Week 13: Pharmacotherapy (Bishop)

How do antipsychotics exhibit dose-response?

increase in efficacy → plateau at moderate doses

How do side effects relate to dose?

linear increase (no plateau)

What is the optimal D2 receptor occupancy range?

60-80%

Why is dose optimization important?

higher doses → more side effects without significant added efficacy

What are the main CYP enzymes for antipsychotics?

CYP2D6, CYP3A4, CYP1A2

Which antipsychotic has minimal hepatic metabolism?

paliperidone (renal elimination)

What is paliperidone pharmacologically?

active metabolite of risperidone

Why are primary metabolic pathways important?

determine drug interactions + PGx relevance

Typical half-life range of antipsychotics?

~7-24 hours

Which antipsychotics have long half-lives?

aripiprazole (~75-94h), brexpiprazole (~91h), cariprazine (48-96h)

+ active metabolites

Which first-gen antipsychotics have LAIs?

fluphenazine, haloperidol

Which second-gen antipsychotics have LAIs?

aripiprazole, olanzapine, paliperidone, risperidone

What is unique about olanzapine LAI?

REMS program due to dose-dumping/sedation risk

Which antipsychotic LAI has the longest dosing interval?

paliperidone (up to every 6 months)

Which antipsychotic commonly uses TDM?

clozapine; routine TDM not commonly recommended for others

What is clozapine's therapeutic level threshold?

>350 ng/mL (12-hour level)

At what level is clozapine toxicity a concern?

~≥1000 ng/mL (↑ seizure risk)

When is TDM useful for other antipsychotics?

poor response, decompensation, ADEs, DDIs, altered PK, suspected nonadherence

What happens to half-life in CYP2D6 poor metabolizers?

↑ (often ~2x longer

What happens to drug exposure (AUC)?

↑ significantly (up to >600% for some drugs)

What is the clinical consequence of poor metabolism?

↑ side effects (dose-dependent)

How does CYP2D6 genotype affect dosing?

Ultra-rapid → higher dose

Poor metabolizer → lower dose

What happens to CYP2D6 poor metabolizers in youth?

↑ discontinuation + ↑ weight gain

What are common SEs seen in pediatric patients using risperidone?

weight gain, sedation, movement disorders

Which second-gen drug uses CYP3A4 PGx?

quetiapine

Which first-gen antipsychotics have CYP2D6 PGx relevance?

haloperidol, perphenazine, pimozide, thioridazine

What is the key PGx dosing principle for poor metabolizers?

Which drug is contraindicated in poor metabolizers?

thioridazine

Which second-gen antipsychotics have CYP2D6 PGx relevance?

aripiprazole, brexpiprazole, iloperidone, risperidone

What is the general PGx dosing adjustment for poor metabolizers?

~50% dose reduction

What is an alternative strategy instead of dose reduction?

choose drug not metabolized by CYP2D6

What are examples of alternatives to CYP2D6-heavy drugs?

olanzapine, clozapine, quetiapine, lurasidone