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Stahl Chapter 5: Antipsychotics
1. which FGAs are low potency and which ones are high potency?: Low potency FGAs:
- chlorpromazine (thorazine)
- mesoridazine (serentil); QTc issues so 2nd line
- thioridazine (mellaril); QTc issues so 2nd line
High potency FGAs:
- Fluphenazine (prolixin); available as LAI
- Haloperidol (Haldol); available as LAI
- Perphenazine (trilafon)
- Pimozide (orap); tx for tourettes but QTc issues so 2nd line
- Thiothixene (navane)
- Trifluoperazine (stelazine)
Note: low potency requires higher doses but tend to have more additional properties (anticholinergic, antihistaminer- gic, alpha 1 antagonist) so they are usually more sedating.
2. whats neurolepsis?: extreme form of slowness or absence of motor movements as well as emotional
quieting and attective inditterence.
- FGAs are known to cause this, where the term neuroleptic comes from.
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- its caused by D2 blockade in the NA which is the pleasure center of the brain. This causes pts to not experience any pleasure resulting in apathy, anhedonia, lack of motivation, interest, and joy from social interactions. This may be the reason why schizophrenia has a large comorbidity of smoking and drug abuse. D2 blockade in the mesocortical pathway (where DA is already deficient) worsens negative and cognitive sxs even though theres a low D2 density in PFC.
3. what differentiates FGAs from SGAs?: FGAs act primarily on D2.
4. what causes the SEs with FGAs?: due to blockade of D2 in the mesolimbic DA pathway. This reduces the hyperactivity in this pathway that causes the
positive sxs. All FGAs tx positive sxs equally well if dosed to block 60% of D2's in the mesolimbic pathway. In order to do this you have to also block the same D2 receptors throughout the brain which causes the SEs due to D2 blockade in the nigrostriatal pathway in the dorsal striatum (motor), ventral limbic area (the NA in the mesolimbic pathway), the PFC of the mesocortical pathway, and in the pituitary gland of tuberoinfundibular DA pathway.
5. whats the neuroleptic induced deficit syndrome?: adverse behavioral state produced by D2 blockade in FGAs because it looks so much like the
negative sxs produced in schizophrenia. This is similar to neurolepsis but specifically the emotional inditterence.
6. what causes the parkinsonian sxs? what causes TD? who's at risk for TD?: D
blockade in the nigrostriatal pathway which is part of the EPS nervous system. If this occurs chronically it causes a hyperkinetic movement disorder called TD. TD is characteristic of facial and tongue movements (constant chewing, tongue protrusions, facial grimacing) and quick, jerky, or choreiform (dancing) movements. TD is usually due to long term administration of FGAs. Its caused by changes that are sometimes irreversible to the D2 receptors of the nigrostriatal pathway where they become supersensitive or upregulate (increase in number) to overcome drug induced blockade of D2 receptors in the striatum.
- 5% of pts on chronic FGAs get TD every year and 25% of pts on chronic FGAs for 5 yrs but if elderly then 25% in the first yr. If FGA is removed early enough then TD will reverse back but if you wait the receptors lose the ability to do that. Those who get EPS early in tx are 2x as likely to get TD.
7. what are the sxs of NMS? cause?: extreme muscular rigidity
high fevers coma or death
4 / 22 Note: Haldol has little anticholinergic or antihistamine binding. Chlorpromazine has potent anticholinergic and anti- histamine binding.
10. what makes SGAs atypical?: have clinical profile of equal positive sx antipsychotic actions but low
EPS and less hyperprolactinemia compared to FGAs. This began with clozapine. Current SGAs are defined as 5HT-DA antagonists with 5HT2A antagonism along with D antagonism. 5HT2A antagonism can mediate the SGA profile of low EPS and less hyperprolactinemia. They also have SGAs with partial agonism at 5HT1A and D2 receptors.
11. How is 5HT synthesized? Hows it terminated?: amino acid tryptophan is transported into the
brain from plasma to make 5HT. 2 enzymes convert tryptophan into 5HT. tryptophan hydroxylase converts tryptophan into 5-hydroxytryptophan, then aromatic amino acid decarboxylase (AAACD) converts 5HTP into 5HT which is then taken into vesicles by VMAT2. 5HT action is terminated when destroyed by MAO and converted into inactive metabolite. 5HT neurons contain MAO-B has low aflnity for 5HT so much of the 5HT is degraded by MAO-A outside the neuron. 5HT is also reuptaken by SERT to be restored in vesicles.
