Positive symptoms of psychosis (hallucinations, delusions) are linked to excess dopamine activity in the mesolimbic pathway. Most antipsychotics block dopamine D2 receptors. Blocking D2 in other pathways explains the main adverse effects:

First-generation (typical) drugs are strong D2 blockers. High-potency drugs (haloperidol, fluphenazine) cause more EPS; low-potency drugs (chlorpromazine) cause more sedation, anticholinergic effects, and orthostatic hypotension because they also block histamine, muscarinic, and alpha-1 receptors.

Second-generation (atypical) drugs block D2 and serotonin 5-HT2A receptors, which lowers EPS risk but increases metabolic effects (weight gain, diabetes, dyslipidemia). Aripiprazole, brexpiprazole, and cariprazine are D2 partial agonists (less prolactin rise, more akathisia).

Xanomeline-trospium is a newer class without direct dopamine blockade: xanomeline stimulates central muscarinic receptors, and trospium blocks peripheral muscarinic receptors to limit cholinergic side effects.

Agitation settles within hours to days; full antipsychotic effect takes several weeks.

Uses: schizophrenia and other psychotic disorders, acute mania and bipolar maintenance, bipolar depression (quetiapine, lurasidone, cariprazine), adjunct in major depression (aripiprazole, brexpiprazole, quetiapine), acute agitation, Tourette syndrome, delirium with severe distress (short term), and antiemetic use (prochlorperazine).

Long-acting injectables (LAIs) — haloperidol and fluphenazine decanoate, paliperidone palmitate, aripiprazole, risperidone, and olanzapine pamoate — improve adherence and reduce relapse. Olanzapine pamoate can cause post-injection delirium/sedation syndrome; observe for 3 hours after each injection.

Class boxed warning (dopamine-blocking first- and second-generation antipsychotics): increased mortality in older adults with dementia-related psychosis, mainly from cardiovascular events and infections. Antipsychotics are not approved for this use; nonpharmacologic approaches come first. (Xanomeline-trospium does not carry this boxed warning.)

Suicidality boxed warning: antipsychotics approved for depression — aripiprazole, brexpiprazole, cariprazine, lurasidone, quetiapine — also carry the antidepressant boxed warning for increased suicidal thoughts and behavior in children, adolescents, and young adults under 25. Monitor mood closely early in treatment and after dose changes.

Extrapyramidal and movement effects

Metabolic — weight gain, insulin resistance and type 2 diabetes, dyslipidemia (highest with olanzapine and clozapine, lowest with aripiprazole, ziprasidone, lurasidone).

Other effects

• Anticholinergic: dry mouth, constipation, urinary retention, blurred vision, confusion
• Orthostatic hypotension and reflex tachycardia (alpha-1 blockade); sedation
• QT prolongation (ziprasidone, IV haloperidol, thioridazine) — torsades de pointes
• Hyperprolactinemia (risperidone, paliperidone, first-generation drugs); long-term bone loss
• Lowered seizure threshold; impaired temperature regulation (heat stroke risk)
• Photosensitivity and skin pigmentation (chlorpromazine)
• Leukopenia and neutropenia (class warning; much higher risk with clozapine)
• Neuroleptic malignant syndrome (Section 7)

Clozapine-specific (boxed warnings)

• Severe neutropenia/agranulocytosis
• Orthostatic hypotension, bradycardia, syncope — slow titration; restart at a low dose if 2 or more days are missed
• Seizures (dose-related)
• Myocarditis and cardiomyopathy — mostly in the first 2 months: chest pain, tachycardia, fever, dyspnea
• Increased mortality in older adults with dementia-related psychosis
• Also: severe constipation progressing to ileus, hypersalivation (drooling, especially at night), weight gain and diabetes, early benign fever

Xanomeline-trospium — nausea, vomiting, dyspepsia, constipation, urinary retention, increased heart rate and BP; angioedema reported.

• Comatose or severely CNS-depressed states; known hypersensitivity
• Parkinson disease and Lewy body dementia: avoid haloperidol and other strong D2 blockers (severe rigidity, sensitivity reactions); low-dose quetiapine, clozapine, or pimavanserin are used when needed
• QT prolongation, recent MI, uncompensated heart failure, hypokalemia or hypomagnesemia — caution with QT-prolonging antipsychotics
• Seizure disorder, narrow-angle glaucoma, prostatic hyperplasia (anticholinergic drugs), diabetes (metabolic effects)
• Xanomeline-trospium: contraindicated in urinary retention, moderate or severe liver impairment, gastric retention, and untreated narrow-angle glaucoma
• Clozapine: do not start if baseline ANC is below 1,500/µL (1.5 × 10⁹/L) (below 1,000/µL [1.0 × 10⁹/L] in benign ethnic neutropenia); avoid other drugs that suppress the marrow (e.g., carbamazepine)

Major interactions

• Other QT-prolonging drugs: ondansetron, methadone, fluoroquinolones, macrolides, citalopram, class IA/III antiarrhythmics
• CNS depressants (alcohol, opioids, benzodiazepines) — additive sedation and respiratory depression; IM olanzapine with parenteral benzodiazepine is avoided
• Levodopa and dopamine agonists — opposing effects
• Anticholinergic drugs — additive toxicity
• Smoking induces CYP1A2: stopping smoking raises clozapine and olanzapine levels (toxicity); starting smoking lowers them
• CYP inhibitors (fluvoxamine, ciprofloxacin — raise clozapine) and inducers (carbamazepine, rifampin)

Pregnancy and lactation — use in the third trimester can cause neonatal EPS and withdrawal symptoms (agitation, tremor, feeding difficulty, respiratory distress); relapse risk from stopping is also serious, so the decision is individualized. Lactation varies by drug.

