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Vitamin D and Schizophrenia

Vitamin D and Schizophrenia. By: Sonja Julian. Outline. Introduction Fetal programming Vitamin D Schizophrenia Methodology Results 4 human studies 2 rat studies Discussion Recommendations References. Introduction. Fetal Programming. Dr. David Barker’s Fetal Origins Hypothesis:

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Vitamin D and Schizophrenia

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  1. Vitamin D and Schizophrenia By: Sonja Julian

  2. Outline • Introduction • Fetal programming • Vitamin D • Schizophrenia • Methodology • Results • 4 human studies • 2 rat studies • Discussion • Recommendations • References

  3. Introduction

  4. Fetal Programming • Dr. David Barker’s Fetal Origins Hypothesis: • Low birth weight is associated with an increased risk of hypertension, stroke, and type 2 diabetes • Nutrition and health in utero has implications for offspring • Epigenetic changes that modify gene expression: • Methylation of DNA, accetylation of histones and role of micro RNAs (1, 2)

  5. Vitamin D • Forms: • Inactive, circulating (25(OH)D3) and active (1,25(OH)2D3) • Many major functions and both genomic and non-genomic actions • RDA: • Children to adults 600 IU/day • Sources: • Fish, beef, eggs, dairy, fortified foods, sunlight • Some factors that affect absorption: • Age, skin pigmentation, sunlight exposure, latitude, time of day, season, inactivity and obesity • Potential involvement in etiology of schizophrenia (3, 4, 5)

  6. Schizophrenia • Complex mental disorder that makes it difficult to: • Tell the difference between real and unreal experiences • Think logically • Have normal emotional responses • Behave normally in social situations • No identified cause • Certain environmental events may trigger if genetically predisposed • Individuals born in winter/spring have an increased risk of developing the disease (6, 7)

  7. Research Question Does maternal exposure to vitamin D during pregnancy influence the development of schizophrenia in offspring?

  8. Methodology

  9. Methodology • Definition of fetal programming • PubMed • Fetal programming and micronutrients • Vitamin D and offspring health • Cross-check • 6 articles • Inclusions • Human and animal, past 10 years • Exclusions • Non-English and review

  10. Results 4 Human and 2 Rat Studies

  11. 4 Human Studies

  12. Study 1: Trends in Sunshine Duration • 6630 Queensland and 24,474 Netherlands • Born between 1931-1970; admitted 1972-1994 • Sunshine duration information from institutes of meteorology • Assessed men and women separately • Special sample from each health register: • Queensland 2583 “first-ever admission” • Netherlands 15, 308 “1950-1970 born” (8)

  13. Study 1 Results • Sunshine duration and risk of schizophrenia • Males • Queensland p = 0.002; Netherlands p = 0.004 • Females • Queensland p = 0.54; Netherlands p = 0.004 in opposite direction • Sunshine duration and age of first registration • Males • Queensland p < 0.001; Netherlands p < 0.001 • Females • Queensland p < 0.001; Netherlands p < 0.001 (8)

  14. Study 1 Results Continued • Queensland “first-ever registration” • Males p = 0.02 • Females p = 0.02 • Netherlands “1950-1970 born” • Males p < 0.001 • Females p < 0.001 (8)

  15. Study 2: Supplementation during first year of life • Northern Finish 1966 Birth Cohort (N = 10,934) • Measures of vitamin D supplementation • Frequency • (3) “none,” “irregularly,” or “regularly” • Dose • (2) < 2000 IU/day, 2000 IU or greater/day • Outcome measures • Schizophrenia (100), psychotic disorders other than schizophrenia (55), and non-psychotic disorders (315); 10,464 without psychiatric hospitalization by age 31 • Men and women examined separately • Single and multiple-term Cox-proportional hazards (9)

