Vitamin D for Bipolar Depression?

Patients with depression often have low vitamin D levels.¹ But so do people who aren’t depressed. Does it make any sense to measure vitamin D levels in patients with depression? How about giving vitamin D as a treatment? If so, at what dose?

A review in Psychiatric Times in 2014 noted the generally poor quality of available studies and concluded:
• The evidence for a cross-sectional association between vitamin D deficiency and depression is weak.
• Oral supplements of vitamin D showed no effect on depression symptoms.²

What’s new since then? At least 2 more meta-analyses have been published, the most recent in 2015, which reached a similar conclusion regarding vitamin D as a treatment for depression: no significant benefit.³ But wait. You wouldn’t set out to test the benefits of a cholesterol-lowering drug in people whose cholesterol was already low, right? And you would measure cholesterol levels at the end of the trial to demonstrate that the desired reductions were significant, relative to a placebo. Surprisingly, many of the tests of vitamin D have not been designed thus.⁴

As a curious clinician, not a researcher in this field, I may be missing something in this literature. But after digging a bit, I was disappointed to find that the one analysis which focuses on studies without “biological flaws” (vitamin D deficient to begin, and demonstrated replete on follow-up level) seems to sweep in trials that did not study Major Depression.⁴ Another recent meta-analysis found only 2 studies of patients with depression who were shown to be deficient in vitamin D and then replete at study end. There, vitamin D supplementation had a moderate, statistically significant effect.⁵ But one of those studies used a very large intramuscular (IM) dose, not practical for most psychiatrists; however, a smaller IM dose was not effective.⁶ In the other unflawed study, vitamin D was an adjunct to fluoxetine, not a monotherapy for depression.⁷A valid randomized trial
Treating bipolar depression sometimes requires extrapolating from research in unipolar depression, looking for approaches with high appeal to hesitant patients (tolerability over known efficacy, as discussed last month). Thus, a new randomized trial of vitamin D in Major Depression by Sepehrmanesh and colleagues⁸ is of interest. All subjects were deficient before the trial began. And the doses were large enough to bring them into the laboratory normal range, verified by post-test versus placebo (50,000 IU per week for 8 weeks; see caution regarding this dose below). Results are shown in the Figure.

True, the P value is .06, just below “significant.” Replication with a larger sample is needed: consider this a pilot study. There are other randomized trials of note (courtesy of colleague Dr. Aiken’s additional review): depression in dialysis⁹ (no benefit); premenstrual dysphoric disorder¹⁰ (better than placebo); seasonal affective disorder¹¹ (no benefit); and autism¹² (better than placebo). But remarkably, this Sepehrmanesh study is the only “biologically valid” trial of vitamin D as monotherapy in Major Depression that I could find.

Dose and safety
The dose used in the Sepehrmanesh study, 50,000 IU per week-or about 7000 IU per day-is much higher than has been advised. A 2011 Institute of Medicine report noted possible harm (eg, hypercalcemia, soft tissue or vascular calcification) for “intakes above the tolerable upper limit of 4000 IU/d.”¹³ The aggressive research dose allowed rapidly reaching blood levels of vitamin D within the normal range, but is not appropriate for routine clinical use.

Conclusion
After years of skepticism, I’ve finally found some evidence in the Sepehrmanesh study that vitamin D actually might be a treatment for depression-but not at doses we might routinely use (eg, 600 to 2000 IU per day).¹⁴ It appears that these lower doses have not been properly studied as yet. Omega-3 fatty acids have far more data in support of their use in depression (as long as they’re EPA-rich, according to one important meta-analysis¹⁵).

References:

1. Anglin RE, Samaan Z, Walter SD, McDonald SD. Vitamin D deficiency and depression in adults: systematic review and meta-analysis. Br J Psychiatry. 2013;202:100-107. doi: 10.1192/bjp.bp.111.106666.
2. Samaan Z, Anglin RE. What is the role of vitamin D in depression?Psychiatric Times. April 21, 2014.
3. Gowda U, Mutowo MP, Smith BJ, et al. Vitamin D supplementation to reduce depression in adults: meta-analysis of randomized controlled trials. Nutrition. 2015;31:421-429.
4. Spedding S. Vitamin D and depression: a systematic review and meta-analysis comparing studies with and without biological flaws. Nutrients. 2014;6:1501-1518.
5. Shaffer JA, Edmondson D, Wasson LT, et al. Vitamin D supplementation for depressive symptoms: a systematic review and meta-analysis of randomized controlled trials. Psychosom Med. 2014;76:190-196.
6. Mozaffari-Khosravi H, Nabizade L, Yassini-Ardakani SM, et al. The effect of 2 different single injections of high dose of vitamin D on improving the depression in depressed patients with vitamin D deficiency: a randomized clinical trial. J Clin Psychopharmacol. 2013;33:378-385.
7. Khoraminya N, Tehrani-Doost M, Jazayeri S, et al. Therapeutic effects of vitamin D as adjunctive therapy to fluoxetine in patients with major depressive disorder. Aust N Z J Psychiatry. 2013;47:271-275.
8. Sepehrmanesh Z, Kolahdooz F, Abedi F, et al. Vitamin D supplementation affects the Beck Depression Inventory, insulin resistance, and biomarkers of oxidative stress in patients with major depressive disorder: a randomized, controlled clinical trial. J Nutr. 2016;146:243-248.
9. Wang Y, Liu Y, Lian Y, et al. Efficacy of high-dose supplementation with oral vitamin D3 on depressive symptoms in dialysis patients with vitamin D3 insufficiency: a prospective, randomized, double-blind study. J Clin Psychopharmacol. 2016;36:229-235.
10. Tartagni M, Cicinelli MV, Tartagni MV, et al. Vitamin D supplementation for premenstrual syndrome-related mood disorders in adolescents with severe hypovitaminosis D. J Pediatr Adolesc Gynecol. 2016;29:357-361.
11. Frandsen TB, Pareek M, Hansen JP, Nielsen CT. Vitamin D supplementation for treatment of seasonal affective symptoms in healthcare professionals: a double-blind randomised placebo-controlled trial. BMC Res Notes. 2014;7:528.
12. Saad K, Abdel-Rahman AA, Elserogy YM, et al. Randomized controlled trial of vitamin D supplementation in children with autism spectrum disorder. J Child Psychol Psychiatry. 2016 Nov 21. [Epub ahead of print]
13. Ross CR, Taylor CL, Yaktine AL, et al. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academies Press; 2011; cited in Rooney MR, Harnack L, Michos ED, et al. Trends in use of high-dose vitamin D supplements exceeding 1000 or 4000 international units daily, 1999-2014. JAMA. 2017;317:2448-2450.
14. Drake M. Quoted in Rapaport L. Many Americans taking too much vitamin D. Health News, Reuters. June 20, 2017.
15. Sublette ME, Ellis SP, Geant AL, Mann JJ. Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. J Clin Psychiatry. 2011;72:1577-1584.