The effect of vitamin D supplementation on depressive symptoms in adults: A systematic review and meta‐analysis of randomized controlled trials

Abstract

Neurosteroid and immunological actions of vitamin D may regulate depression-linked physiology. Meta‐analyses investigating the effect of vitamin D on depression have been inconsistent. This meta-analysis investigated the efficacy of vitamin D in reducing depressive symptoms among adults in randomized placebo-controlled trials (RCT). General and clinical populations, and studies of ill individuals with systemic diseases were included. Light therapy, co-supplementation (except calcium) and bipolar disorder were exclusionary. Databases Medline, PsycINFO, CINAHL and The Cochrane Library were searched to identify relevant articles in English published before April 2022. Cochrane risk-of-bias tool (RoB 2) and GRADE were used to appraise studies. Forty-one RCTs (n = 53,235) were included. Analyses based on random-effects models were performed with the Comprehensive Meta-analysis Software. Results for main outcome (n = 53,235) revealed a positive effect of vitamin D on depressive symptoms (Hedges’ g = −0.317, 95% CI [−0.405, −0.230], p < 0.001, I² = 88.16%; GRADE: very low certainty). RoB assessment was concerning in most studies. Notwithstanding high heterogeneity, vitamin D supplementation ≥ 2,000 IU/day appears to reduce depressive symptoms. Future research should investigate possible benefits of augmenting standard treatments with vitamin D in clinical depression. PROSPERO registration number: CRD42020149760. Funding: Finnish Medical Foundation, grant 4120 and Juho Vainio Foundation, grant 202100353.

Keywords:

• Vitamin D
• cholecalciferol
• supplementation
• major depressive disorder
• depressive symptoms

Amendments

There were some minor differences between our protocol and review: We did not use Mesh terms or Emtree keywords in the EMBASE database for database searches. The EMBASE was used only in the primary database searches. We did not include studies which compared lower vitamin D supplementation to higher vitamin D supplementation without placebo control group. The decision to exclude these studies was made before meta-analysis phase. Risk of bias was assessed using the Cochrane Collaboration’s tool updated version 2 (ROB 2.0). Updated PRISMA 2020 guidelines were used in writing this report.

Author contribution

AR and TM designed this study. TM conducted the literature search and screened articles with AR. TM, AR, MH, AL, TR, and SR reviewed the literature and extracted data. TM, ML, and AR assessed the risk of bias. WM analyzed the data. WM made the certainty assessment with TM and AR. All authors contributed to interpreting the results and drafting the manuscript. SR passed away before the manuscript was completed.

Availability of data, code and other materials

The data, code and other materials that support the findings of this review study are available from the corresponding author, TM, upon reasonable request.

Declaration of interest

The authors declare that they have no competing of interests.

TM has received grants from The Finnish Medical Foundation (grant number 4120) and The Juho Vainio Foundation (grant number 202100353).

WM is currently funded by an Alfred Deakin Postdoctoral Research Fellowship and a Multiple Sclerosis Research Australia early-career fellowship. He has previously received funding from the NHMRC, Clifford Craig Foundation, Cancer Council Queensland and university grants/fellowships from La Trobe University, Deakin University, University of Queensland, and Bond University, received industry funding and has attended events funded by Cobram Estate Pty. Ltd, received travel funding from Nutrition Society of Australia, received consultancy funding from Nutrition Research Australia, and has received speakers honoraria from The Cancer Council Queensland and the Princess Alexandra Research Foundation.

MML is supported by a Deakin University Scholarship and has received research funding support from Be Fit Foods.

MH is supported by an Australian Rotary Health PhD Scholarship and has received research support from The a2 Milk Company.

AL has received grants, fellowships and research support from the University of New South Wales, the University of Melbourne, RMIT University, Deakin University, the National Health and Medical Research Council (NHMRC), Australian Academy of Science, National Institutes of Health (NIH), and The Jack Brockhoff Foundation. AL has received honoraria and travel funds from Sydney University, the University of Technology Sydney, American Epilepsy Society, Epilepsy Society of Australia, International Human Microbiome Congress, European Society of Neurogastroenterology, Australian and New Zealand College of Anesthetists, Falk Foundation and Fonds de la Recherche Scientifique (FNRS).

SR has been funded by the Doctoral School of the University of Eastern Finland. Previously she has received grants from the Finnish Cultural Foundation and travel grants from the Finnish Association for the Study of Obesity and the Finnish Society for Nutrition Research.

TR has received grants, fellowships and research support from University of the Sunshine Coast, Australian Postgraduate Awards, Fernwood Foundation, Wilson Foundation, Robertsa Family Foundation, and Be Fit Food. TR received consultancy, honoraria and travel funds from Oxford University Press, the University of Melbourne, the University of Sydney, Bond University, University of Southern Queensland, Dietitians Association of Australia, Nutrition Society of Australia, The Royal Australian and New Zealand College of Psychiatrists, Academy of Nutrition and Dietetics, Black Dog Institute, Australian Rotary Health, Australian Disease Management Association, Department of Health and Human Services, Primary Health Networks, Barwon Health, West Gippsland Healthcare Group, Central West Gippsland Primary Care Partnership, Parkdale College, City of Greater Geelong and Global Age.

AO is supported by a Heart Foundation Future Leader Fellow (#101160) from the Heart Foundation, Australia.

DM has received research support from Nordic Naturals and heckel medizintechnik GmbH. He has received honoraria for speaking from the Massachusetts General Hospital Psychiatry Academy. He also works with the MGH Clinical Trials Network and Institute (CTNI), which has received research funding from multiple pharmaceutical companies and NIMH.

MV-K: None.

SML: None.

AR: None.

Funding and acknowledgements

This review study received financial support in the form of scholarships from The Finnish Medical Foundation (TM, grant number 4120) and The Juho Vainio Foundation (TM, grant number 202100353) for research, writing, and publishing this article. The literature search strategy was developed in consultation with an experienced librarian (Ms. Tuulevi Ovaska) at Kuopio University Hospital Medical library. Ms. Josephine Russell assisted in the data extraction phase. Supporters had no input into the study design.

Registration and protocol

Methods of the systematic review and inclusion criteria were specified in advance and documented in a study protocol published in in the international prospective register of systematic reviews (PROSPERO) under the registration number: CRD42020149760. Details of the protocol can be accessed at www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42020149760.