• J Moncrieff, S Wessely, and R Hardy.
• Psychiatry, University College London, Warley hospital, Mascalls Lane, Brentwood, Essex, UK, CM14 4TU.
• Cochrane Db Syst Rev. 2004 Jan 1; 2004 (1): CD003012CD003012.

BackgroundAlthough there is a consensus that antidepressants are effective in depression, placebo effects are also thought to be substantial. Side effects of antidepressants may reveal the identity of medication to participants or investigators and thus may bias the results of conventional trials using inert placebos. Using an 'active' placebo which mimics some of the side effects of antidepressants may help to counteract this potential bias.ObjectivesTo investigate the efficacy of antidepressants when compared with 'active' placebos.Search StrategyThe Cochrane Collaboration Depression, Anxiety and Neurosis review groups's search strategy was used to search MEDLINE (1966-2000), PsychLIT (1980-2000) and EMBASE (1974-2000) and this was last done in July 2000. Reference lists from relevant articles and textbooks were searched and 12 specialist journals were handsearched up to 1996.Selection CriteriaRandomised and quasi randomised controlled trials comparing antidepressants with active placebos in people with depression.Data Collection And AnalysisSince many different outcome measures were used a standard measure of effect was calculated for each trial. A subgroup analysis of inpatient and outpatient trials was conducted. Two reviewers independently assessed whether each trial met inclusion criteria.Main ResultsNine studies involving 751 participants were included. Two of them produced effect sizes which showed a consistent and statistically significant difference in favour of the active drug. Combining all studies produced a pooled estimate of effect of 0.39 standard deviations (confidence interval, 0.24 to 0.54) in favour of the antidepressant measured by improvement in mood. There was high heterogeneity due to one strongly positive trial. Sensitivity analysis omitting this trial reduced the pooled effect to 0.17 (0.00 to 0.34). The pooled effect for inpatient and outpatient trials was highly sensitive to decisions about which combination of data was included but inpatient trials produced the lowest effects.Reviewer's ConclusionsThe more conservative estimates from the present analysis found that differences between antidepressants and active placebos were small. This suggests that unblinding effects may inflate the efficacy of antidepressants in trials using inert placebos. Further research into unblinding is warranted.

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