vitamin D vid depression, ångest och bipolär sjukdom

Fråga: Skulle behöva hjälp att se över evidensläget för användning av peroralt D-vitamin vid affektiva psykiatriska indikationer. Vi arbetar med en generell rekommendation.

Svar: Sammanfattning
Due to the amount of heterogeneity between studies as well as lack of controls for outside variables, it is difficult to ascertain if there is an independent correlation between depression and vitamin D deficiency.

There is no clear agreement that addition of vitamin D improves or is related to a beneficial effect on mental health. Vitamin D supplementation should be used in caution due to inconclusive evidence for vitamin D supplementation for treatment in psychiatric illness

Svar
Vitamin D receptors (VDR) have been found in areas of the brain responsible for mood disorders and is postulated to be involved in the modulation of neurotransmitters (1).

Theodoratou E, et al (2), evaluated the breadth, validity, and presence of biases of the associations of vitamin D with 137 diverse outcomes including depression. The authors found that meta-analysis of observational studies of depression was suggestive of a decreased risk for depression and mood disorders with high 25(OH)D concentrations. However, the authors concluded that highly convincing evidence of a clear role of vitamin D does not exist for any of the 137-outcome measured in randomized controlled studies, with possibly four exceptions not including depression.

Population based epidemiological and clinical studies showed an association of low 25(OH)-vitamin D serum levels (25(OH)D) with depressed mood in children and adolescents (3) and adults (4, 5). However, an observational study (6) conducted on geriatric patients, a population already at increased risk for vitamin D deficiency and depression, found no independent correlation between vitamin D deficiency and depression over a 4-year period.

Substantial discrepancies have continued to emerge between results of observational studies and of randomized trials with respect to vitamin D and health (7). Aanalyses of randomized trial data in people with non-skeletal health conditions, including mood disorders, with 25(OH)D concentrations below 50 nmol/L did not show that vitamin D supplementation offered health benefits (7).

19 randomize clinical trials (RCTs) on adults and two RCTs included both adolescents and adults evaluated the association of, and intervention with vitamin D levels and mental health conditions (for details see (3)). Four meta-analyses and systemic reviews include most of the 21 RCT on adults with depression revealed conflicting results according to Föcker M et al (3). Two reported no significant effects of vitamin D supplementation on depression scores (8, 9). Shaffer et al. (10) found no general effect of vitamin D supplementation on depressive symptoms, but a subgroup analysis revealed a moderate, statistically significant effect in participants with clinically significant depressive symptoms or depressive disorders and a small, but non-significant effect for those without clinically significant depression. In the metanalysis of Spedding et al. (11) with the highest number of RCTs (N = 15), a statistically significant improvement in depression with vitamin D supplements was demonstrated in studies where a diagnosed vitamin D deficiency at baseline was used as an inclusion criterion and the dose of vitamin D was sufficient to achieve adequate levels of 25(OH)D during the trial. Four RCTs (12-15) presented by Föcker M et al. (3) and not covered in one of the above-described metanalyses revealed conflicting results as well. Two (12, 13) showed a beneficial effect of vitamin D supplementation on perinatal depression or emotional symptoms while two others (14, 15) observed no effects.

According to the Akademiska Laboratory in Uppsala, 25-OH vitamin D levels below 25 nmol/L are regarded as Vitamin D deficiency “D-vitaminbrist”, while 25-75 nmol/L is termed "vitamin D insufficiency". It is the manufacturer's recommended limits which are not evidence-based (16). Håkan Melhus, clinical pharmacologist and researcher in University Hospital, an expert in the area, stated that a 25-OH-D value between 25 and 75 nmol/L is not an indication for treatment. However, treatment might be applicable when 25-OHD level is 25-50 nmol/L in combination with low serum calcium and elevated levels of parathyroid hormone (PTH) and/or alkaline phosphatase (16). All currently used levels are related to bone health outcomes and based on suppression of parathyroid hormone (PTH) levels with no evidence available with respect to an “optimal-level” for mental health (17).

According to Mulcahy KB et al (1) it is unknown if vitamin D insufficiency or deficiency in psychiatric patients is due to a consequence of psychiatric disease or has a role in pathogenesis from a common pathway. The authors stated that due to the amount of heterogeneity between studies as well as lack of controls for outside variables, it is difficult to ascertain if there is in fact an independent correlation between depression and vitamin D deficiency or if the impact of vitamin D as a therapeutic intervention for depression is meaningful (1). The authors concluded that vitamin D supplementation should be used in caution due to inconclusive evidence for vitamin D supplementation for treatment in psychiatric illness.

A recent literature review on the current knowledge about the association between vitamin D deficiency, cognition, and mental disorders by Lerner PP et al published January 2018 (18) summarized all relevant publications during the last 22 years and 3 months (1995–2017). Although the authors found. an association between low vitamin D serum levels and different mental disorders, they concluded that there is no clear agreement that addition of vitamin D improves or is related to a beneficial effect on mental health

No guidelines currently available for the use of vitamin D as an adjunctive treatment for other conditions than for management bone health (1).

