Research Question

  1. What are the efficacy and safety of omega-3 fatty acid supplements, as an adjunctive or monotherapy, for depressive symptoms and quality of life in adults with major depressive disorder compared with placebo or active comparator?

RAND researchers conducted a systematic review that synthesized evidence from randomized controlled trials of omega-3 fatty acids — used adjunctively or as monotherapy — to provide estimates of their efficacy and safety in treating adults with major depressive disorder.

Outcomes of interest included changes in depressive symptomatology, quality of life, and adverse effects. Efficacy meta-analyses used the Hartung-Knapp-Sidik-Jonkman method for random-effects models. Quality of evidence was assessed using a modification of the Grades of Recommendation, Assessment, Development, and Evaluation (or GRADE) approach.

In total, 24 studies met inclusion criteria. All studies combined showed a small but significant effect of omega-3 fatty acids compared with placebo on depression scale scores and the proportion of treatment responders, but there was evidence of publication bias. Only two studies compared eicosapentaenoic acid (EPA) with docosahexaenoic acid (DHA) head to head. Pooling studies of EPA alone and those with a high EPA:DHA ratio revealed a significant effect on depression scale scores and on the proportion of treatment responders compared with placebo, but studies that administered DHA alone or a high DHA:EPA ratio showed no effect. Very few studies specified depression severity, and few studies assessed effects on quality of life. Omega-3 fatty acids were associated with an increased risk for mild gastrointestinal symptoms compared with placebo but not with other categories of mild adverse events or serious adverse events.

The omega-3 fatty acid EPA may have a small benefit in improving depression symptoms compared with placebo, with relatively minor gastrointestinal adverse events for adults with MDD, but the existing evidence base is weak.

Key Findings

Eicosapentaenoic Acid (EPA) for Mild and Moderate Depression Might Have a Small Benefit, but the Evidence Base Is Weak

  • The review showed that dietary supplements of omega-3 fatty acids may have a small benefit in improving depression symptoms compared with placebo; however, the quality of evidence for this conclusion is weak.
  • Subgroup analyses indicated higher efficacy of supplements that contain EPA or higher concentrations of EPA than DHA.
  • Benefits compared with placebo were primarily based on monotherapy studies.
  • Too few studies assessed effects of omega-3 fatty acids on remission and quality of life to draw conclusions.
  • Omega-3 fatty acids were associated with an increased risk for mild gastrointestinal symptoms but not with other categories of adverse events or serious adverse events.


  • Based on our assessment of the limitations of the existing literature and the relatively low risks involved, we believe two large trials are warranted. One trial should employ a 2x2 factorial design to assess the effects of mono- and adjunctive therapy in patients who have already responded to antidepressant therapy. A second trial should assess the effects of EPA monotherapy in individuals who may not be able to take antidepressants, including community-dwelling elderly, pregnant/postpartum women, and those with end-stage renal disease.
  • Research on differential effects of omega-3 fatty acids for individuals of different depression severity are needed, particularly their use in severe depression.
  • Assessment is also needed to identify those most likely to respond, presumably via a simple rapid biomarker test.

This research was sponsored by the Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury and conducted within the Forces and Resources Policy Center of the RAND National Defense Research Institute, a federally funded research and development center sponsored by the Office of the Secretary of Defense, the Joint Staff, the Unified Combatant Commands, the Navy, the Marine Corps, the defense agencies, and the defense Intelligence Community.

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