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Efficacy of antidepressants over placebo is similar in two-armed versus three-armed or more-armed randomized placebo-controlled trials

Ogawa, Yusukea; Furukawa, Toshi A.a,b; Takeshima, Nozomia; Hayasaka, Yua; Atkinson, Lauren Z.d,e; Tanaka, Shiroc; Cipriani, Andreae,f; Salanti, Georgiag

International Clinical Psychopharmacology: March 2018 - Volume 33 - Issue 2 - p 66–72
doi: 10.1097/YIC.0000000000000201

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 We searched published and unpublished randomized-controlled trials that compared placebo with 21 antidepressants for the acute treatment of major depression in adults.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 Two hundred and fifty-eight trials (66 two-armed and 192 multiarmed trials; 80 454 patients; 43.0% with unpublished data) were included in the present analyses.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.

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

Correspondence to Toshi A. Furukawa, MD, PhD, Departments of Health Promotion and Human Behavior and of Clinical Epidemiology, Kyoto University Graduate School of Medicine/School of Public Health, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan Tel: +81 75 753 9491; fax: +81 75 753 4641; e-mail:

Received August 1, 2017

Accepted September 26, 2017

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