pathophysiology of Schizophrenia/psychotic disorders Flashcards
what are effects of psychosis
hallucinations (auditory and visual), delusions (paranoia and grandiosity), catatonia
Psychosis is a part of the following neurological conditions.
schizophrenia, BPD, psychotic depression, and senile psychosis
what is schizophrenia?
a chronic severe illness; most debilitating of psychotic disorders core symptoms:cognitive dysfunction.vocational and social disability likely a spectrum or syndrome
what are positive symptoms
(psychosis) hallucinations (auditory, visual )delusions bizarre behavior disorganize thoughts and speech respond well to drug therapy
what is psychosis?
an altered state of mind
What are negative symptoms?
social withdrawl, poor self care, reduced speech lack of interest or drive(avolition) blunted emotion lack of pleasure (anhedonia) have generally responded poorly to drug therapy though some newer drugs appear to be more effective
what are cognitive symptoms?
decrease in cognitive function (poor attention and memory, weakened executive function) involves D1 receptors and glutamate receptors
what are the genetic links to schizophrenia?
Schizophrenia involves complex interactions between genetic predisposition and environmental risk
GWAS
genome wide association studies.SNPs associated with schizophrenia risk occur in genes related to dopaminergic systems glutamatergic or GABAergic systems and neuron development
COMT
A gene catecholamine metabolism
DISC1
a gene
cell morphology migration
DTNBP1
a gene
axon stability
GABRB2
a gene
GABA system
NRG1
cell growth and differentiation
what are obsterical complications?
Hemorrhage, pre term labor, nutrition, maternal stress
Infections and inflammations
more schizophrenia for winter pregnancies and flu epidemics due to immune response antibody production and proinflammatory cytokines
environmental risks
urban environment, minority status,childhood adversity,racial and ethnic status drugs and substance use
marijuana use especially for individuals with a particular COMT polymorphism (Homozygous valine)
what is the hypothesis for schizophrenia?
gene-enviornment interations during neurodevelopment have substantial impact on schizophrenia risk. These interactions can lead to changes in brain structure
what are the changes in brain structure related to schizophrenia
increased ventricle size reduced density of dendritic spines and changes in grey and white matter. These changes in brain structure are associated with altered neuron activity and neurocircuitry function
What is the supportive evidence of the dopamine hypothesis of schizophrenia?
- D 2 receptor antagonists - strong correlation of receptor binding affinity vs. clinical effectiveness (see above).
- Imaging studies show increased D2 receptor density, DA release, and DA receptor occupancy in schizophrenia patients.
- Dopaminergic agents (e.g. L-DOPA, amphetamine, DA receptor agonists) worsen schizophrenia symptoms.
- Dopaminergic agents (e.g., DA receptor agonists) can produce psychosis when used to treat PD.
- Genes related to catecholamine neurotransmission are linked to schizophrenia risk (e.g., COMT, DRD4).
- Smoking – nicotine alters DA transmission (may explain the apparent connection between smoking and schizophrenia risk).
what is the evidence against the dopamine hypothesis of schizophrenia?
- D2 antagonists aren’t universally effective.
- Atypical antipsychotic drugs with lower D2 affinity and added serotonin pharmacology are effective.
- Blocking NMDA receptors produces psychosis.
- Schizophrenia involves widespread anatomical abnormalities (not limited to dopamine-related brain structures).
what is the serotonin hypothesis?
- The hallucinogens LSD and mescaline are 5HT agonists.
- Pharmacological studies with 5HT receptors identified the 5HT2A receptor as a key mediator of hallucinations.
- 5HT2A antagonism and inverse agonism are linked to
antipsychotic activity. - 5HT2A receptors modulate dopamine release in the cortex, limbic region, and striatum (link to dopamine hypothesis see previous slide).
- 5HT2A receptors modulate glutamate release and NMDA receptor function (link to glutamate hypothesis – see next slide).
- 5HT2C agonists may also be beneficial in schizophrenia.
what is the Glutamate hypothesis
- phencyclidine and ketamine noncompetitive inhibitors of NMDA receptors exacerbate psychosis and cognitive deficits in schizophrenia
- LY2140023 an mGLuR2/3 agonist is effective in treating schizophrenia
- Ampakine (targeting AMPA receptors) is effective in animal models of schizo
- GlyT inhibitors are under development as adjuncts
what is binding affinity?
intermolecular force between ligand and receptor
what is Kd or Ki
Is the estimated concentration at which 1/2 of the receptors are occupied
what is a saturation binding experiment
vary concentration of radio-labeled ligands
what is competition binding experiments
constant radioligand (hot) concentration competing with unlabeled ligand (cold). it is used to assess the binding of antipsychotic drugs to the D2/3 or 5HT2 receptor in the brain
What does the affinity of a drug for its target receptor determine?
the affinity of a drug for its target receptor determines its selectivity and therapeutic index
receptors with known or predicted beneficial activities in schizophrenia.
D2- like receptors (D2,D3, and D4)
5HT2A
Major receptors
Dopamine: D1- like receptors (D1 and D5)D2-like receptors (D2,D3, and D4)
Serotonin (5HT) 5HT2A
minor receptors
Norepinephrine (NE)
a1 receptor blockade: hypotension sedation
a2 receptor blockade may be helpful in therapy
Acetylcholine:muscarinic receptors-anticholinergic
Histamine: H1 receptor Antagonists:sedation weight gain
