Haloperidol (Haldol)
FGA • Last reviewed 2025-09-23
General information
Haloperidol (brand name Haldol) is a high-potency first-generation (typical) antipsychotic approved for the treatment of schizophrenia, acute psychosis, and Tourette syndrome with severe tics. Parenteral formulations are indicated for the rapid control of severe agitation in psychotic disorders. The oral solution and tablets were originally approved in 1967; generic products are widely available. A long-acting decanoate formulation (intramuscular every 4 weeks) is marketed separately and is frequently used for maintenance therapy in patients with adherence challenges.
Oral dosage forms include tablets (0.5, 1, 2, 5, 10, 20 mg) and an oral concentrate (2 mg/mL). Haloperidol lactate injection (5 mg/mL) is available for short-acting intramuscular or intravenous use, while haloperidol decanoate (50 mg/mL, 100 mg/mL) provides long-acting intramuscular dosing. Recommended oral starting doses for schizophrenia or acute psychosis are 0.5–5 mg two or three times daily, titrated every 1–7 days based on response and tolerability; typical maintenance ranges 5–20 mg/day in divided or single doses. In the elderly or debilitated, start 0.25–0.5 mg BID/TID and titrate cautiously. Acute agitation may be managed with 2–5 mg IM every 4–8 hours (maximum 20 mg/day). No therapeutic drug monitoring range is routinely used, though some centers reference trough levels of 5–15 ng/mL for efficacy-safety balance.
Haloperidol exerts potent antagonism at dopamine D2 receptors in mesolimbic and nigrostriatal pathways, accounting for antipsychotic efficacy but also conferring substantial risk of extrapyramidal symptoms (EPS) and hyperprolactinemia. It shows lower affinity for D1, 5-HT2, α1-adrenergic, and H1-histaminic receptors, which explains minimal anticholinergic and sedating properties relative to low-potency FGAs. Inhibition of D2 signaling in the chemoreceptor trigger zone also underlies its antiemetic effects.
Haloperidol is well absorbed orally with bioavailability ~60–70%, reaching peak concentrations in 2–6 hours. It is highly protein bound (~92%) and widely distributed (volume of distribution 18–21 L/kg). Hepatic metabolism occurs via CYP3A4 and CYP2D6 with contributions from carbonyl reductase to reduced haloperidol. The terminal half-life is 14–37 hours after oral dosing and ~21 hours after IM lactate; haloperidol decanoate exhibits an apparent half-life of 3 weeks. About 30% of a dose is excreted in urine (1% unchanged), with the remainder in feces. Genetic CYP2D6 variability and interacting medications significantly influence plasma levels.
Dosing & administration
Schizophrenia/psychosis (oral): initiate 0.5–5 mg BID/TID; titrate by 0.5–2 mg increments daily to weekly. Maintenance 5–20 mg/day, occasionally up to 30 mg/day in resistant cases.
Elderly or debilitated: start 0.25–0.5 mg BID/TID; increase cautiously to minimize EPS, orthostasis, and sedation.
Acute agitation (IM lactate): 2–5 mg IM every 4–8 hours; maximum 20 mg/day. Intravenous administration is off-label and requires ECG monitoring.
Tourette syndrome: begin 0.5 mg/day divided BID; titrate by 0.5 mg increments every 5–7 days to 3–5 mg/day (children) or 10 mg/day (adults) depending on response.
Transition to haloperidol decanoate: administer 10–20 times the previous daily oral dose as a monthly IM injection; continue oral supplementation for 1–2 weeks during conversion.
Dose reductions are required with strong CYP3A4 or CYP2D6 inhibitors (e.g., ketoconazole, paroxetine). Avoid high cumulative doses in hepatic impairment; haloperidol is not dialyzable and should be used cautiously in severe renal impairment.
Typical dosing targets
- Schizophrenia (adults)
- Start 0.5–5 mg BID/TID; maintenance 5–20 mg/day (max 30 mg/day).
- Elderly/debilitated
- Start 0.25–0.5 mg BID/TID; titrate slowly acknowledging increased sensitivity.
- Acute agitation (IM)
- 2–5 mg IM q4–8h (max 20 mg/day); monitor QT and vitals.
- Tourette syndrome
- 0.5 mg/day titrated to 3–10 mg/day depending on age and response.
- Decanoate conversion
- Monthly dose = 10–20 × daily oral dose (e.g., 10 mg/day oral → 100–200 mg IM monthly).
Mechanism of action
Haloperidol’s antipsychotic effect is mediated through high-affinity antagonism of dopamine D2 receptors, reducing mesolimbic hyperactivity associated with positive symptoms. High potency at D2 receptors also results in strong EPS liability and prolactin elevation.
Additional antagonism at D1, 5-HT2, α1-adrenergic, and H1 receptors is weaker but contributes to orthostatic hypotension and modest sedation. Minimal M1 muscarinic activity explains the low anticholinergic burden compared with low-potency FGAs.
Reduced haloperidol, a metabolite formed via carbonyl reduction, retains some D2 antagonism but has lower potency; interconversion is reversible and influenced by pH and oxidative stress.
- High potency D2 receptor antagonism (Ki ~1 nM).
- Moderate antagonism at 5-HT2A and α1 receptors (orthostatic hypotension).
- Low H1 and negligible muscarinic activity (limited sedation/anticholinergic effects).
Metabolism & pharmacokinetics
Haloperidol is extensively distributed (Vd 18–21 L/kg) and highly protein bound (92%). Bioavailability is ~60–70%, with peak plasma levels achieved in 2–6 hours after oral dosing. Food does not significantly affect absorption.