Listed in priority order.

1. Recognize emergencies — NMS, laryngeal dystonia, agranulocytosis (fever, sore throat), myocarditis, torsades, severe constipation or ileus with clozapine.
2. Acute dystonia — give IM/IV benztropine or diphenhydramine as ordered; stay with the client; watch the airway.
3. Clozapine ANC monitoring — weekly for the first 6 months, every 2 weeks for months 6–12, then monthly. Action thresholds (general population, current labeling):
   • 1,000–1,499/µL (1.0–1.49 × 10⁹/L, mild) → continue; ANC three times weekly
   • 500–999/µL (0.5–0.99 × 10⁹/L, moderate) → interrupt clozapine, notify prescriber, hematology consult; resume when ANC is at least 1,000/µL
   • Below 500/µL (below 0.5 × 10⁹/L, severe) → discontinue; hematology consult
   • Benign ethnic neutropenia: 500–999/µL → continue with ANC three times weekly; below 500/µL → discontinue
4. Vital signs — orthostatic BP before doses early in treatment; temperature (fever may signal NMS, agranulocytosis, or myocarditis); pulse.
5. Metabolic monitoring (second-generation drugs) — weight/BMI monthly for 3 months, then quarterly; waist, BP, fasting glucose or A1C, and lipids at baseline, 12 weeks, then yearly. Normal fasting glucose is 99 mg/dL (5.5 mmol/L) or less.
6. Movement screening — AIMS at baseline and at least every 6 months (every 12 months for lower-risk clients); observe for akathisia and parkinsonism.
7. ECG — baseline and follow-up with QT-prolonging drugs or cardiac risk; hold and report QTc above 500 ms; check potassium and magnesium.
8. Clozapine — bowel regimen and bowel-movement tracking; troponin and CRP early in treatment per protocol; ask about smoking changes.
9. Adherence and safety — mouth checks for "cheeking" in acute settings; consider LAIs; fall precautions; heat precautions.

• Take the medicine every day even when feeling well; relapse often follows stopping. Do not stop suddenly.
• Rise slowly from lying or sitting.
• Report fever, stiff muscles, confusion, or sweating at once (NMS).
• Report muscle spasms of the neck, eyes, or tongue, trouble swallowing, restlessness, or repetitive mouth movements.
• Watch diet and exercise; expect regular weight, glucose, and lipid checks; report excessive thirst or urination.
• Avoid overheating and dehydration; use sunscreen and protective clothing (especially chlorpromazine).
• Relieve dry mouth with sugar-free gum or sips of water; eat fiber and drink fluids for constipation.
• Avoid alcohol and do not drive until the drug's effect is known.
• Clozapine: keep every blood test; report fever, sore throat, flu-like symptoms, chest pain, shortness of breath, fast heartbeat, or no bowel movement for more than 2–3 days or abdominal pain; tell the prescriber before starting or stopping smoking.
• Xanomeline-trospium: take at least 1 hour before or 2 hours after a meal; report trouble urinating.
• Discuss pregnancy plans with the prescriber.

Neuroleptic malignant syndrome (NMS) — rare, life-threatening; develops over days, often early in treatment or after dose increases, with high-potency or injectable drugs, and with dehydration.

• High fever, lead-pipe muscle rigidity, altered consciousness, autonomic instability (labile BP, tachycardia, diaphoresis)
• Labs: markedly elevated CK, leukocytosis, myoglobinuria → acute kidney injury
• Treatment: stop the antipsychotic, cooling, IV fluids, ICU support; dantrolene (muscle relaxant) and bromocriptine (dopamine agonist); benzodiazepines. Rechallenge only after at least 2 weeks with a low-potency drug and close monitoring.
• Serotonin syndrome, by contrast, is rapid (within 24 hours) with clonus and hyperreflexia.

Acute overdose — sedation to coma, hypotension, tachycardia, QT prolongation and dysrhythmias, seizures, severe EPS, anticholinergic toxicity. Support airway and BP (fluids; norepinephrine or phenylephrine rather than epinephrine, whose beta effect can worsen hypotension with alpha blockade), cardiac monitoring, magnesium for torsades. There is no specific antidote.

Anticholinergic toxicity — hot, dry, flushed skin, dilated pupils, urinary retention, delirium.

• Boxed warning (dopamine blockers): increased death in older adults with dementia-related psychosis; antipsychotics with depression indications also carry the suicidality-under-25 boxed warning
• First-generation = high EPS; second-generation = metabolic syndrome (worst with olanzapine and clozapine)
• Acute dystonia → IM/IV benztropine or diphenhydramine; laryngospasm is an emergency
• Akathisia = restlessness → propranolol; TD = late, may be permanent → AIMS, valbenazine or deutetrabenazine; anticholinergics do not help
• NMS: slow onset, high fever, lead-pipe rigidity, high CK → stop drug, cool, dantrolene, bromocriptine
• Clozapine: treatment-resistant schizophrenia; REMS eliminated June 13, 2025, but boxed warnings and label ANC monitoring remain; interrupt at ANC 500–999/µL, stop below 500/µL (general population)
• Clozapine also: myocarditis, seizures, constipation/ileus, orthostasis, drooling
• Stopping smoking raises clozapine and olanzapine levels
• QT: ziprasidone, IV haloperidol — hold for QTc above 500 ms
• Risperidone → prolactin rise; aripiprazole → akathisia, impulse control problems
• Metabolic labs at baseline, 12 weeks, then yearly; weight monthly for 3 months