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Effect of Long-term Vitamin D3 Supplementation vs Placebo on Risk of Depression or Clinically Relevant Depressive Symptoms and on Change in Mood ScoresA Randomized Clinical Trial

Educational Objective
To understand the relationship of vitamin D3 supplementation to late-life depression.
1 Credit CME
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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Article Information

Corresponding Author: Olivia I. Okereke, MD, SM, Massachusetts General Hospital, One Bowdoin Square, 7th Floor, Boston, MA 02114 (olivia.okereke@mgh.harvard.edu).

Accepted for Publication: May 26, 2020.

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, analysis, or interpretation of data: All authors.

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, or 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 for a book on late-life depression prevention. Dr Reynolds reported receiving payment from the American Association of Geriatric Psychiatry as editor-in-chief of the American Journal of Geriatric Psychiatry; receiving royalty income for intellectual property as coinventor of the Pittsburgh Sleep Quality Index; and receiving honoraria from Merck. Dr Mischoulon reported receiving research support from Nordic Naturals; serving as an unpaid consultant to Pharmavite LLC and Gnosis USA; receiving honoraria for speaking from the Massachusetts General Hospital Psychiatry Academy, Peerpoint Medical Education Institute LLC, the Harvard University blog, and Blackmores; and receiveing royalties from Lippincott Williams & Wilkins for a book on natural medications for psychiatric disorders. Dr Chang reported receiving royalties from Up-to-Date. Dr Buring reported that her spouse is on the scientific advisory board of Pharmavite LLC; and receiving personal fees from Pharmavite. Dr Manson reported receiving grants from Mars Symbioscience. No other disclosures were reported.

Funding/Support: Pharmavite LLC (vitamin D3) and Pronova BioPharma/BASF (Omacor fish oil) donated the study agents, matching placebos, and packaging in the form of calendar packs. VITAL-DEP was supported by grant R01 MH091448 from the National Institute of Mental Health. VITAL was supported by grants U01 CA138962 and R01 CA138962 from the National Cancer Institute, the National Heart, Lung, and Blood Institute, the Office of Dietary Supplements, the 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 were supported by grants DK088078 and R01 DK088762 from the National Institute of Diabetes and Digestive and Kidney Diseases, grants R01 HL101932 and R01 HL102122 from the National Heart, Lung, and Blood Institute, grant R01 AG036755 from the National Institute on Aging, grants R01 AR059086 and R01 AR060574 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and grant R01 MH091448 from the National Institute of Mental Health. Dr Reynolds’ participation also received support from grant P30 MH090333 from the National Institute of Mental Health and funding from the University of Pittsburgh Medical Center Endowment in Geriatric Psychiatry.

Role of the Funder/Sponsor: The funders/sponsors 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 at the North American Menopause Society 2019 Annual Meeting; September 26, 2019; Chicago, Illinois.

Data Sharing Statement: See Supplement 3.

Additional Contributions: We acknowledge the invaluable contributions and dedication of the 25 871 participants in VITAL and the entire staff of the VITAL trial. Voting members of the data and safety monitoring board for VITAL and the 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). The ex-officio members included: Josephine Boyington, PhD, MPH, Rebecca Costello, PhD, Cindy Davis, PhD, Peter Greenwald, MD, Gabriela Riscuta, MD, and Harold Seifried, PhD.

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