12. what do 5HT2A receptors do?: All 5HT2A receptors are postsynaptic and are in many brain regions.
When located on pyramidal neurons they are excitatory and enhance downstream glutamate release, thus Stimulating or blocking 5HT2A receptors can also regulate downstream DA release.
- 5HT2A stimulation of pyramidal neurons by 5HT blocks downstream DA release in the striatum via stimulation of glutamate release in the brainstem that triggers release of GABA which inhibits DA release in the striatum.
- 5HT2A antagonism of pyramidal neurons by SGAs interferes with 5HT applying its breaks on DA release. Thus 5HT2A antagonism in cortex hypothetically stimulates downstream DA release in the striatum. This happens due to reducing glutamate release in the brainstem which fails to trigger the release of inhibitory GABA at DA neurons. DA release from neurons downstream from the striatum is thus disinhibited which should mitigate EPS SEs.
13. what do 5HT1A receptors do?: regulate downstream DA release. 5HT projections from the raphe
nucleus to the cortex synapse on glutamatergic pyramidal neurons. 5HT released at these synapses binds to 5HT1A receptors which causes inhibition of glutamate neurons. If glutamate is not released from glutamate pyramidal neurons into the brainstem then GABA isn't released and doesn't inhibit DA release from the substantia nigra into the striatum. So 5HT1A stimulation does the same thing as 5HT2A receptor blockade. Both leads to increased DA release.
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14. How does 5HT2A antagonism decrease EPS?: usually 5HT reduces DA release from the
striatum by actions of 5HT at 5HT2A receptors. when 5HT2A is blocked DA is released more which competes at D2 receptors with the SGA in the striatum and reduces D binding below 80% to closer to 60% which eliminates EPS. Note: 5HT2A acts as an autoreceptor on presynaptic DA neurons, when its stimulated theres no DA release (inhibits) when its not stimulated theres no inhibition and DA is released.
15. How does 5HT2A antagonism lower hyperprolactinemia?: 5HT and DA have reciprocal
roles in regulation of prolactin from pituitary lactotroph cells. DA inhibits prolactin release by stimulating D2 receptors. 5HT promotes prolactin release by stimulating 5HT2A receptors. When D2 receptors alone are blocked, DA can't inhibit prolactin so it rises. With SGAs theres inhibition of 5HT2A so it can't stimulate prolactin release which mitigates the hyperprolactinemia of D2 receptor blockage. Note: not all SGAs reduce prolactin the same amount
16. Why doesn't 5HT2A antagonism reverse the antipsychotic actions?: The actions of increased DA release due to 5HT2A
antagonism varies in ditterent parts of the brain. In nigrostriatal and tuberoin- fundibular DA pathways theres suflcient DA release by SGAs to reverse in part EPS and hyperprolactinemia. But in the mesolimbic pathway theres not enough DA released to reverse the antipsychotic ettects. So in the limbic areas theres an 80% blockade but in the pituitary and striatum theres only 60% blockade. Eventually at high enough doses both will be 80% and this is what the therapeutic window represents (this gap). This gap is created by the fact that SGAs almost always have higher aflnity for 5HT2A than for D2. Note: those that have the highest aflnity for 5HT2A have the lowest EPS and hyperprolactinemia. Those are the Pines and then the Dones. Two pips and a rip have more of this, but because they are partial D2 antagonists and have other actions like on 5HT1A, they still don't get these SEs.
17. what do 5HT1A receptors in the PFC do to DA release in the striatum?: 5HT1A
receptors in the PFC accelerate DA release when activate: 5HT1A is located on postsynaptic pyramidal neurons in the cortex. When stimulated the cortex stimulates downstream DA release in the striatum by reducing glutamate release in the brainstem which fails to trigger release GABA at DA neurons there which disinhibits them just like when
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- Clozapine, olanzapine, and asenapine bind weakly to 5HT1B, quetiapine and asenapine bind strongly to 5HT1D, Risperidone, paliperidone, ziprasidone and iloperidone bind to the 5HT1B and 1D. Ziprasidone binds more potently to 5HT1B that to D2. Lurasidone doesn't bind to 5HT1B/D. Aripiprazole and brexiprazole bind weakly to 5HT1B. Aripiprazole binds to 5HT1D while cariprazone doesn't bind to either.
