zuclopenthixol

Zuclopenthixol is available in three major preparations:

• As zuclopenthixol decanoate (Clopixol Depot, Cisordinol Depot), it is a long-acting intramuscular injection. Its main use is as a long-acting injection given every two or three weeks to people with schizophrenia who have a poor compliance with medication and suffer frequent relapses of illness.{{cite journal | vauthors = da Silva Freire Coutinho E, Fenton M, Quraishi SN | title = Zuclopenthixol decanoate for schizophrenia | journal = The Cochrane Database of Systematic Reviews | issue = 2 | pages = CD001164 | publisher = John Wiley and Sons, Ltd. | year = 1999 | volume = 1999 | url = http://www.cochrane.org/reviews/en/ab001164.html | doi = 10.1002/14651858.CD001164 | pmid = 10796607 | pmc = 7032616 | access-date = 2007-06-12 | archive-date = 2007-06-13 | archive-url = https://web.archive.org/web/20070613153843/http://www.cochrane.org/reviews/en/ab001164.html | url-status = live }} There is some evidence it may be more helpful in managing aggressive behaviour.{{Cite journal |vauthors=Haessler F, Glaser T, Beneke M, Pap AF, Bodenschatz R, Reis O | title = Zuclopenthixol in adults with intellectual disabilities and aggressive behaviours | journal = British Journal of Psychiatry | volume = 190 | issue = 5 | pages = 447–448 | year = 2007 | doi = 10.1192/bjp.bp.105.016535 | pmid = 17470962 | doi-access = free }}
• As zuclopenthixol acetate (Clopixol-Acuphase, Cisordinol-Acutard), it is a shorter-acting intramuscular injection used in the acute sedation of psychotic inpatients. The effect peaks at 48–72 hours providing 2–3 days of sedation.{{cite web | author = Lundbeck P/L | title = Clopixol Acuphase 50 mg/mL Injection Clopixol Acuphase 100 mg / 2 mL Injection | publisher = Lundbeck P/L | year = 1991 | url = http://home.intekom.com/pharm/lundbeck/clopixac.html | access-date = 2007-06-12 | archive-date = 2007-06-09 | archive-url = https://web.archive.org/web/20070609192828/http://home.intekom.com/pharm/lundbeck/clopixac.html | url-status = live }}
• As zuclopenthixol dihydrochloride (Clopixol, Cisordinol), it is a tablet used in the treatment of schizophrenia in those who are compliant with oral medication.{{cite journal | vauthors = Bryan EJ, Purcell MA, Kumar A | title = Zuclopenthixol dihydrochloride for schizophrenia | journal = The Cochrane Database of Systematic Reviews | volume = 2017 | issue = 11 | pages = CD005474 | date = November 2017 | pmid = 29144549 | pmc = 6486001 | doi = 10.1002/14651858.CD005474.pub2 }}

It is also used in the treatment of acute bipolar mania.

As a long-acting injection, zuclopenthixol decanoate comes in a 200 mg and 500 mg ampoule. Doses can vary from 50 mg weekly to the maximum licensed dose of 600 mg weekly. In general, the lowest effective dose to prevent relapse is preferred. The interval may be shorter as a patient starts on the medication before extending to 3 weekly intervals subsequently. The dose should be reviewed and reduced if side effects occur, though in the short-term an anticholinergic medication benztropine may be helpful for tremor and stiffness, while diazepam may be helpful for akathisia. 100 mg of zuclopenthixol decanoate is roughly equivalent to 20 mg of flupentixol decanoate or 12.5 mg of fluphenazine decanoate.

In oral form zuclopenthixol is available in 2, 10, 25 and 40 mg tablets, with a dose range of 20–60 mg daily.{{Cite web |title=Clopixol 2 mg film-coated tablets - Summary of Product Characteristics (SmPC) - (emc) |url=https://www.medicines.org.uk/emc/product/994/#gref |access-date=2023-03-28 |website=www.medicines.org.uk |archive-date=2023-03-28 |archive-url=https://web.archive.org/web/20230328180621/https://www.medicines.org.uk/emc/product/994/#gref |url-status=live }}

Chronic administration of zuclopenthixol (30 mg/kg/day for two years) in rats resulted in small, but significant, increases in the incidence of thyroid parafollicular carcinomas and, in females, of mammary adenocarcinomas and of pancreatic islet cell adenomas and carcinomas. An increase in the incidence of mammary adenocarcinomas is a common finding for D₂ antagonists which increase prolactin secretion when administered to rats. An increase in the incidence of pancreatic islet cell tumours has been observed for some other D₂ antagonists. The physiological differences between rats and humans with regard to prolactin make the clinical significance of these findings unclear.

Withdrawal syndrome: Abrupt cessation of therapy may cause acute withdrawal symptoms (eg, nausea, vomiting, or insomnia). Symptoms usually begin in 1 to 4 days of withdrawal and subside within 1 to 2 weeks.{{Cite web|url=https://www.medicines.org.uk/emc/product/994/smpc|title=Clopixol 2 mg film-coated tablets - Summary of Product Characteristics (SmPC) - (emc)|website=www.medicines.org.uk}}{{Cite web|url=https://www.uptodate.com/contents/zuclopenthixol-united-states-not-available-drug-information?search=Zuclopenthixol&topicRef=15250&source=see_link#F236382|title=UpToDate|website=www.uptodate.com}}

Other permanent side effects are similar to many other typical antipsychotics, namely extrapyramidal symptoms as a result of dopamine blockade in subcortical areas of the brain. This may result in symptoms similar to those seen in Parkinson's disease and include a restlessness and inability to sit still known as akathisia, a slow tremor and stiffness of the limbs. Zuclopenthixol is thought to be more sedating than the related flupentixol, though possibly less likely to induce extrapyramidal symptoms than other typical depots. As with other dopamine antagonists, zuclopenthixol may sometimes elevate prolactin levels; this may occasionally result in amenorrhoea or galactorrhoea in severe cases. Neuroleptic malignant syndrome is a rare but potentially fatal side effect. Any unexpected deterioration in mental state with confusion and muscle stiffness should be seen by a physician.

