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 | Complementary and Alternative Medicine | JAMA | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 35.170.64.36. Please contact the publisher to request reinstatement.
1.
Mathers  CD, Loncar  D.  Projections of global mortality and burden of disease from 2002 to 2030.   PLoS Med. 2006;3(11):e442. doi:10.1371/journal.pmed.0030442PubMedGoogle Scholar
2.
Unützer  J, Simon  G, Belin  TR, Datt  M, Katon  W, Patrick  D.  Care for depression in HMO patients aged 65 and older.   J Am Geriatr Soc. 2000;48(8):871-878. doi:10.1111/j.1532-5415.2000.tb06882.xPubMedGoogle ScholarCrossref
3.
Beekman  AT, Geerlings  SW, Deeg  DJ,  et al.  The natural history of late-life depression: a 6-year prospective study in the community.   Arch Gen Psychiatry. 2002;59(7):605-611. doi:10.1001/archpsyc.59.7.605PubMedGoogle ScholarCrossref
4.
Reynolds  CF  III, Cuijpers  P, Patel  V,  et al.  Early intervention to reduce the global health and economic burden of major depression in older adults.   Annu Rev Public Health. 2012;33:123-135. doi:10.1146/annurev-publhealth-031811-124544PubMedGoogle ScholarCrossref
5.
Li  H, Sun  D, Wang  A,  et al.  Serum 25-hydroxyvitamin D levels and depression in older adults: a dose-response meta-analysis of prospective cohort studies.   Am J Geriatr Psychiatry. 2019;27(11):1192-1202. doi:10.1016/j.jagp.2019.05.022PubMedGoogle ScholarCrossref
6.
Stewart  AE, Roecklein  KA, Tanner  S, Kimlin  MG.  Possible contributions of skin pigmentation and vitamin D in a polyfactorial model of seasonal affective disorder.   Med Hypotheses. 2014;83(5):517-525. doi:10.1016/j.mehy.2014.09.010PubMedGoogle ScholarCrossref
7.
Dumville  JC, Miles  JN, Porthouse  J, Cockayne  S, Saxon  L, King  C.  Can vitamin D supplementation prevent winter-time blues? a randomised trial among older women.   J Nutr Health Aging. 2006;10(2):151-153.PubMedGoogle Scholar
8.
Committee on Prevention of Mental Disorders; Institute of Medicine.  Reducing Risks for Mental Disorders: Frontiers for Preventive Intervention Research. National Academy Press; 1994.
9.
Bot  M, Brouwer  IA, Roca  M,  et al; MooDFOOD Prevention Trial Investigators.  Effect of multinutrient supplementation and food-related behavioral activation therapy on prevention of major depressive disorder among overweight or obese adults with subsyndromal depressive symptoms: the MooDFOOD randomized clinical trial.   JAMA. 2019;321(9):858-868. doi:10.1001/jama.2019.0556PubMedGoogle ScholarCrossref
10.
de Koning  EJ, Lips  P, Penninx  BWJH,  et al.  Vitamin D supplementation for the prevention of depression and poor physical function in older persons: the D-Vitaal study, a randomized clinical trial.   Am J Clin Nutr. 2019;110(5):1119-1130. doi:10.1093/ajcn/nqz141PubMedGoogle ScholarCrossref
11.
Okereke  OI, Singh  A.  The role of vitamin D in the prevention of late-life depression.   J Affect Disord. 2016;198:1-14. doi:10.1016/j.jad.2016.03.022PubMedGoogle ScholarCrossref
12.
Jorde  R, Kubiak  J.  No improvement in depressive symptoms by vitamin D supplementation: results from a randomised controlled trial.   J Nutr Sci. 2018;7:e30. doi:10.1017/jns.2018.19PubMedGoogle Scholar
13.
Jorde  R, Sneve  M, Figenschau  Y, Svartberg  J, Waterloo  K.  Effects of vitamin D supplementation on symptoms of depression in overweight and obese subjects: randomized double blind trial.   J Intern Med. 2008;264(6):599-609. doi:10.1111/j.1365-2796.2008.02008.xPubMedGoogle ScholarCrossref
14.
Cuijpers  P.  Examining the effects of prevention programs on the incidence of new cases of mental disorders: the lack of statistical power.   Am J Psychiatry. 2003;160(8):1385-1391. doi:10.1176/appi.ajp.160.8.1385PubMedGoogle ScholarCrossref
15.
Okereke  OI, Reynolds  CF  III, 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. doi:10.1016/j.cct.2018.02.017PubMedGoogle ScholarCrossref
16.