21. what do 5HT2C receptors do?: They're postsynaptic and regulate DA and NE release. Stimula-
tion suppresses DA release and usually more in the mesolimbic system than the nigrostriatal pathway (making an antipsychotic without EPS). An agent that selectively agonizes these is vabacaserin. This may also cause wt loss (how locaserin works). Blocking 5HT2C stimulates DA and NE release in the PFC. This is good for cognitive sxs and antidepressant actions. Mirtazapine and agomelatine do this. The pines have potent 5HT2C antagonism (esp quetiapine and olanzapine) this is why quetiapine is often combined with fluoxetine to boost antidepressant actions in tx resistant BPAD. Fluoxetine is a potent 5HT2C antagonist which is why this is a good combo. Olanzapine + fluoxetine is also a good combo for the same reason. Quetiapine also blocks NET, so these 2 combined is great for depression to boost DA and NE in the PFC. Asenapine also is a potent 5HT2C antagonist so it could be a good antidepressant as well but the other SGAs bind relatively weak to 5HT2C.
- all the pines (clozapine, olanzapine, quetiapine, asenapine) bind more potently to 5HT2C than to D2. All of the dones (risperidone, paliperidone, ziprasidone, iloperidone, lurasidone) have some aflnity for 5HT2C but not with more potency than at D2. Aripiprazole, brexpiprazole and cariprazine bind weakly to 5HT2C.
22. What do the 5HT3 receptors do?: They are postsynaptic and regulate inhibitor GABA interneurons
in brain areas that in turn regulate release of many NTs including 5HT, ACH, NE, DA and histamine. Also important for central vomiting centers. Peripheral 5HT3 receptors in the gut regulate bowel motility. Blocking these in the CTZ of the brainstem treats nausea and vomiting. Blocking 5HT3 receptors on GABA interneurons increases release of 5HT, DA, NE, ACH, and histamine in the cortex so it can be precognitive in depression. Mirtazapine and vortioxetine are potent 5HT3 antagonists which is why they combine well with drugs that inhibit SERT, NET or DAT. Among the SGAs only clozapine binds to 5HT3 potently compared to its D2m the others have almost no aflnity.
23. what do the 5HT6 receptors do?: they are postsynaptic and regulate the release of ACH and cogni-
tive processes. Blocking them improves learning and memory. 5HT6 antagonists could tx cognitive sxs in schizophrenia when added onto SGAs. Clozapine, olanzapine, asenapine are potent 5HT6 antagonists relative to D2 binding. The others have moderate-weak binding to 5HT6 receptors relative to D2 (quetiapine, ziprasidone, iloperidone, aripiprazole, brexpiprazole).
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24. what do 5HT7 receptors do?: postsynaptic and important for 5HT release. When blocked 5HT
is disinhibited esp if 5HT7 antagonism is combined SRI. They can also regulate circadian rhythms. amoxapine, desipramine, imipramine, fluoxetine, vortioxetine have moderate aflnity for 5HT7. Several pines and dones are potent 5HT7 antagonists relative to D2 including clozapine, quetiapine, and asenapine; risperidone, paliperidone, and lurasidone. this may be why quetiapine is a good adjunct to SRIs in addition to its NET inhibition, 5HT2C antagonism and 5HT1A partial agonism. 5HT7 antagonism could also cause aripiprazoles antidepressant action esp if combined with its 5HT1A partial agonism. Lurasidone, asenapine, brexpiprazole could also be adjuncts for unipolar MDD. Lurasidone is already known to be ettective in BPAD depression.
25. explain D2 partial agonism and which drugs do this: some antipsychotics stabilize DA neurotransmission between silent
antagonism and full stimulation/agonist action by being a partial agonist at D2. Balance for each drug in the D2 partial agonist class is ditterent. They have the intrinsic ability to bind receptors in a manner that causes signal transduction from the receptor to be intermediate between full output and no output. Partial agonists have many degrees possible in this window. For example, Aripiprazole improved positive sxs without activating negative sxs at higher doses while proving to be an antidepressant at lower doses. But it still has some akathisia because it might be too close to the antagonist end of the spectrum. So then bifeprunox was made to be more of an agonist than aripiprazole hoping for improvement but less akathisia. But this was too much of an agonist and it caused nausea and vomiting from DA agonist actions and wasn't antagonistic enough to be an antipsychotic so it wasn't approved by the FDA. So the partial agonists can be anywhere in this window and depending on where they are can have very ditterent clinical profiles.
