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Original Investigation
August 4, 2020

Effect of Long-term Vitamin D3 Supplementation 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 and Harvard Medical School, Boston
  • 2Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
  • 3Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
  • 4Department of Psychiatry, UPMC and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
  • 5Department of Psychiatry, VA Boston Healthcare System, Brockton, Massachusetts
  • 6Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
JAMA. 2020;324(5):471-480. doi:10.1001/jama.2020.10224
Key Points

Question  Can long-term supplementation with vitamin D3 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, vitamin D3 supplementation compared with placebo did not result in statistically significant differences in the incidence and recurrence of depression or clinically relevant depressive symptoms (hazard ratio, 0.97) or for change in mood scores over a 5-year treatment period.

Meaning  These findings do not support the use of vitamin D3 in adults to prevent depression.

Abstract

Importance  Low levels of 25-hydroxyvitamin D have been associated with higher risk for depression later in life, but there have been few long-term, high-dose large-scale trials.

Objective  To test the effects of vitamin D3 supplementation on late-life depression risk and mood scores.

Design, Setting, and Participants  There were 18 353 men and women aged 50 years or older in the VITAL-DEP (Vitamin D and Omega-3 Trial-Depression Endpoint Prevention) ancillary study to VITAL, a randomized clinical trial of cardiovascular disease and cancer prevention among 25 871 adults in the US. There were 16 657 at risk for incident depression (ie, no depression history) and 1696 at risk for recurrent depression (ie, depression history but no treatment for depression within the past 2 years). Randomization occurred from November 2011 through March 2014; randomized treatment ended on December 31, 2017, and this was the final date of follow-up.

Intervention  Randomized assignment in a 2 × 2 factorial design to vitamin D3 (2000 IU/d of cholecalciferol) and fish oil or placebo; 9181 were randomized to vitamin D3 and 9172 were randomized to matching placebo.

Main Outcomes and Measures  The primary outcomes were the risk of depression or clinically relevant depressive symptoms (total of incident and recurrent cases) and the mean difference in mood scores (8-item Patient Health Questionnaire depression scale [PHQ-8]; score range, 0 points [least symptoms] to 24 points [most symptoms]; the minimal clinically important difference for change in scores was 0.5 points).

Results  Among the 18 353 randomized participants (mean age, 67.5 [SD, 7.1] years; 49.2% women), the median treatment duration was 5.3 years and 90.5% completed the trial (93.5% among those alive at the end of the trial). Risk of depression or clinically relevant depressive symptoms was not significantly different between the vitamin D3 group (609 depression or clinically relevant depressive symptom events; 12.9/1000 person-years) and the placebo group (625 depression or clinically relevant depressive symptom events; 13.3/1000 person-years) (hazard ratio, 0.97 [95% CI, 0.87 to 1.09]; P = .62); there were no significant differences between groups in depression incidence or recurrence. No significant differences were observed between treatment groups for change in mood scores over time; mean change in PHQ-8 score was not significantly different from zero (mean difference for change in mood scores, 0.01 points [95% CI, −0.04 to 0.05 points]).

Conclusions and Relevance  Among adults aged 50 years or older without clinically relevant depressive symptoms at baseline, treatment with vitamin D3 compared with placebo did not result in a statistically significant difference in the incidence and recurrence of depression or clinically relevant depressive symptoms or for change in mood scores over a median follow-up of 5.3 years. These findings do not support the use of vitamin D3 in adults to prevent depression.

Trial Registration  ClinicalTrials.gov Identifiers: NCT01169259 and NCT01696435

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