Haloperidol

Indications

• FDA-approved for schizophrenia in adults, including the decanoate depot for patients requiring prolonged parenteral antipsychotic therapy.
• FDA-approved for control of tics and vocal utterances of Tourette syndrome in adults and in children aged 3 years and older.
• FDA-approved for severe behavior problems and short-term treatment of hyperactivity in children aged 3 to 12 years unresponsive to other agents.
• Off-label mainstay for acute undifferentiated agitation, often given IM with lorazepam, and for agitated hyperactive delirium in medically ill adults.
• Off-label use in acute bipolar mania as adjunct to a mood stabilizer, and off-label IV use for refractory nausea or intractable hiccups.
• Off-label first-line for chorea and severe behavioral disturbance in Huntington disease when a VMAT2 inhibitor is unavailable or ineffective.

Mechanism of action

• Potent postsynaptic dopamine D2 receptor antagonist; roughly 65-80 percent striatal D2 occupancy gives antipsychotic effect with acceptable motor burden.
• Occupancy above about 80 percent drives acute dystonia, akathisia, and parkinsonism, so higher doses add extrapyramidal risk without more efficacy.
• Tuberoinfundibular D2 blockade removes dopaminergic brake on prolactin, producing dose-dependent hyperprolactinemia, amenorrhea, and sexual dysfunction.
• Negligible muscarinic and histamine H1 affinity explains the low sedation and dry mouth relative to chlorpromazine, but also the high extrapyramidal rate.
• Weak alpha-1 antagonism means less orthostasis than low-potency phenothiazines; the parent drug and reduced haloperidol both block hERG potassium channels.

Pharmacokinetics

• Oral bioavailability is 60-70 percent with first-pass metabolism; IM lactate peaks in 20-40 minutes and gives essentially complete absorption.
• Elimination half-life is about 18 hours after oral dosing (range 14-37 h) and roughly 21 days for the decanoate, which reaches steady state in 2-3 months.
• Metabolized by CYP3A4 and CYP2D6 plus glucuronidation; reduced haloperidol is an interconverting metabolite with minimal antipsychotic activity.
• Highly protein bound at about 90 percent and extensively distributed, so dialysis does not meaningfully remove the drug during overdose.
• It is a moderate CYP2D6 inhibitor, so plasma concentrations of 2D6 substrates such as venlafaxine or tricyclics can rise during co-administration.

Dosing

• Oral start is 0.5-2 mg two or three times daily for moderate symptoms; severe or chronic illness may begin at 3-5 mg two or three times daily.
• Titrate every 1-3 days by clinical response to a usual target of 5-15 mg/day; doses above 30 mg/day rarely add benefit and sharply raise EPS.
• Acute agitation is typically 2-5 mg IM repeated every 4-8 hours as needed; elderly or delirious patients start at 0.25-0.5 mg per dose.
• Decanoate initial dose is 10-20 times the stabilized oral daily dose, capped at 100 mg for the first injection, then given every 4 weeks.
• No formal renal adjustment; reduce and titrate slowly in hepatic impairment since clearance falls and free drug rises with low albumin.
• Taper oral therapy over weeks rather than stopping abruptly to avoid cholinergic rebound, insomnia, and withdrawal dyskinesia.

Adverse effects

• Extrapyramidal symptoms are the dominant burden: acute dystonia in up to 10 percent, akathisia in 20-40 percent, and parkinsonism in 20-30 percent.
• Tardive dyskinesia accrues at roughly 4-5 percent per year of exposure in nonelderly adults and several times that rate in older patients.
• Neuroleptic malignant syndrome is rare but disproportionately reported with high-potency agents; fever, rigidity, autonomic lability, and high creatine kinase.
• Hyperprolactinemia is common and symptomatic, causing galactorrhea, menstrual disruption, sexual dysfunction, and long-term bone density loss.
• QT prolongation and torsades de pointes occur mainly with intravenous or high cumulative dosing; IV administration is not an FDA-approved route.
• Metabolic effects and weight gain are modest compared with second-generation agents; sedation and orthostasis are relatively mild.

Monitoring

• Baseline and periodic extrapyramidal exam with a formal AIMS every 6 months, or every 3 months in patients at high tardive dyskinesia risk.
• ECG at baseline and after dose increases when cardiac disease, electrolyte disturbance, other QT drugs, or parenteral dosing is involved.
• Check potassium and magnesium before parenteral or high-dose therapy and correct deficits, since hypokalemia amplifies torsades risk.
• Prolactin only if symptomatic; obtain CBC in the first months when baseline neutrophil count is low or there is a history of drug-induced leukopenia.
• Weight, blood pressure, glucose, and lipids at baseline and annually, plus creatine kinase whenever rigidity or unexplained fever appears.

Interactions

• Strong CYP3A4 inducers such as carbamazepine, rifampin, and phenytoin can halve haloperidol levels and precipitate loss of symptom control.
• CYP2D6 inhibitors including fluoxetine, paroxetine, and bupropion raise concentrations and extrapyramidal risk, warranting a lower dose.
• Additive QT risk with methadone, ondansetron, fluoroquinolones, azole antifungals, and class III antiarrhythmics; avoid or monitor with ECG.
• Rare encephalopathic syndrome with confusion and cerebellar signs has been reported when haloperidol is combined with lithium at high levels.
• Contraindicated in severe CNS depression, comatose states, Parkinson disease, dementia with Lewy bodies, and known haloperidol hypersensitivity.

Special populations

• In pregnancy it is among the better-characterized antipsychotics; third-trimester exposure carries a class risk of neonatal EPS and withdrawal signs.
• Excreted into breast milk in low relative infant dose; breastfeeding is usually acceptable with monitoring for infant sedation and motor signs.
• Pediatric use is labeled from age 3; dose by weight starting at 0.5 mg/day and titrate in 0.5 mg increments given the high dystonia risk.
• In older adults use one-quarter to one-half the adult dose; dementia-related psychosis carries the boxed mortality warning and no approval.
• Renal impairment needs no adjustment, but hepatic impairment or hypoalbuminemia raises free drug and warrants slower, lower dosing.

Clinical pearls

• IM lorazepam 1-2 mg with haloperidol cuts total antipsychotic dose and blunts akathisia and dystonia.
• Keep IM benztropine or diphenhydramine at hand; acute dystonia peaks in the first 24-72 hours.
• Decanoate takes 2-3 months to reach steady state, so overlap oral therapy rather than chasing doses.