Omega-3 fatty acids for the treatment of depression: systematic review and meta-analysis

Abstract

We conducted a meta-analysis of randomized, placebo-controlled trials of omega-3 fatty acid (FA) treatment of major depressive disorder (MDD) in order to determine efficacy and to examine sources of heterogeneity between trials. PubMed (1965-May 2010) was searched for randomized, placebo-controlled trials of omega-3 FAs for MDD. Our primary outcome measure was standardized mean difference in a clinical measure of depression severity. In stratified meta-analysis, we examined the effects of trial duration, trial methodological quality, baseline depression severity, diagnostic indication, dose of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in omega-3 preparations, and whether omega-3 FA was given as monotherapy or augmentation. In 13 randomized, placebo-controlled trials examining the efficacy of omega-3 FAs involving 731 participants, meta-analysis demonstrated no significant benefit of omega-3 FA treatment compared with placebo (standard mean difference (SMD)=0.11, 95% confidence interval (CI): -0.04, 0.26). Meta-analysis demonstrated significant heterogeneity and publication bias. Nearly all evidence of omega-3 benefit was removed after adjusting for publication bias using the trim-and-fill method (SMD=0.01, 95% CI: -0.13, 0.15). Secondary analyses suggested a trend toward increased efficacy of omega-3 FAs in trials of lower methodological quality, trials of shorter duration, trials which utilized completers rather than intention-to-treat analysis, and trials in which study participants had greater baseline depression severity. Current published trials suggest a small, non-significant benefit of omega-3 FAs for major depression. Nearly all of the treatment efficacy observed in the published literature may be attributable to publication bias.

Figure 1. Forest Plot of Omega-3 Fatty Acids for Depression

There was no significant effect of omega-3 fatty acids for major depression compared to placebo. There was significant evidence of heterogeneity between trials. Significant publication bias was also evident using the rank correlation test (τ_b=0.47, z=2.3, p=0.02).

Figure 2. Funnel Plot Examining Publication Bias in Omega-3 Fatty Acid Trials to Treat Major Depression

This funnel plot depicts the effect size of trials versus their inverse standard error. Published trials are depicted as circles and are shaded from darkest to lightest based on their publication year. White squares represent potentially missing trials that were imputed based on the trim-and-fill method. The red line represents the point estimate for omega-3 treatment effects based on published trials (SMD=0.11, 95% CI: -0.04, 0.26), p=0.14). The red curves bracket the 95% CI for the expect results of trials given this estimated underlying effect size. The black vertical line represents the new point estimate for the effect size of omega-3 fatty acids when publication bias is adjusted for using the trim-and-fill method. (SMD=0.01, 95% CI: -0.13, 0.15). Abbreviations: SMD=standardized mean difference, CI=confidence interval.

Figure 3. Forest Plot of Omega-3 Fatty Acids for Depression Stratified by Baseline Depression Severity

Trials in which participants were at least moderately depressed on average before starting treatment reported a greater efficacy of omega-3 fatty acids when compared to trials in which participants were only mildly depressed (test for subgroup differences: χ² = 11.7, df = 1 (P < 0.0006), I² = 91%). For stratification of trials by baseline depression severity we used traditional cutoffs for the HAM-D-17 (mild: <18, moderate: 18-28, severe: >28) . Trials that measured initial depression severity on scales other than the HAM-D-17 were converted to this scale based on previously defined algorithms . Abbreviation: CI= confidence interval.

Figure 4. Meta-Regression of Effect Size of Omega-3 Fatty Acids versus Trial Duration

Trials of shorter duration tended to show a greater efficacy of omega-3 fatty acid. The size of the circle representing each trial is proportional to its weighting on the overall analysis (β=-0.11 ± 0.04, 95%CI: (-0.20, -0.01), p=0.028, R=0.37). Trials were weighted using the generic inverse variance method.

Figure 5. Forest Plot of Omega-3 Fatty Acids for Depression Stratified by Methodological Quality of Trials

Omega-3 fatty acids tended to show greater efficacy in trials judged of lower quality (JADAD=3 or 4) than in trials judged of higher quality (JADAD=5 Test for subgroup differences: Chi² = 7.2, df = 1 (P = 0.007), I² = 86%). Clinical trials were stratified based on a median split of scores on the JADAD Scale The JADAD scale rates trials on presence and appropriateness of randomization and blinding as well as whether the number and reasons for dropouts was described in each trial.

Figure 6. Forest Plot of Omega-3 Fatty Acids for Depression Stratified by Method of Accounting for Dropouts

Omega-3 fatty acids tended to shower greater efficacy in trials that utilized completers analysis compared to trials that employed a modified intention-to-treat or an intention-to-treat analysis (Test for subgroup differences: Chi² = 9.5, df = 1 (P = 0.009), I = 79%).