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Previous studies have reported that effect sizes of antidepressants were larger in two-armed than in three-armed or more-armed (multiarmed) randomized trials, where the probability of being allocated to placebo is lower. However, these studies have not taken into account the publication bias, differences among antidepressants, or covariance in multiarmed studies, or examined sponsorship bias. We searched published and unpublished randomized-controlled trials that compared placebo with 21 antidepressants for the acute treatment of major depression in adults. We calculated the ratio of odds ratios (ROR) of drug response over placebo in two-armed versus multiarmed trials for each antidepressant, and then synthesized RORs across all the included antidepressants using the multivariate meta-analysis. A random-effects model was used throughout. Two hundred and fifty-eight trials (66 two-armed and 192 multiarmed trials; 80 454 patients; 43.0% with unpublished data) were included in the present analyses. The pooled ROR for response of two-armed trials over multiarmed trials was 1.09 (95% confidence interval: 0.96-1.24). The ROR did not materially change between types of antidepressants, publication year, or sponsorship. The differences between two-armed versus multiarmed studies were much smaller than were suggested in previous studies and were not significant.

Original publication




Journal article


International clinical psychopharmacology

Publication Date



Departments of aHealth Promotion and Human Behavior bClinical Epidemiology, Kyoto University Graduate School of Medicine/School of Public Health cDepartment of Clinical Biostatistics, Kyoto University Graduate School of Medicine, Kyoto, Japan dOxford Centre for Human Brain Activity, Wellcome Centre for Integrative Neuroimaging eDepartment of Psychiatry, University of Oxford fOxford Health NHS Foundation Trust, Warneford Hospital, Oxford, UK gInstitute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.