Jury Is Out on Omega-3 for Major Depression


Here: Insights regarding both the potential positive and negative effects of omega-3 fatty acids on depressive symptoms.

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Does omega-3 fatty acid supplementation have a therapeutic impact on MDD? The jury is still out, according to an abridged Cochrane review published in BMJ.1Early research, which has been duplicated, has drawn associations between low rates of MDD and population groups that have diets rich in omega-3 fatty acids.2

Furthermore, some clinical trial data show that levels of omega-3 fatty acids are low in persons in whom MDD has been diagnosed3,4 and that omega-3 supplementation may be of benefit.4 Yet other studies have found no association between omega-3 supplementation and amelioration of depression.

To gain more clarity on the issue, a team of researchers affiliated with the University of Bristol in the UK conducted a systematic review and meta-analysis to assess the effects of n-3 polyunsaturated fatty acids (n-3PUFAs, or omega-3 fatty acids) against comparators in patients with MDD.

The team culled randomized clinical trials of omega-3 fatty acids in depression from the Cochrane Collaboration Depression, Anxiety, and Neurosis Controlled Trials Register; Cumulative Index to Nursing and Allied Health Literature database; and international trial registries.

Only trials that enrolled adults in whom major or unipolar depression had been diagnosed by a trained professional or validated rating scale were included in the analysis. In all, 26 relevant studies were identified. The quality of evidence was assessed using Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) criteria.5

Twenty five of the 26 studies (n = 1373) compared eicosapentaenoic acid (EPA) and/or docosahexaenoic acid or a mix of various omega-3 fatty acids with placebo. The 1 remaining study, which included 40 subjects, compared EPA at a dosage of 1 g/d with 20 mg/d of fluoxetine.6

Meta-analysis of the studies of omega-3 supplements vs placebo showed a small to modest benefit in relation to relief of depressive symptoms (standardized mean difference in relation to Hamilton Depression Rating Scale scores, -0.32%). The research team, however, deemed the quality of the studies to be very low and their heterogeneity confounding for proper analysis.

As for the 1 study that compared EPA with fluoxetine, no difference was found between treatments.6 The research team deemed the evidence promising but of low quality per GRADE assessment.

Assessment of adverse events-derived from 19 of the studies that compared omega-3 supplements and placebo (inclusive of 1207 subjects)-found little difference between treatment groups. Adverse events in the EPA vs fluoxetine trial were reported as number of events rather than number of subjects who experienced at least 1 event; thus, the researchers deemed interpretation of safety results not feasible.

“Given the high rates of adverse events associated with some antidepressants, n-3PUFAs may offer an alternative treatment of possible benefit and reduced side effects, but more evidence regarding both the potential positive and negative effects of n-3PUFAs for MDD is required before such a suggestion can be advocated,”1 the research team concluded.

They noted that the evidence is limited and highly heterogeneous, which renders their own finding of a small to modest benefit of omega-3 fatty acids on depressive symptoms imprecise and potentially biased.


1. Appleton KM, Sallis HM, Perry R, et al. ω-3 Fatty acids for major depressive disorder in adults: an abridged Cochrane review. BMJ Open. 2016;6(3):e010172.
2. Hibbeln JR. Fish consumption and major depression. Lancet 1998;351:1213.
3. Edwards R, Peet M, Shay J, et al. Depletion of docosahexaenoic acid in red blood cell membranes of depressive patients. Biochem Soc Trans. 1998;26:S142.
4. Peet M, Murphy B, Shay J, et al. Depletion of omega-3 fatty acid levels in red blood cell membranes of depressive patients. Biol Psychiatry. 1998;43:315-319.
5. Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions. 5.1. Chichester, UK: The Cochrane Collaboration & John Wiley & Sons, Ltd; 2011.
6. Jazayeri S, Tehrani-Doost M, Keshavarz SA, et al. Comparison of therapeutic effects of omega3 fatty acid eicosapentaenoic acid and fluoxetine, separately and in combination, in major depressive disorder. Aust N Z J Psychiatry. 2008;42:192-198.

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