Evidence-Based Reviews

Vitamin D deficiency and psychiatric illness

Current Psychiatry. 2013 April;12(4):18-27

Supplementation might help patients with depression, seasonal mood disturbances

References

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2. Tsiaras WG, Weinstock MA. Factors influencing vitamin D status. Acta Derm Venereol. 2011;91(2):115-124.

3. Adams JS, Clemens TL, Parrish JA, et al. Vitamin-D synthesis and metabolism after ultraviolet irradiation of normal and vitamin-D-deficient subjects. N Engl J Med. 1982;306(12):722-725.

4. Jones G. Pharmacokinetics of vitamin D toxicity. Am J Clin Nutr. 2008;88(2):582S-586S.

5. Holick MF. Vitamin D: importance in the prevention of cancers type 1 diabetes, heart disease, and osteoporosis. Am J Clin Nutr. 2004;79(3):362-371.

6. Fakih MG, Trump DL, Muindi JR, et al. A phase I pharmacokinetic and pharmacodynamic study of intravenous calcitriol in combination with oral gefitinib in patients with advanced solid tumors. Clin Cancer Res. 2007;13(4):1216-1223.

7. Holick MF, Chen TC. Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr. 2008;87(4):1080S-1086S.

8. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):266-281.

9. Matsuoka LY, Ide L, Wortsman J, et al. Sunscreens suppress cutaneous vitamin D₃ synthesis. J Clin Endocrinol Metab. 1987;64(6):1165-1168.

10. Norval M, Wulf HC. Does chronic sunscreen use reduce vitamin D production to insufficient levels? Br J Dermatol. 2009;161(4):732-736.

11. Linos E, Keiser E, Kanzler M, et al. Sun protective behaviors and vitamin D levels in the US population: NHANES 2003-2006. Cancer Causes Control. 2012;23(1):133-140.

12. Prüfer K, Veenstra TD, Jirikowski GF, et al. Distribution of 1,25-dihydroxyvitamin D3 receptor immunoreactivity in the rat brain and spinal cord. J Chem Neuroanat. 1999;16(2):135-145.

13. 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.

14. Garcion E, Wion-Barbot N, Montero-Menei CN, et al. New clues about vitamin D functions in the nervous system. Trends Endocrinol Metab. 2002;13(3):100-105.

15. Smith MP, Fletcher-Turner A, Yurek DM, et al. Calcitriol protection against dopamine loss induced by intracerebroventricular administration of 6-hydroxydopamine. Neurochem Res. 2006;31(4):533-539.

16. Garcion E, Nataf S, Berod A, et al. 1,25-dihydroxyvitamin D3 inhibits the expression of inducible nitric oxide synthase in rat central nervous system during experimental allergic encephalomyelitis. Brain Res Mol Brain Res. 1997;45(2):255-267.

17. Baas D, Prüfer K, Ittel ME, et al. Rat oligodendrocytes express the vitamin D(3) receptor and respond to 1,25-dihydroxyvitamin D(3). Glia. 2000;31(1):59-68.

18. Brewer LD, Thibault V, Chen KC, et al. Vitamin D hormone confers neuroprotection in parallel with downregulation of L-type calcium channel expression in hippocampal neurons. J Neurosci. 2001;21(1):98-108.

19. Almeras L, Eyles D, Benech P, et al. Developmental vitamin D deficiency alters brain protein expression in the adult rat: implications for neuropsychiatric disorders. Proteomics. 2007;7(5):769-780.

20. Berg AO, Melle I, Torjesen PA, et al. A cross-sectional study of vitamin D deficiency among immigrants and Norwegians with psychosis compared to the general population. J Clin Psychiatry. 2010;71(12):1598-1604.

21. Hedelin M, Löf M, Olsson M, et al. Dietary intake of fish, omega-3, omega-6 polyunsaturated fatty acids and vitamin D and the prevalence of psychotic-like symptoms in a cohort of 33,000 women from the general population. BMC Psychiatry. 2010;10:38.-

22. McGrath J, Saari K, Hakko H, et al. Vitamin D supplementation during the first year of life and risk of schizophrenia: a Finnish birth cohort study. Schizophr Res. 2004;67(2-3):237-245.

23. McGrath J, Eyles D, Mowry B, et al. Low maternal vitamin D as a risk factor for schizophrenia: a pilot study using banked sera. Schizophr Res. 2003;63(1-2):73-78.

24. Przybelski RJ, Binkley NC. Is vitamin D important for preserving cognition? A positive correlation of serum 25-hydroxyvitamin D concentration with cognitive function. Arch Biochem Biophys. 2007;460(2):202-205.

