A Null Finding: Vitamin D3 Supplementation Not Associated with Depression Prevention
July 1, 2021
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By Ellen Feldman, MD
Altru Health System, Grand Forks, ND
SUMMARY POINTS
• In all, 18,353 nondepressed adults older than 50 years of age participated in this five-year randomized controlled trial investigating a role for vitamin D3 in the prevention of depression.
• Half of subjects received placebo while participants randomized to the intervention arm received 2,000 IU/day of cholecalciferol and daily omega fatty acids.
• There was no statistically significant difference between incidence of depression, clinically relevant symptoms of depression, and mood scores when comparing these outcomes in participants in the active intervention arm to those in the placebo arm.
SYNOPSIS: This randomized clinical trial involving more than 18,000 nondepressed adults at baseline and followed for five years concludes that supplementation with vitamin D3 (vs. placebo) is not associated with a decrease in symptoms of depression.
SOURCE: Okereke OI, Reynolds CF, 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;324:
471-480.
In 2010, former U.S. Surgeon General David Satcher, MD, PhD., said, “The nation is now poised to take the next step toward realizing the vision of integrating mental health and public health described a decade ago in the Surgeon General’s report. Spiraling healthcare costs and the rising number of uninsured Americans have built momentum for healthcare reform, and it is clear that a population-based, public health approach — one that encompasses mental health — will be needed as a foundation for that reform.”1
It has been more than 10 years since Dr. Satcher accurately predicted the integration of mental health with public health efforts.1 Today, fighting depression is recognized as a public health priority, but depression in the elderly presents unique challenges. Often, providers and patients perceive symptoms of depression in this population as a normal reaction or component of aging, rather than a treatable condition.
Unfortunately, untreated depression may have devastating effects in this vulnerable age group, with a decline in cognitive and physical functioning that is difficult to reverse. Although rates of major depression are less frequent among older adults than the younger population, suicide rates by age are highest in persons aged 85 years and older, and higher in the ≥ 50-year-old demographic than any younger age group.2,3
Investigations into interventions to prevent depression in this older age group are ongoing. Observational studies have shown an association between low serum 25-hydroxyvitamin D and later life depression.4 Okereke et al noted these findings have spurred efforts to understand if supplementing with vitamin D3 can prevent depression.
For background, Okereke et al cited 13 randomized controlled trials (RCTs) looking into use of vitamin D3 during middle to later life to prevent development of depression and noted all but one of these studies were unable to confirm a role for vitamin D3 in depression prevention.
However, few of the studies used robust doses of vitamin D3, some participants had subclinical levels of depression at the onset of the studies, and none of the studies were adequate in length to draw firm conclusions.
In contrast to these previous studies, this investigation lasted five years, included 18,353 adults without symptoms of depression at study entrance, and used high-dose vitamin D3 (2,000 IU/daily). Participants were recruited from a larger study of 25,871 men and women enrolled in the vitamin D and omega-3 trial (VITAL) investigating the use of high dose vitamin D and omega-3 fatty acids in the prevention of cancer and cardiovascular disease.
This ancillary trial looking at development of depression, recurrence of depression (in patients with such a history), and mood trajectory over the five years is known as VITAL-DEP.5
Exclusion criteria for participation in VITAL-DEP included any of the following:
- having current symptoms of depression (defined as a Patient Health Questionnaire [PHQ-8] score of > 10);
- having a core symptom of depression for more than two weeks over the previous two years;
- receiving current treatment for depression;
- abusing alcohol or substances within the past year;
- having a current diagnosis of another psychiatric illness, such as schizophrenia or bipolar disorder.
All participants were followed annually with questionnaires about symptoms until study end, with a median time in the study of 5.3 years and an impressive 90.5% completion rate. Baseline and end of study serum levels of 25-hydroxyvitamin D were collected from a representative sample of the participants and confirmed expected increase in levels of vitamin D3. Another subset of the participants underwent in-person psychiatric interviews to validate findings from the questionnaires.
Identified outcomes included a self-report of a diagnosis of depression from a medical provider, treatment of depression, and/or a PHQ-8 score > 10 on an annual questionnaire. At study onset, participants were randomized into either an active treatment or placebo group with efforts to balance each arm according to age, sex, and race.
