Fish Oil Does Not Prevent Depression

Daily use of marine omega-3 fatty acid supplements does not prevent later-life depression in adults, according to the results of a recent randomized clinical trial.

To better understand the relationship between long-term omega-3 supplementation and depression, the researchers conducted the Vitamin D and Omega-3 Trial-Depression Endpoint Prevention study. Included were 18,353 adults aged 50 years or older who were at risk of incident depression but did not have previous depression or were at risk of recurrent depression but had not had clinically relevant depressive symptoms for 2 years.

Participants were randomly assigned to receive 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. The primary outcomes included the risk of depression or clinically relevant depressive symptoms, and the mean difference in the 8-item Patient Health Questionnaire (PHQ-8).

The results indicated that while the risk of depression was significantly higher among participants taking omega-3 (651 events, 13.9 per 1000 person-years) compared with those taking placebo (583 events, 12.3 per 1000 person-years), there were no significant differences between the groups for longitudinal mood scores. The mean difference in change for the PHQ-8 score was 0.03 points. No significant interaction was observed between the omega-3 and vitamin D agents.

In addition, the omega-3 and placebo groups had similar prevalence of adverse events:

  • Major cardiovascular events (2.7% and 2.9%)
  • All-cause mortality (3.3% and 3.1%)
  • Suicide (0.02% and 0.01%)
  • Gastrointestinal bleeding (2.6% and 2.7%)
  • Easy bruising (24.8% and 25.1%)
  • Stomach upset or pain (35.2% and 35.1%)

“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,” the researchers concluded. “These findings do not support the use of omega-3 supplements in adults to prevent depression.”


—Leigh Precopio



Okereke OI, Vyas CM, Mischoulon D, et al. 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. JAMA. 2021;326(23):2385-2394. doi:10.1001/jama.2021.21187