Haloperidol

Haloperidol is used in the control of the symptoms of:

• Acute psychosis, such as drug-induced psychosis caused by ketamine,{{cite journal | vauthors = Giannini AJ, Underwood NA, Condon M | title = Acute ketamine intoxication treated by haloperidol: a preliminary study | journal = American Journal of Therapeutics | volume = 7 | issue = 6 | pages = 389–391 | date = November 2000 | pmid = 11304647 | doi = 10.1097/00045391-200007060-00008 }}{{Unreliable medical source|reason=Primary study|date=November 2024}} and phencyclidine,{{cite journal | vauthors = Giannini AJ, Eighan MS, Loiselle RH, Giannini MC | title = Comparison of haloperidol and chlorpromazine in the treatment of phencyclidine psychosis | journal = Journal of Clinical Pharmacology | volume = 24 | issue = 4 | pages = 202–204 | date = April 1984 | pmid = 6725621 | doi = 10.1002/j.1552-4604.1984.tb01831.x | s2cid = 42278510 }} and psychosis associated with high fever or metabolic disease. Some evidence has found haloperidol to worsen psychosis due to psilocybin.{{cite journal | vauthors = Johnson M, Richards W, Griffiths R | title = Human hallucinogen research: guidelines for safety | journal = Journal of Psychopharmacology | volume = 22 | issue = 6 | pages = 603–620 | date = August 2008 | pmid = 18593734 | pmc = 3056407 | doi = 10.1177/0269881108093587 | publisher = SAGE Publications }}
• Adjunctive treatment of alcohol and opioid withdrawal
• Agitation and confusion associated with cerebral sclerosis
• Alcohol-induced psychosis
• Hallucinations in alcohol withdrawal
• Hyperactive delirium (to control the agitation component of delirium)
• Hyperactivity, aggression
• Otherwise uncontrollable, severe behavioral disorders in children and adolescents
• Schizophrenia
• Therapeutic trial in personality disorders, such as borderline personality disorder
• Treatment of intractable hiccups{{cite book |isbn = 978-0-85711-084-8 |title = British National Formulary (BNF) | author = Joint Formulary Committee |year = 2013 |publisher = Pharmaceutical Press |location = London, England |edition = 65th |pages = [https://archive.org/details/bnf65britishnati0000unse/page/229 229–30] |url = https://archive.org/details/bnf65britishnati0000unse/page/229 }}
• Treatment of neurological disorders, including tic disorders such as Tourette syndrome, and chorea
• Treatment of severe nausea and emesis in postoperative and palliative care, especially for palliating adverse effects of radiation therapy and chemotherapy in oncology. Also used as a first line antiemetic for acute cannabinoid hyperemesis syndrome.
• As chemical restraint in acute care psychiatry, mainly for violent and self-harming patients (controversial use but very commonly found in movies).

Haloperidol was considered indispensable for treating psychiatric emergency situations.{{cite journal | vauthors = Currier GW | title = The controversy over "chemical restraint" in acute care psychiatry | journal = Journal of Psychiatric Practice | volume = 9 | issue = 1 | pages = 59–70 | date = January 2003 | pmid = 15985915 | doi = 10.1097/00131746-200301000-00006 | publisher = Lippincott Williams & Wilkins | s2cid = 22342074 }}{{cite journal |vauthors=Cavanaugh SV |date=September 1986 |title=Psychiatric emergencies |journal=The Medical Clinics of North America |volume=70 |issue=5 |pages=1185–1202 |doi=10.1016/S0025-7125(16)30919-1 |pmid=3736271}} However, the newer atypical drugs have gained a greater role in a number of situations, as outlined in a series of consensus reviews published between 2001 and 2005.{{cite journal | vauthors = Allen MH, Currier GW, Hughes DH, Reyes-Harde M, Docherty JP | title = The Expert Consensus Guideline Series. Treatment of behavioral emergencies | journal = Postgraduate Medicine | issue = Spec No | pages = 1–88; quiz 89–90 | date = May 2001 | pmid = 11500996 }}{{cite journal | vauthors = Allen MH, Currier GW, Hughes DH, Docherty JP, Carpenter D, Ross R | title = Treatment of behavioral emergencies: a summary of the expert consensus guidelines | journal = Journal of Psychiatric Practice | volume = 9 | issue = 1 | pages = 16–38 | date = January 2003 | pmid = 15985913 | doi = 10.1097/00131746-200301000-00004 | s2cid = 29363701 }}{{cite journal | vauthors = Allen MH, Currier GW, Carpenter D, Ross RW, Docherty JP | title = The expert consensus guideline series. Treatment of behavioral emergencies 2005 | journal = Journal of Psychiatric Practice | volume = 11 | issue = Suppl 1 | pages = 5–25 | date = November 2005 | pmid = 16319571 | doi = 10.1097/00131746-200511001-00002 | s2cid = 72366588 }}