  16. Study 2 Results • Based on 9,114 cohort members • Males • Frequency: “Irregularly” or “Regularly” vs “None” • “Irregularly” RR= 0.08, 95% CI 0.01-0.95 • “Regularly” RR = 0.12, 95% CI 0.02-0.90 • Dose: 2000 IU or greater vs < 2000 IU • 77% decreased risk • Females • No cases of schizophrenia • No association with other psychiatric outcomes (9)

  17. Study 3: Maternal Banked Sera • 11,971 pregnant women (1959-1966) and 15,721 surviving offspring Boston, MA and Providence, RI • Maternal serum collected at various points throughout pregnancy • Psychotic illnesses of offspring • Identified by: • Personal interviews • Record linkage with psychiatric treatment facilities • 119 adult psychotic disorder • 39 schizophrenia or schizoaffective disorder • 27 of 39 matched with 2 healthy controls • Blind study assessing calcidiol levels by RIA using conditional logistic regression (10)

  18. Study 3 Results • 26 cases and 51 matched controls • No significant difference in maternal calcidiol levels between cases and controls • OR, 0.98; 95% CI 0.92-1.05 • Maternal calcidiol levels of 12/26 cases and 15/51 controls < 15 ng/ml • OR, 2.06; 95% CI 0.77-5.47 • No association between maternal calcidiol levels during 3rd trimester and risk of offspring schizophrenia (10)

  19. Study 4: Neonatal Vitamin D Status • Danish psychiatric and civil register + dried blood spots • 424 subjects matched 1:1 • Blood measured for • 25(OH)D3 • 25(OH)D2 • Blood samples divided into 5 categories (nmol/L) • 1) <19.7 2) 19.7 – 30.9 3) 31-40.4 4) 40.5-50.9 5) > 51 (7)

  20. Study 4 Results • Monthly variance of 25(OH)D3 levels • p < 0.001 • Neonatal vitamin D3status and risk of schizophrenia • p = 0.01 • Compared to fourth/fifth category (> 40.5 nmol/L) • First: OR, 1.7; 95% CI, 1.1-2.5 • Second: OR, 1.8; 95% CI, 1.2-2.6 • 1st and 2nd: 2-fold increased risk • Third: OR, 1.4; 95% CI, 0.9-2.0 • Fifth had increased risks compared to fourth (7)

  21. Study 4 Results Cont. (7)

  22. 2 Rat Studies DVD – developmental vitamin D deficiency

  23. Study 5: Protein Expression in Brain Females  Dams • 12 vitamin D-depleted females • vitamin D deficient diet and incandescent light • 12 control females • Normal diet and UVB-emitting light • 6 weeks: serum levels checked • 10 weeks: mated with vitamin D-normal males • Conception to birth: respective diets and housing • At birth: all control diet and UVB lighting (11)

  24. Pups • 3 weeks: weaned • Same sex housing • 10 weeks: death • Brains obtained immediately • Protein spots on frontal cortices and hippocampi • Analysis: • Silver staining and 2-D gel image analysis • Western Blot and protein data mining (11)

  25. Study 5 Results • 643 hippocampal & 681 frontal cortex spots • 28/643 and 22/681 (p< 0.05, p< 0.02, p< 0.01) • Spots correspondence to distinct proteins • 28 hippocampal = 23 proteins • 22 frontal cortex = 17 proteins • 40(23+17) -4 (overlap) = 36 dysregulated proteins • 28 of 36 related to: • Mitochondria, cytoskeleton and synapses • Postmortem and genetic studies of humans with schizophrenia • Hyperlocomotion (11)

  26. Study 6: MK-801-induced Hyperlocomotion • 108 dams • Housing • non UVB-emitting light, 12h light/dark cycle, 21 ± 2°C, 60% humidity • 4 dietary groups • 1) control: replete (1000 IU/kg); entire study • 2) early-DVD deficient: deficient (0 IU/kg) with normal Ca2+ and P; 4 weeks - conception, replete until birth • 3) late-DVD deficient: replete until conception, deplete until birth • 4) full-DVD deficient: deplete 6 weeks post-conception until birth (12)

