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40 Third-Degree Relative
20 17%
13%
10 9%
5% 6% 6%
4%
1% 2% 2% 2%
0
Spouse Grand- Offspring of Offspring of
child Half One Two
First Schizophre- Schizophre-
Cousin Sibling nic Parent nic Parents
Uncle Parent
or Aunt
General Nephew Sibling
Population or Niece Fraternal Twin Identical
Twin
Family, Twin and Adoption Study Results
• Relatives of patients have a 5–10 fold increased risk versus
the general population which decreases by distance.
• The adopted away child of an ill mother has the same risk as
if she raises the child herself, although the adoptive
environment may slightly alter risk.
RR
Malaspina et al 2001
Examples of gene –
environment interaction
COMT (the catechol-O-methyl transferase Val158Met
polymorphism) moderates the onset of psychosis in
response to stress and to cannabis use
Neurodevelopment genes, such as AKT1 (serine-threonine
kinase), BDNF (brain-derived neurotrophic factor),
DTNBP1 (dysbindin) and GRM3 (metabotropic glutamate
receptor increase the incidence with perinatal obstetric
complications.
Neurocognitive deficits (also considered to be
endophenotypes) are linked risk alleles for schizophrenia
including COMT, neuregulin (NRG1), BDNF, Disrupted-In-
Schizophrenia 1 (DISC1) and dysbindin.
Cognitive improvement during rehabilitation therapy is
related to COMT (Val158Met) polymorphism.
Biomarkers of genetic vulnerability:
Endophenotypes
1. Smooth
pursuit eye
movements in
schizophrenia
show saccadic
intrusions
2. Auditory Evoked
Potentials: (Gating.) The
response to 1st click
(conditioning) is larger
than to the 2nd (test)
click; in schizophrenia
there is less inhibition of
the response to 2nd
stimulus
3. OTHERS: smell identification, continuous performance test -
attention, working memory, brain activation, soft neurological
signs, Wisconsin card sort test…
BrainVolume :
Larger fluid spaces, diffuse loss of gray matter
Reduced hippocampal volume
smaller frontal and temporal lobes
reduced corpus callosum thickness
Loss of normal assymetry
Normal Schizophrenia
Theory of Increased
synaptic “pruning”
Schizophrenia
Normal
Thalamus
The hippocampus is a complex circuit of
subregions that differ in neuronal populations
and susceptibility to different pathologies
Rate of gray matter loss in adolescence
Normal Schizophrenia
Adolescents
Mental disorders are brain disorders:
Loss of gray matter in childhood
schizophrenia
Dopamine theory of
schizophrenia: increased DA
Psychosis
Psychosis Healthy
D2
blocking
drugs
Negative Symptoms
Evidence for glutaminergic
abnormality in schizophrenia
Decreased expression of hippocampal non- ++
NMDA receptors
Increased cortical expression of some NMDA ++
receptor subunits
Increased glutamate reuptake in frontal cortex +
SUBTYPES? ETIOLOGIES?
Adults
Natural History of Schizophrenia
Stages of Illness Progression
Premorbid Prodrome
Deterioration Residual
Phase
Psychosis
More symptoms
Higher Function
Gestation/Birth
10 20 30 40 50
Puberty
Age in Years
Disease Progression & Treatment Goals
Constitutional
Healthy
Vulnerability
Prodromal Recovery
State
Psychosis Remission
Deterioration
“It Seems the Fertility Clock Ticks for Men, Too”