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Original Investigation
December 21, 2021

Effect of Long-term Supplementation With Marine Omega-3 Fatty Acids vs Placebo on Risk of Depression or Clinically Relevant Depressive Symptoms and on Change in Mood Scores: A Randomized Clinical Trial

Author Affiliations
  • 1Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston
  • 2Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 3Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
  • 4Department of Psychiatry, VA Boston Healthcare System, Brockton, Massachusetts
  • 5Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
  • 6Department of Psychiatry, UPMC and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
JAMA. 2021;326(23):2385-2394. doi:10.1001/jama.2021.21187
Visual Abstract. Effect of Long-term Supplementation With Marine Omega-3 Fatty Acids vs Placebo on Risk of Depression
Effect of Long-term Supplementation With Marine Omega-3 Fatty Acids vs Placebo on Risk of Depression
Key Points

Question  Does long-term supplementation with marine omega-3 fatty acids (omega-3) prevent depression in the general adult population?

Findings  In this randomized clinical trial that included 18 353 adults aged 50 years or older without depression or clinically relevant depressive symptoms at baseline, daily omega-3 supplementation compared with placebo resulted in mixed findings of a statistically significant increase in risk of depression or clinically relevant depressive symptoms (hazard ratio, 1.13) but no significant difference in change in 8-item Patient Health Questionnaire depression scale mood scores (0.03 points, comparing omega-3 with placebo), over a 5-year treatment period.

Meaning  These findings do not support the use of omega-3 fatty acid supplements in adults to prevent depression.

Abstract

Importance  Marine omega-3 fatty acid (omega-3) supplements have been used to treat depression but their ability to prevent depression in the general adult population is unknown.

Objective  To test effects of omega-3 supplementation on late-life depression risk and mood scores.

Design, Setting, and Participants  A total of 18 353 adults participated in the VITAL-DEP (Vitamin D and Omega-3 Trial-Depression Endpoint Prevention) ancillary study to VITAL, a randomized trial of cardiovascular disease and cancer prevention among 25 871 US adults. There were 16 657 at risk of incident depression (no previous depression) and 1696 at risk of recurrent depression (previous depression, but not for the past 2 years). Randomization occurred from November 2011 through March 2014; randomized treatment ended on December 31, 2017.

Interventions  Randomized 2 × 2 factorial assignment to vitamin D3 (2000 IU/d), marine omega-3 fatty acids (1 g/d of fish oil, including 465 mg of eicosapentaenoic acid and 375 mg of docosahexaenoic acid) or placebo; 9171 were randomized to omega-3 and 9182 were randomized to matching placebo.

Main Outcomes and Measures  Prespecified coprimary outcomes were risk of depression or clinically relevant depressive symptoms (total of incident + recurrent cases); mean difference in mood score (8-item Patient Health Questionnaire [PHQ-8] depression scale).

Results  Among 18 353 participants who were randomized (mean age, 67.5 [SD, 7.1] years; 49.2% women), 90.3% completed the trial (93.5% among those alive at the end of the trial); the median treatment duration was 5.3 years. The test for interaction between the omega-3 and the vitamin D agents was not significant (P for interaction = .14). Depression risk was significantly higher comparing omega-3 (651 events, 13.9 per 1000 person-years) with placebo (583 events, 12.3 per 1000 person-years; hazard ratio [HR], 1.13; 95% CI, 1.01-1.26; P = .03). No significant differences were observed comparing omega-3 with placebo groups in longitudinal mood scores: the mean difference in change in PHQ-8 score was 0.03 points (95% CI, −0.01 to 0.07; P = .19). Regarding serious and common adverse events, the respective prevalence values in omega-3 vs placebo groups were major cardiovascular events (2.7% vs 2.9%), all-cause mortality (3.3% vs 3.1%), suicide (0.02% vs 0.01%), gastrointestinal bleeding (2.6% vs 2.7%), easy bruising (24.8% vs 25.1%), and stomach upset or pain (35.2% vs 35.1%).

Conclusions and Relevance  Among adults aged 50 years or older without clinically relevant depressive symptoms at baseline, treatment with omega-3 supplements compared with placebo yielded mixed results, with a small but statistically significant increase in risk of depression or clinically relevant depressive symptoms but no difference in mood scores, over a median follow-up of 5.3 years. These findings do not support the use of omega-3 supplements in adults to prevent depression.

Trial Registration  ClinicalTrials.gov Identifiers: NCT01696435 and NCT01169259

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