Dr. Howland is Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania.
The author discloses that he has no significant financial interests in any product or class of products discussed directly or indirectly in this activity, including research support.
Address correspondence to Robert H. Howland, MD, Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213; e-mail: HowlandRH@upmc.edu.
Vitamin D is an essential nutrient proven to be important for bone health (Holick, 2007). Additional preclinical and clinical studies have suggested that vitamin D has other physiological functions—such that deficiencies may be associated with various adverse health outcomes. However, a recent report from the Institute of Medicine (IOM, 2010) concluded that there was no compelling evidence from currently available scientific studies that vitamin D deficiency is causally related to any nonbone-health-related outcome or that vitamin D intakes greater than the recommended Dietary Reference Intakes have benefits for health.
The two main forms of vitamin D are vitamin D2 (ergocalciferol), which is derived from plant sources, and vitamin D3 (cholecalciferol), which is derived from animal sources and from sun exposure (ultraviolet B radiation converts 7-dehydrocholesterol in the skin to vitamin D3) (Bertone-Johnson, 2009). Both forms are converted in the liver to 25-hydroxyvitamin D (25[OH]D). In the kidneys and elsewhere, the enzyme 1-alpha-hydroxylase converts 25(OH)D to 1,25-dihydroxyvitamin D, which is the biologically active vitamin D metabolite that binds to vitamin D receptors throughout the body to regulate its physiological functions. Human and animal studies have demonstrated that vitamin D receptors and 1-alpha-hydroxylase enzymes are found in the brain, which suggests that vitamin D has some ill-defined role in central nervous system function. This finding, together with the putative relationship between decreased sunlight exposure and the increased risk of seasonal depression, has been used to support a plausible role for vitamin D in the pathophysiology of depression or as a potential treatment of depression (Berk et al., 2007; Bertone-Johnson, 2009). Because of the interest generated by the IOM (2010) report, I will briefly review what is known about vitamin D and depression.
Vitamin D and Nonseasonal Depression
Although vitamin D receptors and 1-alpha-hydroxylase are found in the brain, I am unaware of any published studies investigating these in human beings with depressive disorders or in animal models of depression.
A number of cross-sectional clinical and epidemiological studies have investigated the relationship between vitamin D levels (using measures of 25[OH]D) and depressive symptoms or vitamin D levels in depressed versus nondepressed individuals. Some studies (Armstrong et al., 2007; Eskandari et al., 2007; Ganji, Milone, Cody, McCarty, & Wang, 2010; Hoogendijk et al., 2008; Jorde, Sneve, Figenschau, Svartberg, & Waterloo, 2008; Knippenberg, Bol, Damoiseaux, Hupperts, & Smolders, 2010; Lee et al., 2010; Murphy, Mueller, Hulsey, Ebeling, & Wagner, 2010; Stewart & Hirani, 2010), but not all studies (Herrán et al., 2000; Michelson et al., 1996; Pan et al., 2009; Schneider, Weber, Frensch, Stein, & Fritz, 2000) found that low levels of vitamin D were significantly associated with higher levels of depressive symptoms or with a depression diagnosis. In the study by Schneider et al. (2000), participants with schizophrenia and those with major depression had significantly lower levels of 1,25-dihydroxyvitamin D compared with normal controls, but only participants with schizophrenia had significantly lower levels of 25(OH)D compared with normal controls. In a large cohort follow-up study of individuals with cardiovascular disease who were initially not depressed, those who had the lowest baseline levels of 25(OH)D were most likely to develop a clinical diagnosis of depression during follow up (May et al., 2010).
The therapeutic use of vitamin D for nonseasonal depression has not been rigorously studied. The only controlled study investigated the effects of high-dose vitamin D3 supplementation in a group of 441 individuals who were recruited because they were overweight or obese (Jorde et al., 2008). Participants did not have a clinical diagnosis of any type of depression, but they were assessed using the Beck Depression Inventory (BDI). They were randomized to receive double-blind supplementation with vitamin D3 40,000 IU per day, 20,000 IU per day, or placebo for 1 year. Participants receiving vitamin D3 at either dosage showed significant improvements on BDI scores compared with those taking placebo.
