Vitamin D and mental health: reflection on U-shaped relationships

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1 ILSI SEA Region Vit D Conference, Australia, June 2012 ( Region) Vitamin D and mental health: reflection on U-shaped relationships John McGrath

2 Schizophrenia a neurodevelopmental disorder Neuropathology Antecedents Early life risk factors Genetic factors impacting on brain development

The vitamin D hypothesis Low pre- and perinatal vitamin D impacts adversely on brain development, leaving the affected offspring at increased risk of

3 The vitamin D hypothesis Low pre- and perinatal vitamin D impacts adversely on brain development, leaving the affected offspring at increased risk of schizophrenia. McGrath J. (1999) Hypothesis: Is low prenatal vitamin D a risk-modifying factor for schizophrenia? Schizophrenia Research 40:

The vitamin D receptor (VDR) and 1 α hydroxylase are present in the human brain Neurofilament 200 and 1 α hydoxylase Neurofilament 200 and VDR GFAP and VDR GFAP and 1 α hydoxylase McGrath et al.

4 The vitamin D receptor (VDR) and 1 α hydroxylase are present in the human brain Neurofilament 200 and 1 α hydoxylase Neurofilament 200 and VDR GFAP and VDR GFAP and 1 α hydoxylase McGrath et al. Vitamin D: the neglected neurosteroid? Trends in Neuroscience. 2001;24(10): Eyles et al (2005) Distribution of the vitamin D receptor and 1-hydroxylase in human brain. J Chem Neuroanat: 29(1):21-30.

Vitamin D supplementation study Collaboration Oulo University, Cambridge University North Finnish 1966 Birth cohort, n = 9144 Vitamin D supplementation during first year.

5 Vitamin D supplementation study Collaboration Oulo University, Cambridge University North Finnish 1966 Birth cohort, n = 9144 Vitamin D supplementation during first year. Schizophrenia by age 31 Association between lack of vitamin D supplementation and increased risk of schizophrenia in males only McGrath et al (2004) Vitamin D supplementation during the first year of life and risk of schizophrenia: a Finnish birth-cohort study. Schizophrenia Research. 67 (2-3):

6 Developmental vitamin D (DVD) model Mothers Normal diet Vitamin D deficient diet Pups Control pup Deficient pup Adults 10 week adult 10 week adult

7 Ventricle size Control - pup Depleted - pup Compared to control rats, depleted rats have larger ventricle/brain ratio as pups Eyles et al. (2003) Vitamin D3 and brain development. Neuroscience, 118(3):

DVD behavioural phenotype Mostly normal, except hyperlocomotion response to MK801 response to amphetamine response to haloperidol altered latent inhibition Burne et al (2004) Combined prenatal and

8 DVD behavioural phenotype Mostly normal, except hyperlocomotion response to MK801 response to amphetamine response to haloperidol altered latent inhibition Burne et al (2004) Combined prenatal and chronic postnatal vitamin D deficiency in rats impairs prepulse inhibition. Physiology and Behavior 81(4), Burne et al (2004) Transient prenatal vitamin D deficiency is associated with hyperlocomotion in adult rats. Behavioural Brain Research 154(2): Becker et al (2005) Transient prenatal vitamin D deficiency is associated with subtle alterations in learning and memory functions in adult rats Behavioural Brain Research 161 Burne et al. (2006) Hyperlocomotion associated with transient prenatal vitamin D deficiency is ameliorated by acute restraint. Behavioural Brain Research 174 (1), Eyles et al (2006) Developmental vitamin D (DVD) deficiency in the rat alters adult behaviour independently of HPA function. Psychoneuroendocrinology 31(8): Kesby et al (2006) Developmental vitamin D deficiency is associated with MK 801-induced hyperlocomotion in the adult rat: an informative animal model of schizophrenia. Biological Psychiatry 15;60(6):591-6

9 Analytic epidemiology Measuring 25 OH vitamin D 3 in neonatal dried blood spots. Nested case-control study

403(1-2):145-51. D Eyles, R Morley, C Anderson, P Ko, T Burne, M Permezel, P Mortensen, B Nørgaard-Pedersen, D Hougaard, J McGrath.

