Vitamin D and Schizophrenia By: Sonja Julian. Outline Introduction ▫Fetal programming ▫Vitamin D ▫Schizophrenia Methodology Results ▫4 human studies ▫2.

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.