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

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.

Conflict of interest statement

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.

Figures

Figure 1.. Flow of Participants in the VITAL-DEP Ancillary Study to the VITAL Trial

ICD-9 indicates International Classification of Diseases, Ninth Revision; OCD, obsessive-compulsive disorder; PHQ-8, 8-item Patient Health Questionnaire depression scale; PTSD, posttraumatic stress disorder; VITAL, Vitamin D and Omega-3 Trial; VITAL-DEP, Vitamin D and Omega-3 Trial-Depression Endpoint Prevention. aThe flow diagram for the VITAL trial has been published. bIndividuals could have met more than 1 exclusion criteria.

Figure 2.. Cumulative Incidence Since Randomization Until Occurrence of Primary and Secondary Outcomes

Panels B and C are provided to illustrate the cumulative incidence curves for incidence and recurrence separately from the total (panel A). aSum of incidence and recurrence of depression or clinically relevant depressive symptoms. This is the primary outcome. bAmong the 16 657 participants without a history of depression at baseline. This is a secondary outcome. cAmong the 1696 participants with a history of depression at baseline who were not receiving treatment within the past 2 years. This is a secondary outcome.

Figure 3.. Box Plots of Crude Scores for the 8-Item Patient Health Questionnaire Depression Scale (PHQ-8) During Each Study Year

Figure 4.. Primary, Secondary, and Nonprespecified and Post Hoc Outcomes

To convert 25-hydroxyvitamin D to nmol/L, multiply by 2.5. The analyses were not adjusted for multiple comparisons. MET indicates metabolic equivalent task; VITAL-DEP, Vitamin D and Omega-3 Trial-Depression Endpoint Prevention. aCalculated using Cox regression models that were controlled for age, sex, and fish oil group. For the subgroup analyses, the interactions were tested using multiplicative interaction terms. bSum of incidence and recurrence of depression or clinically relevant depressive symptoms. cAmong the 16 657 participants without a history of depression at baseline. dAmong the 1696 participants with a history of depression at baseline who were not receiving treatment within the past 2 years. eIncludes Hispanic, Asian/Pacific Islander, Native American/Alaskan Native, and other or multiple or unspecified race/ethnicity. fRestricted to 800 IU/d or less from all sources combined (individual supplements and multivitamins). gCalculated as weight in kilograms divided by height in meters squared.