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

B. Timothy Walsh, MD; Stuart N. Seidman, MD; Robyn Sysko, BA; Madelyn Gould, PhD
JAMA. 2002;287(14):1840-1847. doi:10.1001/jama.287.14.1840.
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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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Figure. Proportion of Patients Assigned to Placebo, Tricyclic Antidepressants (TCAs), and Selective Serotonin Reuptake Inhibitors (SSRIs) Who Showed a 50% or Greater Improvement in Hamilton Rating Scale For Depression Score by Year of Publication
Graphic Jump Location
For studies that did not provide data on response using this criterion, an estimated proportion was calculated based on the proportion of patients rated moderately or markedly improved on the Clinical Global Impression (see "Results" section). The lines are the best-fit straight lines describing the relationship between proportion of patients responding and year of publication for placebo (r = 0.45, n = 75, P<.001), TCAs (r = 0.29, n = 43, P = .06), and SSRIs (r = 0.47, n = 33, P = .006).

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