Manson  JE, Cook  NR, Lee  IM,  et al; VITAL Research Group.  Vitamin D supplements and prevention of cancer and cardiovascular disease.   N Engl J Med. 2019;380(1):33-44. doi:10.1056/NEJMoa1809944PubMedGoogle ScholarCrossref
17.
Kroenke  K, Strine  TW, Spitzer  RL, Williams  JB, Berry  JT, Mokdad  AH.  The PHQ-8 as a measure of current depression in the general population.   J Affect Disord. 2009;114(1-3):163-173. doi:10.1016/j.jad.2008.06.026PubMedGoogle ScholarCrossref
18.
Luijendijk  HJ, van den Berg  JF, Dekker  MJ,  et al.  Incidence and recurrence of late-life depression.   Arch Gen Psychiatry. 2008;65(12):1394-1401. doi:10.1001/archpsyc.65.12.1394PubMedGoogle ScholarCrossref
19.
Fitzmaurice  GM, Laird  NM, Ware  JH. Modelling the mean: analyzing response profiles. In: Fitzmaurice  GM, Laird  NM, Ware  JH, eds.  Applied Longitudinal Analysis. John Wiley & Sons; 2004:103-139.
20.
Pan  A, Sun  Q, Czernichow  S,  et al.  Bidirectional association between depression and obesity in middle-aged and older women.   Int J Obes (Lond). 2012;36(4):595-602. doi:10.1038/ijo.2011.111PubMedGoogle ScholarCrossref
21.
Drincic  AT, Armas  LA, Van Diest  EE, Heaney  RP.  Volumetric dilution, rather than sequestration best explains the low vitamin D status of obesity.   Obesity (Silver Spring). 2012;20(7):1444-1448. doi:10.1038/oby.2011.404PubMedGoogle ScholarCrossref
22.
Fine  JP, Gray  RJ.  A proportional hazards model for the subdistribution of a competing risk.   J Am Stat Assoc. 1999;94(446):496-509. doi:10.1080/01621459.1999.10474144Google ScholarCrossref
23.
Sanders  KM, Stuart  AL, Williamson  EJ,  et al.  Annual high-dose vitamin D3 and mental well-being: randomised controlled trial.   Br J Psychiatry. 2011;198(5):357-364. doi:10.1192/bjp.bp.110.087544PubMedGoogle ScholarCrossref
24.
Libuda  L, Laabs  BH, Ludwig  C,  et al.  Vitamin D and the risk of depression: a causal relationship? findings from a mendelian randomization study.   Nutrients. 2019;11(5):E1085. doi:10.3390/nu11051085PubMedGoogle Scholar
25.
Milaneschi  Y, Peyrot  WJ, Nivard  MG, Mbarek  H, Boomsma  DI, W J H Penninx  B.  A role for vitamin D and omega-3 fatty acids in major depression? an exploration using genomics.   Transl Psychiatry. 2019;9(1):219. doi:10.1038/s41398-019-0554-yPubMedGoogle ScholarCrossref
26.
Kim  SM, Lutsey  PL, Michos  ED.  Vitamin D and cardiovascular disease: can novel measures of vitamin D status improve risk prediction and address the vitamin D racial paradox?   Curr Cardiovasc Risk Rep. 2017;11(1):3. doi:10.1007/s12170-017-0528-7PubMedGoogle ScholarCrossref
Original Investigation
August 4, 2020

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

Author Affiliations
  • 1Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston
  • 2Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
  • 3Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
  • 4Department of Psychiatry, UPMC and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
  • 5Department of Psychiatry, VA Boston Healthcare System, Brockton, Massachusetts
  • 6Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
JAMA. 2020;324(5):471-480. doi:10.1001/jama.2020.10224
Key Points

Question  Can long-term supplementation with vitamin D3 prevent depression in the general adult population?

Findings  In this randomized clinical trial that included 18 353 adults aged 50 years or older without depression or clinically relevant depressive symptoms at baseline, vitamin D3 supplementation compared with placebo did not result in statistically significant differences in the incidence and recurrence of depression or clinically relevant depressive symptoms (hazard ratio, 0.97) or for change in mood scores over a 5-year treatment period.

Meaning  These findings do not support the use of vitamin D3 in adults to prevent depression.

Abstract

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

×