Chemistry:Haloperidol

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Short description: Typical antipsychotic medication
Haloperidol
Haloperidol.svg
Haloperidol-from-xtal-3D-balls.png
Clinical data
Pronunciation/ˌhæloʊˈpɛrɪdɒl/
Trade namesHaldol, Serenace, others
AHFS/Drugs.comMonograph
MedlinePlusa682180
License data
Pregnancy
category
  • AU: C[1]
  • US: C (Risk not ruled out)[1]
Routes of
administration		By mouth, intramuscular, intravenous, depot (as decanoate ester)
Drug classTypical antipsychotic
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability60–70% (by mouth)[2]
Protein binding~90%[2]
MetabolismLiver-mediated[2]
Elimination half-life14–26 hours (IV), 20.7 hours (IM), 14–37 hours (oral)[2]
ExcretionBiliary (hence in feces) and in urine[2][3]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC21H23ClFNO2
Molar mass375.87 g·mol−1
3D model (JSmol)
  (verify)

Haloperidol, sold under the brand name Haldol among others, is a typical antipsychotic medication.[4] Haloperidol is used in the treatment of schizophrenia, tics in Tourette syndrome, mania in bipolar disorder, delirium, agitation, acute psychosis, and hallucinations from alcohol withdrawal.[4][5][6] It may be used by mouth or injection into a muscle or a vein.[4] Haloperidol typically works within 30 to 60 minutes.[4] A long-acting formulation may be used as an injection every four weeks by people with schizophrenia or related illnesses, who either forget or refuse to take the medication by mouth.[4]

Haloperidol may result in a movement disorder known as tardive dyskinesia which may be permanent.[4] Neuroleptic malignant syndrome and QT interval prolongation may occur, the latter particularly with IV administration.[4] In older people with psychosis due to dementia it results in an increased risk of death.[4] When taken during pregnancy it may result in problems in the infant.[4][7] It should not be used by people with Parkinson's disease.[4]

Haloperidol was discovered in 1958 by Paul Janssen,[8] prepared as part of a structure-activity relationship investigation into analogs of pethidine (meperidine).[9] It is on the World Health Organization's List of Essential Medicines.[10] It is the most commonly used typical antipsychotic.[11] In 2020, it was the 303rd most commonly prescribed medication in the United States, with more than 1 million prescriptions.[12]

Physicochemical properties

Haloperidol is a crystalline material with a melting temperature of 150 °C.[13] 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.[14]

Medical uses

Haloperidol is used in the control of the symptoms of:

  • Acute psychosis, such as drug-induced psychosis caused by amphetamines, ketamine,[15] and phencyclidine,[16] and psychosis associated with high fever or metabolic disease. Some evidence has found haloperidol to worsen psychosis due to psilocybin.[17]
  • Adjunctive treatment of alcohol and opioid withdrawal
  • Agitation and confusion associated with cerebral sclerosis
  • Alcohol-induced psychosis
  • Hallucinations in alcohol withdrawal[5]
  • Hyperactive delirium (to control the agitation component of delirium)
  • Hyperactivity, aggression
  • Otherwise uncontrollable, severe behavioral disorders in children and adolescents
  • Schizophrenia[18]
  • Therapeutic trial in personality disorders, such as borderline personality disorder
  • Treatment of intractable hiccups[19][20]
  • 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.

Haloperidol was considered indispensable for treating psychiatric emergency situations,[21][22] although 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.[23][24][25]

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.[26] A 2013 systematic review compared haloperidol to placebo in schizophrenia:[27]

Summary
Haloperidol often causes troublesome adverse effects. If there is no other antipsychotic drug, using haloperidol to offset the consequences of untreated schizophrenia is justified. Where a choice of drug is available, however, an alternative antipsychotic with less likelihood of adverse effects such as parkinsonism, akathisia and acute dystonias may be more desirable.[27]

Pregnancy and lactation

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.[18]

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.[28]

Other considerations

Skeletal formula of haloperidol decanoate. The decanoate group is highlighted in 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] 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.[29]

