Schizophrenia Patho Flashcards
Psychosis overview
-disorder or single event (drug, toxin, injury)
-hallucinations, delusions, catatonia
-seen in schizophrenia, bipolar, psychotic depression, senile psychosis
-pre1950s: lobotomy, hydrotherapy, electro, institutionalize
Schizophrenia overview
-cognitive dysfunction
-spectrum
-more likely in men and onset is sooner than in women
Positive symptoms of schizophrenia (psychosis)
-hallucinations
-delusions
-bizarre behavior
-disorganized thoughts/speech
-respond well to drug therapy
Negative symptoms
-social withdrawal, poor self-care
-reduce speech
-lack of interest
-blunted emotion
-lack of pleasure
-not as responsive to drug therapy
Cognitive symptoms of schizophrenia
-dec in cognitive function (poor attention/memory/executive functions)
-D1 and glutamate receptors
Genetic links to schizophrenia
-genetic predisposition + environmental risk
-SNPs related to dopaminergic systems, gluat/GABAergic systems, and neuron development (graphic slide 6)
-COMT (catecholamine metabolism) mutation
Environmental risks of schizophrenia
-obsterical complications (hemorrhage, pre-term labor, nutrition, maternal stress)
-infections/inflammation
-more schizophrenia in winter pregnancies and flu epidemics (immune, antibodies, cytokines, inflammation)
-weed :( esp w COMT homozygous polymorphism
SCZ and gene-environment interactions
-big scz risk during neurodevelopment
=change in brain structure: inc ventricle size, dec density of dendritic spines, changes in gray and white matter
-brain changes associated w altered neuron activity and neurocircuitry function
Dopamine hypothesis of SCZ (supportive evidence)
- D2 antagonists show receptor affinity and clinical effectiveness (antagonist drugs w higher affinity (low IC50) for DA receptor have better clinical effect, linear graph)
- Imaging studies show inc D2 receptor density, DA release, and DA receptor occupancy
- Dopamine agents WORSEN sx and can produce psychosis in PD
- Genes related to catecholamine NT linked to scz risk (COMT, DRD4)
- smoking- nicotine alters DA transmission
evidence against scz hypothesis
-D2 antagonists aren’t universally effective!
-atypical antipsychotic drugs w lower D2 affinity and added serotonin pharmacology ARE effective!
-blocking NMDA receptors induces psychosis
-SCZ involves widespread anatomical abnormalities
Serotonin hypothesis of scz
-hallucinogens LSD and mescaline are 5HT agonists
-5HT2a key mediator of hallucinations
-5HT2A antagonism linked to antipsychotic activity
-5HT2A receptors modulate dopamine release in the cortex, limbic region, and striatum (link to DA hypothesis) also modulate glutamate release and NMDA receptor function (lnk to glutamate hypothesis
-5HT2C may be beneficial in scz
Glutamate hypothesis
-phencyclidine and ketamine (NMDA inhibitors) exacerbate psychosis and cognitive defects in scz!
-LY2140023 (mGluR2/3 agonist) tx scz!
-Ampakine effective in animal models
-GlyT inhibitors under development
Methods used to determine binding affinity
-force btw ligand and receptor
-Kd or Ki: estimated concentration at wich 1/2 receptors are occupies
-saturation binding experiements (vary concentration of radio-labeled ligands)
-competition binding experiments (constant radioligand, hot, concentration competing w unlabeled ligand,cold)
-competition experiemnt to assess binding of antipsychotic drugs to the D2/3 or 5HT2 receptor in brains of living marmoset
Drug concentration determines
-receptor occupancy in relation to Kd
-for D2 receptor antagonists used to treat scz, occupancy for 60-70% of receptors is required for therapeutic efficacy
-slide 15 need to know
The affinity of a drug for its target receptor vs other receptors determines
-selectivity and therapeutic index
-more selective = lower KD
-selectivity = Kd drug 1 / kd drug 2
-therapeutic index: therapuetic effect at lower ED 50 than toxic effect (toxic effect higher TD50) = TD50/ED50(slope may be steep)
-need to know graphs slide 16
Receptors w antipsychotic activity when bound by ANTAgonist
-Major: D2-D4, 5HT2A!
-minor: a2
-multiple receptors targeted by antipsychotics with benefit
-nonspecificity
-combination of alterations varies across different pt and determine scz patho
The activity of each of the following drugs contradicts the
dopamine hypothesis of schizophrenia EXCEPT?
(A) ketamine (glutamate)
(B) LSD (5HT agonist)
(C) pramipexole (Mirapex) (dopamine agonist)
(D) olanzapine (Zyprexa) (5HTa antagonist)
(C) pramipexole (Mirapex)
-DA agonist (likely supportive of hx)
-need to know specific drugs
