Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression

Abstract

Objective: Randomized trials of omega-3 polyunsaturated fatty acid (PUFA) treatment for depression have differed in outcome. Recent meta-analyses ascribe discrepancies to differential effects of eicosapentaenoic acid (EPA) versus docosahexaenoic acid (DHA) and to diagnostic heterogeneity. This meta-analysis tests the hypothesis that EPA is the effective component in PUFA treatment of major depressive episodes.

Data sources: PubMed/MeSH was searched for studies published in English from 1960 through June 2010 using the terms fish oils (MeSH) AND (depressive disorder [MeSH] OR bipolar depression) AND randomized controlled trial (publication type). The search was supplemented by manual bibliography review and examination of relevant review articles.

Study selection: The search yielded 15 trials involving 916 participants. Studies were included if they had a prospective, randomized, double-blinded, placebo-controlled study design; if depressive episode was the primary complaint (with or without comorbid medical conditions); if omega-3 PUFA supplements were administered; and if appropriate outcome measures were used to assess depressed mood.

Data extraction: Extracted data included study design, sample sizes, doses and percentages of EPA and DHA, mean ages, baseline and endpoint depression ratings and standard deviations for PUFA and placebo groups, and P values. The clinical outcome of interest was the standardized mean difference in the change from baseline to endpoint scores on a depression rating scale in subjects taking PUFA supplements versus subjects taking placebo.

Data synthesis: In a mixed-effect model, percentage of EPA in the supplements was the fixed-effect predictor, dichotomized into 2 groups: EPA < 60% or EPA ≥ 60% of the total EPA + DHA. Secondary analyses explored the relevance of treatment duration, age, and EPA dose.

Results: Supplements with EPA ≥ 60% showed benefit on standardized mean depression scores (effect size = 0.532; 95% CI, 0.277-0.733; t = 4.195; P < .001) versus supplements with EPA < 60% (effect size = -0.026; 95% CI, -0.200 to 0.148; t = -0.316; P = .756), with negligible contribution of random effects or heteroscedasticity and with no effects of treatment duration or age. Supplements with EPA < 60% were ineffective. Exploratory analyses supported a nonlinear model, with improvement determined by the dose of EPA in excess of DHA, within the range of 200 to 2,200 mg/d of EPA.

Conclusions: Supplements containing EPA ≥ 60% of total EPA + DHA, in a dose range of 200 to 2,200 mg/d of EPA in excess of DHA, were effective against primary depression. Translational studies are needed to determine the mechanisms of EPA's therapeutic benefit.

Figure 1

Standardized Mean Differences and 95% Confidence Intervals for Studies in Depressive Episodes Comparing Antidepressant Effect Between Omega-3 Polyunsaturated Fatty Acids and Placebo, Arranged by Percentage of Eicosapentaenoic Acid (EPA) in the Supplements.

Figure 2

Funnel Plot of Effect Sizes for Clinical Trials Included in the Meta-Analysis.

Figure 3

Exploratory Study of the Relationship between Unopposed PUFA Dose and Effect Size in Clinical Trials Comparing PUFA with Placebo Supplementation. Abbreviations: SD = Standard Deviation; EPA=Eicosapentaenoic acid; DHA=Docosahexaenoic acid; PUFA=Polyunsaturated Fatty Acid. Unopposed PUFA supplement doses are defined as the absolute values of the difference between EPA (mg/day) and DHA (mg/day) and presented in a continuum, left to right, from the greatest unopposed DHA dose to the greatest unopposed EPA dose.