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Reviews and Overviews   |    
A Model of Placebo Response in Antidepressant Clinical Trials
Bret R. Rutherford, M.D.; Steven P. Roose, M.D.
Am J Psychiatry 2013;170:723-733. doi:10.1176/appi.ajp.2012.12040474
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Dr. Rutherford reports no financial relationships with commercial interests. Dr. Roose has served as a consultant to Pfizer and Forest Laboratories.

Supported by NIMH grant K23 MH085236 to Dr. Rutherford and grant T32 MH015144 to Dr. Roose; by a Hope for Depression Research Foundation grant to Dr. Rutherford; and by a NARSAD Young Investigator Award to Dr. Rutherford.

From Columbia University College of Physicians and Surgeons and New York State Psychiatric Institute, New York.

Address correspondence to Dr. Rutherford (brr8@columbia.edu).

Copyright © 2013 by the American Psychiatric Association

Received April 11, 2012; Revised July 13, 2012; Accepted August 13, 2012.

Abstract

Placebo response in clinical trials of antidepressant medications is substantial and has been increasing. High placebo response rates hamper efforts to detect signals of efficacy for new antidepressant medications, contributing to trial failures and delaying the delivery of new treatments to market. Media reports seize upon increasing placebo response and modest advantages for active drugs as reasons to question the value of antidepressant medication, which may further stigmatize treatments for depression and dissuade patients from accessing mental health care. Conversely, enhancing the factors responsible for placebo response may represent a strategy for improving available treatments for major depressive disorder. A conceptual framework describing the causes of placebo response is needed in order to develop strategies for minimizing placebo response in clinical trials, maximizing placebo response in clinical practice, and talking with depressed patients about the risks and benefits of antidepressant medications. In this review, the authors examine contributors to placebo response in antidepressant clinical trials and propose an explanatory model. Research aimed at reducing placebo response should focus on limiting patient expectancy and the intensity of therapeutic contact in antidepressant clinical trials, while the optimal strategy in clinical practice may be to combine active medication with a presentation and level of therapeutic contact designed to enhance treatment response.

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FIGURE 1. A Model of Placebo Response in Antidepressant Clinical Trials

FIGURE 2. Response Rates to Antidepressant Medication in Placebo-Controlled and Comparator Study Designs for Children and Adolescents, Adults, and Older Adults

*p<0.05.

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TABLE 1.Sources of Placebo Response in Antidepressant Clinical Trials
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TABLE 2.Study Design Features Influencing Placebo Response in Antidepressant Clinical Trials
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