In a 2013 comparison of 15 antipsychotics in schizophrenia, haloperidol demonstrated standard effectiveness. It was 13–16% more effective than ziprasidone, chlorpromazine, and asenapine, approximately as effective as quetiapine and aripiprazole, and 10% less effective than paliperidone.{{cite journal | vauthors = Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, Samara M, Barbui C, Engel RR, Geddes JR, Kissling W, Stapf MP, Lässig B, Salanti G, Davis JM | title = Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis | journal = Lancet | volume = 382 | issue = 9896 | pages = 951–962 | date = September 2013 | pmid = 23810019 | doi = 10.1016/S0140-6736(13)60733-3 | s2cid = 32085212 }} A 2013 systematic review compared haloperidol to placebo in schizophrenia:{{cite journal | vauthors = Adams CE, Bergman H, Irving CB, Lawrie S | title = Haloperidol versus placebo for schizophrenia | journal = The Cochrane Database of Systematic Reviews | volume = 2013 | issue = 11 | pages = CD003082 | date = November 2013 | pmid = 24242360 | doi = 10.1002/14651858.CD003082.pub3 | url = http://www.cochrane.org/CD003082/SCHIZ_haloperidol-versus-placebo-for-schizophrenia | url-status = live | doi-access = free | pmc = 11558230 | archive-url = https://web.archive.org/web/20170820120020/http://www.cochrane.org/CD003082/SCHIZ_haloperidol-versus-placebo-for-schizophrenia | archive-date = 20 August 2017 }}

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In contrast to certain other antipsychotics like risperidone, haloperidol is ineffective as a hallucinogen antidote or "trip killer" in blocking the effects of serotonergic psychedelics like psilocybin and lysergic acid diethylamide (LSD).{{cite journal | vauthors = Halman A, Kong G, Sarris J, Perkins D | title = Drug-drug interactions involving classic psychedelics: A systematic review | journal = J Psychopharmacol | volume = 38 | issue = 1 | pages = 3–18 | date = January 2024 | pmid = 37982394 | pmc = 10851641 | doi = 10.1177/02698811231211219 | url = }}{{cite journal | vauthors = Halberstadt AL | title = Recent advances in the neuropsychopharmacology of serotonergic hallucinogens | journal = Behav Brain Res | volume = 277 | issue = | pages = 99–120 | date = January 2015 | pmid = 25036425 | pmc = 4642895 | doi = 10.1016/j.bbr.2014.07.016 | url = }}{{cite journal | vauthors = Vollenweider FX, Vollenweider-Scherpenhuyzen MF, Bäbler A, Vogel H, Hell D | title = Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action | journal = NeuroReport | volume = 9 | issue = 17 | pages = 3897–3902 | date = December 1998 | pmid = 9875725 | doi = 10.1097/00001756-199812010-00024 | url = }}

Data from animal experiments indicate haloperidol is not teratogenic, but is embryotoxic in high doses. In humans, no controlled studies exist. Reports in pregnant women revealed possible damage to the fetus, although most of the women were exposed to multiple drugs during pregnancy. In addition, reports indicate neonates exposed to antipsychotic drugs are at risk for extrapyramidal and/or withdrawal symptoms following delivery, such as agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder. Following accepted general principles, haloperidol should be given during pregnancy only if the benefit to the mother clearly outweighs the potential fetal risk.{{cite web |url = https://www.drugs.com/pro/haldol.html |title = Haldol Official FDA information, side effects and uses |publisher = Drugs.com |access-date = 3 October 2013 |url-status = live |archive-url = https://web.archive.org/web/20131005001049/http://www.drugs.com/pro/haldol.html |archive-date = 5 October 2013 }}

Haloperidol is excreted in breast milk. A few studies have examined the impact of haloperidol exposure on breastfed infants and in most cases, there were no adverse effects on infant growth and development.{{Cite web|url=http://toxnet.nlm.nih.gov/cgi-bin/sis/search2/r?dbs+lactmed:@term+@DOCNO+132|title=LACTMED: Haloperidol|date=31 October 2018|access-date=18 January 2019}}

File:Haloperidol decanoate highlighting ester group.svg of haloperidol decanoate. The decanoate group is highlighted in {{color|red|red}}.]]

During long-term treatment of chronic psychiatric disorders, the daily dose should be reduced to the lowest level needed for maintenance of remission. Sometimes, it may be indicated to terminate haloperidol treatment gradually.{{citation needed|date=April 2022}} In addition, during long-term use, routine monitoring including measurement of BMI, blood pressure, fasting blood sugar, and lipids, is recommended due to the risk of side effects.

