Download What can the skull teach us about schizophrenia The impact of low

A Review of Risk Factors
for Schizophrenia
Joy Welham
Sukanta Saha
John McGrath
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
Functional
Minor 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 excess
eg
• 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 – 4.2
Relative risk 2.4 but PAF about 30%
Risk proxy (3)
Migration
Estimated effect size 4 - 14
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
Brain maturational changes (normal
or abnormal)
Adolescence
Adolescence/adult Stress/adverse events; alcohol/drug
hood
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 & 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
Brain maturational changes (normal
or abnormal)
Adolescence
Adolescence/adult Stress/adverse events; alcohol/drug
hood
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