We propose to evaluate the effects of vitamin D3 (1600 IU/day) and omega-3 fatty acid (eicosapentaenoic acid [EPA] + docosahexaenoic acid [DHA], 1g/day) supplements on risk of late-life depression and depressive symptoms in the setting of an NIH-funded large-scale randomized trial, the VITamin D and OmegA-3 TriaL (VITAL, 1 U01 CA 138962). VITAL is a 2x2 factorial RCT designed to evaluate the efficacy of vitamin D3 and marine omega-3 fatty acid supplements in the primary prevention of cardiovascular disease and cancer among 20,000 older U.S. men and women. We will address two primary aims. First, we will test whether vitamin D or omega-3 supplementation reduces incident and recurrent depression rates among all participants in the trial. Cases of depression will be identified using questionnaires and additional data on psychiatric visits, diagnoses, and medications from the Centers for Medicare and Medicaid Services database. Second, we will test whether vitamin D or omega-3 supplementation yields better continuous mood scores on repeated measures over the 5-year study period. In addition, we will address three secondary aims. First, in a substudy of 1,000 high-risk participants, defined as persons with known risk factors for late-life depression (selective prevention) or with subsyndromal depressive symptoms (indicated prevention), we will test whether the agents are effective at reducing risk of depression and at yielding lower depression scores over time. Participants in this substudy will be recruited at four Clinical and Translational Science Center (CTSC) sites across the U.S. (Boston, Chicago, San Francisco, and Houston), and will undergo a psychiatric interview at baseline and at 2 years of follow-up (visits will be matched for season, to avoid seasonal bias for vitamin D). Second, we will address whether African-American race modifies effects of vitamin D supplementation on depression risk and on mood scores in the entire VITAL cohort (African-Americans are disproportionately affected by vitamin D insufficiency). Third, in a nested case-control design, we will assess whether baseline plasma levels of vitamin D and omega-3 fatty acids are related to depression risk, and whether they modify treatment effects. We will also be able to explore additive and/or synergistic effects of the agents, as well as effect modification by age, gender, baseline nutrient levels, baseline medical comorbidity, latitude, and physical activity. In summary, this proposal presents a highly efficient and innovative strategy to evaluate simultaneously the efficacy of vitamin D and omega-3 fatty acid supplementation for universal, selective and indicated prevention of late-life depression, as well as to provide characterization of relevant physiologic parameters that may influence this benefit. We request funds for depression case ascertainment, psychiatric assessments, and assays of pre-randomization blood levels of vitamin D and fatty acids in a nested case-control sample. In order to test our hypotheses and to complete pre- randomization psychiatric assessments, it is critically important and time-sensitive that this ancillary study be undertaken in parallel to the enrollment period for the parent VITAL trial, which is scheduled to begin in 2010.

Public Health Relevance

Biologic and observational evidence supports potential mental health benefits of both vitamin D and marine omega-3 fatty acids. However, it remains unclear whether the use of these supplements can prevent onset of late-life depression or can significantly reduce depressive symptoms in late-life. Findings from this proposed study, conducted within a large clinical trial among U.S. adults aged 60 years and above, will clarify whether vitamin D and/or omega-3 fatty acid supplementation reduces risk of late-life depression and depressive symptoms, and will provide important data that will be applicable to public health and clinical guidelines for both primary and secondary prevention of depression.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Adult Psychopathology and Disorders of Aging Study Section (APDA)
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Evans, Jovier D
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Brigham and Women's Hospital
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Okereke, Olivia I; Reynolds 3rd, Charles F; Mischoulon, David et al. (2018) The VITamin D and OmegA-3 TriaL-Depression Endpoint Prevention (VITAL-DEP): Rationale and design of a large-scale ancillary study evaluating vitamin D and marine omega-3 fatty acid supplements for prevention of late-life depression. Contemp Clin Trials 68:133-145
Chang, Shun-Chiao; Cassidy, Aedin; Willett, Walter C et al. (2016) Dietary flavonoid intake and risk of incident depression in midlife and older women. Am J Clin Nutr 104:704-14
Chang, Shun-Chiao; Wang, Wei; Pan, An et al. (2016) Racial Variation in Depression Risk Factors and Symptom Trajectories among Older Women. Am J Geriatr Psychiatry 24:1051-1062
Chang, Shun-Chiao; Pan, An; Kawachi, Ichiro et al. (2016) Risk factors for late-life depression: A prospective cohort study among older women. Prev Med 91:144-151
Okereke, Olivia I; Singh, Ankura (2016) The role of vitamin D in the prevention of late-life depression. J Affect Disord 198:1-14
Vanyukov, Polina M; Szanto, Katalin; Siegle, Greg J et al. (2015) Impulsive traits and unplanned suicide attempts predict exaggerated prefrontal response to angry faces in the elderly. Am J Geriatr Psychiatry 23:829-39
Okereke, Olivia I; Cook, Nancy R; Albert, Christine M et al. (2015) Effect of long-term supplementation with folic acid and B vitamins on risk of depression in older women. Br J Psychiatry 206:324-31
Tsai, Alexander C; Lucas, Michel; Okereke, Olivia I et al. (2014) Suicide mortality in relation to dietary intake of n-3 and n-6 polyunsaturated fatty acids and fish: equivocal findings from 3 large US cohort studies. Am J Epidemiol 179:1458-66
Okereke, Olivia I; Lyness, Jeffrey M; Lotrich, Francis E et al. (2013) Depression in Late-Life: a Focus on Prevention. Focus (Am Psychiatr Publ) 11:22-31
Pan, An; Keum, Nana; Okereke, Olivia I et al. (2012) Bidirectional association between depression and metabolic syndrome: a systematic review and meta-analysis of epidemiological studies. Diabetes Care 35:1171-80

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