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Original Research

Complementary and Alternative Medicine for Major Depressive Disorder: A Meta-Analysis of Patient Characteristics, Placebo-Response Rates, and Treatment Outcomes Relative to Standard Antidepressants

Marlene P. Freeman, MD; David Mischoulon, MD, PhD; Enrico Tedeschini, MD; Tracie Goodness, BS; Lee S. Cohen, MD; Maurizio Fava, MD; and George I. Papakostas, MD

Published: June 15, 2010

Article Abstract

Objective: To compare patient characteristics, placebo-response rates, and outcome differences in active treatment compared to placebo in randomized controlled trials (RCTs) of complementary and alternative medicine (CAM) and standard antidepressants for major depressive disorder (MDD).

Data Sources: Eligible studies were first identified using searches of PubMed/MEDLINE, restricted to English, by cross-referencing the search term placebo with each of the antidepressants (those that had received letters of approval by the US, Canadian, or EU drug regulatory agencies for the treatment of MDD) and selected CAM agents. These searches were limited to articles published between January 1, 1980, and September 15, 2009 (inclusive). Reference lists from identified studies were also searched for studies eligible for inclusion.

Study Selection: We selected RCTs for MDD that included validated diagnostic assessment and baseline/outcome measures of illness severity. Assessment was limited to widely used CAM agents most frequently studied in RCTs with pill placebo: St John’s wort, omega-3 fatty acids, and S-adenosyl-l-methionine (SAMe).

Data Synthesis: Of eligible publications, 173 reported results of 1 trial, and 5 included > 1 trial, representing a total of 185 RCTs. Patient variables, including illness severity, were similar across CAM and antidepressant RCTs, except for a higher proportion of women in CAM studies (P = .0003). Random-effects meta-analysis indicated that both antidepressant and CAM monotherapy resulted in superior response rates compared with placebo. Placebo-response rates were significantly lower for patients enrolled in CAM versus antidepressant RCTs (P = .002). Meta-regression analyses yielded no significant differences in the relative risk of prematurely discontinuing therapy due to any reason between active treatment and placebo for antidepressant and CAM RCTs, although discontinuation due to adverse events was higher in antidepressant RCTs compared to CAM RCTs (P = .007).

Conclusions: Participants in CAM trials were more likely to be female and to have a lower placebo-response rate compared to those in standard antidepressant trials for MDD. Trials of standard antidepressants and CAM therapies were composed of patients with similar depression severity.

J Clin Psychiatry 2010;71(6):682-688

Submitted: January 12, 2010; accepted March 16, 2010 (doi:10.4088/JCP.10r05976blu).

Corresponding author: Marlene P. Freeman, MD, Perinatal and Reproductive Psychiatry Program, Massachusetts General Hospital, 185 Cambridge St, 2nd Floor, Boston, MA 02114 (

Volume: 71

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