26. How are antipsychotics used in BPAD depression and MDD?: antipsychotics are
misnamed because they have antidepressant actions. D2 and 5HT2A antagonism is not the action of this because the agents with only these don't work for depression. The ones that have the antidepressant properties are only ettective at low doses. In addition to the above mechanisms for antidepressant activity quetiapine is a greater SERT and NET inhibiter than D2 inhibitor. ziprasidone only has weak binding at these sites though. alpha 2 antagonism is how mirtazapine works but all the pines (esp quetiapine and clozapine) and dones (esp risperidone) and aripiprazole also have this mechanism.
27. How are antipsychotics used for mania?: all antipsychotics are ettective in psychotic mania but
SGAs are better than FGAs for nonpsychotic mania. D2 antagonism/partial agonism combine with 5HT2A antagonism is what causes this. The best for tx is aripiprazole and then cariprazine. Partial D3 agonists with 5HT1A partial agonism
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- clozapine
- quetiapine
- olanzapine All bind potently to M1 receptors where as theres no M1 binding for other SGAs including asenapine
33. what SGAs are potent alpha1 antagonists?: all SGAs have some potency for these but most potent relative to their D2 are:
- clozapine
- quetiapine
- risperidone
- iloperidone
34. which SGAs have highest metabolic risks, moderate metabolic risks, and lowest metabolic risks?:
highest: clozapine, olanzapine moderate: risperidone, paliperidone, quetiapine, iloperidone (wt only) lowest: ziprasidone, aripiprazole, lurasidone, iloperidone (low for dyslipidemia), asenapine, brexpiprazole, cariprazine
35. what causes the metabolic SEs seen with SGAs?: the metabolic highway begins with increased appetite which causes wt gain and
eventually obesity which causes insulin resistance and dyslipidemia with increasing fasting triglyceride levels. Ultimately hyperinsulinemia advances to pancreatic beta cell failure, prediabetes and then DM. Once DM happens then theres risk for CV events and premature death. Receptors associated with increased wt are H1 and 5HT2C blockers. If blocked at the same time wt gain is worse.
36. Alpha 1 binding from best to worst (weakest to strongest) for SGAs: brexpipra- zole
11 / 22 aripiprazole cariprazine ziprasidone lurasidone paliperidone asenapine olanzapine iloperidone risperidone quetiapine clozapine
37. H1/anticholinergic binding from best to worst (weakest to strongest) for SGAs: brexipiprazole, aripiprazole
cariprazine ziprasidone paliperidone risperidone iloperidone lurasidone asenapine olanzapine quetiapine clozapine
38. what medications will cause the most wt gain and why?: clozapine olanzapine
13 / 22 pros: more potent than clozapine, lacks EPS at moderate and high doses, not as sedating as clozapine, doesn't raise prolactin with long term use cons: can still be sedating (blocks h1, a1, and m1), lots of wt gain (due to h1 and 5HT2C blocking), has some of the worst cardiometabolic risks (that's not just associated with wt gain) dose: typically at least 15mg/day (due to better eflcacy)
- in pt can be up to 40mg/day
- available in ODT and LAI (risk for severe sedation with LAI) indications: schizophrenia, BPAD, tx resistant depression (esp with fluoxetine due to both blocking 5HT2C and olanza- pine blocking 5HT7 and a2 as well) guide: go to olanzapine when those with lesser cardiometabolic SEs don't work and use higher doses for eflcacy.
41. Quetiapine (Seroquel) overview: MOA, indications, dose, forms, when to use each form, pros and cons: MOA:
structure similar to clozapine. antagonist at 5HT2A and D2. At ditterent doses/forms has ditterent properties due to combined actions of quetiapine vs norqetiapine (metabolite). Norqetiapine is a NET inhibitor, and inhibitor of 5HT7, 5HT2C, 5HT1B/D and alpha 2. partial agonist of 5HT1A. These are a big reason it's a good antidepressant.
- IR: rapid onset, short duration but usually still only have to take at night (due to sedation from H1 inhibtion at peak which is reached quickly), max dose of 800mg lasts for about 12 hrs so you could get break through sxs at the end of the day
- XR: slower to hit peak, less sedation, above 60% D2 occupancy for a full 24 hrs (if you use it for sleep it will delay sleep onset and cause hangover ettect), if taken at bedtime peak is reached at time you would wake up (so take this in the morning). Longer peak also makes it better as an antidepressant. (binds to NET and 5HT2C longer, so when combined with SRI increases all 3 monoamines). dose
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- IR: 300-800 QD (300mg is usually the lowest ettective dose as an antipsychotic, this gets to the 60% of D2 but short duration makes it fall below this quickly which means you either have to dose it multiple times, increase the dose, or go to XR. 800mg gets coverage for about 12 hrs)
- XR: 300-800mg QD (binds 60% of D2 for a full 24 hrs) note: higher doses bind more receptors to the right of D2, lower doses to the left of D2 (sedating receptors are to the left) when to use IR and when to use XR: IR for sleep, XR for antipsychotic indications and dosing: schizophrenia, BPAD, augment SRI for MDD.
