Original Article
Efficacy of vitamin D supplementation in major
depression: A meta‑analysis of randomized
controlled trials
Vellekkatt F, Menon V
Department of Psychiatry, ABSTRACT
Jawaharlal Institute
Background: There is a need to develop and periodically evaluate new treatment strategies in major depression
of Post Graduate
Medical Education and
due to the high burden of nonresponse and inadequate response to antidepressants. Aim: We aimed to assess
Research (JIPMER), the effect of vitamin D supplementation on depression symptom scores among individuals with clinically
Puducherry, India diagnosed major depression. Materials and Methods: Electronic search of databases was carried out for
published randomized controlled trials in English language, peer‑reviewed journals from inception till August
Address for correspondence: 2017. Outcome measure used for effect size calculation was depression symptom scores. Effect sizes for
Dr. Menon V, the trials were computed using standardized mean difference (Cohen’s d), and I2 test was used to assess
E‑mail: drvmenon@gmail.
com
sample heterogeneity. Pooled mean effect sizes were derived using both fixed and random‑effects model.
Critical appraisal of studies was done using the Cochrane risk of bias assessment tool. Results: A total of
four trials involving 948 participants were included in the study. In three trials, the intervention group received
oral vitamin D supplementation whereas in one parenteral vitamin D was given. Pooled mean effect size for
vitamin D supplementation on depressive symptom ratings in major depression was 0.58 (95% confidence
interval, 0.45–0.72). The I2 value for heterogeneity was 0 suggesting low heterogeneity among studies. Egger
plot intercept indicated minimal publication bias. Conclusion: Vitamin D supplementation favorably impacted
depression ratings in major depression with a moderate effect size. These findings must be considered tentative
owing to the limited number of trials available and inherent methodological bias noted in few of them.
Received : 02-10-2017
Review completed : 29-11-2017
Accepted : 27-12-2017 KEY WORDS: Depressive disorder, meta‑analysis, randomized controlled trials, vitamin D
Introduction areas and alteration in many biochemical functions such as
gene expression and immune response.[4,5] However, classical
W orldwide, it is estimated that more than 300 million
people are affected by depression.[1] Unipolar depressive
disorders were the third leading cause of disability‑adjusted life
antidepressants mainly function by correction of monoamine
imbalance. This may be a possible reason for the low rates
of treatment‑induced remission often noted in clinical trials
years (DALY) lost based on the WHO report of 2004,[2] and were on depressed patients.[6,7] Therefore, there is a pressing need
projected to rise to the second leading cause of DALY across to look at other treatment targets that can optimize clinical
all age group by 2020.[3] Despite burgeoning research on its management of depression.
neurobiological basis in the last decade, a significant gap exists
in our understanding of the origins and progression of depressive A growing body of literature links vitamin D to the pathophysiology
disorders. Studies have suggested that depression may have of depression.[8–11] This has mainly come from three lines of
multifactorial origins involving dysfunction of multiple brain
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10.4103/jpgm.JPGM_571_17
How to cite this article: Vellekkatt F, Menon V. Efficacy of vitamin D
PubMed ID:
supplementation in major depression: A meta-analysis of randomized
29943744 controlled trials. J Postgrad Med 2019;65:74-80.
74 © 2018 Journal of Postgraduate Medicine | Published by Wolters Kluwer - Medknow
, Vellekkatt and Menon: Vitamin D and depression
evidence; first, lower serum vitamin D levels in depressed persons Comparison – With a control group of any nature
compared to controls;[8,10,12,13] second, presence of vitamin D
receptors in various parts of the brain limbic system, cerebellum, Outcomes – Primary outcome expressed in terms of depression
and cortex,[14–16] which controls emotions and behavior; and symptom scores
third, the important modulatory role that vitamin D plays in
regulating immunoinflammatory pathways that have been We included only randomized controlled trials meeting the
found to be relevant to the pathophysiology of depression.[5,17,18] above criteria [Table 1]. Studies done on healthy volunteers or
This evidence has spawned a series of trials that have tried to nonpsychiatric populations were excluded.[8,24–27] The excluded
answer the question whether vitamin D supplementation among studies with relevant details are given in Table 2.
