Zuclopenthixol

Zuclopenthixol is a thioxanthene antipsychotic used for schizophrenia and other psychoses in three forms: the oral dihydrochloride, a short-acting acetate injection for acute disturbance, and a long-acting decanoate depot for maintenance. It is not available in the United States.

Classification. First-generation (typical) antipsychotic, thioxanthene.

Mechanism. Potent antagonism of dopamine D1 and D2 receptors, with additional 5-HT2, alpha-1 and histamine H1 blockade.

Pharmacokinetics. Oral bioavailability about 44%; half-life about 20 hours orally. The acetate (in oil) peaks at 24 to 48 hours and acts for 2 to 3 days. The decanoate peaks at 3 to 7 days with a half-life of about 19 days.

Schizophrenia and other psychoses, adults (oral).

• Start 20 to 30 mg daily in divided doses.
• Titration: increase by 10 to 20 mg every few days based on response.
• Usual maintenance 20 to 50 mg daily. Maximum 150 mg daily.

Acute disturbance (acetate, deep intramuscular).

• 50 to 150 mg, repeated after 2 to 3 days if needed.
• Maximum 400 mg in a course and 4 injections. Do not continue for more than 2 weeks.
• When changing to the decanoate, give the first decanoate injection 2 to 3 days after the last acetate injection, or at the same time at a different site.

Maintenance depot (decanoate, deep intramuscular).

• Test dose 100 mg. Wait 7 to 10 days.
• Then 200 to 400 mg every 2 to 4 weeks. Maximum 600 mg weekly.
• Maximum volume 2 mL each injection site.

Older adults. Use one third to one half of the usual dose; test dose 25 to 50 mg.

Contraindications. Coma or severe CNS depression, circulatory collapse, bone marrow suppression, phaeochromocytoma, acute porphyria, known QT prolongation, hypersensitivity. Boxed-warning-level increase in mortality in older adults with dementia-related psychosis.

Serious adverse effects. Neuroleptic malignant syndrome, acute dystonia, parkinsonism, akathisia, tardive dyskinesia, torsades de pointes, seizures, agranulocytosis (rare), cholestatic jaundice (rare), venous thromboembolism.

Common adverse effects. Extrapyramidal symptoms, sedation, dry mouth, constipation, orthostatic hypotension, weight gain, galactorrhoea, injection site pain.

Interactions. QT-prolonging drugs (macrolides, quinolones, quinine, artemether-lumefantrine, chloroquine, ondansetron) add risk. Fluoxetine, paroxetine and bupropion raise levels. Carbamazepine and rifampicin lower levels. Alcohol and sedatives add effects. Anticholinergics add peripheral effects. Levodopa is antagonised.

Common prescribing errors. Giving the acetate for longer than 2 weeks; starting the decanoate without a test dose; not rotating injection sites; exceeding 2 mL each site.

Special groups.

• Pregnancy: use only if benefit outweighs risk; third-trimester exposure can cause neonatal extrapyramidal symptoms and withdrawal.
• Breastfeeding: excreted in milk; avoid or use with infant monitoring.
• Children: not advised.
• Older adults: lower doses; high risk of parkinsonism and falls; mortality in dementia.
• Kidney impairment: start low.
• Liver impairment: reduce the dose and monitor liver tests.

Formulations. Tablets 2 mg, 10 mg, 25 mg and 40 mg; acetate injection 50 mg/mL and 100 mg/mL in oil; decanoate injection 200 mg/mL in oil. Deep intramuscular injection only, in the gluteal region; do not give intravenously.

Baseline. ECG, potassium and magnesium, weight, blood pressure, fasting glucose or HbA1c, lipids, full blood count, liver tests, and a baseline rating of extrapyramidal symptoms.

Monitoring. After an acetate injection, check pulse, blood pressure, temperature and level of consciousness regularly until the sedative effect settles. Weight and waist at baseline, 4, 8 and 12 weeks, then annually; fasting glucose or HbA1c and lipids at baseline, 12 weeks, then annually. Check extrapyramidal symptoms at each review. Repeat the ECG after dose increases; stop or reduce if QTc is over 500 ms. For acute dystonia give procyclidine 5 to 10 mg by intramuscular or slow intravenous injection.

Stopping. Stop depot injections gradually; relapse may take weeks to appear because of the long half-life.

Referral and escalation. Refer to psychiatry for first-episode psychosis, treatment resistance or persistent extrapyramidal symptoms. Fever with rigidity, respiratory depression, syncope or QTc over 500 ms needs emergency care.