The active treatment consisted of the
2,000 IU of vitamin D3 as well as fish oil or alpha omega-3 (1 g/day of 465 mg of eicosapentaenoic acid and 375 mg of docosahexaenoic acid).
RESULTS
Relevant characteristics of the study population included:
- 49% female
- 27% racial minority
- Mean age of 67.5 years at study onset
Table 1 shows the results of primary outcome (development of depression, including incident and recurrent episode) during the five-year study period. There were no statistically significant differences between development of depression (either incident or recurrent) between the active treatment and placebo groups. When PHQ-8 scores were compared between the two groups, there was a mean difference of 0.01 points with a 95% confidence interval of 0.04 to 0.05 points (essentially, the difference between group PHQ-8 score was 0 throughout the study period).
Table 1. Number of Patients Developing Depression During the Study Period | ||||
|
Study Arm |
Number of Participants |
Depression or Clinically Relevant Depressive Symptoms |
New-Onset Depression |
Recurrent Depression |
|
Vitamin D3 and omega-3 |
9,181 |
609 |
150 |
|
|
Placebo |
9,172 |
625 |
164 |
|
|
Hazard ratio = 0.97; P = 0.62 |
Hazard ratio = 0.99 |
Hazard ratio = 0.95 | ||
COMMENTARY
This ambitious study, including more than 18,000 nondepressed, older U.S. adults followed for five years, found no measurable evidence supporting prevention of depression with supplementation of daily vitamin D3 2,000 IU and alpha omega-3 fish oil.
This study was rigorous, with adequate numbers and length and built-in redundancy to double-check accuracy of measures (for example, in-person psychiatric interview in a subset of participants to validate questionnaire results and serum monitoring to verify vitamin D3 compliance.) Maintaining racial and ethnic diversity during randomization adds to the strength of the study, given that cultural influences may affect questionnaire results and that baseline 25-hydroxyvitamin D3 levels tend to vary among racial lines.
One study limitation was that the population was limited to older adults. There is no evidence that findings may be extrapolated to a younger age group. In addition, although serum levels of 25-hydroxyvitamin D were measured in a subset of participants (to check compliance), the majority of participants in both arms of the study had adequate levels of this vitamin at baseline.
Since randomization did not occur according to vitamin D serum level, there is no indication from this study that supplementation can or cannot prevent depression if an individual is deficient in this vitamin. This is an avenue ripe for exploration in future studies.
Additionally, this study was limited to a nondepressed population at baseline, and conclusions regarding patients with existing depression cannot be drawn at this time. Furthermore, the effect of vitamin D3 on individuals taking antidepressants remains unclear and open for future study.
For now, it does seem that this study reinforces past investigations finding a lack of evidence that vitamin D3 is associated with depression prevention. However, the results contrast with observational studies noting that low levels of vitamin D3 are associated with depression. It may be that these later studies can be re-examined now in light of the findings from this study and with a consideration that confounding factors may have affected original findings.
The clinical implications from this study are simple: There is no association found between supplementation of vitamin D3 and depression prevention in a nondepressed older adult population. This certainly does not extend to the potential for vitamin D3 in maintaining and improving skeletal health — there remains a well-established place for vitamin D3 in this realm. In addition, use of vitamin D3 in other populations (including younger age groups and in depressed patients) remains to be explored.
REFERENCES
- Satcher D, Druss BG. Bridging mental health and public health. Prev Chronic Dis 2010;7:A03.
- Centers for Disease Control and Prevention and National Association of Chronic Disease Directors. The state of mental health and aging in America issue brief 2: Addressing depression in older adults: Selected evidence-based programs. Atlanta, GA: National Association of Chronic Disease Directors; 2009.
- American Foundation for Suicide Prevention. Suicide statistics. Updated Feb. 9, 2021. https://afsp.org/suicide-statistics
- Cuomo A, Giordano N, Goracci A, Fagiolini A. Depression and vitamin D deficiency: Causality, assessment, and clinical practice implications. Neuropsychiatry 2017;7:606-614.
- Okereke OI, Reynolds CF 3rd, Mischoulon D, et al. 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 2018;68:133-145.
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