Joy Welham Sukanta SahaJohn McGrath
A Review of Risk Factors for Schizophrenia
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.
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
Outline
• Defining risk factors
• Risk indicators
• Risk proxies
• Putative risk factors
• Caveats and conclusions
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
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
Risk indicators throughout development
Early childhood Developmental delays Later childhood Neurological/cognitive anomalies Psycho-social deficits Brain anomalies Structural FunctionalMinor physical anomalies Dermatoglyphic anomalies
Proxy variables
• Season-of-birth
• Place-of-birth
• Migration
Proxy variables (1)
Perinatal
Season-of-birth
Estimated effect size 5-15% winter/spring excesseg• relative risk =1.11 • but population attributable fraction (PAF) about
10.5%
Risk proxy (2)
Perinatal
Place-of-birth; Urban vs rural birth
Estimated effect size = 1.5 – 4.2Relative risk 2.4 but PAF about 30%
Risk proxy (3)
Migration
Estimated effect size 4 - 14
Putative risk factorsPre- or peri-natal Genetic &/or environmental risk
factors (infection, injury, malnutrition)
Childhood Childhood infection/brain injuryCognitive, motor & social deficits, odd ideation
Adolescence Brain maturational changes (normal or abnormal)
Adolescence/adulthood
Stress/adverse events; alcohol/drug use
Genetic Factors
Other genetic
Non-hereditary genetic risk factors
• Paternal age/mutation
(no estimated effect size available)
Environmental exposures: prenatal (1)
Prenatal nutrition
• Macro-nutrition; eg calories/kilojoules
• Micro-nutrition; eg specific vitamins
Estimated effect size for prenatal famine = 2.0
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)
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)
Environmental exposures: adolescence/adulthood (1)
Adverse life events
•Social isolation
• Stress
Estimated effect size =1.5 - 6
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
Environmental exposures: childhood
Infections Estimated effect size =4.0
Brain injury
No estimated effect size available
Environmental exposures: adolescence/adulthood (1)
Adverse life events
• social isolation
• stress
• other
Estimated effect size = 1.5 – 6.0
Environmental exposures: adolescence/adulthood (2)
Drug use
• Alcohol
• Marihuana
• Other
Estimated effect size =2.0
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
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
Summary: RF & developmentPre- 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
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
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
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