- papa bear: for antipsychotic use 800mg XR QD. at this dose completely saturates h1 and 5HT2A. binds to D2 at above 60% better with XR.
- mama bear: for antidepressant use 300mg XR. This is one of the best antidepressants available for BPAD depression. This is due to norqetiapine actions. Together DA and NE is increased. studies show 300mg binds to these the same amount as 600mg, so increasing dose won't improve antidepressant ettect, but does increase SEs. Can still tx sxs of insomnia and anxiety due to h1 blocking.
- baby bear: for hypnotic use 50mg IR but know that these doses aren't approved for insomnia and due to wt gain aren't first line for sleep. also with both forms (IR and XR) at 50mg 5HT2C and NET (the antidepressant receptors) are mildly blocked so it's likely not very ettective for depression. And D2 is blocked below 60% so it's not good as an antipsychotic. pros to use: almost no EPS or prolactinemia at any dose (along with cloazapine it's the best for Parkinson's pts that have psychosis). cons of use: wt gain (worse with moderate to high doses as h1 and 5HT2C blockade increases), cardiometabolic SEs (esp at moderate to high doses) that are middle to higher risk than other SGAs.
42. Asenapine (Saphris) Overview: MOA, good for, forms, dose interval, pros,
cons: MOA: Newer SGA Potent antagonist to 5HT2C (for mood and cognitive sxs), 5HT7 (for mood, cognitive, and sleep symptoms) which makes it similar to mirtazapine. Also antagonist of 5HT2A, 5HT2C, H1, A2 and D2.
16 / 22 indications: schizophrenia, BPAD, esp good for kids because low doses can be used, irritability in ASD (ages 5-16), dementia sxs (of label) good for those: who just need a low to moderate dose like in kids with psychotic disorders. ASD with sxs of aggression towards others, deliberate SH, tantrums, quicky changing moods, BP (ages 10-17), and schizophrenia (ages 13-17). Also good for agitation and psychosis in dementia cons: at higher doses it becomes an FGA and can cause EPS. at all doses can increase prolactin. moderate risk for wt gain and dyslipidemia (esp risky with kids) what's the concern with using antipsychotics in elderly: increased risk of death (but still very low risk) forms:
- LAI q2wks
- ODT
- liquid dosing: give BID (esp in children/elderly) to avoid hypotension and sedation.
- SEs are due to rapid absorption rate and higher peaks with shorter duration and more level fluctuations throughout.
44. How does 5HT inhibit NE and DA release?: 5HT binds to 5HT2C receptors on GABA interneurons which inhibits NE and DA release
in the PFC. Note: most SGAs are 5HT2C inhibitors which reverses this and increases NE and DA release.
45. Paliperidone (Invega) overview: MOA, differences from risperdal, pros, forms, cons, dose: MOA: active
metabolite of dispersal. Binds to D2 and 5HT2A strongly. Major ditterence between it and risperdal: paliperidone isn't hepatically metabolized, it's just excreted out the kidneys.
17 / 22 Also available in SR form. SR can be given QD where as risperidone needs BID pros: due to excretion it has few drug interactions, more tolerable than risperdal (less sedation, hypotension, and EPS) forms: IR, SR, LAI (q4wks)
- if giving SR dose QD, this form eliminates the hypotension/sedation SEs of risperdal
- with LAI no bridge cons: wt gain, cardiometabolic SEs, elevated prolactin dose: start at 6mg; increase to 9mg in 1wk and then 12mg a wk later if needed
- can start at 9mg if immediate risk or pt has Hx of higher SGA doses. only start at 3mg if sensitive to SEs.
46. Ziprasidone (geodon) overview: MOA, pros, forms, dosing: MOA: 5HT2C, 5HT7, 5HT1B/D, alpha 2, NET, and SERT
antagonism and alpha 1 partial antagonism (all have antidepressant mechanisms). D2 antagonism.
