Effect of Long-term Supplementation With Marine Omega-3 Fatty Acids vs Placebo on Risk of Depression | Complementary and Alternative Medicine | JN Learning | AMA Ed Hub [Skip to Content]
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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 ScoresA Randomized Clinical Trial

Educational Objective
To learn whether omega-3 supplementation is effective for the prevention of depression.
1 Credit CME
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.


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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Article Information

Corresponding Author: Olivia I. Okereke, MD, SM, Massachusetts General Hospital, One Bowdoin Square, Seventh Floor, Boston, MA 02114 (olivia.okereke@mgh.harvard.edu).

Accepted for Publication: November 7, 2021.

Author Contributions: Dr Okereke had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Okereke, Reynolds, Mischoulon, Chang, Cook, Manson.

Acquisition of data: All authors.

Analysis and Interpretation of data: All authors.

Initial drafting of the manuscript: Okereke.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Okereke, Vyas, Cook, Bubes.

Obtained funding: Okereke, Buring, Manson.

Administrative, technical, and material support: Vyas, Weinberg, Copeland, Friedenberg.

Supervision: Okereke, Reynolds, Mischoulon, Chang, Cook, Lee, Buring, Manson.

Conflict of Interest Disclosures: Dr Okereke reported receiving royalties from Springer Publishing. Dr Mischoulon reported receiving nonfinancial support from Nordic Naturals and heckel medizintechnik GmbH outside the submitted work; speaking honoraria from the Massachusetts General Hospital Psychiatry Academy; and working with the Massachusetts General Hospital Clinical Trials Network and Institute, which has received research funding from multiple pharmaceutical companies and from the National Institute of Mental Health (NIMH). Dr Manson reported receiving grants from Mars Edge and nonfinancial support from Pronova BioPharma/BASF. No other disclosures were reported.

Funding/Support: VITAL-DEP was supported by grants R01 MH091448 from NIMH. VITAL is supported by grants U01 CA138962, R01 CA138962, and R01 AT011729, which included support from the National Cancer Institute; National Heart, Lung, and Blood Institute (NHLBI); Office of Dietary Supplements; National Institute of Neurological Disorders and Stroke; and the National Center for Complementary and Integrative Health. The VITAL ancillary studies and the Clinical and Translational Science Center component are supported by grants DK088078 and R01 DK088762 from the National Institute of Diabetes and Digestive and Kidney Diseases; R01 HL101932 and R01 HL102122 from NHLBI; R01 AG036755 from the National Institute on Aging (NIA); R01 AR059086 and R01 AR060574 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases; and R01 MH091448 from the NIMH. Dr Reynolds’ participation was supported by grant P30 MH090333 from the NIMH and the University of Pittsburgh Medical Center Endowment in Geriatric Psychiatry. The study agents, matching placebo, and packaging were donated by Pharmavite LLC (vitamin D) and Pronova BioPharma (fish oil).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Meeting Presentation: Portions of this study were presented in summary at the North American Menopause Society 2019 Annual Meeting; September 26, 2019; Chicago, Illinois.

Data Sharing Statement: See Supplement 3.

Additional Contributions: We thank the participants in this study. Voting members of the data and safety monitoring board for VITAL and ancillary studies, including VITAL-DEP, included Lawrence S. Cohen, MD; Theodore Colton, ScD; Mark A. Espeland, PhD; Craig Henderson, MD; Alice H. Lichtenstein, ScD; Rebecca A. Silliman, MD, PhD; and Nanette Wenger, MD (chair). Ex-officio members include Josephine Boyington, PhD, MPH; Rebecca Costello, PhD; Cindy Davis, PhD; Peter Greenwald, MD; Gabriela Riscuta, MD; and Harold Seifried, PhD; none of whom were compensated.

Additional Information: VITAL-DEP has been approved by the institutional review board of Partners Healthcare and Brigham and Women’s Hospital. The VITAL study agents have received Investigational New Drug Approval from the US Food and Drug Administration.

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