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Okereke OI, Reynolds CF 3rd, Mischoulon D, et al. 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. JAMA. 2020 Aug 4;324(5):471-480. doi: 10.1001/jama.2020.10224. (Original study)

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.

Discipline Area Score
FM/GP/Mental Health 6 / 7
General Internal Medicine-Primary Care(US) 6 / 7
Psychiatry 6 / 7
Family Medicine (FM)/General Practice (GP) 6 / 7
Public Health 6 / 7
Comments from MORE raters

FM/GP/Mental Health rater

This is another nail in the coffin of vitamin D as a wonder drug. It's unclear if supplementation would affect depression risk in individuals with low vitamin D levels.

General Internal Medicine-Primary Care(US) rater

As the authors noted, the average vitamin D level in this trial was normal; that may have been why no benefit to vitamin D supplementation was seen. I think subgroup analysis should have been done for all participants with vitamin D levels under 30 ng/ml, which is the lowest sufficient level endorsed by the Endocrine Society in its guidelines.

Public Health rater

It is, of course, important that negative studies be published and that practitioners take this kind of evidence into account. However, I suspect that most practitioners are not surprised by the results.

Public Health rater

Although the overall results indicate no effect for vitamine D3 supplementation, this conclusion certainly contributes to avert the over-prescription of vitamin E among mood disordered patients.
Comments from EvidenceAlerts subscribers

Dr. Gabriel Symonds (9/1/2020 8:03 AM)

What is the difference between ‘depression’ and ‘clinically relevant depressive symptoms’? Presumably, the researchers were not interested in clinically irrelevant depressive symptoms, so this distinction, if it exists, is pointless. In any case, depression is indeed a symptom, not a diagnosis.
The entirely predictable conclusion was that taking vitamin D3 does not prevent depression. But suppose, however, that a statistically significant reduction in the incidence of depression was found in those given D3 supplements. Would we then be recommending everyone to take long-term D3 supplementation to try to avoid become depressed?