Chapter 5: Targeting for psychosis Flashcards
neurolepsis
extreme slwoness or absence of motor movements as well as behavioral indifference
what are seconday negative symptoms
negative symptoms that are caused by side effects of other drugs for psychosis
which dopamine pathway has a major role in regulating motivation and reward
D2 receptors in the mesolimbic pathway that targets the nucleus accumbens
which mesocortical dopamine pathways that are thought to be hypoactive in untreated schizophrenia
DLPFC
VMPFC
hypoactivity of which mesocortical dopamine pathway leads to cognitive symptoms of schizophrenia
DLPFC
hypoactvity of which mesocortical dopamine pathways lead to negative symptoms of schizophrenia
DLPFC and VMPFC
hypoactivity of which mesocortical dopamine pathway is thought to cause affective symptoms of schizophrenia
VMPFC
when schizophrenia is untreated are mesocortical dopamine pathways thought to be hypoactive or hyperactive
hypoactive
prolactin elevation is a result of targeting which D2 receptors
tuberoinfundibular D2 receptors
why do D2 blockers cause increased prolactin
they reduce activity in the tuberoinfundibular dopamine pathway by preventing dopamine from binding to D2 receptors, causing prolactin levels to rise
what two neurotransmitters have a reciprocal relationship in the nigrostriatal dopamine pathway
dopamine and acetylcholine
what type of drugs are typically used to combat side effects caused by D2 blockers in the nigrostriatal pathway (motor side effects)
anticholinergics (often benztropine)
what is a medications that can be used to treat drug induced parkinsonism that lacks anticholinergic effects
amantadine
can you treat late-onset drug-induced dystonia from chronic D2 blockade with anticholinergics? why or why not?
No. Anticholinergics can make this type of dystonia worse
treatment for drug-induced acute dystonia
IM anticholinergic injection usually effective within 20 minutes
how do you treat drug-induced akathisia
usually with B-adrenergic blockers or benzodiazepines. Not well treated with anticholinergics
what is neuroleptic malignant syndrome
potentially fatal complication of D2 blockade in the nigrostriatal pathway that causes extreme muscle rigidity, high fever, coma, and death
treatment of neuroleptic malignant syndrome
-withdraw D2 blocker
-muscle-relaxing agents (dantrolene, dopamine agonists, intensive supportive medical treatments)
3 ways to treat TD
-increase D2 blocker dose (helps in short term by blocking super sensitive D2 receptors but can ultimately make TD worse)
-stop D2 blocker and hope effects reverse
-VMAT inhibitors
2 types of VMAT inhibitors
reserpine
tetrabenazine-related drugs
mechanism of action for reserpine
irreversibley inhibits VMAT1 (central and periphery) and VMAT2 (CNS only)
3 tetrabenazine-related drugs
tetrabenazine
deutetrabenazine
valbenazine
what enzyme metabolizes tetrabenazine-related drugs
2D6
tetrabenazine
inactive prodrug metabolized by carbonyl reductase into 4 active metabolites
deutetrabenazine
inactive prodrug metabolized by 2D6 into 4 active metabolites
what is deuteration
when a drug that is a good substrate for 2D6 is converted to a poorer substrate
chlorpromazine
1st gen antipsychotic
thorazine
low potency
valbenazine
amino acid valine linked to an enaniomer of tetrabenazine
fluphenazine
1st gen antipsychotic
prolixin
high potency
comes in depot
haloperidol
1st gen antipsychotic
haldol
high potency
comes in depot
loxapine
1st gen antipsychotic
loxitane
perphenazine
1st gen antipsychotic
trilafon
high potency
pimozide
1st gen antipsychotic
orap
high potency
QTC issues
2nd line for tourettes
thioridazine
1st gen antipsychotic
mellaril
low potency
QTC issues
second line
thiothixene
1st gen antipsychotic
navane
high potency
trifluoperazine
1t gen antipsychotic
stelazine
high potency
drugs targeting 5HT2A in schizophrenia
the more potent the 5HT2A/D2 is for 5HT2A, the lower the D2 antagonism needed so the drug may be better tolerated.
treating parkinson and dementia related psychosis
5HT2A antagonism alone may be enough to treat psychosis
all 5HT2A receptors are…
postsynaptic and excitatory
How does 5HT2A receptors regulate dopamine release in the first downstream pathway and how do you treat it
glutaminergic neurons directly innervate mesolimbic/mesostriatal dopamine neurons projecting to the emotional striatum. Decrease dopamne release at D2 receptors at the end of the pathway and reduce excitatory property of 5HT2A receptors at the begining of the pathway
How does 5HT2A receptors regulate dopamine release in the second downstream pathway and how do you treat it
glutaminergic neurons indirectly innervate nigrostriatal dopamine neurons that project to the motor striatum.
