Exam 4: Rochet Flashcards
What are positive symptoms of schizophrenia?
psychosis like symptoms
what is the definition of pyschosis (characteristics)?
hallucinations (auditory, visual), delusions, bizarre behavior, disorganized thoughts and speech
what is the response of drug therapy for positive hallucinations?
well
what are negative symptoms of schizophrenia?
social withdrawal, reduced speech, lack of interest, blunted emotion, lack of pleasure
what is the response of drug therapy on negative symptoms?
generally responded poorly to drug therapy, though some newer drugs appear to be more effective
Schizophrenia involves complex interactions between ____ and environmental risk
genetic predisposition
SNPs associated with schizophrenia risk occur in genes related to ____, glutamatergic/ GABAergic system and _____.
- dopaminergic systems
- neuron development
what is the hypothesis regarding gene-environment interactions?
interactions during neurodevelopment have a substantial impact on schizophrenia risk
what can the interactions with gene-environment lead to?
changes in brain structure
what are the changes in brain structure associated with?
altered neuron activity & neurocircuitry function
What is the dopamine hypothesis of schizophrenia – supportive evidence?
- D2 receptor antagonists –> strong correlation of receptor binding affinity vs. clinical effectiveness
- imaging studies show increased D2 receptor density, DA release, and DA receptor occupancy in schizophrenia patients
- Dopaminergic agents (L-DOPA, amphetamine, DA receptor agonists) WORSEN schiz. symptoms
- Dopaminergic agents (DA agonists) can produce psychosis when used to treat PD
- genes related to catecholamine neurotransmission are linked to schiz. risk (COMT,DRD4)
What is the dopamine hypothesis of schizophrenia – evidence against?
- D2 antagonists aren’t universally effective
- Atypical antipsychotic drugs with lower D2 affinity and added serotonin pharmacology are effective
what is the Serotonin hypothesis of schizophrenia?
- 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)
What is the Glutamate hypothesis of schizophrenia?
Phencyclidine and ketamine, noncompetitive inhibitors of
NMDA receptors, exacerbate psychosis and cognitive
deficits in schizophrenia.
2. LY2140023, an mGluR2/3 agonist, is effective in treating
schizophrenia.
For D2 receptor antagonists used to treat schizophrenia, occupy ______ is required for efficacy.
60-70%
Where is the 10% of occupancy on the line?
3rd dot
what is the 90% occupancy on the line?
5th dot
What is the Kd value of the receptor affinity?
50% of the receptors
The affinity of a drug for its target receptor vs. other non-specific receptors determines its ___ and ____.
selectivity and therapeutic index
What selectivity does the receptor have for D2 as compared to H1?
10x
what is the formula for selectivity?
Kd (H1)/ Kd (D2)
What is the equation for TI? (toxic effect)
TI= TD50/ED50
How can the slope be for the toxic side effect?
steep
An increase in ____ and ____ dependent signaling (maybe A2 as well) play a role in patho of schiz.
D2/D3/D4 and 5HT2A
What do they say about the no clear pattern for medications referring to schizophrenia/ psych disorders?
There are multiple receptors that are targeted by antipsychotics with beneficial activity, suggesting that a combo of neurotransmitter alterations determine schizophrenia patho in the first place.
- this combo of alterations varies across differ pts.
What are the autonomic manifestations (adverse effects) of antipsych drugs?
dry mouth, difficulty urinating, constipation, orthostatic hypotension
What are the CNS manifestations (adverse effects) of antipsych drugs?
Parkinsons sundrome, akathasia, dystonias, tardive dyskinesia, toxic-confusional state, sedation
What are the autonomic mechanisms (adverse effects) of the orthostatic hypotension side effect?
alpha adrenoceptor blocker
What are the autonomic mechanisms (adverse effects) of the dry mouth, constipation, and difficulty urinating side effects?
muscarinic cholinoceptor blockers
What are the CNS mechanisms (adverse effects) of the parkisons, akathasia, and dystonias side effects?
dopamine receptor blockers
What are the CNS mechanisms (adverse effects) of the tardive dyskinesia side effect?
supersensitivity of dopamine receptors
What are the CNS mechanisms (adverse effects) of the toxic-confusional state side effect?
muscarinic blockers
What are the CNS mechanisms (adverse effects) of the sedation side effect?
histamine receptor blockers
For typical (1st gen) antipsychs, where do strong D2 antagonists have their primary therapeutic effect?
Mesolimbic system
what type of drug is chlorpromazine?
1st typical antipsychotic, D2 antagonist (clinically important at 5HT2A)
what do they call chlorpromazine? Why is it not used as first line anymore?
“dirty drug”, it has multiple undesired targets
What drug is this?
Chlorpromazine
what kind of drug is haloperidol and why is it not used first line anymore?
- more D2 selective than chlorpromazine and has unfavorable SEs, typical antipsych
what drug is this?
haloperidol
What is the delay phase of typical antipsychotics?
blockade at postsynaptic D2 receptors, initially offset by antagonist binding to D2 autoreceptors
what is the antagonism phase of the typical antipsychs?
