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D for Depression? Researchers performed a 12-week, randomized, double-blind placebo-controlled trial of vitamin D augmentation for major depression with vitamin D deficiency.
“Mr Regina” is a 48-year-old African-American male with a history of recurrent major depressive disorder. He is currently maintained on citalopram 40 mg daily, and he sees a psychologist for cognitive-behavioral therapy. He has mild residual symptoms of depression. He recently saw his primary care physician, who ordered routine annual screening labs. Mr Regina was found to have vitamin D deficiency, with a level of 11 ng/mL. He was started on replacement with 50,000 IUs of vitamin D weekly. He asks whether this treatment will have any impact on his mood. As his psychiatrist, how would you respond?
There is evidence for abnormalities in vitamin D and its signaling pathways in the pathophysiology of depression.1 Vitamin D is also suggested to play a neuroprotective role through anti-inflammatory effects.2 Pooled findings of the effects of vitamin D supplementation in major depression, however, have been inconclusive.3 The prevalence of vitamin D deficiency is high in India.4
The Current Study
Kumar and colleagues5 performed a 12-week, randomized, double-blind, placebo-controlled trial of vitamin D supplementation in patients with major depression and concurrent vitamin D deficiency at a psychiatry clinic in India. They included outpatients aged 18 to 65 years with DSM-5 major depressive disorder without psychotic features. Participants had a score of ≥ 15 on the 17-item Hamilton Depression Rating Scale (HAM-D). They had no antidepressant or antipsychotic exposure in the past 2 months, and their serum 25-hydroxy vitamin D (25(OH)D) level was < 20 ng/mL.
Individuals were excluded if they had suicidal ideation, major comorbid psychiatric disorders, comorbid unstable medical disorder, or pregnancy or lactation.
The authors measured 25(OH)D levels in 140 consenting participants, of whom 59 had vitamin D deficiency and were randomized. Participants were randomized to vitamin D 60000 IU every 5 days or placebo. All participants received escitalopram 10 mg/day, which could be titrated to a maximum of 20 mg/day. Oral clonazepam, up to 2 mg/day, was permitted for anxiety or insomnia.
Participants were assessed at baseline and weeks 4, 8, and 12 with the 17-item HAM-D, the Montgomery Asberg Depression Rating Scale (MADRS), and the Beck Depression Inventory (BDI), as well as the Clinical Global Impression (CGI) Severity and Improvement scales. Fasting blood samples for 25(OH)D levels were obtained at baseline and weeks 8 and 12.
The planned study recruitment of 60 participants had 80% power to detect an effect size of 0.75. The primary outcome was intent to treat (ITT) improvement between baseline and week 12 in HAM-D scores in the vitamin D and placebo groups. Response (50% reduction in HAM-D) and remission (HAM-D ≤7) rates were considered as secondary outcomes, as were changes in the other rating scales. Data were analyzed using 2 x 4 two-way repeated measures multivariate analysis of variance (RMANOVA), with group x time interaction as the statistic of interest.
The mean participant age was 37 years, and 72% were female. The mean 25(OH)D level was 11.5 ng/mL, and the mean baseline HAM-D score was 26. Vitamin D and placebo groups were not significant different with regards to sociodemographic or clinical variables. Approximately 41 patients completed the trial. Another 8 patients completed the 4-week assessment, and 7 completed the 8-week assessment. There were no serious adverse events.
Adherence to escitalopram was > 90% based on pill counts. Mean escitalopram dose in the ITT sample was 13.2 and 15.4 mg in the vitamin D and placebo groups, but was about 4.2 mg higher in the completer sample. Mean vitamin D levels increased to 77.9 ng/mL in the vitamin D group, compared to 33.6 ng/mL in the placebo group.
Seven of 28 participants in the placebo group had an increase in 25(OH)D levels of > 10 ng/mL, and 10 of 31 participants in the vitamin D group had a change in 25(OH)D levels of < 10 ng/mL. This raises the possibility that some placebo participants may have taken vitamin D supplements and non-adherence in some of the participants in the vitamin D group. The 25(OH)D levels were not significantly correlated with depression ratings at either baseline or week 12.
Furthermore, in study completers, change in HAM-D scores were not significantly different in patients with versus without a rise in 25(OH)D levels of > 10 ng/mL. Vitamin D (versus placebo) was not associated with significant improvements in HAM-D, MADRS, BDI, or CGI scores across the course of the study. Response and remission rates were also not significantly different between participant groups (approximately 75% and 60%, respectively).
The authors concluded that vitamin D augmentation did not outperform placebo in patients with major depression and vitamin D deficiency. The 25(OH)D levels were not correlated with (subjective or objective) depression ratings at any time point. The inclusion of patients with vitamin D deficiency was a primary strength of the study. Study limitations included inadequate statistical power to detect smaller effect sizes, and potential issues of unauthorized vitamin D supplementation and medication non-adherence. The negative findings of this study do not preclude the possibility of beneficial effects of vitamin D supplementation in antidepressant non-responders.
The Bottom Line
Vitamin D augmentation does not improve antidepressant outcomes with escitalopram in patients with major depression and vitamin D deficiency.
Dr Miller is a professor in the Department of Psychiatry and Health Behavior at Augusta University in Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric TimesTM. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.
1. Eyles DW, Smith S, Kinobe R, et al. Distribution of the vitamin D receptor and 1 alpha-hydroxylase in human brain. J Chem Neuroanat. 2005;29(1):21-30.
2. Song C, Wang H. Cytokines mediated inflammation and decreased neurogenesis in animal models of depression. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(3):760-768.
3. Vellekkatt F, Menon V. Efficacy of vitamin D supplementation in major depression: a meta-analysis of randomized controlled trials. J Postgrad Med. 2019;65(2):74-80.
4. Aparna P, Muthathal S, Nongkynrih B, Gupta SK. Vitamin D deficiency in India. J Family Med Prim Care. 2018;7(2):324-330.
5. Kumar PNS, Menon V, Andrade C. A randomized, double-blind, placebo-controlled, 12-week trial of vitamin D augmentation in major depressive disorder associated with vitamin D deficiency. J Affect Disord. 2022;314:143-149.