For more information on vitamin D and health please refer to two articles published in “Läkartidningen” 2012 and 2015 by two expert professors in the field: Håkan Melhus Karl Michaelsson (19, 20).

1. Mulcahy KB, Trigoboff E, Opler L, Demler TL. Physician Prescribing Practices of Vitamin D in a Psychiatric Hospital. Innov Clin Neurosci. 2016 Jun 1;13(5-6):21-27. eCollection 2016 May-Jun.
2. Theodoratou E, Tzoulaki I, Zgaga L, et al. Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials. BMJ. 2014;348
3. Föcker M, Antel J, Ring S, Hahn D, Kanal Ö, Öztürk D, Hebebrand J, Libuda L. Review Vitamin D and mental health in children and adolescents. Eur Child Adolesc Psychiatry. 2017 Sep; 26(9):1043-1066.
4. Brouwer-Brolsma EM, Feskens EJ, Steegenga WT, de Groot LC. Associations of 25-hydroxyvitamin D with fasting glucose, fasting insulin, dementia and depression in European elderly: the SENECA study. Eur J Nutr. 2013 Apr; 52(3):917-25.
5. Jaddou HY, Batieha AM, Khader YS, Kanaan SH, El-Khateeb MS, Ajlouni KM. Depression is associated with low levels of 25-hydroxyvitamin D among Jordanian adults: results from a national population survey. Eur Arch Psychiatry Clin Neurosci. 2012 Jun; 262(4):321-7.
6. Toffanello ED, Sergi G, Veronese N, et al. Serum 25-hydroxyvitamin D and the onset of late-life depressive mood in older men and women: the Pro.V.A. study. J Gerontol A Biol Sci Med Sci. 2014;69(12):1554–1561.
7. Autier P, Mullie P, Macacu A, Dragomir M, Boniol M, Coppens K, Pizot C, Boniol M. Effect of vitamin D supplementation on non-skeletal disorders: a systematic review of meta-analyses and randomised trials. Lancet Diabetes Endocrinol. 2017 Dec;5(12):986-1004.
8. Gowda U, Mutowo MP, Smith BJ, Wluka AE, Renzaho AM. Vitamin D supplementation to reduce depression in adults: meta-analysis of randomized controlled trials. Nutrition. 2015 Mar;31(3):421-9
9. Li G, Mbuagbaw L, Samaan Z, Falavigna M, Zhang S, Adachi JD, Cheng J, Papaioannou A, Thabane L. Efficacy of vitamin D supplementation in depression in adults: a systematic review. J Clin Endocrinol Metab. 2014, 99(3):757–767.
10. Shaffer JA, Edmondson D, Wasson LT, Falzon L, Homma K, Ezeokoli N, Li P, Davidson KW. Vitamin D supplementation for depressive symptoms: a systematic review and meta-analysis of randomized controlled trials. Psychosom Med. 2014, 76(3):190–196
11. Spedding S Vitamin D and depression: a systematic review and meta-analysis comparing studies with and without biological flaws. Nutrients. 2014, 6(4):1501 1518
12. Tartagni M, Cicinelli MV, Tartagni MV, Alrasheed H, Matteo M, Baldini D, De Salvia M, Loverro G, Montagnani M. Vitamin D supplementation for premenstrual syndrome-related mood disorders in adolescents with severe hypovitaminosis D. J Pediatr Adolesc Gynecol. 2016, 29(4):357–361
13. Vaziri F, Nasiri S, Tavana Z, Dabbaghmanesh MH, Sharif F, Jafari P. A randomized controlled trial of vitamin D supplementation on perinatal depression: in Iranian pregnant mothers. BMC Pregnancy Childbirth. 2016, 16:239
14. Wang Y, Liu XJ, Robitaille L, Eintracht S, MacNamara E, Hoffer LJ. Effects of vitamin C and vitamin D administration on mood and distress in acutely hospitalized patients. Am J Clin Nutr. 2013, 98(3):705–711
15. 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 7; 2014:528
16. Region Uppsala. Recept på behandling. Information från läkemedelskommittén. D-vitaminbrist, vad har vi egentligen för evidens? Sida 10. ÅRGÅNG 21, NR 1, MARS 2018 (Attached file).
17. Föcker M, Antel J, Grasemann C, Führer D, Timmesfeld N, Öztürk D, Peters T, Hinney A, Hebebrand J, Libuda L. Effect of an vitamin D deficiency on depressive symptoms in child and adolescent psychiatric patients - a randomized controlled trial: study protocol. BMC Psychiatry. 2018 Mar 1;18(1):57.
18. Lerner PP, Sharony L, Miodownik C. Association between mental disorders, cognitive disturbances and vitamin D serum level: Current state. Clin Nutr ESPEN. 2018 Feb;23:89-102.
19. Håkan Melhus and Karl Michaelsson.Vitamin D och hälsa: Evidensbristen är det stora problemet. läkartidningen nr 12 2012 volym 109.
20. Håkan Melhus and Karl Michaelsson. Tillskott av D-vitamin kan göra mer skada än nytta. Evidensbaserade tröskelvärden för D-vitaminstatus saknas ännu. Läkartidningen. 2015;112:DHFF