lecture 52 Flashcards
rochet - pathophysiology of schizophrenia/psychotic disorders
what are positive symptoms of schizophrenia?
ones that respond well to drug therapy
ex. hallucinations, delusions, bizarre behavior, disorganized thoughts and speech
what are negative symptoms of schizophrenia?
have generally responded poorly to drug therapy, though some newer drugs appear to be more effective
ex. social withdrawal, poor self-care
what are the complex interactions of schizophrenia?
genetic predisposition and environmental risk
how are SNPs associated with schizophrenia risk in genes?
related to dopaminergic systems and neuron development
specific with COMT (catechlamine metabolism)
what is a hypothesis form relating to gene-environment interactions?
gene-environment interactions during neurodevelopment have a substantial impact on schizophrenia risk
what are changes that can occur in the brain due to gene-environment interactions of schizophrenia?
change sin brain structure associated with altered neuron activity and neurocircuitry function
what is the supporting evidence of the dopamine hypothesis of schizophrenia?
D2 receptor antagonist – strong correlation of receptor binding affinity vs clinical effectiveness
imaging studies show icnreased D2 receptor density, DA release, and DA receptor occupancy in pts
DA agents worsen schizophrenia symptoms and can produce psychosis when used to treat PD
genes related to catecholamine nuerotransmission are linked to schizophrenia risk (COMT, DRD4)
what is the evidence against the dopamine hypothesis of schizophrenia?
D2 antagonists arent universally effective
atypical antipsychotic drugs with lower D2 affinity and added serotonin pharmacology are effective
what is the dopamine theory?
hyperactive dopamine at D2 receptors in the mesolimbic pathway
what is the glutamate theory?
NMDA receptor hypofunction
what is the serotonin theory?
5HT2a receptor hyperfunction in the cortex
how does the 5HT2a receptor aid the serotonin hypothesis?
key mediator of hallucinations from 5HT agonist (LSD/mescaline)
linked to DA hypothesis by modulating DA release in the cortex, limbic region, and striatum
linked to Glut hypothesis by modulating glutamate release and NMDA receptor function
what is LY2140023?
mGluR2/3 agonist
tx schizophrenia
shows Glut hypothesis
what drugs in relation to Glutamate lead to worsening conditions of schizophrenia?
phencyclidine and ketamine – noncompetitive inhibitors of NMDA receptors
exacerbate psychosis and cognitive deficits
what does the occupancy % need to be have therapeutic effect?
60-70% for D2 receptor antagonists to tx schizophrenia
how is the therapeutic index (TI) found?
TD50 (when 50% of drug has toxic SE)
/
ED50 (when 50% of drug has therapeutic effect)
what can be the original concluded thought about the pathophysiology of schizophrenia?
increase in D2/D3/D4 and 5HT2a dependent signaling plays a role in development
what is the most updated theory about schizophrenia pathophysiology?
multiple receptors are targeted by antipsychotics with beneficial activity
suggests that a combination of NT alterations determine schizophrenia pathophysi
what drugs contradict the DA hypothesis of schizophrenia?
ketamine
LSD
olanzapine