Other forms of therapy (psychotherapy, occupational therapy/ergotherapy, or social rehabilitation) should be instituted properly.{{Citation needed|date=April 2013}}

PET imaging studies have suggested low doses are preferable. Clinical response was associated with at least 65% occupancy of D2 receptors, while greater than 72% was likely to cause hyperprolactinaemia and over 78% associated with extrapyramidal side effects. Doses of haloperidol greater than 5 mg increased the risk of side effects without improving efficacy.{{cite journal | vauthors = Oosthuizen P, Emsley RA, Turner J, Keyter N | title = Determining the optimal dose of haloperidol in first-episode psychosis | journal = Journal of Psychopharmacology | volume = 15 | issue = 4 | pages = 251–255 | date = December 2001 | pmid = 11769818 | doi = 10.1177/026988110101500403 | s2cid = 40788955 }} Patients responded with doses under even 2 mg in first-episode psychosis.{{cite journal | vauthors = Tauscher J, Kapur S | title = Choosing the right dose of antipsychotics in schizophrenia: lessons from neuroimaging studies | journal = CNS Drugs | volume = 15 | issue = 9 | pages = 671–678 | year = 2001 | pmid = 11580306 | doi = 10.2165/00023210-200115090-00001 | s2cid = 30091494 }} For maintenance treatment of schizophrenia, an international consensus conference recommended a reduction dosage by about 20% every 6 months until a minimal maintenance dose is established.{{cite web | author = Work Group on Schizophrenia |title = Practice Guideline for the Treatment of Patients With Schizophrenia | edition = Second |url = http://psychiatryonline.org/content.aspx?bookID=28§ionID=1665359#45892 |archive-url = https://web.archive.org/web/20120327230029/http://psychiatryonline.org/content.aspx?bookid=28§ionid=1665359#45892 |url-status = dead |archive-date = 27 March 2012 |access-date = 21 April 2014 }}

• Depot forms are also available; these are injected deeply intramuscularly at regular intervals. The depot forms are not suitable for initial treatment, but are suitable for patients who have demonstrated inconsistency with oral dosages.{{Citation needed|date=April 2013}}

The decanoate ester of haloperidol (haloperidol decanoate, trade names Haldol decanoate, Halomonth, Neoperidole) has a much longer duration of action, so is often used in people known to be noncompliant with oral medication. A dose is given by intramuscular injection once every two to four weeks.Goodman and Gilman's Pharmacological Basis of Therapeutics, 10th edition (McGraw-Hill, 2001).{{page needed|date=September 2012}} The IUPAC name of haloperidol decanoate is [4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl] decanoate.

Topical formulations of haloperidol should not be used as treatment for nausea because research does not indicate this therapy is more effective than alternatives.{{Cite journal |author1 = American Academy of Hospice and Palliative Medicine |author1-link = American Academy of Hospice and Palliative Medicine |title = Five Things Physicians and Patients Should Question |publisher = American Academy of Hospice and Palliative Medicine |journal = Choosing Wisely: An Initiative of the ABIM Foundation |url = http://www.choosingwisely.org/doctor-patient-lists/american-academy-of-hospice-palliative-medicine/ |access-date = 1 August 2013 |url-status = live |archive-url = https://web.archive.org/web/20130901101934/http://www.choosingwisely.org/doctor-patient-lists/american-academy-of-hospice-palliative-medicine/ |archive-date = 1 September 2013 }}, which cites

• {{cite journal | vauthors = Smith TJ, Ritter JK, Poklis JL, Fletcher D, Coyne PJ, Dodson P, Parker G | title = ABH gel is not absorbed from the skin of normal volunteers | journal = Journal of Pain and Symptom Management | volume = 43 | issue = 5 | pages = 961–966 | date = May 2012 | pmid = 22560361 | doi = 10.1016/j.jpainsymman.2011.05.017 | doi-access = free }}
• {{cite journal | vauthors = Weschules DJ | title = Tolerability of the compound ABHR in hospice patients | journal = Journal of Palliative Medicine | volume = 8 | issue = 6 | pages = 1135–1143 | date = December 2005 | pmid = 16351526 | doi = 10.1089/jpm.2005.8.1135 }}

Sources for the following lists of adverse effects:Product Information [Internet]. 2011 [cited 2013 Sep 29]. Available from: {{cite web |url = https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2011-PI-03532-3 |title = TGA eBS - Product and Consumer Medicine Information Licence |access-date = 29 May 2014 |url-status = live |archive-url = https://web.archive.org/web/20170314204106/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2011-PI-03532-3 |archive-date = 14 March 2017 }}HALDOL® Injection For Intramuscular Injection Only Product Information [Internet]. Janssen; 2011 [cited 2013 Sep 29]. Available from: {{cite web |url = https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2009-PI-00998-3 |title = TGA eBS - Product and Consumer Medicine Information Licence |access-date = 29 September 2013 |url-status = live |archive-url = https://web.archive.org/web/20170314204054/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2009-PI-00998-3 |archive-date = 14 March 2017 }}Truven Health Analytics, Inc. DrugPoint® System (Internet) [cited 2013 Sep 29]. Greenwood Village, CO: Thomsen Healthcare; 2013.Joint Formulary Committee. British National Formulary (BNF) 65. Pharmaceutical Pr; 2013.

As haloperidol is a high-potency typical antipsychotic, it tends to produce significant extrapyramidal side effects. According to a 2013 meta-analysis of the comparative efficacy and tolerability of 15 antipsychotic drugs it was the most prone of the 15 for causing extrapyramidal side effects.

