Antipsychotics

Smoking and Olanzapine

Smoking induces CYP1A2, lowering drug levels; cessation can lead to toxicity

Clozapine REMS

Mandatory safety program requiring enrollment of prescriber, pharmacy, and patient to monitor ANC

Clozapine unique side effects

Agranulocytosis (low WBC), seizures, myocarditis, and sialorrhea (drooling)

Acute EPS Treatment

Anticholinergic agents (e.g., benztropine or trihexyphenidyl) to rebalance DA/ACh

NMS Management

Stop the offending agent immediately and provide intensive supportive care

Tardive Dyskinesia Treatment

VMAT2 inhibitors (valbenazine, deutetrabenazine); avoid anticholinergics

Mesolimbic pathway

Dopamine pathway responsible for positive symptoms (hallucinations/delusions)

Positive vs. Negative Symptoms

Positive = DA excess (mesolimbic); Negative = DA deficiency (mesocortical)

EPS Mechanism

D2 blockade removes DA restraint on ACh → unopposed acetylcholine in nigrostriatal pathway

Positive symptoms of schizophrenia — definition and pathway

Things ADDED (hallucinations, delusions, disorganized thought); caused by DOPAMINE EXCESS in the MESOLIMBIC pathway

Negative symptoms of schizophrenia — definition and pathway

Things TAKEN AWAY (flat affect, anhedonia, social withdrawal); caused by DOPAMINE DEFICIENCY in the MESOCORTICAL pathway

Nigrostriatal pathway — D2 blockade effect

EPS (movement side effects)

Tuberoinfundibular pathway — D2 blockade effect

Prolactin elevation (dopamine normally INHIBITS prolactin; blocking D2 removes that inhibition)

Why does one antipsychotic dose affect all 4 dopamine pathways?

Systemic drugs circulate through the whole brain; D2 receptors exist in all 4 pathways; the drug has no anatomical selectivity

Core mechanism shared by ALL antipsychotics (FGA + SGA)

D2 receptor blockade (aripiprazole = partial agonism instead of full antagonism)

Potency vs Efficacy

Potency = dose needed for effect; Efficacy = how well the drug works — NOT the same concept

High-potency FGAs (3) — EPS risk

Haloperidol, fluphenazine, pimozide — HIGH D2 affinity relative to other receptors = HIGHEST EPS risk

Low-potency FGAs (2) — receptor profile

Chlorpromazine, thioridazine — more competing affinity at alpha-1/5-HT2A/H1/M1 = LOWER EPS, more sedation/anticholinergic/hypotension

Chlorpromazine unique use

Intractable hiccups (historic); most sedating/anticholinergic FGA

Haloperidol distinguishing feature

Highest relative D2 blockade = highest EPS risk of the class; available as LAI

Fluphenazine distinguishing feature

High-potency, D2-predominant; available as depot/LAI

Thioridazine distinguishing feature

Most anticholinergic FGA; QT prolongation risk

Pimozide distinguishing feature

Drug of choice for Tourette's tics; QT prolongation, requires ECG monitoring

D2:5-HT2A ratio — what determines EPS risk

LOWER ratio (relatively more 5-HT2A blockade) → 5-HT2A blockade disinhibits (releases) dopamine in nigrostriatal/mesocortical pathways → offsets D2 blockade there → less EPS/negative symptom worsening

SGA requiring REMS + ANC monitoring

Clozapine — risk of agranulocytosis

Clozapine REMS requirements (traditional, 4 things)

All prescribers certified, all pharmacies certified, all patients enrolled, ANC checked/documented before every dispense

Clozapine other serious ADEs

Seizures, myocarditis, bone marrow suppression, sedation, weight gain, sialorrhea

Clozapine clinical role

Drug of choice for TREATMENT-REFRACTORY schizophrenia (10-20% who fail FGA + SGA trials) — NOT first-line

SGA that is a D2/D3 partial agonist ("dopamine stabilizer")

Aripiprazole — dampens excess DA signaling (mesolimbic), boosts deficient DA signaling (mesocortical/nigrostriatal) — low EPS overall but can cause paradoxical akathisia

Two SGAs with lowest D2 affinity/occupancy

Clozapine and quetiapine

SGA preferred to minimize EPS/prolactin via low D2 + high H1/alpha-1

Quetiapine — sedation/orthostasis instead of EPS

Olanzapine distinguishing receptor and effect

Highest H1 affinity of the SGAs → sedation + among highest metabolic burden (weight gain, dyslipidemia, hyperglycemia)