D2 receptors are internalized (desensitization), and D2 autoreceptors respond better to DA inhibitory effect (sensitization)
A drug dose of 70-80% receptor occupancy is required for _____.
therapeutic efficacy
A drug dose resulting in >80% receptor occupancy leads to _____.
extrapyramidal symptoms (EPS)
In regards to movement disorders induced by D2 antagonists, what does the TIMING look like for EPS?
early (days/weeks after tx), reversible
In regards to movement disorders induced by D2 antagonists, what does the SYMPTOMS look like for EPS?
dystonia, tremor, akathisia, pseudoparkinsonism
In regards to movement disorders induced by D2 antagonists, what does the DRUG THERAPY look like for EPS?
Anticholinergic agents: benztropine, trihexphenidyl, akineton
Antihistamines: benadryl
Amantadine: dopamine releasing agent
BBs: propranolol (akathisia)
In regards to movement disorders induced by D2 antagonists, what does the TIMING look like for Tardive Dyskinesia?
late (months to years after tx)
IRREVERSIBLE
In regards to movement disorders induced by D2 antagonists, what does the SYMPTOMS look like for Tardive Dyskinesia?
ehythmic involuntary movements of the mouth, choreiform movements: irregular purposelessness, athetoid, axial hyperkinesias
In regards to movement disorders induced by D2 antagonists, what does the MOA look like for Tardive Dyskinesia?
supersensitivity of receptors to dopamine, possible neuroadaptive repsosne
In regards to movement disorders induced by D2 antagonists, what does the MONITORING look like for Tardive Dyskinesia?
AIMS, rating scale (q6m checks)
In regards to movement disorders induced by D2 antagonists, what does the TREATMENTS look like for Tardive Dyskinesia?
PREVENTION (lowest doses), VMAT2 inhibitors, eliminate anticholinergics, change to differ drug, reduce current dose
what are some newer VMAT2 inhibitors for tardive dyskinesia
tetrabenazine (xenazine), valbenazine (ingrezza), deutetrabenazine (auestdo)
In regards to movement disorders induced by D2 antagonists, what does the TIMING look like for NMS?
a few days to 2 weeks after start of tx
In regards to movement disorders induced by D2 antagonists, what does the SYMPTOMS look like for NMS?
EPS symtpoms with fever, impaired cognition (agitation, delirium, coma), muscle rigidity
In regards to movement disorders induced by D2 antagonists, what does the TREATMENT look like for NMS?
- restore dopamine balance
- d/c drug
- dopamine receptor agonists
- diazepam (relaxant, agitation)
- dantrolene (muscle relaxant)
What generation is atypical antipsychotics?
2nd and 3rd
What is the MOA of atypical antipsychotics?
- primarily mesolimbic system
- act as 5HT2A antagonists
What is the clinical features of atypical antipsychotics?
- controlling positive symptoms
- some provide better negative control symptoms
- lower risk of EPS
- some cause metabolic problems
what drugs are atypical antipsychotics?
clozapine, olanzapine, quetiapine, asenapine, risperidone, ziprasidone, lurasidone, aripiprazole, pimavanserin
Presynaptic 5-HT2A receptors on dopaminergic neurons projecting from _______ to the ______ play a KEY ROLE.
the substantia nigra pars compacta to the striatum
How does atypical antipsychotic drugs have a lower risk of EPS compared to typical drugs?
In the presence of an atypical antipsychotic, post-synaptic D2 receptors are blocked, but the drug,s antagonism of presynaptic 5-HT2A receptors leads to greater dopamine release into the synapse, partially offsetting the D2 antagonism ( –> fewer EPS).
What is there to know about clozapine?
- 1st atypical antipsych drug
- high efficacy (positive mostly and some negative)
- lower D2 potency, so reduced risk of EPS
What are the side effects for clozapine? (regular and metabolic)
- Side effects: anticholinergic, sedation, orthostatic hypotension
- metabolic side effects: weight gain, risk of diabetes
what is a serious side effect with clozapine? How often does it occur?
Agranulocytosis- serious side-effect involving a drop in neutrophil counts (occur 1-2% of individuals within 6 months); weekly blood monitoring is needed
what is there to know about olanzapine? Include side effects?
- similar features as clozapine (low risk of EPS)
- similar side effect profile as clozapine – anticholinergic, sedation, orthostatic hypotension, weight gain, diabetes risk – but generally less severe
What is there to know about quetiapine?
- similar clinical features as clozapine and olanzapine
- antagonists D2, 5HT2A, with low risk of EPS
- low muscarinic activity
what are the side effects to know for quetiapine? (for side effects/metabolic).
- Sedation, orthostatic hypotension
- weight gain, risk of diabetes
what are the side effects in order of most to least pronounced?
most ( clozapine = olanzapine > quetiapine = risperidone = asenapine = brexpiprazole > ziprasidone = lurasidone (least pronounced)
What is there to know about the risperidone?
- rationally designed to be a combined D2 & 5HT2A antagonist
- low risk for EPS
what are the side effects for risperidone?
sedation, orthostatic hypotension, low antimuscarinic activity, weight gain, risk of diabetes
What is there to know about ziprasidone? Side effects?
- similar clinical features as risperidone
- sedation, OH, weight gain, diabetes risk (less severe)
what is there to know about lurasidone? side effects?
- similar clinical features as risperidone and ziprasidone
- similar side effect as ziprasidone (less severe compared to risperidone)
What is there to know about pimavanserin? Used for?
- inverse agonist targeting 5HT2A
- used to reduce PD psychosis, including hallucinations and delusions caused by dopamine treatments
what is important about Cobenfy?
first ever approved SZ drug that doesn’t target the D2 target
