Vitamin D3 supplementation did not lower the incidence of major depressive disorder during the 5-year supplementation period among largely vitamin D sufficient aging adults, though there was a borderline indication of benefit during a longer follow-up, possibly suggesting a delayed effect of supplementation.
Key Findings
Results
Vitamin D3 supplementation did not significantly reduce incidence of MDD during the primary 5-year supplementation period.
During the mean 4.2-year follow-up, there were 14, 11, and 8 MDD events in the placebo, 1600 IU/day, and 3200 IU/day arms, respectively.
HR for 1600 IU/day vs. placebo: 0.78 (95% CI 0.35–1.71; P = 0.53).
HR for 3200 IU/day vs. placebo: 0.57 (95% CI 0.24–1.35; P = 0.20).
Neither dose reached statistical significance for the primary endpoint.
Results
During extended follow-up, the 3200 IU/day dose showed a borderline statistically significant reduction in MDD incidence.
Extended mean follow-up was 7.8 years.
Total MDD events were 29, 18, and 16 in the placebo, 1600 IU/day, and 3200 IU/day arms, respectively.
HR for 1600 IU/day: 0.61 (95% CI 0.34–1.10; P = 0.10).
HR for 3200 IU/day: 0.54 (95% CI 0.30–1.00; P = 0.05), described as a 'borderline indication of benefit'.
Authors suggest this may indicate a delayed effect of supplementation.
Results
Participants were largely vitamin D sufficient at baseline, with mean serum 25-hydroxyvitamin D concentration of 75 ± 18 nmol/L in the sub-cohort.
The sub-cohort consisted of 542 participants with detailed in-person investigations.
Baseline serum 25-hydroxyvitamin D was 75 ± 18 nmol/L (mean ± SD).
After 12 months, concentrations were 73 ± 18 nmol/L in the placebo arm, 100 ± 21 nmol/L in the 1600 IU/day arm, and 120 ± 22 nmol/L in the 3200 IU/day arm.
The authors characterize this population as 'largely vitamin D sufficient aging adults.'
Methods
The trial enrolled older adults and randomized them to one of three arms for a 5-year supplementation period.
Study was conducted from 2012 to 2018 as a randomized placebo-controlled clinical trial.
Participants were randomized to 1600 IU/day (n = 814), 3200 IU/day (n = 817), or placebo (n = 803).
Among 2434 total participants, mean age was 68.2 years and 42.5% were women.
1786 participants completed the 5-year intervention.
Registered at ClinicalTrials.gov: NCT01463813.
Methods
The primary endpoint was incident MDD diagnosed by a physician during the 5-year supplementation period, with a secondary endpoint extending follow-up through end of 2021.
Incident MDD was defined as physician-diagnosed major depressive disorder.
The primary endpoint covered the 5-year supplementation period (mean 4.2-year follow-up).
The secondary endpoint extended follow-up to the end of 2021, yielding a mean 7.8-year follow-up.
A sub-cohort of 542 participants underwent more detailed in-person investigations.
Ahl N, Hantunen S, Tuomainen T, Lamberg-Allardt C, Manson J, Nurmi T, et al.. (2026). Vitamin D supplementation and incidence of major depressive disorder - A randomized clinical trial.. Clinical nutrition (Edinburgh, Scotland). https://doi.org/10.1016/j.clnu.2025.106570