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1. Etiology

genes
- alpha-7 nicotinic receptor, DISC1 GRM3 COMT NRG1 RGS4 G72 dystrobrevin and neureglin 1
family hx: likelihood increases with closeness of relationship
- High proportion of variance
- additive genetic effects
- linked with schizotypal PD
- 50% concordance with monozygotic twins (5x more than dizygotic)
- +environmental contribution
- mode of transmission unknown
age of father >60yo

Dopamine hypothesis
- too much dopamine
- from potency of antipsychotics at D2
- cocaine and amphetamine increase dopamine and are psychotomimetic
- mesocortical and mesolimbic tracts, also amygdala and caudate nucleus
- severity of positive symptoms
Serotonin
- too much
- both + and - symptoms
- clozapine and other second-gen anti-serotonin activity
Norepinephrine
- anhedonia
- neuronal degeneration within the norepinephrine reward neural system
- inconclusive
GABA
- loss of GABAergic neurons in hippocampus
- has regulatory effect on dopamine
  - loss of inhibitory GABAergic
    - hyperactivity of dopaminergic neurorns
Neuropeptides
- substance P and neurotensin
  - localized with catecholamine and indolamines and affect them
Glutamate
- ingestion of phencyclidine (glutamate antagonist) produces an acute syndrome similar to schizophrenia
- hyperactivity, hypoactivity, and glutamate-induced neurotoxicity

Found pathology in end of 20th century
lateral and 3rd ventricle enlargement
- static vs progressive is uncertain
reduced symmetry in temporal, frontal, and occipital lobes
- indicative of disruption in brain lateralization during neurodevelopment
decrease in size of limbic system
- amygdala, hippocampus, parahippocampal gyrus
- hippocampus is also functionally abnormal
anatomical and functional abnormalities in prefrontal cortex
- mimic those of frontal lobe syndromes
neuronal loss in thalamus
- has reciprocal connections with prefrontal cortex
- total neurons is reduced by 30-45%
Neural circuits
- prefrontal cortex to hippocampus and cerebellum
- anterior cingulate basal ganglia thalamo-cortical circuit
  - positive symptoms
- dorsolateral prefrontal circuit
  - negative symptoms

2+ of
- delusions
- hallucinations
- disorganized speech
- disorganized behaviour
- negative symptoms: avolition, anhedonia, social withdrawal, affective blunting, alogia
level of functioning has deteriorated or not expected level in 1+ areas
6+ months of disturbances (1 month of symptoms from criterion A)
r/o schizoaffective, mood+psychosis
not physiological
r/o Autism or communication d/o
specify
- first/multiple/continuous/unspecified, currently in acute/partial/full
- with catatonia

Nothing is pathognomonic
premorbid
- before the disease process evidences itself
- schizoid or schizotypal PD as quiet, passive, introverted
- as children: few friends
- adolescent: no close friends, no dates, avoid team sports, enjoy watching tv shows and movies, games, exclusion of social activities
prodromal
- somatic complaints dx as malingering, chronic fatigue syndrome, or somatization disorder
- then family and friends notice decrease in functioning
- may begin to show interest in abstract ideas, philosophy, occult or religious questions
- peculiar behaviour, abnormal affect, unusual speech, bizarre ideas, strange perceptual disturbances

weak relationship to biological variables, poor long-term stability, poor predictive value
Paranoid
- preoccupation with one or more delusions or frequent auditory hallucinations
- often delusions of persecution or grandeur
- usually older first episode vs catatonic or disorganized
- less regression of mental faculties, emotional responses, and behaivour
- intelligence in areas not invaded by their psychosis tends to remain intact
Disorganized
- marked regression to primitive, disinhibited, unorganized behaviour and absence of catatonia
- usually early onset <25
- active but aimless manner
- thought disorder is pronounced, contact with reality is poor
- usually inappropriate emotional and social responses
Catatonic
- marked disturbance in motor function
- stupor, negativism, rigidity, excitement, posturing
- associated: stereotypies, mannerisms, waxy flexibility, mutism
Undifferentiated
- don't fit anywhere
Residual
- continuing evidence of schizophrenia disturbance, absence of complete set of active symptoms
- emotional blunting, social withdrawal, eccentric behaviour, illogical thinking, mild loosening of associations
- delusions or hallucinations, if present, are not prominent