Vitamin D and Seasonal Affective Disorder
Vitamin D deficiency has been hypothesized to play a role in the pathogenesis of seasonal affective disorder (Berk et al., 2007; Stumpf & Privette, 1989). In at least some groups of individuals, vitamin D deficiency may be associated with decreased sunlight exposure or with living at higher latitudes (Hagenau et al., 2009; Salamone, Dallal, Zantos, Makrauer, & Dawson-Hughes, 1994). Two studies, however, did not find any difference in vitamin D levels in patients with seasonal affective disorder compared with normal controls (Oren, Schulkin, & Rosenthal, 1994; Partonen, Vakkuri, Lamberg-Allardt, & Lonnqvist, 1996). In addition, no observable effect of bright light therapy on vitamin D levels was found in these studies.
Harris and Dawson-Hughes (1993) reported the results of a 1-year prospective study of seasonal mood changes among 250 healthy nondepressed women participating in a study of vitamin D supplementation. All study participants were taking calcium supplements, but they were randomized to take vitamin D 400 IU per day or placebo. Each participant completed the Profile of Mood States (POMS) questionnaire at four study visits. There were significant changes over the year in POMS subscale scores for Tension-Anxiety, Depression-Dejection, Anger-Hostility, Fatigue-Inertia, and Confusion-Bewilderment. These scores were all highest during the fall and lowest during the spring or summer. Supplementation with vitamin D did not appear to affect levels or changes in mood scores.
In another study of healthy non-depressed individuals, 44 participants were given 400 IU per day, 800 IU per day, or no vitamin D3 for 5 days during late winter in a randomized, double-blind, placebo-controlled study (Lansdowne & Provost, 1998). The Positive and Negative Affect Schedule was used as a self-report measure of positive and negative affectivity. Results on this self-report measure showed that vitamin D3 at both dosages significantly enhanced positive affect, with a non-significant trend toward a reduction in negative affect.
A study conducted by Gloth, Alam, and Hollis (1999) was designed to test the hypothesis that vitamin D deficiency might play a role in seasonal affective disorder. This prospective, randomized controlled trial was conducted in a group of 15 participants with seasonal affective disorder. Eight participants received high-dose vitamin D (100,000 IU) and 7 received light therapy. All participants receiving vitamin D improved in all outcome measures. The light therapy group showed no significant change in depression measures. Vitamin D status improved in both groups (74% vitamin D group; 36% light therapy group). Improvement in vitamin D levels was significantly associated with improvement in depression scores.
Vieth, Kimball, Hu, and Walfish (2004) reported the results of two similar studies of nondepressed adults who were recruited through an endocrinology clinic. This study compared the effects of two doses of vitamin D3 (600 IU per day or 4,000 IU per day) on sense of well-being in a blinded, randomized trial. In Study 1, 64 outpatients, recruited in the summer of 2001 because they had low 25(OH)D levels (less than 61 nmol/L), were randomized to take vitamin D3 4,000 IU per day or 600 IU per day beginning in December 2001. Of the 64 patients, 37 completed a well-being questionnaire in December 2001 and February 2002. For Study 2, a second cohort of 66 participants was recruited in the summer of 2002, based on 25(OH)D levels that were less than 51 nmol/L. These participants were also randomized to take vitamin D3 4,000 IU per day or 600 IU per day. Of the 66 participants, 51 completed a well-being questionnaire in December 2002 and February 2003. In Study 1, the well-being score improved more for the 4,000 IU per day group than for the 600 IU per day group. In Study 2, the well-being scores improved with both doses of vitamin D3.
Because vitamin D deficiency may be common in older patients, a study investigated the use of vitamin D supplementation in elderly patients with seasonal affective disorder (Dumville et al., 2006). Participants were women 70 and older recruited in primary care practices in England. They were randomized to receive calcium and vitamin D supplementation (n = 912) or no supplementation (n = 1205). After 6 months, there was no significant difference in outcome between the two groups.
