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

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.

Conflict of interest statement

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.

Figures

Figure 1.. Flow of Participants in the Vitamin D and Omega-3 Trial (VITAL)–Depression Endpoint Prevention Ancillary Study to the VITAL Triala

aThe participant flow diagram for the 25 871 participants randomized in VITAL has been provided elsewhere. bIncluded 76 190 individuals with history of cardiovascular disease, cancer, and/or safety exclusion criteria; 32 647 individuals unwilling to forgo supplemental vitamin D3 intake greater than 800 IU/d, supplemental calcium intake greater than 1200 mg/d, or fish oil supplementation during the trial; 13 521 men younger than 50 years and women younger than 55 years; and 4465 individuals who reported another exclusion criterion (eg, participation in another trial). cParticipants could have had more than 1 exclusion condition. ICD indicates, International Classification of Diseases; OCD, obsessive-compulsive disorder; PHQ-8, 8-item Patient Health Questionnaire; PTSD, posttraumatic stress disorder.

Figure 2.. Cumulative Incidence Since Randomization Until Occurrence of Total Depression, Incident Depression, and Recurrent Depression in Omega-3 and Placebo Groupsa

aTotal depression is the sum of incidence and recurrence of depression or clinically relevant depressive symptoms; incident depression cases arose from among the 16 657 participants with no history of depression at baseline, and recurrent depression cases arose from among the 1696 participants with a history of depression but were not under treatment or active in the past 2 years at baseline. Panels are provided to illustrate the cumulative incidence curves for incidence and recurrence separately from the total.

Figure 3.. Primary, Secondary, and Nonprespecified and Post Hoc Outcomes Comparing Omega-3 Fatty Acids and Placeboa

aAnalyses to compute hazard ratios (HRs) and CIs were from Cox regression models that were controlled for age, sex, and vitamin D3 randomization group; for subgroup analyses, interactions were tested using multiplicative interaction terms. Because of the potential for type I error due to multiple comparisons, findings for analyses of secondary end points and subgroups should be interpreted as exploratory. Total depression is the sum of incidence and recurrence of depression or clinically relevant depressive symptoms. Incident depression cases arose from among the 16 657 participants with no history of depression history at baseline. Recurrent depression arose from among the 1696 participants with a prior history of depression but were without clinically relevant symptoms or treatment for depression within the past 2 years at baseline. bRace and ethnicity were self-reported by participants. cIncluded Hispanic (not African American), Asian, Native Hawaiian or other Pacific Islander, multiple race, or unknown race or unknown ethnicity. dBaseline plasma levels of EPA and DHA were expressed as a percent of total phospholipid fatty acids. Intake of food related to omega-3 fatty acids were assessed by modified version of Harvard food frequency questionnaire. eThe combined category included intake of mackerel, salmon, sardines, bluefish, swordfish, canned tuna, cod, haddock, or halibut; breaded fish cakes, pieces, or fish sticks; shrimp, lobster, or scallops. fThe Charlson-Deyo comorbidity index is a weighted comorbidity score derived from the sum of the scores for each of several major medical comorbid conditions; participants were categorized as having 0, 1, or 2 or more points. DHA indicates docosahexaenoic acid; EPA, eicosapantaenoic acid.