With more than 6 months of use 14 percent of users gain weight.{{cite web | author = FDA Psychopharmacological Drugs Advisory Committee | date = 9 July 2000 |url = https://www.fda.gov/ohrms/dockets/ac/00/backgrd/3619b1a.pdf |title = Briefing Document for ZELDOX CAPSULES (Ziprasidone HCl) |website = Food and Drug Administration |access-date = 30 September 2016 |url-status = dead |archive-url = https://web.archive.org/web/20170119063641/https://www.fda.gov/ohrms/dockets/ac/00/backgrd/3619b1a.pdf |archive-date = 19 January 2017 }} Haloperidol may be neurotoxic.{{cite journal | vauthors = Nasrallah HA, Chen AT | title = Multiple neurotoxic effects of haloperidol resulting in neuronal death | journal = Annals of Clinical Psychiatry | volume = 29 | issue = 3 | pages = 195–202 | date = August 2017 | pmid = 28738100 }}

Prolonged use of the drug can lead to mental dependence.{{Cite web|url=https://consensus.app/questions/haloperidol-withdrawal-symptoms/|title=Haloperidol Withdrawal Symptoms: An Overview}}

Common (>1% incidence)

• Extrapyramidal side effects including:
• Akathisia (motor restlessness)
• Dystonia (continuous spasms and muscle contractions)
• Muscle rigidity
• Parkinsonism (characteristic symptoms such as rigidity)
• Hypotension
• Anticholinergic side effects such as: (These adverse effects are less common than with lower-potency typical antipsychotics, such as chlorpromazine and thioridazine.)
• Blurred vision
• Constipation
• Dry mouth
• Somnolence (which is not a particularly prominent side effect, as is supported by the results of the aforementioned meta-analysis.)

Unknown frequency

• Anemia
• Headache
• Increased respiratory rate
• Orthostatic hypotension
• Prolonged QT interval
• Visual disturbances

Rare (<1% incidence)

{{div col|colwidth=18em}}

• Acute hepatic failure
• Agitation
• Agranulocytosis
• Anaphylactic reaction
• Anorexia
• Bronchospasm
• Cataracts
• Cholestasis
• Confusional state
• Depression
• Dermatitis exfoliative
• Dyspnea
• Edema
• Extrasystoles
• Face edema
• Gynecomastia
• Hepatitis
• Hyperglycemia
• Hypersensitivity
• Hyperthermia
• Hypoglycemia
• Hyponatremia
• Hypothermia
• Increased sweating
• Injection site abscess
• Insomnia
• Itchiness
• Jaundice
• Laryngeal edema
• Laryngospasm
• Leukocytoclastic vasculitis
• Leukopenia
• Liver function test abnormal
• Nausea
• Neuroleptic malignant syndrome
• Neutropenia
• Pancytopenia
• Photosensitivity reaction
• Priapism
• Psychotic disorder
• Pulmonary embolism
• Rash
• Retinopathy
• Seizure
• Sudden death
• Tardive dyskinesia
• Thrombocytopenia
• Torsades de pointes
• Urinary retention
• Urticaria
• Ventricular fibrillation
• Ventricular tachycardia
• Vomiting

{{div col end}}

• Pre-existing coma, acute stroke
• Severe intoxication with alcohol or other central depressant drugs
• Known allergy against haloperidol or other butyrophenones or other drug ingredients
• Known heart disease, when combined will tend towards cardiac arrest{{Citation needed|date=April 2013}}

• A multiple-year study suggested this drug and other neuroleptic antipsychotic drugs commonly given to people with Alzheimer's with mild behavioral problems often make their condition worse and its withdrawal was even beneficial for some cognitive and functional measures.{{cite journal | vauthors = Ballard C, Lana MM, Theodoulou M, Douglas S, McShane R, Jacoby R, Kossakowski K, Yu LM, Juszczak E | title = A randomised, blinded, placebo-controlled trial in dementia patients continuing or stopping neuroleptics (the DART-AD trial) | journal = PLOS Medicine | volume = 5 | issue = 4 | pages = e76 | date = April 2008 | pmid = 18384230 | pmc = 2276521 | doi = 10.1371/journal.pmed.0050076 | veditors = Brayne C | quote = Neuroleptics provided no benefit for patients with mild behavioural problems, but were associated with a marked deterioration in verbal skills | doi-access = free }}{{cite web | title=Medication 'worsens Alzheimer's' | website=BBC NEWS | date=1 April 2008 | url=http://news.bbc.co.uk/1/hi/health/7319393.stm | access-date=3 August 2016}}
• Elderly patients with dementia-related psychosis: analysis of 17 trials showed the risk of death in this group of patients was 1.6 to 1.7 times that of placebo-treated patients. Most of the causes of death were either cardiovascular or infectious in nature. It is not clear to what extent this observation is attributed to antipsychotic drugs rather than the characteristics of the patients. The drug bears a boxed warning about this risk.
• Impaired liver function, as haloperidol is metabolized and eliminated mainly by the liver
• In patients with hyperthyroidism, the action of haloperidol is intensified and side effects are more likely.
• IV injections: risk of hypotension or orthostatic collapse
• Patients at special risk for the development of QT prolongation (hypokalemia, concomitant use of other drugs causing QT prolongation)
• Patients with a history of leukopenia: a complete blood count should be monitored frequently during the first few months of therapy and discontinuation of the drug should be considered at the first sign of a clinically significant decline in white blood cells.
• Pre-existing Parkinson's disease{{cite journal | vauthors = Leentjens AF, van der Mast RC | title = Delirium in elderly people: an update | journal = Current Opinion in Psychiatry | volume = 18 | issue = 3 | pages = 325–330 | date = May 2005 | pmid = 16639157 | doi = 10.1097/01.yco.0000165603.36671.97 | s2cid = 24709695 }} or dementia with Lewy bodies

