To test vitamin D3 and omega-3s for late-life depression prevention under the National Academy of Medicine framework for indicated (targeting subthreshold depression) and selective (targeting presence of high-risk factors) prevention.

VITamin D and OmegA-3 TriaL (VITAL) is a 2x2 factorial trial of vitamin D3 (2000 IU/day) and/or omega-3s (1 g/day) for cardiovascular and cancer prevention (enrollment: November 2011-March 2014; end date: December 31, 2017). In this targeted prevention study, we included 720 VITAL clinical sub-cohort participants who completed neurobehavioral assessments at baseline and 2 years (91.9% retention). High-risk factors were: subthreshold or clinical anxiety, impaired activities of daily living, physical/functional limitation, medical comorbidity, cognitive impairment, caregiving burden, problem drinking, and low psychosocial support. Co-primary outcomes were: incident major depression (MDD), adjudicated using DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition); change in mood (Patient Health Questionnaire-9 [PHQ-9]). We used exact tests to determine treatment effects on MDD incidence and repeated measures models to determine treatment effects on PHQ-9.

11.1% had subthreshold depression, 60.8% had ≥1 high-risk factors, MDD incidence=4.7% (5.0% among completers), and mean PHQ-9 change=0.02 points. Among those with subthreshold depression, the MDD risk ratio (95% confidence intervals)=0.36 (0.06 to 1.28) for vitamin D3 and 0.85 (0.25 to 2.92) for omega-3s, compared to placebos; results were also null among those with ≥1 high-risk factors [vitamin D3 vs. placebo: 0.63 (0.25 to 1.53); omega-3s vs. placebo: 1.08 (0.46 to 2.71)]. There were no significant differences in PHQ-9 change comparing either supplement with placebo.

Neither vitamin D3 nor omega-3s showed benefits for indicated and selective prevention of late-life depression; statistical power was limited.