Solving the antidepressant efficacy question: effect sizes in major depressive disorder

Background: Numerous reviews and meta-analyses of the antidepressant literature in major depressive disorders (MDD), both acute and maintenance, have been published, some claiming that antidepressants are mostly ineffective and others that they are mostly effective, in either acute or maintenance treatment.

Objective: The aims of this study were to review and critique the latest and most notable antidepressant MDD studies and to conduct our own reanalysis of the US Food and Drug Administration database studies specifically analyzed by Kirsch et al.

Methods: We gathered effect estimates of each MDD study. In our reanalysis of the acute depression studies, we corrected analyses for a statistical floor effect so that relative (instead of absolute) effect size differences were calculated. We also critiqued a recent meta-analysis of the maintenance treatment literature.

Results: Our reanalysis showed that antidepressant benefit is seen not only in severe depression but also in moderate depression and confirmed a lack of benefit for antidepressants over placebo in mild depression. Relative antidepressant versus placebo benefit increased linearly from 5% in mild depression to 12% in moderate depression to 16% in severe depression. The claim that antidepressants are completely ineffective, or even harmful, in maintenance treatment studies involves unawareness of the enriched design effect, which, in that analysis, was used to analyze placebo efficacy. The same problem exists for the standard interpretation of those studies, although they do not prove antidepressant efficacy either, since they are biased in favor of antidepressants.

Conclusions: In sum, we conclude that antidepressants are effective in acute depressive episodes that are moderate to severe but are not effective in mild depression. Except for the mildest depressive episodes, correction for the statistical floor effect proves that antidepressants are effective acutely. These considerations only apply to acute depression, however. For maintenance, the long-term efficacy of antidepressants is unproven, but the data do not support the conclusion that they are harmful.