• Amiodarone: Q-Tc interval prolongation (potentially dangerous change in heart rhythm).{{cite journal | vauthors = Bush SE, Hatton RC, Winterstein AG, Thomson MR, Woo GW | title = Effects of concomitant amiodarone and haloperidol on Q-Tc interval prolongation | journal = American Journal of Health-System Pharmacy | volume = 65 | issue = 23 | pages = 2232–2236 | date = December 2008 | pmid = 19020191 | doi = 10.2146/ajhp080039 }}
• Amphetamine and methylphenidate: counteracts increased action of norepinephrine and dopamine in patients with narcolepsy or ADD/ADHD
• Epinephrine: action antagonized, paradoxical decrease in blood pressure may result
• Guanethidine: antihypertensive action antagonized
• Levodopa: decreased action of levodopa
• Lithium: rare cases of the following symptoms have been noted: encephalopathy, early and late extrapyramidal side effects, other neurologic symptoms, and coma.{{cite journal | vauthors = Sandyk R, Hurwitz MD | title = Toxic irreversible encephalopathy induced by lithium carbonate and haloperidol. A report of 2 cases | journal = South African Medical Journal = Suid-Afrikaanse Tydskrif vir Geneeskunde | volume = 64 | issue = 22 | pages = 875–876 | date = November 1983 | pmid = 6415823 }}
• Methyldopa: increased risk of extrapyramidal side effects and other unwanted central effects
• Other central depressants (alcohol, tranquilizers, narcotics): actions and side effects of these drugs (sedation, respiratory depression) are increased. In particular, the doses of concomitantly used opioids for chronic pain can be reduced by 50%.
• Other drugs metabolized by the CYP3A4 enzyme system: inducers such as carbamazepine, phenobarbital, and rifampicin decrease plasma levels and inhibitors such as quinidine, buspirone, and fluoxetine increase plasma levels
• Tricyclic antidepressants: metabolism and elimination of tricyclics significantly decreased, increased toxicity noted (anticholinergic and cardiovascular side effects, lowering of seizure threshold)

Several lines of evidence suggest that haloperidol exhibits neurotoxicity.{{cite journal | vauthors = Nasrallah HA, Chen AT | title = Multiple neurotoxic effects of haloperidol resulting in neuronal death | journal = Annals of Clinical Psychiatry | volume = 29 | issue = 3 | pages = 195–202 | date = August 2017 | pmid = 28738100 | doi = }}{{cite journal | vauthors = Pierre JM | title = Time to retire haloperidol? | journal = Current Psychiatry | volume = 19 | issue = 5 | page = 19 | url = https://www.mdedge.com/psychiatry/article/221293/schizophrenia-other-psychotic-disorders }} Some studies report an association between antipsychotic medications, especially first-generation agents, and a decline in gray matter volume.Id. Haloperidol irreversibly blocks the sigma σ¹ receptor.{{cite journal | vauthors = Cobos EJ, del Pozo E, Baeyens JM | title = Irreversible blockade of sigma-1 receptors by haloperidol and its metabolites in guinea pig brain and SH-SY5Y human neuroblastoma cells | journal = Journal of Neurochemistry | volume = 102 | issue = 3 | pages = 812–825 | date = August 2007 | pmid = 17419803 | doi = 10.1111/j.1471-4159.2007.04533.x }} It may exert deleterious effects on the dorsolateral prefrontal cortex (DLPFC) by attenuating brain-derived neurotrophic factor (BDNF) transcription and expression, associated with an increase in the long non-coding RNA BDNF-AS in the DLPFC.{{cite journal | vauthors = Hemby SE, McIntosh S | title = Chronic haloperidol administration downregulates select BDNF transcript and protein levels in the dorsolateral prefrontal cortex of rhesus monkeys | journal = Frontiers in Psychiatry | volume = 14 | issue = | pages = 1054506 | date = 2023 | pmid = 36816400 | pmc = 9932326 | doi = 10.3389/fpsyt.2023.1054506 | doi-access = free }} Besides the preceding mechanisms, haloperidol metabolizes into HPP⁺, a monoaminergic neurotoxin related to MPTP. This might be involved in the extrapyramidal symptoms that develop with long-term haloperidol therapy.

