidone, and Lurasidone were the only drugs without significantly more weight gain than placebo.
  • EPS: Haloperidol showed the most EPS, followed by zotepine and chlorpromazine. Five second-generation drugs were associated with significantly more EPS than placebo. Clozapine actually had less EPS than placebo.
  • Prolactin increase: Paliperidone and risperidone had greatest prolactin increase. Aripiprazole and quetiapine had the least.
  • QTc prolongation: Sertindole had the greatest QTc prolongation, followed by amisulpride and ziprasidone. Lurasidone had the least.
  • Sedation: Clozapine, zotepine, and chlorpromazine were most sedating. Amisulpride was not significantly more sedating than placebo, which may be accounted for by the absence of histaminergic receptor blockade. Paliperidone was also not significantly more sedating than placebo, potentially due to its slow-release mechanism limiting plasma peaks.


Leucht S, Cipriani A, Spineli L, Mavridis D, rey D, Richter F, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 2013; 382: 951–962

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