25. Lee DM, Tajar A, Ulubaev A, et al. Association between 25-hydroxyvitamin D levels and cognitive performance in middle-aged and older European men. J Neurol Neurosurg Psychiatry. 2009;80(7):722-729.

26. Buell JS, Dawson-Hughes B, Scott TM, et al. 25-hydroxyvitamin D, dementia, and cerebrovascular pathology in elders receiving home services. Neurology. 2010;74(1):18-26.

27. Llewellyn DJ, Lang IA, Langa KM, et al. Vitamin D and risk of cognitive decline in elderly persons. Arch Intern Med. 2010;170(13):1135-1141.

28. Wilkins CH, Sheline YI, Roe CM, et al. Vitamin D deficiency is associated with low mood and worse cognitive performance in older adults. Am J Geriatr Psychiatry. 2006;14(12):1032-1040.

29. Annweiler C, Rolland Y, Schott AM, et al. Higher vitamin D dietary intake is associated with lower risk of Alzheimer’s disease: a 7-year follow-up. J Gerontol A Biol Sci Med Sci. 2012;67(11):1205-1211.

30. Kuningas M, Mooijaart SP, Jolles J, et al. VDR gene variants associate with cognitive function and depressive symptoms in old age. Neurobiol Aging. 2009;30(3):466-473.

31. Ganji V, Milone C, Cody MM, et al. Serum vitamin D concentrations are related to depression in young adult US population: the Third National Health and Nutrition Examination Survey. Int Arch Med. 2010;3:29.-

32. Hoogendijk WJ, Lips P, Dik MG, et al. Depression is associated with decreased 25-hydroxyvitamin D and increased parathyroid hormone levels in older adults. Arch Gen Psychiatry. 2008;65(5):508-512.

33. Pan A, Lu L, Franco OH, et al. Association between depressive symptoms and 25-hydroxyvitamin D in middle-aged and elderly Chinese. J Affect Disord. 2009;118(1-3):240-243.

34. Högberg G, Gustafsson SA, Hällström T, et al. Depressed adolescents in a case-series were low in vitamin D and depression was ameliorated by vitamin D supplementation. Acta Paediatr. 2012;101(7):779-783.

35. Jorde R, Sneve M, Figenschau Y, et al. Effects of vitamin D supplementation on symptoms of depression in overweight and obese subjects: randomized double blind trial. J Intern Med. 2008;264(6):599-609.

36. Kjærgaard M, Waterloo K, Wang CE, et al. Effect of vitamin D supplement on depression scores in people with low levels of serum 25-hydroxyvitamin D: nested case-control study and randomised clinical trial. Br J Psychiatry. 2012;201(5):360-368.

37. Lansdowne AT, Provost SC. Vitamin D3 enhances mood in healthy subjects during winter. Psychopharmacology (Berl). 1998;135(4):319-223.

38. Shipowick CD, Moore CB, Corbett C, et al. Vitamin D and depressive symptoms in women during the winter: a pilot study. Appl Nurs Res. 2009;22(3):221-225.

39. Gloth FM 3rd, Alam W, Hollis B. Vitamin D vs broad spectrum phototherapy in the treatment of seasonal affective disorder. J Nutr Health Aging. 1999;3(1):5-7.

40. Vieth R, Kimball S, Hu A, et al. Randomized comparison of the effects of the vitamin D3 adequate intake versus 100 mcg (4000 IU) per day on biochemical responses and the wellbeing of patients. Nutr J. 2004;3:8.-

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42. Dumville JC, Miles JN, Porthouse J, et al. Can vitamin D supplementation prevent winter-time blues? A randomised trial among older women. J Nutr Health Aging. 2006;10(2):151-153.

43. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(7):1911-1930.

44. Thacher TD, Clarke BL. Vitamin D insufficiency. Mayo Clin Proc. 2011;86(1):50-60.

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In the United States, >50% of psychiatric inpatients have vitamin D deficiency—<30 nmol/L (<12 ng/mL).¹ A growing body of literature has found associations between vitamin D deficiency and psychiatric illnesses, particularly depression. Several randomized controlled trials (RCTs) have demonstrated that vitamin D supplementation can benefit depression symptoms. In this article, we discuss the current literature on vitamin D and psychiatric illness, and provide practical information for clinicians on the use of vitamin D supplementation.