Zuclopenthixol decanoate induces a transient dose-dependent sedation. However, if the patient is switched to maintenance treatment with zuclopenthixol decanoate from oral zuclopenthixol or from i.m. zuclopenthixol acetate the sedation will be no problem. Tolerance to the unspecific sedative effect develops rapidly.{{Cite web|url=https://www.hpra.ie/img/uploaded/swedocuments/LicenseSPC_PA0115-005-007_03062015110150.pdf|title=Summary of Product Characteristics|access-date=2017-03-28|archive-date=2017-03-28|archive-url=https://web.archive.org/web/20170328105635/https://www.hpra.ie/img/uploaded/swedocuments/LicenseSPC_PA0115-005-007_03062015110150.pdf|url-status=live}}

;Very common Adverse Effects (≥10% incidence) {{Cite web|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-05705-3|title=TGA eBS - Product and Consumer Medicine Information Licence|access-date=2013-08-08|archive-date=2018-06-15|archive-url=https://web.archive.org/web/20180615111308/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-05705-3|url-status=live}}

• Hypersalivation
• Somnolence
• Akathisia
• Hyperkinesia
• Hypokinesia

;Common (1–10%)

• Tachycardia
• Heart palpitations
• Vertigo
• Accommodation disorder
• Abnormal vision
• Salivary hypersecretion
• Constipation
• Vomiting
• Dyspepsia
• Diarrhoea
• Asthenia
• Fatigue
• Malaise
• Pain (at the injection site)
• Increased appetite
• Weight gain
• Myalgia
• Tremor
• Dystonia
• Hypertonia
• Dizziness
• Headache
• Paraesthesia
• Disturbance in attention
• Amnesia
• Abnormal gait
• Insomnia
• Depression
• Anxiety
• Abnormal dreams
• Agitation
• Decreased libido
• Nasal congestion
• Dyspnoea
• Hyperhidrosis
• Pruritus

;Uncommon (0.1–1%)

• Hyperacusis
• Tinnitus
• Mydriasis
• Abdominal pain
• Nausea
• Flatulence
• Thirst
• Injection site reaction
• Hypothermia
• Pyrexia
• Abnormal liver function tests
• Decreased appetite
• Weight loss
• Muscle rigidity
• Trismus
• Torticollis
• Tardive dyskinesia
• Hyperreflexia
• Dyskinesia
• Parkinsonism
• Syncope
• Ataxia
• Speech disorder
• Hypotonia
• Convulsion
• Migraine
• Apathy
• Nightmares
• Libido increased
• Confused state
• Ejaculation failure
• Erectile dysfunction
• Female orgasmic disorder
• Vulvovaginal
• Dryness
• Rash
• Photosensitivity
• Pigmentation disorder
• Seborrhoea
• Dermatitis
• Purpura
• Hypotension
• Hot flush

;Rare (0.01–0.1%)

• Thrombocytopenia
• Neutropenia
• Leukopenia
• Agranulocytosis
• QT prolongation
• Hyperprolactinaemia
• Hypersensitivity
• Anaphylactic reaction
• Hyperglycaemia
• Glucose tolerance impaired
• Hyperlipidaemia
• Gynaecomastia
• Galactorrhoea
• Amenorrhoea
• Priapism
• Withdrawal symptoms

;Very rare (<0.01%)

• Cholestatic hepatitis
• Jaundice
• Neuroleptic malignant syndrome
• Venous thromboembolism

File:Cisordinol.jpg

Zuclopenthixol antagonises both dopamine D₁ and D₂ receptors, α₁-adrenoceptors and 5-HT₂ receptors with a high affinity, but has no affinity for muscarinic acetylcholine receptors. It weakly antagonises the histamine (H₁) receptor but has no α₂-adrenoceptor blocking activity {{Citation needed|date=August 2020}}.

Evidence from in vitro work and clinical sources (i.e. therapeutic drug monitoring databases) suggests that both CYP2D6 and CYP3A4 play important roles in zuclopenthixol metabolism.{{Cite journal |vauthors=Davies SJ, Westin AA, Castberg I, Lewis G, Lennard MS, Taylor S, Spigset O | title = Characterisation of zuclopenthixol metabolism by in vitro and therapeutic drug monitoring studies. | journal = Acta Psychiatrica Scandinavica | volume = 122 | issue = 6 | pages = 445–453 | year = 2010 | doi = 10.1111/j.1600-0447.2010.01619.x | pmid = 20946203 | s2cid = 41869401 }}

{{Pharmacokinetics of long-acting injectable antipsychotics}}

Zuclopenthixol was introduced by Lundbeck in 1978.{{cite book|author=William Andrew Publishing|title=Pharmaceutical Manufacturing Encyclopedia|url=https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA1102|date=22 October 2013|publisher=Elsevier|isbn=978-0-8155-1856-3|pages=1102–|access-date=27 September 2017|archive-date=14 January 2023|archive-url=https://web.archive.org/web/20230114123157/https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA1102|url-status=live}}

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