- No studies show it has antidepressant ettects though pros: almost no wt gain (despite binding to 5HT2C and H1) or cardiometabolic SEs. If switching from other SGAs that caused wt gain to this, there can be wt loss and reversal of cardiometabolic SEs this is because it doesn't bind to receptors that mediate insulin resistance and hypertriglyceridemia. Doesn't raise QTc (thought it raised QTc significantly but this isn't supported by studies). Few drugs increase it's level (few interactions) dosing: give BID with food (500+ calories, increases absorption x2) forms: IM (for rapid use in urgent situations)
47. what history is significant for starting an SGA?: cardiac Hx taking other QTc
prolonging drugs Hx of syncope
19 / 22 indications: schizophrenia, BPAD depression, mixed depression, tx resistant MDD
- depression ettects due to 5HT7, 5HT1A, and a2 receptors, great augmentor to SSRI/SNRI
- 5HT7 inhibition is procognitive as DA increases and helps with circadian rhythms pros: no sedation (esp if doses at night), very little wt gain or dyslipidemia you (along with geodon and abilify), if gained wt on another SGA it can reverse on latuda, no QTc prolongation cons: can be moderate EPS (risk reduced if given at night), must be given with 500+ calories dose: start at 40mg; go up to 160mg
52. how do 5HT7 blockers work as antidepressants?: 5HT7 receptors are on GABA neurons in
the raphe and PFC. In both areas stimulation of 5HT7 releases GABA. In the brainstem stimulation serves as a negative feedback loop and turns ott 5HT release. In the cortex stimulation excites GABA interneurons and inhibits neurons in the cortex reducing glutamate release downstream. If you block 5HT7 in the raphe you prevent inhibition of GABA and there's increased release of 5HT causing antidepressant action.
53. how does a1 Stimulation/blocking increase/decrease DA release?: stimulation:
NE projections from the LC to the cortex synapses on pyramidal neurons where NE binds to a1 receptors on cortical glutamate neurons. this causes glutamate release which causes GABA Release in substantia nigra which inhibits DA release in striatum blocking: a1 is blocked on glutamate pyramidal neurons, decreasing glutamate and GABA isn't released. without GABA DA neurons from the substantia nigra to the striatum activate and DA is released.
54. Aripiprazole (abilify) overview: MOA, indications, pros, cons, doses, forms: -
MOA: D2 partial agonist, partial D3 agonist (thought partial D2 and D3 causes increase in DA which is why it acts as an antidepressant), 5HT2A antagonism, 5HT1A partial agonist (more potent than at 5HT2A but less than at D2, cause for antidepressant ettects), 5HT7 antagonism (cause for antidepressant ettects) indications: schizophrenia, mania, BPAD depression (ott label) and depression augmentation with SSRI/SNRI in tx resistant MDD; C&A indications for schizophrenia (13+ y/o), acute mania/mixed mania (10+ y/o), ASD related irritability
20 / 22 (6-17 y/o) Pros: due to D2 partial agonism it has less EPS and hyperprolactinemia without blocking 5HT2A more than it blocks D2 (almost all other SGAs block 5HT2A more than D2). Doesn't bind to H1, M1 so theirs typically not sedation. Very little wt gain (like Geodon and Latuda). Very little cardiometabolic ettects. When switching to abilify cardiometabolic ettects can reverse (likely due to its inability to bind to receptor X). In newly dx or early onset psychosis this is great because of the tolerability profile, can try it out and see if it works. Cons: may have too much DA agonism and not enough antagonism and this can cause abilify to be activating in some pts causing mild agitation along with n/v. In diflcult to tx pts its not antipsychotic enough. Higher doses are no more ettective than moderate doses. On the other hand it could be too antagonistic because some pts get akathisia which can be decreased by dose reduction or administering an anticholinergic or benzo. dosing:
- low doses for depression forms: IM for short term use, ODT and liquid, LAI (q4wks)
55. How does 5HT7 effect the brain?: stimulation: when 5HT binds to 5HT7 receptors on GABA interneurons in the raphe nucleus
then GABA inhibits 5HT neurons in the PFC to release 5HT. inhibition: when 5HT7 receptors on GABA interneurons in the raphe nucleus are blocked then GABA doesn't release and 5HT neurons in the PFC become overactivated and increase 5HT release in the PFC. function of 5HT7 in the brain: to regulate 5HT-glutamate interactions. 5HT neurons from the raphe nucleus synapse on GABA interneurons in the PFC that have 5HT receptors. The GABA neurons then synapse on glutamate neurons. So if these receptors are stimulated in the PFC on the GABA interneurons the GABA is released and glutamate release is inhibited. If these receptors are blocked in the PFC on GABA interneurons then GABA isn't released and glutamate release is excessive.
