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.