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse.{{cite book |editor1-first=BMJ | editor = Joint Formulary Committee | title = British National Formulary | edition = 57 | date = March 2009 |publisher=Royal Pharmaceutical Society of Great Britain |location=United Kingdom |isbn=978-0-85369-845-6 |page=192 |chapter=4.2.1 |quote=Withdrawal of antipsychotic drugs after long-term therapy should always be gradual and closely monitored to avoid the risk of acute withdrawal syndromes or rapid relapse.}} Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.{{cite book | vauthors = Haddad PM, Dursun S, Deakin B |title=Adverse Syndromes and Psychiatric Drugs: A Clinical Guide |date=2004 |publisher=OUP Oxford |isbn=9780198527480 |pages=207–216 |url=https://books.google.com/books?id=CWR7DwAAQBAJ&pg=PA207 |language=en}} Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly there may be a feeling of the world spinning, numbness, or muscle pains. Symptoms generally resolve after a short period of time.

There is tentative evidence that discontinuation of antipsychotics can result in psychosis.{{cite journal | vauthors = Moncrieff J | title = Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse | journal = Acta Psychiatrica Scandinavica | volume = 114 | issue = 1 | pages = 3–13 | date = July 2006 | pmid = 16774655 | doi = 10.1111/j.1600-0447.2006.00787.x | s2cid = 6267180 }} It may also result in reoccurrence of the condition that is being treated.{{cite book | vauthors = Sacchetti E, Vita A, Siracusano A, Fleischhacker W |title=Adherence to Antipsychotics in Schizophrenia |date=2013 |publisher=Springer Science & Business Media |isbn=9788847026797 |page=85 |url=https://books.google.com/books?id=odE-AgAAQBAJ&pg=PA85 |language=en}} Rarely tardive dyskinesia can occur when the medication is stopped.

Symptoms are usually due to side effects. Most often encountered are:

• Anticholinergic side effects (dry mouth, constipation, paralytic ileus, difficulties in urinating, decreased perspiration)
• Coma in severe cases, accompanied by respiratory depression and massive hypotension, shock
• Hypotension or hypertension
• Rarely, serious ventricular arrhythmia (torsades de pointes), with or without prolonged QT-time
• Sedation
• Severe extrapyramidal side effects with muscle rigidity and tremors, akathisia, etc.

Treatment is mostly symptomatic and involves intensive care with stabilization of vital functions. In early detected cases of oral overdose, induction of emesis, gastric lavage, and the use of activated charcoal can be tried. In the case of a severe overdose, antidotes such as bromocriptine or ropinirole may be used to treat the extrapyramidal effects caused by haloperidol, acting as dopamine receptor agonists.{{Citation needed|date=April 2013}} ECG and vital signs should be monitored especially for QT prolongation and severe arrhythmias should be treated with antiarrhythmic measures.

An overdose of haloperidol can be fatal,{{cite web |url = https://www.drugs.com/mtm/haloperidol.html |title = Haloperidol at Drugs.com |url-status = live |archive-url = https://web.archive.org/web/20111122170902/http://www.drugs.com/mtm/haloperidol.html |archive-date = 22 November 2011 }} but in general the prognosis after overdose is good, provided the person has survived the initial phase.

File:Haloperidol 10 MG Oral Tablet.jpg

Haloperidol is a typical butyrophenone-type antipsychotic that exhibits high-affinity dopamine D₂ receptor antagonism and slow receptor dissociation kinetics.{{cite journal | vauthors = Seeman P, Tallerico T | title = Antipsychotic drugs which elicit little or no parkinsonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors | journal = Molecular Psychiatry | volume = 3 | issue = 2 | pages = 123–134 | date = March 1998 | pmid = 9577836 | doi = 10.1038/sj.mp.4000336 | doi-access = free }} It has effects similar to the phenothiazines.{{cite web |title = Haloperidol |work = Martindale: The Complete Drug Reference |publisher = Pharmaceutical Press |date = 13 December 2013 |access-date = 29 May 2014 |url = http://www.medicinescomplete.com/mc/martindale/current/ms-18332-f.htm |editor = Brayfield, A |location = London, UK }} The drug binds preferentially to D₂ and α₁ receptors at low dose (ED₅₀ = 0.13 and 0.42 mg/kg, respectively), and 5-HT₂ receptors at a higher dose (ED₅₀ = 2.6 mg/kg). Given that antagonism of D₂ receptors is more beneficial on the positive symptoms of schizophrenia and antagonism of 5-HT₂ receptors on the negative symptoms, this characteristic underlies haloperidol's greater effect on delusions, hallucinations and other manifestations of psychosis.{{cite journal | vauthors = Schotte A, Janssen PF, Megens AA, Leysen JE | title = Occupancy of central neurotransmitter receptors by risperidone, clozapine and haloperidol, measured ex vivo by quantitative autoradiography | journal = Brain Research | volume = 631 | issue = 2 | pages = 191–202 | date = December 1993 | pmid = 7510574 | doi = 10.1016/0006-8993(93)91535-z | s2cid = 34455982 }} Haloperidol's negligible affinity for histamine H₁ receptors and muscarinic M₁ acetylcholine receptors yields an antipsychotic with a lower incidence of sedation, weight gain, and orthostatic hypotension though having higher rates of treatment emergent extrapyramidal symptoms.