Biosynthesis of vitamin D

Biosynthesis of vitamin D begins with the sterol provitamin D₃ molecule 7-dehydrocholesterol (Figure).² When skin is exposed to sunlight, 7-dehydrocholesterol absorbs UV radiation and forms provitamin D₃, which undergoes rapid transformation to vitamin D₃.² Vitamin D₃ is released from the plasma membrane and enters systemic circulation in a protein-bound form that has a serum half-life of 36 to 78 hours.³ Vitamin D₃ can be taken up by adipocytes and stored in fat deposits, where it has a half-life of approximately 2 months.⁴

Figure: Biosynthesis of vitamin D
Provitamin D₃ (7-dehydrocholesterol) in the skin absorbs UV radiation and undergoes isomerization to form vitamin D₃. Endogenously produced vitamin D₃ along with dietary vitamin D₂ and vitamin D₃ absorbed in the gastrointestinal tract are metabolized in the liver to 25-hydroxyvitamin D (25[OH]D), which re-enters the circulation and is metabolized in the kidney and other tissues to the active metabolite 1,25-dihydroxyvitamin D (1,25[OH]2D). Catabolism of 25(OH)D and 1,25(OH)2D into biologically-inactive molecules is primarily mediated by the cytochrome P450 (CYP) enzymes CYP24 and CYP3A4.
Source: Reference 2Circulating vitamin D₃ is metabolized in the liver by the enzyme vitamin D-25-hydroxylase to 25-hydroxyvitamin D (25[OH]D₃), which has a serum half-life of approximately 15 days.⁴ Circulating 25(OH)D₃ is not biologically active at the physiological level, and requires activation by conversion to 1,25-dihydroxyvitamin D (1,25[OH]2D₃) in the kidneys by the enzyme 25(OH)D-1α-hydroxylase. Production of 1,25(OH)2D₃ is regulated by serum phosphorus and parathyroid hormone levels and other factors.⁵ Catabolism of 1,25(OH)2D₃ is rapid, with a serum half-life of 3.5 to 21 hours.⁶ Vitamin D₂ is structurally similar to vitamin D₃, but occurs primarily in fungi, yeasts, and some invertebrates.

Risk factors for deficiency

A patient’s vitamin D status is determined by measuring 25(OH)D (Box 1). Risk factors for vitamin D deficiency include conditions that affect cutaneous production (insufficient sunlight exposure), obesity, gastrointestinal disorders, aging, renal disorders, and medications (Table 1). ^2,5,7,8 The link between sunscreen use, either alone or in cosmetics, and vitamin D deficiency continues to be debated. While controlled studies have found that application of sunscreen with high sun protection factor can significantly reduce vitamin D production, ⁹ studies in clinical populations have failed to confirm these findings.^10,11 See Box 2 for a discussion of these risk factors and Box 3 for a discussion of acute and long-term medical manifestations of deficiency.

Box 1

Measuring vitamin D levels

Although 1,25-dihydroxyvitamin D (1,25[OH]2D₃) is the biologically active form of vitamin D, its circulating half-life is only 4 to 6 hours.^a,b Therefore, 25-hydroxyvitamin D (25[OH]D) is the principal vitamin D metabolite measured to determine vitamin D status. Vitamin D levels commonly are expressed as ng/mL or nmol/L; the conversion factor from ng/mL to nmol/L is 2.496. The Institute of Medicine has defined vitamin D deficiency as a serum 25(OH)D level of <30 nmol/L (<12 ng/mL).^c However, many experts define vitamin D insufficiency as a 25(OH)D level of 21 to 29 ng/ml, and deficiency as <20 ng/mL.^a,d The upper limit is more difficult to define, but symptoms of vitamin D intoxication appear with blood levels >150 to 200 ng/mL.^a

References

Holick MF. High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc. 2006;81(3):353-373.
Holick MF. Vitamin D status: measurement, interpretation, and clinical application. Ann Epidemiol. 2009;19(2):73-78.
Aloia JF. Clinical review: the 2011 report on dietary reference intake for vitamin D: where do we go from here? J Clin Endocrinol Metab. 2011;96(10):2987-2996.
Bischoff-Ferrari HA, Giovannucci E, Willett WC, et al. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr. 2006;84(1):18-28.

