A Double-Blind, Randomized Controlled Trial of Ethyl-Eicosapentaenoate for Major Depressive Disorder

Objective: To examine the efficacy and tolerability of ethyl-eicosapentaenoate (EPA-E) monotherapy for major depressive disorder (MDD).

Method: Fifty-seven adults with DSM-IV MDD were randomly assigned from January 2003 until June 2006 to receive 1 g/d of eicosapentaenoic acid (EPA) or placebo for 8 weeks in a double-blind, randomized, controlled pilot study. Response criteria were on the basis of the 17-item Hamilton Depression Rating Scale (HDRS-17). Subjects’ plasma lipid profiles were examined by gas chromatography.

Results: Thirty-five subjects (63% female; mean±SD age=45±13 years) were eligible for the intent to treat (ITT) analysis. In the ITT sample, mean±SD HDRS-17 scores decreased from 21.6±2.7 to 13.9±8.9 for the EPA group (n=16) and from 20.5±3.6 to 17.5±7.5 for the placebo group (n=19) (P=.123); the effect size for EPA was 0.55. ITT response rates were 38% (6/16) for EPA, and 21% (4/19) for placebo (P=.45). Among the 24 study completers, mean±SD HDRS-17 scores decreased from 21.3±3.0 to 11.1±8.1 for the EPA group and from 20.5±3.8 to 16.3±6.9 for the placebo group (P=.087); the effect size for EPA was 0.73. Completer response rates were 45% (5/11) for EPA, and 23% (3/13) for placebo (P=.39). Among EPA subjects, baseline n-6/n-3 ratio was associated with decrease in HDRS-17 score (r=−0.686, P=.030) and with treatment response (P=.032); change in n-6/n-3 ratio was associated with change in HDRS-17 score (r=.784, P=.032). Side effects, reported in 2 EPA subjects and 5 placebo subjects, were exclusively gastrointestinal, mild, and not associated with discontinuation.

Conclusions: EPA demonstrated an advantage over placebo that did not reach statistical significance, possibly due to the small sample and low completer rates, which were the major study limitations.

Trial Registration: clinicaltrials.gov Identifier: NCT00096798

Submitted: August 7, 2008; accepted November 10, 2008.

Online ahead of print: August 25, 2009.

Corresponding author: David Mischoulon, PhD, 50 Staniford St, Suite 401, Massachusetts General Hospital, Boston, MA 02114 (dmischoulon@partners.org).

J Clin Psychiatry 2009;70(12):1636-1644