The bioavailability of oral haloperidol ranges from 60 to 70%. However, there is a wide variance in reported mean T_max and T_1/2 in different studies, ranging from 1.7 to 6.1 hours and 14.5 to 36.7 hours respectively.{{cite journal | vauthors = Kudo S, Ishizaki T | title = Pharmacokinetics of haloperidol: an update | journal = Clinical Pharmacokinetics | volume = 37 | issue = 6 | pages = 435–456 | date = December 1999 | pmid = 10628896 | doi = 10.2165/00003088-199937060-00001 | s2cid = 71360020 }}

File:Haldol Decanoate.jpg

The drug is well and rapidly absorbed with a high bioavailability when injected intramuscularly. The T_max is 20 minutes in healthy individuals and 33.8 minutes in patients with schizophrenia. The mean T_1/2 is 20.7 hours. The decanoate injectable formulation is for intramuscular administration only and is not intended to be used intravenously. The plasma concentrations of haloperidol decanoate reach a peak at about six days after the injection, falling thereafter, with an approximate half-life of three weeks.{{cite web |url = https://www.drugs.com/pro/haldol-decanoate.html |title = drugs.com |url-status = live |archive-url = https://web.archive.org/web/20110810064415/http://www.drugs.com/pro/haldol-decanoate.html |archive-date = 10 August 2011 }}

The bioavailability is 100% in intravenous (IV) injection, and the very rapid onset of action is seen within seconds. The T_1/2 is 14.1 to 26.2 hours. The apparent volume of distribution is between 9.5 and 21.7 L/kg. The duration of action is four to six hours.

Plasma levels of five to 15 micrograms per liter are typically seen for therapeutic response (Ulrich S, et al. Clin Pharmacokinet. 1998). The determination of plasma levels is rarely used to calculate dose adjustments but can be useful to check compliance.

The concentration of haloperidol in brain tissue is about 20-fold higher compared to blood levels. It is slowly eliminated from brain tissue,{{cite journal | vauthors = Kornhuber J, Schultz A, Wiltfang J, Meineke I, Gleiter CH, Zöchling R, Boissl KW, Leblhuber F, Riederer P | title = Persistence of haloperidol in human brain tissue | journal = The American Journal of Psychiatry | volume = 156 | issue = 6 | pages = 885–890 | date = June 1999 | pmid = 10360127 | doi = 10.1176/ajp.156.6.885 }} which may explain the slow disappearance of side effects when the medication is stopped.{{cite journal | vauthors = Kornhuber J, Wiltfang J, Riederer P, Bleich S | title = Neuroleptic drugs in the human brain: clinical impact of persistence and region-specific distribution | journal = European Archives of Psychiatry and Clinical Neuroscience | volume = 256 | issue = 5 | pages = 274–280 | date = August 2006 | pmid = 16788768 | doi = 10.1007/s00406-006-0661-7 | s2cid = 9565741 }}

Haloperidol is heavily protein bound in human plasma, with a free fraction of only 7.5 to 11.6%. It is also extensively metabolized in the liver with only about 1% of the administered dose excreted unchanged in the urine. The greatest proportion of the hepatic clearance is by glucuronidation, followed by reduction and CYP-mediated oxidation, primarily by CYP3A4. Haloperidol is metabolized into HPP⁺, a monoaminergic neurotoxin related to MPTP, by CYP3A enzymes.{{cite book | vauthors = Kostrzewa RM | title=Handbook of Neurotoxicity | chapter=Survey of Selective Monoaminergic Neurotoxins Targeting Dopaminergic, Noradrenergic, and Serotoninergic Neurons | publisher=Springer International Publishing | publication-place=Cham | date=2022 | isbn=978-3-031-15079-1 | doi=10.1007/978-3-031-15080-7_53 | pages=159–198}}{{cite journal | vauthors = Igarashi K | title=The Possible Role of an Active Metafbollte Derived from the Neuroleptic Agent Haloperidol in Drug-Induced Parkinsonism | journal=Journal of Toxicology: Toxin Reviews | volume=17 | issue=1 | date=1998 | issn=0731-3837 | doi=10.3109/15569549809006488 | pages=27–38}}{{cite journal | vauthors = Górska A, Marszałł M, Sloderbach A | title = Neurotoksyczność pirydyniowych metabolitów haloperydolu | trans-title = The neurotoxicity of pyridinium metabolites of haloperidol | language = Polish | journal = Postepy Hig Med Dosw (Online) | volume = 69 | issue = | pages = 1169–1175 | date = October 2015 | pmid = 26561842 | doi = 10.5604/17322693.1175009 | doi-broken-date = 1 November 2024 | url = | doi-access = free }}