Other forms of therapy (psychotherapy, occupational therapy/ergotherapy, or social rehabilitation) should be instituted properly.[citation needed] 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.[30] Patients responded with doses under even 2 mg in first-episode psychosis.[31] 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.[29]

  • 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]

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.[32] 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.[33]

Adverse effects

Sources for the following lists of adverse effects:[34][35][36][37]

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.[26]

With more than 6 months of use 14 percent of users gain weight.[38] Haloperidol may be neurotoxic.[39]

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.[26])

Unknown frequency

Rare (<1% incidence)


Contraindications

  • 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]

Special cautions

  • 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.[40] [41]
  • 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.[18]
  • 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.[18]
  • Pre-existing Parkinson's disease[42] or dementia with Lewy bodies

Interactions

  • Amiodarone: Q-Tc interval prolongation (potentially dangerous change in heart rhythm).[43]
  • 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.[44]
  • 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[18]
  • Tricyclic antidepressants: metabolism and elimination of tricyclics significantly decreased, increased toxicity noted (anticholinergic and cardiovascular side effects, lowering of seizure threshold)

Potential neurotoxicity

Several lines of evidence suggest that haloperidol exhibits neurotoxicity.[45][46] Some studies report an association between antipsychotic medications, especially first-generation agents, and a decline in gray matter volume.[47] Haloperidol may exert deleterious effects on the dorsolateral prefrontal cortex (DLPFC) by attenuating BDNF transcription and expression, associated with an increase in the long non-coding RNA BDNF-AS in the DLPFC.[48]

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse.[49] Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.[50] Other symptoms may include restlessness, increased sweating, and trouble sleeping.[50] Less commonly there may be a feeling of the world spinning, numbness, or muscle pains.[50] Symptoms generally resolve after a short period of time.[50]

There is tentative evidence that discontinuation of antipsychotics can result in psychosis.[51] It may also result in reoccurrence of the condition that is being treated.[52] Rarely tardive dyskinesia can occur when the medication is stopped.[50]

Overdose

Symptoms

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

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] ECG and vital signs should be monitored especially for QT prolongation and severe arrhythmias should be treated with antiarrhythmic measures.[18]

Prognosis

An overdose of haloperidol can be fatal,[53] but in general the prognosis after overdose is good, provided the person has survived the initial phase.

Pharmacology

Haloperidol, 10-mg oral tablet

Haloperidol is a typical butyrophenone-type antipsychotic that exhibits high-affinity dopamine D2 receptor antagonism and slow receptor dissociation kinetics.[54] It has effects similar to the phenothiazines.[20] 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.[55] 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.

Haloperidol binding profile
Receptor Action Ki (nM)
D1 silent antagonist Unknown efficiency [citation needed]
D5 silent antagonist
D2 inverse agonist 0.7[56]
D3 inverse agonist 0.2[57]
D4 inverse agonist 5–9[58]
σ1 (irreversible inactivation by haloperidol metabolite HPP+) 3[59]
σ2 agonist 54[60]
5-HT1A agonist
5-HT2A silent antagonist 53[61]
5-HT2C silent antagonist 10,000[61]
5-HT6 silent antagonist 3,666[61]
5-HT7 irreversible silent antagonist 377.2[61]
H1 silent antagonist 1,800[61]
M1 silent antagonist 10,000[61]
α1A silent antagonist 12[61]
α2A silent antagonist 1,130[61]
α2B silent antagonist 480[61]
α2C silent antagonist 550[61]
NR1/NR2B subunit containing NMDA receptor antagonist; ifenprodil site IC50 – 2,000[62]

Pharmacokinetics

By mouth

The bioavailability of oral haloperidol ranges from 60 to 70%. However, there is a wide variance in reported mean Tmax and T1/2 in different studies, ranging from 1.7 to 6.1 hours and 14.5 to 36.7 hours respectively.[2]

Intramuscular injections

Haldol Decanoate for injection into muscle[63]

The drug is well and rapidly absorbed with a high bioavailability when injected intramuscularly. The Tmax is 20 minutes in healthy individuals and 33.8 minutes in patients with schizophrenia. The mean T1/2 is 20.7 hours.[2] 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.[64]

Intravenous injections

The bioavailability is 100% in intravenous (IV) injection, and the very rapid onset of action is seen within seconds. The T1/2 is 14.1 to 26.2 hours. The apparent volume of distribution is between 9.5 and 21.7 L/kg.[2] The duration of action is four to six hours.