Table 1

Risk factors associated with vitamin D deficiency

Age (>65)
Insufficient sunlight
Breastfeeding
Dark skin
Malabsorption diseases
Obesity (BMI >30 kg/m²)
Use of medications that alter vitamin D metabolism (eg, anticonvulsants, glucocorticoids)
Hepatobiliary disease
Renal disease
BMI: body mass index Source: References 2,5,7,8

Box 2

Risk factors for vitamin D deficiency

Any factor that diminishes UV radiation penetration into the skin will affect cutaneous synthesis of vitamin D.^a,b For example, sunscreen with a sun protection factor of 15 can decrease vitamin D synthesis by 98%.^c Geography and its impact on yearly sunlight exposure is a well-known factor in vitamin D deficiency. Individuals who live below a latitude of approximately 35° North—approximately the southern border of Tennessee and through Albuquerque, NM—receive sufficient UV radiation exposure to ensure adequate vitamin D production throughout the year, but at higher latitudes, adequate vitamin D is not produced during winter months.^d Melanin affects UV radiation absorption in a manner that prevents vitamin D production, and increased skin pigmentation markedly reduces vitamin D synthesis.^e African Americans with very dark skin have significantly diminished cutaneous production of vitamin D.^e,f

Renal 1α-hydroxylase activity decreases with aging in parallel with age-related decreases in glomerular filtration.^g In addition, aging is associated with increased clearance of 1,25-dihydroxyvitamin D (1,25[OH]2D₃).^h However, vitamin D absorption generally is adequate even at older ages.ⁱ Studies have shown that obese individuals tend to have lower serum concentrations of vitamin D and 25-hydroxyvitamin D (25[OH]D) than those at a normal weight.^j,k Obese patients have been shown to have lower cutaneous production of vitamin D₃ and display lower bioavailability of orally administered vitamin D₂.^j

For patients with chronic renal insufficiency, creatinine clearance is positively correlated with serum 1,25(OH)2D levels.^l Any process that results in malabsorption of intestinal fat may impair vitamin D absorption. In patients with celiac disease, biliary obstruction, or chronic pancreatitis, absorption consistently is reduced.^m Individuals taking bile acid-binding medications, such as cholestyramine for hypercholesterolemia, also may have impaired vitamin D absorption.ⁿ In addition, hepatobiliary disease is associated with low levels of 25(OH)D.^o Some drugs that alter hepatic metabolism are associated with vitamin D deficiency, including anticonvulsants or glucocorticoids, which can increase catabolism or vitamin D.^p

References

Holick MF. The vitamin D deficiency pandemic and consequences for nonskeletal health: mechanisms of action. Mol Aspects Med. 2008;29(6):361-368.
Holick MF, Chen TC. Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr. 2008;87(4):1080S-1086S.
Matsuoka LY, Ide L, Wortsman J, et al. Sunscreens suppress cutaneous vitamin D₃ synthesis. J Clin Endocrinol Metab. 1987;64(6):1165-1168.
Holick MF. Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. Am J Clin Nutr. 2004;79(3):362-371.
Clemens TL, Adams JS, Henderson SL, et al. Increased skin pigment reduces the capacity of skin to synthesise vitamin D₃. Lancet. 1982;1(8263):74-76.
Chen TC, Chimeh F, Lu Z, et al. Factors that influence the cutaneous synthesis and dietary sources of vitamin D. Arch Biochem Biophys. 2007;460(2):213-217.
Slovik DM, Adams JS, Neer RM, et al. Deficient production of 1,25-dihydroxyvitamin D in elderly osteoporotic patients. N Engl J Med. 1981;305(7):372-374.
Armbrecht HJ, Zenser TV, Davis BB. Effect of age on the conversion of 25-hydroxyvitamin D₃ to 1,25-dihydroxyvitamin D₃ by kidney of rat. J Clin Invest. 1980;66(5):1118-1123.
Lips P, Wiersinga A, van Ginkel FC, et al. The effect of vitamin D supplementation on vitamin D status and parathyroid function in elderly subjects. J Clin Endocrinol Metab. 1988;67(4):644-650.
Wortsman J, Matsuoka LY, Chen TC, et al. Decreased bioavailability of vitamin D in obesity. Am J Clin Nutr. 2000;72(3):690-693.
Bell NH, Epstein S, Greene A, et al. Evidence for alteration of the vitamin D-endocrine system in obese subjects. J Clin Invest. 1985;76(1):370-373.
Pitts TO, Piraino BH, Mitro R, et al. Hyperparathyroidism and 1,25-dihydroxyvitamin D deficiency in mild, moderate, and severe renal failure. J Clin Endocrinol Metab. 1988;67(5):876-881.
Thompson GR, Lewis B, Booth CC. Absorption of vitamin D₃-³H in control subjects and patients with intestinal malabsorption. J Clin Invest. 1966;45(1):94-102.
Lo CW, Paris PW, Clemens TL, et al. Vitamin D absorption in healthy subjects and in patients with intestinal malabsorption syndromes. Am J Clin Nutr. 1985;42(4):644-649.
Pappa HM, Bern E, Kamin D, et al. Vitamin D status in gastrointestinal and liver disease. Curr Opin Gastroenterol. 2008;24(2):176-183.
Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):266-281.