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How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials

Abstract

We conducted a systematic review and meta-analysis of randomized controlled trials that compared second-generation antipsychotic (SGA) drugs with placebo in schizophrenic patients and which considered 13 different outcome measures. Thirty-eight randomized controlled trials with 7323 participants were included. All SGA drugs were more effective than placebo, but the pooled effect size (ES) for overall symptoms (primary outcome) was moderate (−0.51). The absolute difference (RD) in responder rates was at 18% (41% responded to drug compared with 24% to placebo, number needed to treat=6). Similar ESs were found for the other efficacy parameters: negative symptoms (ES=−0.39), positive symptoms (ES=−0.48), depression (ES=−0.26), relapse (RD 20%) and discontinuation due to inefficacy (RD 17%). Curiously, the efficacy of haloperidol for negative and depressive symptoms was similar to that of the SGA drugs. In contrast to haloperidol, there was no difference in terms of EPS between any SGA drugs and placebo, and there was also no difference in terms of dropouts due to adverse events. Meta-regression showed a decline in treatment response over time, and a funnel plot suggested the possibility of publication bias. We conclude that the drug versus placebo difference of SGA drugs and haloperidol in recent trials was moderate, and that there is much room for more efficacious compounds. Whether methodological issues account in part for the relatively low efficacy ESs and the scarcity of adverse event differences compared with placebo needs to be established.

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Acknowledgements

We are much indebted to the Cochrane Schizophrenia Group. Without access to its register of randomized controlled trials, this review would not have been possible. We also thank AstraZeneca, BristolMyersSquibb, EliLilly, Lundbeck and Sanofi-Aventis for providing unpublished data.

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Correspondence to S Leucht.

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Disclosure/Conflict of interest

This meta-analysis received no funding. Stefan Leucht has received speaker or consultancy honoraria from Sanofi-Aventis, BMS, Lilly, Janssen, Lundbeck and Pfizer. Lilly and Sanofi-Aventis sponsored research projects by Dr Leucht. Werner Kissling has received speaker or consultancy honoraria from Sanofi-Aventis, BMS, Lilly, Janssen, Lundbeck, Bayer and Pfizer. Dieter Arbter, Rolf R Engel and John M Davis have no conflict of interest to declare.

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Leucht, S., Arbter, D., Engel, R. et al. How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials. Mol Psychiatry 14, 429–447 (2009). https://doi.org/10.1038/sj.mp.4002136

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Keywords

  • meta-analysis
  • schizophrenia
  • antipsychotic agents
  • treatment outcome
  • bias
  • methodology

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