Therapeutic concentrations

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,[65] which may explain the slow disappearance of side effects when the medication is stopped.[65][66]

Distribution and metabolism

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.[2]

History

Haloperidol was discovered by Paul Janssen.[67] It was developed in 1958 at the Belgian company Janssen Pharmaceutica and submitted to the first of clinical trials in Belgium later that year.[68][69]

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.[68]

Society and culture

Cost

Haloperidol is relatively inexpensive, being up to 100 fold less expensive than newer antipsychotics.[70][71]

Brand names

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]

Veterinary use

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.[72]

References

  1. ↑ 1.0 1.1 "Haloperidol Use During Pregnancy". 10 February 2020. https://www.drugs.com/pregnancy/haloperidol.html. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 "Pharmacokinetics of haloperidol: an update". Clinical Pharmacokinetics 37 (6): 435–456. December 1999. doi:10.2165/00003088-199937060-00001. PMID 10628896. 
  3. ↑ "Product Information Serenace" (PDF). TGA eBusiness Services. Aspen Pharma Pty Ltd. 29 September 2011. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2011-PI-03532-3. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 4.9 "Haloperidol". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/haloperidol.html. 
  5. ↑ 5.0 5.1 "Recognition and management of withdrawal delirium (delirium tremens)". The New England Journal of Medicine 371 (22): 2109–2113. November 2014. doi:10.1056/NEJMra1407298. PMID 25427113. https://escholarship.org/uc/item/08b9z9th. 
  6. ↑ "Quetiapine: a pharmacoeconomic review of its use in bipolar disorder". PharmacoEconomics 30 (7): 611–631. July 2012. doi:10.2165/11208500-000000000-00000. PMID 22559293. 
  7. ↑ "Prescribing medicines in pregnancy database". Australian Government. 3 March 2014. http://www.tga.gov.au/hp/medicines-pregnancy.htm. 
  8. ↑ Drug discovery : a history (Rev. and updated ed.). Chichester: Wiley. 2005. p. 124. ISBN 978-0-471-89979-2. https://books.google.com/books?id=Cb6BOkj9fK4C&pg=PA124. 
  9. ↑ The evolution of drug discovery: from traditional medicines to modern drugs (1. Aufl. ed.). Weinheim: Wiley-VCH. 2011. p. 62. ISBN 978-3-527-32669-3. https://books.google.com/books?id=iDNy0XxGqT8C&pg=PA62. 
  10. ↑ World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. 2021. WHO/MHP/HPS/EML/2021.02. 
  11. ↑ Health care needs assessment: the epidemiologically based needs assessment reviews (2nd ed.). Abingdon: Radcliffe Medical. 2004. p. 202. ISBN 978-1-85775-892-4. https://books.google.com/books?id=HCLIeMG9WgoC&pg=PA202. 
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  13. ↑ "Polymer structure and property effects on solid dispersions with haloperidol: Poly(N-vinyl pyrrolidone) and poly(2-oxazolines) studies". International Journal of Pharmaceutics 590: 119884. November 2020. doi:10.1016/j.ijpharm.2020.119884. PMID 32950665. https://centaur.reading.ac.uk/93015/1/Manuscript-%20accepted.pdf. 
  14. ↑ "Sigma data sheet on haloperidol". https://www.sigmaaldrich.com/deepweb/assets/sigmaaldrich/product/documents/848/112/h1512dat.pdf. 
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  16. ↑ "Comparison of haloperidol and chlorpromazine in the treatment of phencyclidine psychosis". Journal of Clinical Pharmacology 24 (4): 202–204. April 1984. doi:10.1002/j.1552-4604.1984.tb01831.x. PMID 6725621. 