Metabolism occurs primarily via CYP3A4 and CYP2D6, producing inactive metabolites; carbonyl reductase forms reduced haloperidol. Genetic CYP2D6 polymorphisms and inhibitors can elevate plasma concentrations and adverse effect risk.
Elimination half-life averages 14–37 hours orally, ~21 hours IM lactate, and ~3 weeks for the decanoate depot. Renal excretion of unchanged drug is minimal; fecal elimination predominates.
- Time to peak concentration (Tmax)
- 2–6 hours (oral)
- Oral bioavailability
- ~60–70%
- Elimination half-life
- 14–37 h (oral); ~21 h (IM lactate); ~3 weeks (decanoate)
- Protein binding
- ~92%
Drug interactions
Strong CYP3A4 or CYP2D6 inhibitors (ketoconazole, fluoxetine, paroxetine, quinidine) increase haloperidol levels and risk of QT prolongation/EPS; dose reductions and ECG monitoring are recommended.
CYP3A4 inducers (carbamazepine, rifampin, phenobarbital) lower haloperidol concentrations; avoid or adjust doses with careful clinical and ECG monitoring.
Concomitant QT-prolonging drugs (e.g., antiarrhythmics, macrolides, methadone) increase torsades risk—obtain baseline/follow-up ECGs.
Additive CNS depressant effects occur with alcohol, benzodiazepines, or opioids. Haloperidol antagonizes levodopa and dopamine agonists, potentially worsening Parkinsonian symptoms.
| Mechanism | Agents / factors | Management |
|---|---|---|
| Strong CYP3A4/CYP2D6 inhibition | Ketoconazole, itraconazole, fluoxetine, paroxetine, ritonavir | Reduce dose; monitor for EPS/QTc prolongation. |
| CYP3A4 induction | Carbamazepine, rifampin, phenobarbital, St. John’s wort | Avoid or increase dose cautiously with serum level/clinical monitoring. |
| QT prolongation | Class IA/III antiarrhythmics, macrolides, methadone | Baseline and periodic ECGs; avoid combination if possible. |
| Dopaminergic antagonism | Levodopa, dopamine agonists | Avoid or monitor for loss of antiparkinsonian effect. |
| CNS depression | Alcohol, benzodiazepines, opioids | Counsel regarding sedation; monitor vitals. |
Monitoring & safety checks
Extrapyramidal symptoms (EPS) assessment
Each visit during titration and periodically thereafter • High potency D2 blockade confers significant EPS risk.
Prolactin-related symptoms
Baseline discussion and ongoing • Haloperidol elevates prolactin → galactorrhea, gynecomastia, menstrual irregularities.
Baseline and periodically in patients with cardiac risk factors or when using interacting drugs • Risk of QT prolongation and torsades de pointes.
Metabolic panel (weight, lipids, glucose)
Baseline, 3 months, then annually • Metabolic effects less pronounced than SGAs but still warrant surveillance.
CBC if clinically indicated
As needed • Rare blood dyscrasias; monitor if patient develops signs of infection.
Consider prophylactic anticholinergic agents (e.g., benztropine) in high-risk EPS patients, but balance against anticholinergic burden.
Educate patients on recognizing early signs of tardive dyskinesia and to seek evaluation promptly.
Discontinuation guidance
Taper gradually over weeks when feasible to avoid withdrawal dyskinesia, cholinergic rebound, or sudden relapse. Monitor closely for emergent psychotic symptoms during dose reductions.
When switching to another antipsychotic, cross-titration is commonly used; overlapping D2 blockade necessitates monitoring for additive EPS.
Special populations
Hepatic impairment: use lower initial doses and slow titration; haloperidol undergoes extensive hepatic metabolism.
Renal impairment: unchanged haloperidol is minimally excreted renally, but metabolites accumulate; monitor closely in severe impairment.
Geriatric patients: heightened sensitivity to orthostatic hypotension, EPS, and QT prolongation; use low doses with slow titration.
Pregnancy/Lactation: limited controlled data; consider risk-benefit. Neonates exposed in third trimester should be monitored for EPS or withdrawal.
Key adverse effects
Very common: akathisia, Parkinsonism, acute dystonia, sedation, insomnia, anxiety.
Serious: tardive dyskinesia (risk increases with duration/cumulative dose), neuroleptic malignant syndrome, QT prolongation/torsades, sudden death, blood dyscrasias, seizures (dose related).
Endocrine/metabolic: hyperprolactinemia leading to galactorrhea, gynecomastia, menstrual changes; weight gain modest compared with SGAs.
LAI availability
Clozapine does not have an FDA-approved long-acting injectable formulation. Related LAI options for the treatment class are listed below.
References
- HALDOL decanoate prescribing information — DailyMed (2025)
- Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017 — Pharmacopsychiatry (2018) DOI: 10.1007/s00213-017-4813-7
- Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a network meta-analysis — The Lancet (2017) DOI: 10.1016/S0140-6736(17)32455-2
- Efficacy and safety of haloperidol in Tourette syndrome — Child and Adolescent Psychiatric Clinics of North America (2008) DOI: 10.1111/j.1529-1006.2008.00045.x
- Pharmacokinetics of haloperidol: a review — Drug Metabolism Reviews (2012) DOI: 10.3109/01480545.2011.598446
Educational use only — verify details in current prescribing information and authoritative clinical guidelines before making prescribing decisions.