N719 Wk 3 (Shz)

hyperactivity in the mesolimbic pathway

positive symptoms

• Hallucinations, delusions, motor agitation, bizarre behaviors 

• Positive symptoms → highly responsive to antipsychotics

hypoactivity in the mesocortical pathway

• Alogia (impoverished speech), avolition, anhedonia, blunted affect, asociality, lack of energy

glutamate/ NMDA hypothesis

Disconnectivity of NMDA-receptor-containing synapses → overactive glutamate in the prefrontal cortex can stimulate dopamine receptors in the limbic area

first gen (typical) antipsychotics

D2 antagonist actions, which effectively treat positive symptoms but have a higher risk of causing Extrapyramidal Symptoms (EPS) and hyperprolactinemia

second gen (atypical) antipyschotics

Combine D2 antagonism with 5HT2A antagonist/inverse agonist actions or D2 partial agonist actions. 

• Blocking the 5HT2A receptor mitigates EPS and hyperprolactinemia while helping address negative symptoms.

chlorpromazine EPS, wt gain, anticholingeric (sedation), QTc

Chlorpromazine (Thorazine)

+++wt gain, ++anticholinergic, +EPS, 0prolongQT

thioridazine EPS, wt gain, anticholingeric (sedation), QTc

Thioridazine (Mellaril)

+++wt gain/ prolongQT/ anticholinergic, +EPS effect

haloperidol, perphenazine

EPS, wt gain, prolong QT, anticholingeric (sedation)

Haloperidol (Haldol) & Perphenazine (Trilafon):

+++EPS, +wtgain/anticholingeric, 0prolongQT (EXCEPT IV HALDOL)

QTC black box warning

thioridazine, mesoridazine

EPS first generations

• High-potency first-generation antipsychotics → High EPS

  • Haloperidol ↑↑

  • Perphenazine ↑

• Low-potency first-generation antipsychotics → Low EPS, more anticholinergic/sedation

  • Chlorpromazine

  • Thioridazine

  • Mesoridazine

-PINES antipsychotics

clozapine, olanzapine, quetiapine: generally more sedating & carry higher risk of wt gain/ cardiometabolic risk except asenapine

clozapine ind, monitoring (WBC, cardiac, inf/ toxicity, d/c, smoking)

Best to reduce suicidality in schizophrenia; tolerated in PD, LewyBD, TD 

• WBC Monitoring: risk of lowering the seizure threshold and causing agranulocytosis

• Cardiac Monitoring: QTc prolongation

• Infection/Toxicity: fever or flu-like symptoms, alongside signs of clozapine overdose, a 50% dose reduction is suggested.

  • Trough levels 350-600

• Discontinuation: tapered slowly (over at least 4 weeks) to avoid rebound psychosis

• Smoking: decr effectiveness

olanzapine ind, SE, ___ antagonist

• schz, bipolar/ treatement resistant depression w/ fluoxetine

• Less sedating than clozapine, more cardiometabolic risk 

• 5HT2C antagonist —> help w/ cognitive/ affective sx

• easy to initiative/ switch

quetiapine (Seroquel) ind, dosing, inhibitors

• Antipsychotic; mood stabilizer 

  • Dosing: 

    • 400-800mg/ day: schizophrenia, bipolar mania 

    • 300/mg: bipolar depression 

    • 50-150mg: anxiolytic/ hypnotic 

• antidepressant effects; adjunct w/ SSRI/SNRI for unipolar depression

• -azoles & cimetidine inhibit metabolism

asenapine (Saphris)

• Schizophrenia, acute/mixed mania; sublingual formulation only 

  • Avoid eating/ drinking 10 min after admin 

• low cardiometabolic risk

QTC: clozapine, olanzapine, quetiapine, asenapine

clozapine: warning

olanzapine: 0

quetiapine: warning

asenapine: warning

EPS: clozapine, olanzapine, quetiapine, asenapine

clozapine: low (akithesia)

olanzapine: low (sedating)

quetiapine: practically 0

asenapine: low (sedating)

risperidone (Risperidal) ind, SE

• Schizophrenia, acute/mixed mania, BP maintenance/ depression, ASH irritability in children

• SE: anticholinergic SE**, EPS, hyperprolactinemia, dizziness, anxiety, sedation, NV, constipation, weight gain

paliperidone (Invega) benefit, metabolize

• Active metabolite of risperidone; better tolerated w/ less sedation, orthosis, EPS (anecdotal) 

• Not hepatically metabolized, renally excret, so few drug interactions 

iloperidone (Fanapt) ind, SE, ___ antagonism

• Schizophrenia, acute/ mixed mania, BP maint, tx rest. Dep 

• Lowest EPS/ akathisia, dyslipidemia

• alpha-1 antagonism —> PTSD (nightmares)

  • orthostatic hypotension

ziprasidone (Geodon)

• Schizophrenia, acute/ mixed mania, BP maint. 

• Taken w/ food (200-500 cal.)

lurasidone (Latuda)

• SCZ, BP dep 

  • Antidepressant effects

• Low sedation, little/ no weight gain 

• Do NOT use w/ strong 3A4 inhibitor or inducer 

• Eaten w/ meals or 500 cal snack 

QTC: risperidone, paliperidone, iloperidone, ziprasidone, lurasidone

risperidone: 0

paliperidone: warning

iloperidone: warning

ziprasidone: warning

lurasidone: 0

EPS risperidone, paliperidone, iloperidone, ziprasidone, lurasidone

risperidone: moderate/low

paliperidone: moderate/low

iloperidone: lowest among atypical

ziprasidone: moderate/low

lurasidone: low

arpiprazole (Abilify) low risk, SE, adjunct

• Low EPS & hyperprolactinemia, no cardiomet. Risk 

• SE: **AKITHISIA, anticholinergic, dizziness, insomnia, N/V

• Adjunctive tx w/ SSR/NIs in MDD & bipolar dep

cariprazine (Vraylar), ind, ___ agonist

• Scz, acute/ mixed mania 

• SE: akathisia, EPS, GI distress, sedation

• D3-preferring, D3/D2 receptor partial agonist

brexipiprazole (Rexulti)

• SCZ, tx resist. dep.

• SE: weight gain (moderate), akathisia, anxiety, H/A

QTC: aripiprazole, cariprazine, brexiprazole

aripiprazole- 0

cariprazine- 0

brexiprazole- 0

EPS aripiprazole, cariprazine, brexiprazole

aripiprazole- low, akathisia

cariprazine- present

brexiprazole- low, akathisia

pimavenserin (Nuploazid) ind, __ antagonist, warning

• ind: psychosis associated w/ parkinson’s

• 5HT2A antagonist

• warning: incr mortality in elderly pt w/ dementia related psychosis

• QTC prolong

antipyschotics & wt gain

smoking + antipsychotics

smoking = CYP1A2 inducer —> decr levels of olanzapine + clozaril

abrupt cessation —> incr levels

akathisia

dopamine hypoactivity

clozapine, apiprazole most notable