More recently, Shipowick, Moore, Corbett, and Bindler (2009) reported the results of a small pilot study of vitamin D supplementation on depressive symptoms in women during the winter. Nine female participants were recruited from a medical clinic where they were identified as having vitamin D deficiency. They were treated openly with vitamin D3 5,000 IU per day, and depressive symptoms were assessed using the BDI. Six women completed the study, and they showed a significant improvement in their BDI scores after 8 weeks.
Safety and Toxicity of Vitamin D
Safety and toxicity studies of vitamin D (for all types of uses, not just depression) have suggested that daily dosages of less than 4,000 IU are relatively safe. Potential consequences of vitamin D toxicity include hypercalcemia, kidney stones, and soft tissue and vascular calcification. Clinical symptoms of hypercalcemia include nausea, vomiting, increased thirst, and depression.
Although there are plausible reasons for investigating vitamin D in depressive disorders, current evidence does not definitively demonstrate that vitamin D deficiency is a cause of or risk for developing depression or that vitamin D is an effective therapy for depression. Cross-sectional studies cannot establish causality, and the methodology of the studies investigating the association between vitamin D status and depressive symptoms or depression diagnosis have been criticized. The quality of the treatment studies are such that the effectiveness of vitamin D for depression cannot be adequately assessed. Because patients may have questions about the use of vitamin D and many are likely to be taking vitamin D supplements, nurses should be familiar with the studies of vitamin D and depression (Penckofer, Kouba, Byrn, & Estwing Ferrans, 2010).
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- Eskandari, F., Martinez, P.E., Tovik, S., Phillips, T.M., Sternberg, E.M., Mistry, S. & Cizza, G.,… (2007). Low bone mass in premenopausal women with depression. Archives of Internal Medicine, 167, 2329–2336. doi:10.1001/archinte.167.21.2329 [CrossRef]
- Ganji, V., Milone, C., Cody, M.M., McCarty, F. & Wang, Y.T. (2010). Serum vitamin D concentrations are related to depression in young adult US population: The Third National Health and Nutrition Examination Survey. International Archives of Medicine, 3. Retrieved from http://www.intarchmed.com/content/3/1/29 doi:10.1186/1755-7682-3-29 [CrossRef]
- Gloth, F.M. 3rd. , Alam, W. & Hollis, B. (1999). Vitamin D vs broad spectrum phototherapy in the treatment of seasonal affective disorder. Journal of Nutrition, Health & Aging, 3, 5–7.
- Hagenau, T., Vest, R., Gissel, T.N., Poulsen, C.S., Erlandsen, M., Mosekilde, L. & Vestergaard, P. (2009). Global vitamin D levels in relation to age, gender, skin pigmentation and latitude: An ecologic meta-regression analysis. Osteoporosis International, 20, 133–140. doi:10.1007/s00198-008-0626-y [CrossRef]
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- Holick, M.F. (2007). Vitamin D deficiency. New England Journal of Medicine, 357, 266–281. doi:10.1056/NEJMra070553 [CrossRef]
- Hoogendijk, W.J., Lips, P., Dik, M.G., Deeg, D.J., Beekman, A.T. & Penninx, B.W. (2008). Depression is associated with decreased 25-hydroxyvitamin D and increased parathyroid hormone levels in older adults. Archives of General Psychiatry, 65, 508–512. doi:10.1001/archpsyc.65.5.508 [CrossRef]
- Institute of Medicine. (2010). Dietary reference intakes for calcium and vitamin D. Retrieved from http://www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D.aspx
- Jorde, R., Sneve, M., Figenschau, Y., Svartberg, J. & Waterloo, K. (2008). Effects of vitamin D supplementation on symptoms of depression in overweight and obese subjects: Randomized double blind trial. Journal of Internal Medicine, 264, 599–609. doi:10.1111/j.1365-2796.2008.02008.x [CrossRef]