  27. At birth of pups • All dams put on replete diet • Pups placed under control conditions • Sera collected from dams and offspring • Male offspring group (n= 123) • Physical maturity • Drug-induced locomotion • MK-801 or saline (12)

  28. Study 6 Results • Transference of vitamin D • Early- DVD deficient: rapid repletion of calcitriol and calcidiol • Late-DVD deficient: rapid calcidiol depletion, slow calcitriol depletion • Full- DVD deficient: fully deficient • MK-801-induced hyperlocomotion • Full-DVD deficient: 190%; p < 0.01 • Late-DVD deficient: 130%; p < 0.05 • Early-DVD deficient: 22% • Control: 15% • Critical window = late gestation (12)

  29. Discussion • Human studies analyzed secondary data • Study 1: mental health registers and meteorology • Severe prenatal vitamin D deficiency • Young samples • Neonate stores may not reflect maternal stores • Can rat studies for mental disorders be applied to humans? • All studies by same researcher (7,8,9,10,11,12,13)

  30. Recommendations • Controlled human study • Including: dietary recall + recorded sun exposure • Subjects matched for factors that affect absorption • Long-term cohort • Research for increasing RDA • No RDA set for pregnant/lactating women • Address when discussing other prenatal supplements • Test calcidiol and calcitriol levels of mother and fetus to assess status and transfer (14)

  31. References 1) The Barker Theory. 2012; http://www.thebarkertheory.org/science.php. Accessed March 25, 2012. 2) YajnikCS, Deshmukh US. Maternal nutrition, intrauterine programming and consequential risks in the offspring. Reviews in endocrine & metabolic disorders. Sep 2008;9(3):203-211. 3) Gropper S, Smith J., Groff, J. Advanced Nutrition and Human Metabolism. 5 ed. California: Wadsworth, Cengage Learning; 2009. 4) PonsonbyAL, Lucas RM, Lewis S, Halliday J. Vitamin D status during pregnancy and aspects of offspring health. Nutrients. Mar 2010;2(3):389-407. 5) McGrath J. Hypothesis: is low prenatal vitamin D a risk-modifying factor for schizophrenia? Schizophrenia research. Dec 21 1999;40(3):173-177. 6) Schizophrenia. A.D.A.M. Medical Encyclopedia; 2012. 7) McGrath JJ, Eyles DW, Pedersen CB, et al. Neonatal vitamin D status and risk of schizophrenia: a population-based case-control study. Archives of general psychiatry. Sep 2010;67(9):889-894. 8) McGrath J, Selten JP, Chant D. Long-term trends in sunshine duration and its association with schizophrenia birth rates and age at first registration--data from Australia and the Netherlands. Schizophrenia research. Apr 1 2002;54(3):199-212. 9) 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. Schizophrenia research. Apr 1 2004;67(2-3):237-245. 10) McGrath J, Eyles D, Mowry B, Yolken R, Buka S. Low maternal vitamin D as a risk factor for schizophrenia: a pilot study using banked sera. Schizophrenia research. Sep 1 2003;63(1-2):73-78. 11) 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. Mar 2007;7(5):769-780. 12) O'LoanJ, Eyles DW, Kesby J, Ko P, McGrath JJ, Burne TH. Vitamin D deficiency during various stages of pregnancy in the rat; its impact on development and behaviour in adult offspring. Psychoneuroendocrinology. Apr 2007;32(3):227-234. 13) Kovacs CS. Vitamin D in pregnancy and lactation: maternal, fetal, and neonatal outcomes from human and animal studies. The American journal of clinical nutrition. Aug 2008;88(2):520S-528S. 14) Holick MF, Chen TC. Vitamin D deficiency: a worldwide problem with health consequences. The American journal of clinical nutrition. Apr 2008;87(4):1080S-1086S.

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