  17. ↑ "Human hallucinogen research: guidelines for safety". Journal of Psychopharmacology (SAGE Publications) 22 (6): 603–620. August 2008. doi:10.1177/0269881108093587. PMID 18593734. 
  18. ↑ 18.0 18.1 18.2 18.3 18.4 18.5 "Haldol Official FDA information, side effects and uses". Drugs.com. https://www.drugs.com/pro/haldol.html. 
  19. ↑ Joint Formulary Committee (2013). British National Formulary (BNF) (65th ed.). London, England: Pharmaceutical Press. pp. 229–30. ISBN 978-0-85711-084-8. https://archive.org/details/bnf65britishnati0000unse/page/229. 
  20. ↑ 20.0 20.1 Brayfield, A, ed (13 December 2013). "Haloperidol". Martindale: The Complete Drug Reference. London, UK: Pharmaceutical Press. http://www.medicinescomplete.com/mc/martindale/current/ms-18332-f.htm. 
  21. ↑ "Psychiatric emergencies". The Medical Clinics of North America 70 (5): 1185–1202. September 1986. doi:10.1016/S0025-7125(16)30919-1. PMID 3736271. 
  22. ↑ "The controversy over "chemical restraint" in acute care psychiatry". Journal of Psychiatric Practice (Lippincott Williams & Wilkins) 9 (1): 59–70. January 2003. doi:10.1097/00131746-200301000-00006. PMID 15985915. 
  23. ↑ "The Expert Consensus Guideline Series. Treatment of behavioral emergencies". Postgraduate Medicine (Spec No): 1–88; quiz 89–90. May 2001. PMID 11500996. 
  24. ↑ "Treatment of behavioral emergencies: a summary of the expert consensus guidelines". Journal of Psychiatric Practice 9 (1): 16–38. January 2003. doi:10.1097/00131746-200301000-00004. PMID 15985913. 
  25. ↑ "The expert consensus guideline series. Treatment of behavioral emergencies 2005". Journal of Psychiatric Practice 11 (Suppl 1): 5–25. November 2005. doi:10.1097/00131746-200511001-00002. PMID 16319571. 
  26. ↑ 26.0 26.1 26.2 "Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis". Lancet 382 (9896): 951–962. September 2013. doi:10.1016/S0140-6736(13)60733-3. PMID 23810019. 
  27. ↑ 27.0 27.1 "Haloperidol versus placebo for schizophrenia". The Cochrane Database of Systematic Reviews 11 (11): CD003082. November 2013. doi:10.1002/14651858.CD003082.pub3. PMID 24242360. http://www.cochrane.org/CD003082/SCHIZ_haloperidol-versus-placebo-for-schizophrenia. 
  28. ↑ "LACTMED: Haloperidol". 31 October 2018. http://toxnet.nlm.nih.gov/cgi-bin/sis/search2/r?dbs+lactmed:@term+@DOCNO+132. 
  29. ↑ 29.0 29.1 Work Group on Schizophrenia. "Practice Guideline for the Treatment of Patients With Schizophrenia". http://psychiatryonline.org/content.aspx?bookID=28&sectionID=1665359#45892. 
  30. ↑ "Determining the optimal dose of haloperidol in first-episode psychosis". Journal of Psychopharmacology 15 (4): 251–255. December 2001. doi:10.1177/026988110101500403. PMID 11769818. 
  31. ↑ "Choosing the right dose of antipsychotics in schizophrenia: lessons from neuroimaging studies". CNS Drugs 15 (9): 671–678. 2001. doi:10.2165/00023210-200115090-00001. PMID 11580306. 
  32. ↑ Goodman and Gilman's Pharmacological Basis of Therapeutics, 10th edition (McGraw-Hill, 2001).[page needed]
  33. ↑ American Academy of Hospice and Palliative Medicine. "Five Things Physicians and Patients Should Question". Choosing Wisely: An Initiative of the ABIM Foundation (American Academy of Hospice and Palliative Medicine). http://www.choosingwisely.org/doctor-patient-lists/american-academy-of-hospice-palliative-medicine/. Retrieved 1 August 2013. , which cites
  34. ↑ Product Information [Internet]. 2011 [cited 2013 Sep 29]. Available from: "TGA eBS - Product and Consumer Medicine Information Licence". https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2011-PI-03532-3. 