- Knippenberg, S., Bol, Y., Damoiseaux, J., Hupperts, R. & Smolders, J. (2010). Vitamin D status in patients with MS is negatively correlated with depression, but not with fatigue. Acta Neurologica Scandinavica. Advance online publication. doi:10.1111/j.1600-0404.2010.01447.x doi:10.1111/j.1600-0404.2010.01447.x [CrossRef]
- Lansdowne, A.T.G. & Provost, S.C. (1998). Vitamin D3 enhances mood in healthy subjects during winter. Psychopharmacology, 135, 319–323. doi:10.1007/s002130050517 [CrossRef]
- Lee, D.M., Tajar, A., O’Neill, T.W., O’Connor, D.B., Bartfai, G., Boonen, S. & Pendleton, N.,… (2010). Lower vitamin D levels are associated with depression among community-dwelling European men. Journal of Psychopharmacology. Advance online publication. doi:10.1177/0269881110379287 doi:10.1177/0269881110379287 [CrossRef]
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- Michelson, D., Stratakis, C., Hill, L., Reynolds, J., Galliven, E., Chrousos, G. & Gold, P. (1996). Bone mineral density in women with depression. New England Journal of Medicine, 335, 1176–1181. doi:10.1056/NEJM199610173351602 [CrossRef]
- Murphy, P.K., Mueller, M., Hulsey, T.C., Ebeling, M.D. & Wagner, C.L. (2010). An exploratory study of postpartum depression and vitamin D. Journal of the American Psychiatric Nurses Association, 16, 170–177. doi:10.1177/1078390310370476 [CrossRef]
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- Pan, A., Lu, L., Franco, O.H., Yu, Z., Li, H. & Lin, X. (2009). Association between depressive symptoms and 25-hydroxyvitamin D in middle-aged and elderly Chinese. Journal of Affective Disorders, 118, 240–243. doi:10.1016/j.jad.2009.02.002 [CrossRef]
- Partonen, T., Vakkuri, O., Lamberg-Allardt, C. & Lonnqvist, J. (1996). Effects of bright light on sleepiness, melatonin, and 25-hydroxyvitamin D(3) in winter seasonal affective disorder. Biological Psychiatry, 39, 865–872. doi:10.1016/0006-3223(95)00294-4 [CrossRef]
- Penckofer, S., Kouba, J., Byrn, M. & Estwing Ferrans, C. (2010). Vitamin D and depression: Where is all the sunshine?Issues in Mental Health Nursing, 31, 385–393. doi:10.3109/01612840903437657 [CrossRef]
- Salamone, L.M., Dallal, G.E., Zantos, D., Makrauer, F. & Dawson-Hughes, B. (1994). Contributions of vitamin D intake and seasonal sunlight exposure to plasma 25-hydroxyvitamin D concentration in elderly women. American Journal of Clinical Nutrition, 59, 80–86.
- Schneider, B., Weber, B., Frensch, A., Stein, J. & Fritz, J. (2000). Vitamin D in schizophrenia, major depression and alcoholism. Journal of Neural Transmission, 107, 839–842. doi:10.1007/s007020070063 [CrossRef]
- Shipowick, C.D., Moore, C.B., Corbett, C. & Bindler, R. (2009). Vitamin D and depressive symptoms in women during the winter: A pilot study. Applied Nursing Research, 22, 221–225. doi:10.1016/j.apnr.2007.08.001 [CrossRef]
- Stewart, R. & Hirani, V. (2010). Relationship between vitamin D levels and depressive symptoms in older residents from a national survey population. Psychosomatic Medicine, 72, 608–612. doi:10.1097/PSY.0b013e3181e9bf15 [CrossRef]
- Stumpf, W.E. & Privette, T.H. (1989). Light, vitamin D and psychiatry. Role of 1,25 dihydroxyvitamin D3 (soltriol) in etiology and therapy of seasonal affective disorder and other mental processes. Psychopharmacology, 97, 285–294. doi:10.1007/BF00439440 [CrossRef]
- Vieth, R., Kimball, S., Hu, A. & Walfish, P.G. (2004). Randomized comparison of the effects of the vitamin D3 adequate intake versus the 100 mcg (4000 IU) per day on biochemical responses and the wellbeing of patients. Nutrition Journal, 3. Retrieved from http://www.nutritionj.com/content/3/1/8 doi:10.1186/1475-2891-3-8 [CrossRef]