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A Double-blind, Randomized Trial of St John's Wort, Fluoxetine, and Placebo in Major Depressive Disorder

Fava, Maurizio MD*; Alpert, Jonathan MD, PhD*; Nierenberg, Andrew A. MD*; Mischoulon, David MD, PhD*; Otto, Michael W. PhD*; Zajecka, John MD†; Murck, Harald MD‡; Rosenbaum, Jerrold F. MD*

Journal of Clinical Psychopharmacology: October 2005 - Volume 25 - Issue 5 - pp 441-447
Original Contributions

Objective: This study looks to compare the antidepressant efficacy and safety of a standardized extract of St John's wort with both placebo and fluoxetine.

Method: After a 1-week single-blind washout, patients with major depressive disorder diagnosed by Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition were randomized to 12 weeks of double-blind treatment with LI-160 St John's wort extract (900 mg/d), fluoxetine (20 mg/d), or placebo. The 17-item Hamilton Rating Scale for Depression (HAMD-17) was the primary efficacy measure, and analysis of covariance was used to compare differences in end point HAMD-17 scores across the 3 treatment groups, treating the baseline HAMD-17 as the covariate.

Results: One hundred thirty-five patients (57% women; mean age, 37.3 ± 11.0; mean HAMD-17, 19.7 ± 3.2) were randomized to double-blind treatment and were included in the intent-to-treat analyses. Analysis of covariance analyses showed lower mean HAMD-17 scores at end point in the St John's wort group (n = 45; mean ± SD, 10.2 ± 6.6) compared with the fluoxetine group (n = 47; 13.3 ± 7.3; P < 0.03) and a trend toward a similar finding relative to the placebo group (n = 43; 12.6 ± 6.4; P = 0.096). There was also a trend toward higher rates of remission (HAMD-17 <8) in the St John's wort group (38%) compared with the fluoxetine group (30%) and the placebo group (21%). Overall, St John's wort appeared to be safe and well tolerated.

Conclusion: St John's wort was significantly more effective than fluoxetine and showed a trend toward superiority over placebo. A (25%) smaller than planned sample size is likely to account for the lack of statistical significance for the advantage (indicating a moderate effect size, d = 0.45) of St John's wort over placebo.

*Depression Clinical and Research Program, Massachusetts General Hospital, Boston, MA; †Department of Psychiatry, Rush-Presbyterian-St Luke's Medical Center, Chicago, IL and ‡Lichtwer Pharma AG, Wallenroder Straße 8-10, D-13435 Berlin, Germany.

Received August 4, 2003; accepted after revision May 5, 2005.

Address correspondence and reprint requests to Maurizio Fava, MD, Depression Clinical and Research Program, Massachusetts General Hospital, 15 Parkman St, ACC 812, Boston, MA 02114. E-mail: mfava@partners.org.

© 2005 Lippincott Williams & Wilkins, Inc.