  35. ↑ HALDOL® Injection For Intramuscular Injection Only Product Information [Internet]. Janssen; 2011 [cited 2013 Sep 29]. Available from: "TGA eBS - Product and Consumer Medicine Information Licence". https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2009-PI-00998-3. 
  36. ↑ Truven Health Analytics, Inc. DrugPoint® System (Internet) [cited 2013 Sep 29]. Greenwood Village, CO: Thomsen Healthcare; 2013.
  37. ↑ Joint Formulary Committee. British National Formulary (BNF) 65. Pharmaceutical Pr; 2013.
  38. ↑ FDA Psychopharmacological Drugs Advisory Committee (9 July 2000). "Briefing Document for ZELDOX CAPSULES (Ziprasidone HCl)". https://www.fda.gov/ohrms/dockets/ac/00/backgrd/3619b1a.pdf. 
  39. ↑ "Multiple neurotoxic effects of haloperidol resulting in neuronal death". Annals of Clinical Psychiatry 29 (3): 195–202. August 2017. PMID 28738100. 
  40. ↑ "A randomised, blinded, placebo-controlled trial in dementia patients continuing or stopping neuroleptics (the DART-AD trial)". PLOS Medicine 5 (4): e76. April 2008. doi:10.1371/journal.pmed.0050076. PMID 18384230. "Neuroleptics provided no benefit for patients with mild behavioural problems, but were associated with a marked deterioration in verbal skills". 
  41. ↑ "Medication 'worsens Alzheimer's'". April 1, 2008. http://news.bbc.co.uk/1/hi/health/7319393.stm. 
  42. ↑ "Delirium in elderly people: an update". Current Opinion in Psychiatry 18 (3): 325–330. May 2005. doi:10.1097/01.yco.0000165603.36671.97. PMID 16639157. 
  43. ↑ "Effects of concomitant amiodarone and haloperidol on Q-Tc interval prolongation". American Journal of Health-System Pharmacy 65 (23): 2232–2236. December 2008. doi:10.2146/ajhp080039. PMID 19020191. 
  44. ↑ "Toxic irreversible encephalopathy induced by lithium carbonate and haloperidol. A report of 2 cases". South African Medical Journal = Suid-Afrikaanse Tydskrif vir Geneeskunde 64 (22): 875–876. November 1983. PMID 6415823. 
  45. ↑ "Multiple neurotoxic effects of haloperidol resulting in neuronal death". Annals of Clinical Psychiatry 29 (3): 195–202. August 2017. PMID 28738100. 
  46. ↑ "Time to retire haloperidol?". Current Psychiatry 19 (5): 19. https://www.mdedge.com/psychiatry/article/221293/schizophrenia-other-psychotic-disorders. 
  47. ↑ Id.
  48. ↑ "Chronic haloperidol administration downregulates select BDNF transcript and protein levels in the dorsolateral prefrontal cortex of rhesus monkeys". Frontiers in Psychiatry 14: 1054506. 2023. doi:10.3389/fpsyt.2023.1054506. PMID 36816400. 
  49. ↑ Joint Formulary Committee, BMJ, ed (March 2009). "4.2.1". British National Formulary (57 ed.). United Kingdom: Royal Pharmaceutical Society of Great Britain. p. 192. ISBN 978-0-85369-845-6. "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." 
  50. ↑ 50.0 50.1 50.2 50.3 50.4 (in en) Adverse Syndromes and Psychiatric Drugs: A Clinical Guide. OUP Oxford. 2004. pp. 207–216. ISBN 9780198527480. https://books.google.com/books?id=CWR7DwAAQBAJ&pg=PA207. 
  51. ↑ "Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse". Acta Psychiatrica Scandinavica 114 (1): 3–13. July 2006. doi:10.1111/j.1600-0447.2006.00787.x. PMID 16774655. 
  52. ↑ (in en) Adherence to Antipsychotics in Schizophrenia. Springer Science & Business Media. 2013. p. 85. ISBN 9788847026797. https://books.google.com/books?id=odE-AgAAQBAJ&pg=PA85. 
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  54. ↑ "Antipsychotic drugs which elicit little or no parkinsonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors". Molecular Psychiatry 3 (2): 123–134. March 1998. doi:10.1038/sj.mp.4000336. PMID 9577836. 
