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