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
([email protected]).