depressed patients might improve their depression scores with
mixed results. Thus far, a few meta‑analyses have included studies Search strategy and study selection
assessing the effect of vitamin D on depressive symptom scores in Electronic searches of database such as PubMed, ScienceDirect,
individuals without a clinical diagnosis of major depression.[19–23] and Google Scholar were carried out from inception till August
Further, as the authors of these studies point out, many of the 2017. Articles were generated using random combinations
included patients had very low depression scores to begin with of the following search terms: “depression,” “depressive
which may be the reason for the marginal effects noted. Hence, disorder,” “depressed individuals,” “vitamin D,” “vitamin d,”
there is a need to separately examine the effects of vitamin D “25‑hydroxyvitamin D,” “vitamin D3,” “Cholecalciferol,” or
supplementation in populations with major depression. “Calcitriol.” The search was limited to articles published in
English language, peer reviewed journals. The title and abstracts
With this background, we aimed to combine the evidence from of the generated studies were examined by two of the authors
available randomized trials to provide a quantitative estimate independently (Vikas Menon and Favaz V), and a consolidated
of the effect of vitamin D supplementation on depression list of abstracts were drawn up after eliminating duplicates. In
symptom ratings among patients with clinically diagnosed case of inadequate information in the abstract, the corresponding
depression compared to a control group. We also aimed to full texts of potentially relevant articles were retrieved to screen
highlight the research gaps in this area to inform future trials. for inclusion criteria. The reference lists of included studies
were also manually examined for potential articles. We did not
Materials and Methods include gray literature such as conference proceedings primarily
due to concerns about study quality and inadequate reporting.
Inclusion and exclusion criteria The flow chart for the literature search is presented in Figure 1.
Using the patient, intervention, comparison, outcomes, and
study design criteria, all studies that assessed the association Data extraction and selection of outcome measure
between vitamin D and depression or vice versa were included Data were abstracted from articles meeting the inclusion
provided they met the following a priori criteria: criteria on the following items: author and year of study, region
of study, total sample size as well as sample size in each group,
Population – Patients clinically diagnosed with unipolar dosing regimen of vitamin D followed, nature and dose of
depression as per the standard diagnostic criteria antidepressant received by the comparator arm, assessment
time points, total duration of study, and primary and secondary
Intervention – Vitamin D supplementation in any dosage outcome measures. The outcome measure used for calculation
formulation of effect size was the depression symptom score which had to
Table 1: Characteristics of included studies (n=4)
Study Region Type of Sample size Intervention Comparator Duration Primary Effect size (95% CI)
RCT (intervention vs of study Outcome
control) measure
for effect
size
calculation
Wang China Double 746 (373 vs 373) 50,000 IU/wk oral Placebo 52 weeks BDI score 0.5632 (0.4167-0.7097)
et al.,[35] 2016 blind Vitamin D3
Sepehrmanesh Iran Double 40 (20 vs 20) 50,000 IU/wk oral Placebo 8 weeks BDI score 0.4876 (−0.1465-1.1217)
et al.,[34] 2016 blind Vitamin D3
Mozaffari‑Khosravi Iran Nonblinded 120 (40 vs 40 vs 40) 300,000/150,000 IU No treatment 12 weeks BDI score 0.6988 (0.2437-1.1539)
et al.,[32] 2013 I.M single dose
Vitamin D3
Khoraminya Iran Double 42 (21 vs 21) 1500 IU oral Fluoxetine 8 weeks HAM‑D 1.0268 (0.1294-1.9242)
et al.,[33] 2013 blind Vitamin D3 + alone score
20 mg Fluoxetine
daily
RCT: Randomized controlled trial, CI: Confidence intervals, BDI: Beck depression inventory, HAM‑D: Hamilton depression rating scale,
IU: International units
Journal of Postgraduate Medicine | Volume 65 | Issue 2 | April-June 2019 75