10 Vitamin D assay based on archived dried blood spots Eyles D, Anderson C, Ko P, Jones A, Thomas A, Burne T, Morte nsen PB,Nørgaard-Pedersen B, Hougaard DM, McGrath J. (2009) A sensitive LC/MS/MS assay of 25OH vitamin D3 and 25OH vitamin D2 in dried blood spots. Clin Chim Acta. 403(1-2): D Eyles, R Morley, C Anderson, P Ko, T Burne, M Permezel, P Mortensen, B Nørgaard-Pedersen, D Hougaard, J McGrath. (2010) The utility of neonatal dried blood spots for the assessment of neonatal vitamin D status. Pediatric and Perinatal Epidemiology 24:303-8.

11 Danish Neonatal Dried Blood Spots

12 Case-control study Record linkage Biobank and Mental Health Register 430 cases of schizophrenia and 430 matched controls. Population-based sample McGrath JJ, Eyles DW, Pedersen CB, Anderson C, Ko P, Burne TH, Norgaard-Pedersen B, Hougaard DM, Mortensen PB. (2010) Neonatal vitamin D status and risk of schizophrenia: a population-based case-control study. Archives of General Psychiatry 67(9);

13 Relative risk (and 95%CI) of schizophrenia for quintiles of 25 hydroxy-vitamin D 3 Lowest 2.1 ( ) Second 2.0 ( ) Third 2.1 ( ) Fourth reference Highest 1.7 ( )

14 Non-linear exposure risk relationship Deciles Fitted curve Reversed J- shaped curve Mechanism? Population attributable fraction = 44%

15 Mother-to-child transmission of HIV, and child mortality and their association with maternal vitamin D Inflection (54-64 ng/ml) nmo/l

16 Maternal vitamin D versus neonatal small-for-gestational age. Inflection Aprox 60 nmol/l

17 Maternal vitamin D status versus type 1 diabetes in the offspring. Inflection Aprox 120 nmol/l Maternal serum 25-hydroxyvitamin D in pregnancy (nmol/l) Cases (offspring with type 1 diabetes) Controls

18 Serum 25- hydroxyvitamin D versus IgE Inflection Aprox 120 nmo/l

19 Vitamin D status and risk of mortality. Inflection Aprox. (40 ng/ml) 100 nmol/l

20 Vitamin D statis and mortality in older men Inflection Aprox 80 nmol/l

21 Baseline 25OHD versus all cause mortality N = 247,574

22 The gloomy prospect of U-shaped relationships Why do we keep seeing non-linear exposure-risk relationships?

23 What is the meaning of a U- or J-shaped relationship? Is it true like in vitro steroid response? Is it a population wide effect? Is it an admixture of underlying subgroups that could be stratified by some variable?

24 Admixture how to stratify the population Group-specific component (binding protein) may impact on free fraction Different affinity? Different serum concentrations?

25 Ancestral type Affinity = high Binding protein concentration = normal Total 25OH molecules = 5 Free 25OHD molecules = 2

26 Ancestral type Affinity = high Binding protein concentration = normal Total 25OH molecules = 5 Free 25OHD molecules = 2 Derived type Affinity = lower Binding protein concentration = lower Total 25OH molecules = 5 Free 25OHD molecules = 4

27 Admixture how to stratify the population Mild vitamin D resistance CYP27B1 variants? organ specific resistance?

28 Admixture how to stratify the population Could high calcium intake throttle-back PTH and 1,25OHD dynamics? Related species? C3 epimer sulphated vitamin D Gaps in the knowledge base: Transporters for bound and unbound ligands?

29 Do we still love vitamin D?

30 Future directions There is an urgent need to explore the mechanisms underlying the U- shaped curve.

Eyles Tom Burne Pauline Ko Cameron Anderson Funding: National

31 Acknowledgments Danish collaborators Preben Bo Mortensen Carsten Pedersen David Hougaard Bent Nørgaard-Pedersen QBI Team Darryl Eyles Tom Burne Pauline Ko Cameron Anderson Funding: National Health and Medical Research Council, Stanley Medical Research Institute

The impact of vitamin D deficiency on behaviour and brain function in rodents

*Manuscript The impact of vitamin D deficiency on behaviour and brain function in rodents Overeem, K. 1, Eyles, D.W. 1,2, McGrath, J.J. 1,2 and Burne, T.H.J. 1,2 * 1. Queensland Brain Institute, The University