Haloperidol

Typical antipsychotic, Antiemetic

Haloperidol

Haldol, Serenace, Haldol Decanoate

Haloperidol is a butyrophenone-class first-generation ("typical") antipsychotic. Its defining feature is high-affinity, relatively selective D₂ receptor antagonism with minimal anticholinergic activity, making it one of the more behaviorally selective typicals. Despite the broader shift toward atypicals for chronic psychiatric care, haloperidol remains widely used for acute agitation, ICU and postoperative delirium, palliative care nausea, and as a long-acting depot formulation (haloperidol decanoate) for maintenance treatment of schizophrenia.

Experience

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Problems

• Schizophrenia, acute and maintenance (including decanoate for long-acting injectable maintenance)
• Acute psychosis from any cause
• Severe acute agitation, especially hyperactive delirium
• ICU and postoperative delirium (per common protocols, though evidence is contested)
• Tourette syndrome and severe tic disorders (FDA-approved)
• Off-label: refractory nausea/vomiting (palliative care, chemotherapy-associated), hiccups, hyperemesis gravidarum

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Titration strategies

Acute psychosis, oral: 0.5–5 mg PO 2–3 times daily; titrate to 5–20 mg/day total. Max 30 mg/day in severe cases. Acute agitation, IM: 2–10 mg IM, may repeat every 30–60 min as needed. Lower in elderly (0.5–2 mg). Delirium, IV (off-label but common): 0.5–5 mg IV, baseline ECG required. Lower in elderly. Maintenance, decanoate IM: 50–300 mg every 3–4 weeks. Conversion: roughly 10–20× the daily oral dose monthly. Elderly / frail / dementia: start very low (0.25–0.5 mg) and titrate slowly; mortality risk in dementia-related psychosis (FDA black box).

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Effects

Therapeutic: reduction of positive psychotic symptoms (hallucinations, delusions, thought disorder), calming, reduced agitation, antiemesis. Common adverse: extrapyramidal symptoms (acute dystonia, akathisia, parkinsonism), mild sedation, dry mouth, mild orthostatic hypotension, hyperprolactinemia.

• Extrapyramidal symptoms (EPS), the dominant adverse effect profile:
  • Acute dystonia (hours–days), especially young males; treat with IM benztropine or diphenhydramine
  • Akathisia (days–weeks); reduce dose, add propranolol or benzodiazepine
  • Parkinsonism (weeks); reduce dose, add anticholinergic
  • Tardive dyskinesia (months–years); reduce/discontinue, switch to atypical, VMAT2 inhibitor (valbenazine, deutetrabenazine)
• Neuroleptic malignant syndrome, rare but life-threatening: hyperthermia, rigidity, autonomic instability, altered mental status, elevated CK. Stop med, supportive care, ± dantrolene/bromocriptine.
• QT prolongation, significant; baseline ECG and electrolyte monitoring especially with IV or high doses
• Hyperprolactinemia, galactorrhea, gynecomastia, sexual dysfunction, amenorrhea
• Sedation, less than chlorpromazine, more than aripiprazole
• Orthostatic hypotension, α₁ blockade; less than low-potency typicals
• Anticholinergic effects, much milder than chlorpromazine
• Lowered seizure threshold, caution in epilepsy
• Black box warning: increased mortality in elderly patients with dementia-related psychosis

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Pharmacokinetics

Oral bioavailability ~60–70% (substantial first-pass); IM and IV essentially 100%. Highly protein-bound (~92%). Metabolized hepatically by CYP3A4 and CYP2D6 to multiple metabolites, including reduced haloperidol (slightly active and back-converts to parent). Half-life 14–26 hours orally; haloperidol decanoate has a terminal half-life of ~3 weeks, allowing every-3–4-week IM dosing for maintenance.

Pharmacodynamics

Potent D₂ antagonist with high D₂:5-HT_2A affinity ratio, the pharmacologic profile that defines a "typical" antipsychotic and underlies its extrapyramidal side effect liability. Modest α₁-adrenergic and H₁ antagonism (less than chlorpromazine). Minimal muscarinic activity, a key advantage over low-potency typicals, but also why EPS is more prominent (no built-in anticholinergic compensation). Antiemetic effect via D₂ blockade at the chemoreceptor trigger zone.

