Efficacy of Antidepressant Medication vs Placebo Increases With Severity of Depression

Laurie Barclay, MD


January 27, 2010

Antidepressant Drug Effects and Depression Severity: A Patient-Level Meta-analysis

Fournier JC, DeRubeis RJ, Hollon SD, et al
JAMA. 2010;303:47-53


Although antidepressant medications are the gold standard of care for major depressive disorder, evidence is limited to date regarding their efficacy vs pill placebo for patients with less severe depression. The goal of this review was to assess the relative benefit of antidepressant medication compared with placebo in patients with a wide range of initial severity of depressive symptoms.

The reviewers searched PubMed, PsycINFO, and Cochrane Library databases from January 1980 through March 2009, as well as bibliographies of retrieved meta-analyses and reviews, for randomized, placebo-controlled trials of antidepressants approved by the US Food and Drug Administration for treatment of major or minor depressive disorder. Selection criteria were trials in adult outpatients of medication vs placebo for at least 6 weeks, with measurement of the Hamilton Depression Rating Scale (HDRS), without exclusion of patients based on a placebo washout period, and for which the authors provided original, individual patient-level data. Data were analyzed from 6 studies, enrolling a total of 718 patients.

Efficacy of medication vs placebo varied considerably based on severity of depressive symptoms at baseline. For patients with HDRS scores < 23, Cohen d effect sizes for the difference between medication and placebo were estimated to be < 0.20, which is a standard definition of a small effect. With increases in baseline depression severity, estimates of the magnitude of the superiority of medication over placebo increased. At a baseline HDRS score of 25, the magnitude of the superiority of medication vs placebo crossed the threshold defined by the National Institute for Clinical Excellence for a clinically significant difference.


Limitations of this meta-analysis include lack of generalizability to patients with baseline HDRS scores of 13, use of HDRS scores as the primary outcome measure for all analyses, possible publication bias, and inability to extrapolate the findings to continuation or maintenance treatment. Nonetheless, this review suggests that that the magnitude of benefit of antidepressant medication compared with placebo increases with severity of depressive symptoms at baseline. Although the benefit of medications vs placebo is significant in patients with very severe depression, it may be minimal or nonexistent in patients with mild or moderate symptoms. Prescribers, policymakers, and patients could all benefit from being made aware of these important findings.



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