Olanzapine drug interaction

CYP1A2 — smoking INDUCES 1A2 and DECREASES olanzapine levels; smoking cessation INCREASES levels (risk of toxicity/side effects)

Risperidone distinguishing feature

High D2 AND 5-HT2A affinity — EPS risk is DOSE-DEPENDENT, becomes more "FGA-like" at higher doses; also used for autism-related irritability and Tourette's tics (separate indications)

Paliperidone distinguishing feature

Active metabolite of risperidone; RENALLY eliminated — preferred in HEPATIC impairment; most extensive LAI options (monthly, q3mo, q6mo)

Aripiprazole receptor notation (D2=5-HT2A)

Equal AFFINITY but different ACTION — partial agonist at D2, antagonist at 5-HT2A

Aripiprazole side effects

Akathisia (paradoxical), nausea, headache; LOW metabolic burden overall

EPS timeline in order (4 stages)

Dystonia (hours-days) → Akathisia (days-weeks) → Parkinsonism (weeks-months) → Tardive dyskinesia (months-years, possibly irreversible)

Mechanism of acute EPS (dystonia, akathisia, parkinsonism)

D2 blockade removes dopamine's normal restraint on acetylcholine → UNOPPOSED ACETYLCHOLINE → EPS symptoms

Why do anticholinergics (benztropine) treat acute EPS?

They don't reverse D2 blockade — they suppress the now-unopposed acetylcholine, rebalancing the system from the OTHER side

Tardive dyskinesia mechanism (different from acute EPS)

Dopamine receptor SUPERSENSITIVITY/upregulation after chronic D2 blockade — NOT unopposed acetylcholine

Why avoid anticholinergics in tardive dyskinesia?

TD isn't a cholinergic-excess problem, so anticholinergics don't fix the cause and may worsen TD

Drug class for treating tardive dyskinesia

VMAT2 inhibitors (valbenazine, deutetrabenazine) — decrease monoamine release

Class-wide antipsychotic Black Box Warning

Increased mortality risk in ELDERLY patients with DEMENTIA-RELATED PSYCHOSIS/behavioral disturbance

Two main causes of death linked to this BBW

Cardiovascular events (heart failure, sudden death) and infections (mostly pneumonia)

BBW history — FGA vs SGA

Originally SGA-specific (2005), extended to FGAs (2008) after studies showed comparable/higher FGA mortality

Neuroleptic Malignant Syndrome (NMS) — signs and management

Muscle rigidity, hyperthermia, altered mental status, autonomic instability, elevated myoglobin; STOP offending agent + supportive care

Anticholinergic toxicity — signs and drugs most associated

Blurred vision, dry mouth, confusion, constipation, urinary retention; most with thioridazine, chlorpromazine, clozapine, olanzapine

D2 receptor blockade — overall effects

Antipsychotic efficacy (mesolimbic) + EPS (nigrostriatal) + hyperprolactinemia (tuberoinfundibular)

5-HT2A receptor blockade — overall effect

Antipsychotic efficacy; counteracts D2-related EPS (key reason SGAs cause less EPS)

H1 receptor blockade — overall effect

Sedation, weight gain

Alpha-1 receptor blockade — overall effect

Orthostatic hypotension, dizziness, reflex tachycardia

M1/M3 receptor blockade — overall effect

Anticholinergic effects (dry mouth, blurred vision, constipation, urinary retention, confusion)

First-line therapy for most schizophrenia patients today

SGAs — comparable/greater efficacy with lower EPS risk vs FGAs

Why are LAIs (long-acting injectables) important in schizophrenia?

Address adherence — schizophrenia can impair insight (anosognosia) and organized daily routines; LAI removes need for daily pill-taking, reducing relapse risk

Shared antipsychotic pharmacokinetics

Variable oral absorption, extensive first-pass metabolism, cross BBB, highly protein bound, large Vd, metabolized by CYP 2D6/1A2/3A4, natural taper on discontinuation (except clozapine)

Other therapeutic uses of antipsychotics

Agitation/disruptive behavior (autism — risperidone, aripiprazole), Tourette's tics (pimozide = DOC, also risperidone/haloperidol), bipolar mania/depression, adjunct for refractory depression