Interactions

• QT-prolonging agents, azoles, fluoroquinolones, methadone, ondansetron, citalopram, certain antiarrhythmics, additive risk of torsades
• CYP3A4 inhibitors (ketoconazole, ritonavir, clarithromycin), elevated haloperidol levels
• CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion), elevated levels
• CYP3A4 inducers (carbamazepine, rifampin, phenytoin), reduced levels and possible loss of efficacy
• CNS depressants (benzodiazepines, opioids, alcohol), additive sedation and respiratory depression
• Lithium, rare reports of neurotoxicity with combination
• Anticholinergics, may reduce EPS but worsen delirium/cognition
• Levodopa / dopamine agonists, mutual antagonism

Pharmacogenomic + mechanism interactions2 edges

Pharmacogenomic guideline recommendationsCPIC and Dutch Pharmacogenetics Working Group clinical guidelines

Phenotype:CYP2D6 ultrarapid metabolizer prefer alternative DPWG 60 / 100Rate

DPWG guideline: The recommendation for CYP2D6 poor metabolizers is to use 60% of the normal dose of haloperidol and for CYP2D6 ultrarapid metabolizers to use 1.5 times the normal dose or to choose an alternative to haloperidol.

Phenotype:CYP2D6 poor metabolizer prefer alternative DPWG 60 / 100Rate

DPWG guideline: The recommendation for CYP2D6 poor metabolizers is to use 60% of the normal dose of haloperidol and for CYP2D6 ultrarapid metabolizers to use 1.5 times the normal dose or to choose an alternative to haloperidol.

Patient experience

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Pregnancy and lactation

Category C. Has a long clinical track record in pregnancy and is generally considered one of the better-studied antipsychotics for use during pregnancy when treatment is necessary. Third-trimester exposure is associated with neonatal EPS and withdrawal symptoms. Occasionally used for severe hyperemesis gravidarum. Excreted in breast milk; breastfeeding generally permitted with caution.

Monitoring

• Baseline ECG, and after dose changes, especially IV or high oral doses
• Electrolytes (K⁺, Mg²⁺), for QT risk
• AIMS / EPS screening, at baseline, periodically thereafter (every 6 months for chronic use)
• Prolactin, if symptoms suggest hyperprolactinemia
• Glucose and lipids, less metabolic concern than with atypicals, but check periodically
• LFTs, at baseline and if symptoms develop
• Vital signs, orthostatic BP at initiation

  Patient counseling

• Take at the same time each day; capsule/tablet can be taken with or without food.
• Report muscle stiffness, tremor, restlessness, or abnormal involuntary movements promptly.
• Watch for fever + rigidity + confusion, could indicate neuroleptic malignant syndrome (medical emergency).
• Avoid alcohol and other sedatives.
• Use caution with driving until response to the medicine is known.
• Hard candy or sips of water for dry mouth.
• Rise slowly from sitting/lying to minimize dizziness.
• Don't stop abruptly, taper if discontinuing.
• Stay hydrated and avoid overheating; haloperidol impairs thermoregulation.

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Relevant Literature

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See also

Chlorpromazine, Fluphenazine, Perphenazine, Trifluoperazine, Risperidone, Olanzapine, Quetiapine, Aripiprazole

Summary

Classes

Typical antipsychotic, Antiemetic

Common uses

Schizophrenia, acute psychosis, agitation, delirium, Tourette syndrome, severe nausea

Pharmacy

Pharmacology

Routes

Oral, IM, IV

Onset

PO 1–2 h; IM 30–60 min; IV 5–20 min

Duration

12–24 h (oral); decanoate IM 3–4 weeks

Half-life

14–26 h (oral); ~3 weeks (decanoate)

Bioavailability

~60–70% (oral)

Pregnancy

Category C

Legal status

Rx-only

Purported mechanism

High-affinity D2 receptor antagonist