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April 10, 2002

Placebo Response in Studies of Major Depression: Variable, Substantial, and Growing

Author Affiliations

Author Affiliations: Department of Psychiatry, College of Physicians and Surgeons of Columbia University (Drs Walsh, Seidman, and Gould), and New York State Psychiatric Institute (Drs Walsh, Seidman, Gould, and Ms Sysko), New York, NY.

JAMA. 2002;287(14):1840-1847. doi:10.1001/jama.287.14.1840

Context Intense debate persists about the need for placebo-controlled groups in clinical trials of medications for major depressive disorder (MDD). There is continuing interest in the development of new medications, but because effective antidepressants are already available, ethical concerns have been raised about the need for placebo groups in new trials.

Objective To determine whether the characteristics of placebo control groups in antidepressant trials have changed over time.

Data Sources and Study Selection We searched MEDLINE and PsychLit for all controlled trials published in English between January 1981 and December 2000 in which adult outpatients with MDD were randomly assigned to receive medication or placebo. Seventy-five trials met our criteria for inclusion.

Data Extraction Data were extracted from the articles by 2 of the authors and discrepancies were resolved via discussion and additional review by a third author.

Data Synthesis The mean (SD) proportion of patients in the placebo group who responded was 29.7% (8.3%) (range, 12.5%-51.8%). Most studies examined more than a single active medication, and, in the active medication group with the greatest response, the mean (SD) proportion of patients responding was 50.1% (9.0%) (range, 31.6%-70.4%). Both the proportion of patients responding to placebo and the proportion responding to medication were significantly positively correlated with the year of publication (for placebo: n = 75; r = 0.45; 95% confidence interval [CI], 0.25-0.61; P<.001; for medication: n = 75; r = 0.26; 95% CI, 0.03-0.46; P = .02). The association between year of publication and response rate was more statistically robust for placebo than medication.

Conclusions The response to placebo in published trials of antidepressant medication for MDD is highly variable and often substantial and has increased significantly in recent years, as has the response to medication. These observations support the view that the inclusion of a placebo group has major scientific importance in trials of new antidepressant medications and indicate that efforts should continue to minimize the risks of such studies so that they may be conducted in an ethically acceptable manner.

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