Psychosis Flashcards
What is Chlorpromazine? What does it do?
First typical antipsychotic
Similar to Reserpine
Blocks DA-1 and DA-2 receptors (incl. autoreceptors)
Strongly inhibits cAMP production from DA
What is haloperidol? What does it do?
A typical antipsychotic
Very weakly inhibits cAMP production from DA (equally as effective as eg CPZ)
Binds DA-2 preferrentially
What is clozapine? What does it do?
An atypical antipsychotic (in the clozet)
Little or no ACUTE EPS
Pros:
Works in more patients than classical neuroleptics
No EPS or prolactin surge
No tardive dyskinesia
Cons:
Severe, infrequent adverse effect on blood cells
Weight gain (diabetes?)
Risk of seizures
Therefore: not first line
What is Phencyclidine? What does it do?
PCP
NMDA glutamate receptor agonist
Define EPS
ExtraPyramidal Symptoms i.e. Parkinson-like Motor impairment
Define APD
Antipsychotic Drug
Define A neuroleptic
An antipsychotic that produces EPS, especially catalepsy
Define the mesolimbic dopamine pathway and what happens when its DA receptors are blocked
Ventral tegmental area to nucleus accumbens
Block postsynaptic DA receptors : inhibit psychosis
Define the nucleus accumbens
Main terminal area for mesolimbic DA pathway
Define Positron emission tomography
PET scan, allows to test for brain activity
Name 3 of the 7 positive symptoms of schizophrenia
Delusions hallucination thought disorders agitation grandiosity suspiciousness hostility
Name 3 of the 5 negative symptoms of schizophrenia
Blunted emotions (flattened affect) Emotional and social withdrawal Poor rapport passive/apathetic lack of spontaneity
Define the 2 cognitive symptoms of schizophrenia
Poor memory
Poor abstract thinking, etc
What causes schizophrenia?
We have no idea
high inheritability, twins have 50% chance of both having
What do MRI scans of Schizophrenic patients reveal?
Larger ventricle (less cortical matter)
Related somehow to DA
What do MRI scans of Schizophrenic patients reveal?
Larger ventricle (less cortical matter)
Related somehow to DA
True false? Neuroleptics keep the “crazy” at bay by locking it up and lot letting the patient express it
False
Not a chemical straightjacket, takes the crazy away
What is a common side effect of neuroleptics?
Parkinson’s-like symptoms
What are 4 problems with antipsychotic drugs?
Provide only symptomatic relief (doesn’t cure the crazy)
Need to be taken long term
Are often not taken (can forget due to cognitive deficiency)
Block DA receptors (leads ot dysphoria)
What are the two types of DA receptor and what does each one do to cAMP levels when activated?
D1 subtype increases cAMP
D2 subtype decreases cAMP
If drug A has a lower IC50 than Drug B, what can be implied about its potency?
drug A is more potent
It was discovered that typical Neuroleptics have a suspiciously strong correlation between Average Daily dose and IC50 value for which type of DA receptor?
D2 receptor
correlation falls apart when you look at newer drugs
What are the two subtypes of DA receptor and what does each one do to cAMP levels when activated?
D1-like subtype increases cAMP (D1 and D5)
D2-like subtype decreases cAMP (D2, D3, D4)
It was discovered that typical Neuroleptics have a suspiciously strong correlation between Average Daily dose and IC50 value for which type of DA receptor?
D2 receptor
correlation falls apart when you look at newer drugs
What are symptoms of Amphetamine induced psychosis?
Ideas of reference, paranoid delusions
ONLY POSITIVE SYMPTOMS
neuroleptics rapidly reverse symptoms
Schizophrenics are more on the edge for amphetamines
What are some symptoms of PCP induced psychosis?
low doses mimic some positive and negative symptoms
True/False? LSD can cause schizophrenia-like experiences
False
What is the DA hypothesis of schizophrenia? What evidence is there for it (4) and what are its issues (3)?
Excess DA causes schizophrenia
Evidence:
Stimulant psychosis and reversal by DA receptor blockers
Antipsychotics block DA receptors
Increased Brain DA release during acute psychosis
DA receptor abnormalities?
Issues:
Therapeutic delay (unexplained)
Non-responders to antipsychotic drugs
Clozapine (low D2 receptor affinity but still neuroleptic)
Where are D1-like receptors located?
Postsynaptically ONLY
Where are D2-like receptors located?
Autoreceptors on dendrites
Autoreceptors on terminals
AND postynaptic receptors
What is a typical symptom of atypical antipsychotics?
The inhibition of D2 receptors leads to increase of prolactin, which (can) lead to milk secretion
recall DA = “prolactin inhibitory hormone”
True/False? Atypical neuroleptics produce Tardive Dyskinesia
False
What kind of blockade do atypical antipsychotic administration cause?
Mesolimbic DA blockade
no Nigrostriatal blockade
Is there a [Nigrostriatal, Mesolimbic] blockade when given [typical, atypical] antipsychotics?
Classical: NS inhib, ML inhib
Atypical: NS no, ML inhib
Is there a [Nigrostriatal, Mesolimbic] blockade when given [typical, atypical] antipsychotics?
Classical: NS inhib, ML inhib
Atypical: NS no, ML inhib
What receptor needs to be blocked to cause EPS? What level of blockade is required?
D2 receptors
EPS occurs at around 80% blockade
Define Clozapine’s affinity for each DA terminal area
Equal
same for striatum as mesolimbic
True/False? Clozapine provides good blockade aof D2 receptors at low concs
True
True/False? Clozapine has a high affinity for D3 receptors
False
D3 antagonists are not effective antipsychotics
D4 DA receptors have unusually high affinity for clozapine. Are selective D4 antagonists antipsychotic?
No
True/False? Many antipsychotic drugs have high selectivity for DA receptors
False
Antipsychotics are promiscuous - they bind all over the place
Other targets include muscarinic and adrenergic receptors
Compared to classical antipsychotics, atypicals block (more/fewer) D2 receptors, and block (more/fewer) 5HT2A receptors
Fewer D2 (less EPS)
More 5HT2A
NOT ALWAYS TRUE
but general rule
What is the most promising theory for antipsychotics?
The Depolarization inactivation theory
Explains why antipsychotic drugs take a while to work as well as EPS vs no EPS
What is the Depolarization inactivation theory?
Depolarization inactivation occurs selectively in mesolimbic system
CHRONIC action is what counts!
(recall nigrostriatal pathway is not blocked by atypicals)
DA D2 agonists hyperpolarize DA cells by _____
Stimulating autoreceptors
Cells fire slower (or stop firing)
True/False? DA cells have pacemaker activity
True
DA D2 antagonists depolarize DA cells by _____
Blocking autoreceptors
When antagonist is given acutely, the DA cell fires Faster
What happens to DA cells during CHRONIC Antagonist treatment?
DA cells may no longer be able to fire (Silent)
“Depolarization block”
Typical APDs do this to mesolimbic AND nigrostriatal cells
Atypical APDs do this to mesolimbic NOT nigrostriatal cells (reason not known)
Acute APDs Increase cell firing in which pathways?
Nigrostriatal AND mesolimbic pathways
How do atypical APDs, given chronically, preferentially inactivate MESOLIMBIC DA neurons?
¯_(ツ)_/¯
