Joy Welham Sukanta Saha John McGrath

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Joy Welham Sukanta SahaJohn McGrath
A Review of Risk Factors for Schizophrenia
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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.
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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

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Outline

• Defining risk factors
• Risk indicators
• Risk proxies
• Putative risk factors
• Caveats and conclusions

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

• Season-of-birth
• Place-of-birth
• Migration

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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

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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

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Risk proxy (3)

• Migration
• Estimated effect size 4 - 14

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Putative risk factors
Pre- or peri-natal Genetic /or environmental risk factors (infection, injury, malnutrition)
Childhood Childhood infection/brain injury Cognitive, motor social deficits, odd ideation
Adolescence Brain maturational changes (normal or abnormal)
Adolescence/adulthood Stress/adverse events alcohol/drug use

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Genetic Factors
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Other genetic

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

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Environmental exposures prenatal (1)

• Prenatal nutrition
• Macro-nutrition eg calories/kilojoules
• Micro-nutrition eg specific vitamins
• Estimated effect size for prenatal famine 2.0

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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)

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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)

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Environmental exposures adolescence/adulthood (1)

• Adverse life events
• Social isolation
• Stress
• Estimated effect size 1.5 - 6

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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

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Environmental exposures childhood
Infections Estimated effect size 4.0
Brain injury No estimated
effect size available
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Environmental exposures adolescence/adulthood (1)

• Adverse life events
• social isolation
• stress
• other
• Estimated effect size 1.5 6.0

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Environmental exposures adolescence/adulthood (2)

• Drug use
• Alcohol
• Marihuana
• Other
• Estimated effect size 2.0

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Sex differences

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

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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

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Summary RF development
Pre- or peri-natal Genetic /or environmental risk factors (infection, injury, malnutrition)
Childhood Childhood infection/brain injury cognitive motor deficits social and behavioral problems, eg odd ideation
Adolescence Brain maturational changes (normal or abnormal)
Adolescence/adulthood Stress/adverse events alcohol/drug use

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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

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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
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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