treat by blocking 5HT2A receptors in this pathway to change the polarity of upstream glutamate release from stimulating to inhibiting which stimulates downstream dopamine release in the motor striatum. When there is more dopamine available to compete with blockade, motor side effects are improved
How does 5HT2A receptors regulate dopamine release in the third downstream pathway and how do you treat it
-glutaminergic neurons indirectly innervate mesocortical dopamine neurons that project to the PFC
-blocking 5HT2A receptors on these neurons will cause increased downstream dopamine release in the PFC to improve negative cognitive and affective symptoms
what are the reciprocal roles of dopamine and serotonin in relation to prolactin
-dopamine inhibits prolactin release by stimulating D2 receptors (when blocked, prolactin levels rise)
-serotonin promotes prolactin release by stimulating 5HT2A receptors (when blocked, prolactin release decrease and levels drop)
location and action of 5HT1A receptors
always inhibitory and can be presynaptic (on serotonin neurons) or postsynaptic (on any neuron)
how does 5HT1A partial agonism at glutaminergic neurons indirectly innervating nigrostriatal dopamine neurons projecting to the motor striatum improve motor side effects
disinhibits dopamine release in these neurons and the increased release competes w/ D2 blockers for receptors in the motor striatum to reverse side effects
5HT1A partial agonist action at glutaminergic neurons indirectly innervating mesocortical dopamine neurons projecting to the PFC
disinhibits dopamine release in the PFC to improve negative/cognitive/affective/depressive symptoms
mania is thought to result from what
excessive dopamine release from mesolimbic/mesostriatal neurons
how many D2 receptors need to be blocked for therapeutic action
80%
2 antipsychotics with high metabolic risk
olanzapine
clozapine
5 antipsychotics with moderate metabolic risk
risperidone
paliperidone
quetiapine
asenapine
iloperidone
7 antipsychotics with low metabolic risk
lurasidone
cariprazine
lumateperone
ziprasidone
pimvanserin
aripiprazole
brexpiprazole
5HT2A antagonist and/or 5HT1A partial agonist action
-reduced motor side effects
-prolactin elevation
-therapeutic for positive, negative, depressive, and cognitive symptoms
antipsychotics with 5HT2A binding
-the “pines” all have higher potency for 5HT2A than D2
-the “dones and a rone” bind more potently to 5HT2A than D2
-aripiprazole and cariprazine are more potent for D2 than 5HT2A
-brexpiprazole has similiar potency at both receptors
antipsychotics with 5HT1A binding
-clozapine/quetiapine more potent for 5HT1A than D2
-asenapine/zotepine are less potent for 5HT1A than D2
-olanzapine/lumateperone do NOT bind to 5HT1A
-all “dones” less potent for 5HT1A than D2
-aripiprazole, brexpiprazole, cariprazine have similar potency at 5HT1A and D2
what is the only “pine” with monoamine reuptake inhibition
quetiapine
binds to NET similarly as 5HT2A
binds with NET at greater potency than D2
monoamine transporter binding of ziprasidone
binds to NET and SERT but with less potency than D2
monoamine transporter binding of lumateperone
binds to SERT with similiar potency as D2
alpha 2 binding of “pines”
all bind to varying degrees
*clozapine and quetiapine bind to some a2receptors more potently than D2
alpha 2 binding of the “dones”
all bind to varying degrees
risperidone and paliperidone bind to a2C with similar potency as D2
alpha 2 binding of lumateperone
does not bind to a2 receptors
alpha 2 binding of aripiprazole
binds to a2 with less potency than D2
alpha 2 binding of brexpiprazole
binds to a2C
D3 binding of the “pines”
all bind to D3 at varying degrees
D3 binding of the “dones”
all with varying degrees except lumateperone (doesn’t bind at all)
D3 binding of cariprazine
most potent binding is at D3
D3 binding of aripiprazole and brexpiprazole
bind less potently to D3 than D2
5HT2C binding of the “pines”
more potent binding at 5HT2C than D2
5HT2C binding of the “dones”
all have some affinity
only drug that binds to 5HT2C with similar potency as D2
ziprasidone
5HT2C binding in “2 pips and a rip”
weak
5HT3 binding of “pines”
bind with less affinity than D2
5HT3 binding of “dones and a rone”
none have any affinity
aripiprazole 5HT3 binding
weak
which drugs have greater or similiar potency at 5HT7 as D2
clozapine
quetiapine
asenapine
zotepine
drugs with greater or similar potency for 5HT6 as for D2
clozapine
olanzapine
asenapine
zotepine
which 4 drugs bind potently to 5HT7
risperidone
paliperidone
ziprasidone
lurasidone (greater affinity than for D2)
