1. Joy Welham Sukanta Saha John McGrath A Review of Risk Factors for Schizophrenia

2. Schizophrenia is a group of imperfectly understood brain disorders characterized by alterations in higher functions related to perception, cognition, communication, planning and motivation. Signs and symptoms are hallucinations, delusions, thought disorder, and negative symptoms - eg blunted affect and reduced speech. These usually emerge in early adulthood. While many affected individuals recover, others have intermittent/persistent symptoms. Although advances in biological and psychosocial treatments are improving outcomes, schizophrenia is still a leading contributor to the global burden of disease. This keeps research focused on finding the causes of schizophrenia.

3. Aims To examine risk indicators, proxy variables and risk factors in relation to the developmental hypothesis. These may operate: Prenatally Perinatally Post natally - early childhood - later childhood - adolescence/adulthood

4. Outline Defining risk factors Risk indicators Risk proxies Putative risk factors Caveats and conclusions

5. What are risk factors? Risk factoran attribute/exposure which is associated with an increased* probability of schizophrenia; not necessarily causal More specific terms: Putative risk factorsrisk factors commonly supposed to be causally related to schizophrenia Risk modifying factorsrisk factors thought to operate within a causal chain Risk indicatorsprecede an outcome; individual anomalies marking previous risk modifying factor; not directly/causally related to the outcome Proxy variablesprecede an outcome; an ecological level variable reflecting another more directly causal factor; not directly/causally related to the outcome Sequelaecorrelate with an outcome, but do not precede it

6. Developmental models of schizophrenia Schizophrenia as a neurodevelopmental disorder - results from early (pre- or perinatal) events - possibly modified by later events - manifests in late adolescent/early adulthood

7. Risk indicators throughout development Early childhood Developmental delays Later childhood Neurological/cognitive anomalies Psycho-social deficits Brain anomalies Structural Functional Minor physical anomalies Dermatoglyphic anomalies

8. Proxy variables Season-of-birth Place-of-birth Migration

9. Proxy variables (1) Perinatal Season-of-birth Estimated effect size 5-15% winter/spring excess eg relative risk =1.11 but population attributable fraction (PAF) about 10.5%

10. Risk proxy (2) Perinatal Place-of-birth; Urban vs rural birth Estimated effect size = 1.5 – 4.2 Relative risk 2.4 but PAF about 30%

11. Risk proxy (3) Migration Estimated effect size 4 - 14

12. Putative risk factors Pre- or peri-natalGenetic &/or environmental risk factors (infection, injury, malnutrition) ChildhoodChildhood infection/brain injury Cognitive, motor & social deficits, odd ideation AdolescenceBrain maturational changes (normal or abnormal) Adolescence/adult hood Stress/adverse events; alcohol/drug use

13. Genetic Factors

14. Other genetic Non-hereditary genetic risk factors Paternal age/mutation (no estimated effect size available)

15. Environmental exposures: prenatal (1) Prenatal nutrition Macro-nutrition; eg calories/kilojoules Micro-nutrition; eg specific vitamins Estimated effect size for prenatal famine = 2.0

16. Environmental exposures: prenatal (2) Prenatal Infections Influenza (estimated effect size =2.0) Poliomyelitis (estimated effect size = 1.05) Respiratory infection ( estimated effect size = 2.1) Rubella (estimated effect size = 5.2) Toxoplasmosis (uncertain effect size)

17. Environmental exposures: prenatal (3) Maternal stress death of spouse (estimated effect size = 6.2) flood (estimated effect size =1.8) ‘unwanted’ child (estimated effect size = 2.4) depression (estimated effect size = 1.8)

18. Environmental exposures: adolescence/adulthood (1) Adverse life events Social isolation Stress Estimated effect size =1.5 - 6

19. Environmental exposures: perinatal Pregnancy & Birth Complications eg prematurity, high & low birth weight, high & low body mass index, diminished head circumference fetal distress and hypoxia-related PBCs pre-eclampsia, prolonged labour, multiparity Rhesus incompatibility (estimated effect size =2.8) Estimated effect size ≈ 2

20. Environmental exposures: childhood Infections Estimated effect size =4.0 Brain injury No estimated effect size available

21. Environmental exposures: adolescence/adulthood (1) Adverse life events social isolation stress other Estimated effect size = 1.5 – 6.0

22. Environmental exposures: adolescence/adulthood (2) Drug use Alcohol Marihuana Other Estimated effect size =2.0

23. Sex differences Sex is an example of a fixed risk factor Sex modifies the effects of other risk factors Male–female differences in schizophrenia: familial transmission. age at onset symptomatology neurobiological factors (eg brain abnormalities & cognitive function) course of illness treatment response incidence

24. Risk factors and Age-at-onset Variable age-at-onset – wide range from childhood to older ages Different risk indicators/RFs may be involved Earlier onset seems to be associated with male sex positive family history greater history of developmental deviance

25. Summary: RF & development Pre- or peri-natalGenetic &/or environmental risk factors (infection, injury, malnutrition) ChildhoodChildhood infection/brain injury; cognitive & motor & deficits; social and behavioral problems, eg odd ideation AdolescenceBrain maturational changes (normal or abnormal) Adolescence/adult hood Stress/adverse events; alcohol/drug use

26. Caveats Many possible risk factors identified; some RFs have substantial if inconclusive evidence (eg genes, obstetric complications), other RFs have been studied less Mostly ecological studies Risk factors and indicators lack specificity Determining caseness More than one syndrome? Cause versus effect can be difficult to establish

27. Conclusions (1) Some/many risk factors may interact Risk factors may be modified by time, place or person Heterogeneity can lead to further hypotheses & studies

28. Conclusions (2) Improved fetal and infant growth may be a means to improve adult health. Non-specific environmental risk factors may lead to universal prevention Epidemiology has discovered interesting leads …..more studies needed ….epidemiological ….laboratory, and ….clinical