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Original Research

Does Inclusion of a Placebo Arm Influence Response to Active Antidepressant Treatment in Randomized Controlled Trials? Results From Pooled and Meta-Analyses

Mark Sinyor, MD; Anthony J. Levitt, MD; Amy H. Cheung, MD; Ayal Schaffer, MD; Alex Kiss, PhD; Yekta Dowlati, MSc; and Krista L. Lanctôt, PhD

Published: January 26, 2010

Article Abstract

Objective: To determine if the inclusion of a placebo arm and/or the number of active comparators in antidepressant trials influences the response rates of the active medication and/or placebo.

Data Sources: Searches of MEDLINE,
PsycINFO, and pharmaceutical Web sites for published trials or trials conducted but unpublished between January 1996 and October 2007.

Study Selection: 2,275 citations were reviewed, 285 studies were retrieved, and 90 were included in the analysis. Trials reporting response and/or remission rates in adult subjects treated with an antidepressant monotherapy for unipolar major depression were included.

Data Extraction: The primary investigator recorded the number of responders and/or remitters in the intent-to-treat population of each study arm or computed these numbers using the quoted rates.

Data Synthesis: Poisson regression analyses demonstrated that mean response rate for the active medication was higher in studies comparing 2 or more active medications without a placebo arm than in studies comparing 2 or more active medications with a placebo arm (65.4% vs 57.7%, P’ ‰<‘ ‰.0001) or in studies comparing only 1 active medication with placebo (65.4% vs 51.7%, P’ ‰=’ ‰.0005). Mean response rate for placebo was significantly lower in studies comparing 1 rather than 2 or more active medications (34.3% vs 44.6%, P’ ‰=’ ‰.003). Mean remission rates followed a similar pattern. Meta-analysis confirmed results from the pooled analysis.

Conclusions: These data suggest that antidepressant response rates in randomized control trials may be influenced by the presence of a placebo arm and by the number of treatment arms and that placebo response rates may be influenced by the number of active treatment arms in a study.

Submitted: July 3, 2008; accepted January 2, 2009.

Online ahead of print: January 26, 2010.

Corresponding author: Anthony J. Levitt, MD, Sunnybrook Health Sciences Centre, Department of Psychiatry, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada (

Volume: 71

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