  55. ↑ "Occupancy of central neurotransmitter receptors by risperidone, clozapine and haloperidol, measured ex vivo by quantitative autoradiography". Brain Research 631 (2): 191–202. December 1993. doi:10.1016/0006-8993(93)91535-z. PMID 7510574. 
  56. ↑ "In vitro and in vivo receptor binding and effects on monoamine turnover in rat brain regions of the novel antipsychotics risperidone and ocaperidone". Molecular Pharmacology 41 (3): 494–508. March 1992. PMID 1372084. http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=1372084. 
  57. ↑ "Agonist and inverse agonist activity at the dopamine D3 receptor measured by guanosine 5'--gamma-thio-triphosphate--35S- binding". The Journal of Pharmacology and Experimental Therapeutics 285 (1): 119–126. April 1998. PMID 9536001. http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=9536001. 
  58. ↑ "Risperidone: a novel antipsychotic with balanced serotonin-dopamine antagonism, receptor occupancy profile, and pharmacologic activity". The Journal of Clinical Psychiatry 55 Suppl (Suppl): 5–12. May 1994. PMID 7520908. 
  59. ↑ "Irreversible blockade of sigma-1 receptors by haloperidol and its metabolites in guinea pig brain and SH-SY5Y human neuroblastoma cells". Journal of Neurochemistry 102 (3): 812–825. August 2007. doi:10.1111/j.1471-4159.2007.04533.x. PMID 17419803. 
  60. ↑ "Antiproliferative and cytotoxic effects of some sigma2 agonists and sigma1 antagonists in tumour cell lines". Naunyn-Schmiedeberg's Archives of Pharmacology 370 (2): 106–113. August 2004. doi:10.1007/s00210-004-0961-2. PMID 15322732. 
  61. ↑ 61.0 61.1 61.2 61.3 61.4 61.5 61.6 61.7 61.8 61.9 Cite error: Invalid <ref> tag; no text was provided for refs named affindata
  62. ↑ "Subtype-selective inhibition of N-methyl-D-aspartate receptors by haloperidol". Molecular Pharmacology 50 (6): 1541–1550. December 1996. PMID 8967976. http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=8967976. 
  63. ↑ "Haldol Decanoate - Summary of Product Characteristics (SmPC) - (emc)". https://www.medicines.org.uk/emc/product/968/smpc. 
  64. ↑ "drugs.com". https://www.drugs.com/pro/haldol-decanoate.html. 
  65. ↑ 65.0 65.1 "Persistence of haloperidol in human brain tissue". The American Journal of Psychiatry 156 (6): 885–890. June 1999. doi:10.1176/ajp.156.6.885. PMID 10360127. 
  66. ↑ "Neuroleptic drugs in the human brain: clinical impact of persistence and region-specific distribution". European Archives of Psychiatry and Clinical Neuroscience 256 (5): 274–280. August 2006. doi:10.1007/s00406-006-0661-7. PMID 16788768. 
  67. ↑ The psychopharmacologists. 1. London: Chapman and Hall. 1996. ISBN 978-1-86036-008-4. [page needed]
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  69. ↑ "The consolidation of neuroleptic therapy: Janssen, the discovery of haloperidol and its introduction into clinical practice". Brain Research Bulletin 79 (2): 130–141. April 2009. doi:10.1016/j.brainresbull.2009.01.005. PMID 19186209. 
  70. ↑ (in en) Clinical Psychopharmacology: A Practical Approach. World Scientific. 2013. p. 69. ISBN 978-981-4578-37-0. https://books.google.com/books?id=XPy2CgAAQBAJ&pg=PA69. 
  71. ↑ (in en) Emergency Medicine E-Book: Clinical Essentials (Expert Consult -- Online). Elsevier Health Sciences. 2012. p. 1635. ISBN 978-1-4557-3394-1. https://books.google.com/books?id=rpoH-KYE93IC&pg=PA1635. 
  72. ↑ "The use of haloperidol as a long-acting neuroleptic in game capture operations". Journal of the South African Veterinary Association 52 (4): 273–282. December 1981. PMID 6122740. 

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