Haloperidol is a crystalline material with a melting temperature of 150 °C.{{cite journal | vauthors = Shan X, Williams AC, Khutoryanskiy VV | title = Polymer structure and property effects on solid dispersions with haloperidol: Poly(N-vinyl pyrrolidone) and poly(2-oxazolines) studies | journal = International Journal of Pharmaceutics | volume = 590 | pages = 119884 | date = November 2020 | pmid = 32950665 | doi = 10.1016/j.ijpharm.2020.119884 | s2cid = 221826541 | url = https://centaur.reading.ac.uk/93015/1/Manuscript-%20accepted.pdf }} This drug has very low solubility in water (1.4 mg/100 mL), but it is soluble in chloroform, benzene, methanol, and acetone. It is also soluble in 0.1 M hydrochloric acid (3 mg/mL) with heating.{{Cite web |title=Sigma data sheet on haloperidol |url=https://www.sigmaaldrich.com/deepweb/assets/sigmaaldrich/product/documents/848/112/h1512dat.pdf}}

Haloperidol was discovered by Paul Janssen.{{cite book | vauthors = Healy D |author-link = David Healy (psychiatrist) |title = The psychopharmacologists |volume = 1 |year = 1996 |publisher = Chapman and Hall |location = London |isbn = 978-1-86036-008-4 }}{{page needed|date=September 2012}} It was developed in 1958 at the Belgian company Janssen Pharmaceutica and submitted to the first of clinical trials in Belgium later that year.{{cite journal | vauthors = Granger B, Albu S | title = The haloperidol story | journal = Annals of Clinical Psychiatry | volume = 17 | issue = 3 | pages = 137–140 | year = 2005 | pmid = 16433054 | doi = 10.1080/10401230591002048 }}{{cite journal | vauthors = López-Muñoz F, Alamo C | title = The consolidation of neuroleptic therapy: Janssen, the discovery of haloperidol and its introduction into clinical practice | journal = Brain Research Bulletin | volume = 79 | issue = 2 | pages = 130–141 | date = April 2009 | pmid = 19186209 | doi = 10.1016/j.brainresbull.2009.01.005 | s2cid = 7720401 }}

Haloperidol was approved by the U.S. Food and Drug Administration (FDA) on 12 April 1967; it was later marketed in the U.S. and other countries under the brand name Haldol by McNeil Laboratories.

Haloperidol is relatively inexpensive, being up to 100 fold less expensive than newer antipsychotics.{{cite book | vauthors = Escobar JI, Marin H |title=Clinical Psychopharmacology: A Practical Approach |date=2013 |publisher=World Scientific |isbn=978-981-4578-37-0 |page=69 |url=https://books.google.com/books?id=XPy2CgAAQBAJ&pg=PA69 |language=en}}{{cite book | vauthors = Adams JG |title=Emergency Medicine E-Book: Clinical Essentials (Expert Consult -- Online) |date=2012 |publisher=Elsevier Health Sciences |isbn=978-1-4557-3394-1 |page=1635 |url=https://books.google.com/books?id=rpoH-KYE93IC&pg=PA1635 |language=en}}

Haloperidol is the INN, BAN, USAN, AAN approved name.

It is sold under the tradenames Aloperidin, Bioperidolo, Brotopon, Dozic, Duraperidol (Germany), Einalon S, Eukystol, Haldol (common tradename in the US and UK), Halol, Halosten, Keselan, Linton, Peluces, Serenace Norodol (Turkey) and Sigaperidol.{{Citation needed|date=April 2013}}

Haloperidol was under investigation for the treatment of depression.{{cite web | title=CLR 3001 | website=AdisInsight | date=27 August 2019 | url=https://adisinsight.springer.com/drugs/800032468 | access-date=13 August 2024}}{{cite journal | vauthors = Kennedy SH, Giacobbe P, Placenza F, Hudson CJ, Seeman P, Seeman MV | title = Depression treatment by withdrawal of short-term low-dose antipsychotic, a proof-of-concept randomized double-blind study | journal = J Affect Disord | volume = 166 | issue = | pages = 139–143 | date = September 2014 | pmid = 25012422 | doi = 10.1016/j.jad.2014.04.014 | url = }} It was employed as a short-term low-dose dopamine receptor antagonist to upregulate dopamine receptors and produce receptor supersensitivity followed by drug withdrawal as a means of treating depression.{{cite journal | vauthors = Cohen D, Recalt A | title = Discontinuing Psychotropic Drugs from Participants in Randomized Controlled Trials: A Systematic Review | journal = Psychother Psychosom | volume = 88 | issue = 2 | pages = 96–104 | date = 2019 | pmid = 30923288 | doi = 10.1159/000496733 | url = }}

Haloperidol is also used on many different kinds of animals for nonselective tranquilization and diminishing behavioral arousal, in veterinary and other settings including captivity management.{{cite journal | vauthors = Hofmeyr JM | title = The use of haloperidol as a long-acting neuroleptic in game capture operations | journal = Journal of the South African Veterinary Association | volume = 52 | issue = 4 | pages = 273–282 | date = December 1981 | pmid = 6122740 }}

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