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Vitamin D and SchizophreniaBy: 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:▫ 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)
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)
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)
Research QuestionDoes maternal exposure to vitamin D during pregnancy influence the development of schizophrenia in offspring?
Methodology
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
Results4 Human and 2 Rat Studies
4 Human Studies
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)
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)
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)
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)
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)
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)
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)
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)
Study 4 Results• Monthly variance of 25(OH)D3 levels
▫p < 0.001• Neonatal vitamin D3 status 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)
Study 4 Results Cont.
(7)
2 Rat StudiesDVD – developmental vitamin D deficiency
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)
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)
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)
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)
• 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)
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)
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)
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)
References1) The Barker Theory. 2012; http://www.thebarkertheory.org/science.php. Accessed March 25, 2012.2) Yajnik CS, 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) Ponsonby AL, 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'Loan J, 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.