Ziprasidone

Ziprasidone is a second-generation antipsychotic used for schizophrenia, bipolar mania and acute agitation. It causes little weight gain or metabolic change but prolongs the QT interval more than most antipsychotics, and it must be taken with a meal to be absorbed adequately.

Classification. Second-generation antipsychotic, benzisothiazolyl piperazine.

Mechanism. Antagonism of dopamine D2 and 5-HT2A receptors, agonism at 5-HT1A, and inhibition of serotonin and noradrenaline reuptake.

Pharmacokinetics. Oral bioavailability about 60% with a meal and about half that when fasting. Metabolised mainly by aldehyde oxidase and, to a lesser degree, by CYP3A4. Half-life about 7 hours orally and 2 to 5 hours intramuscularly.

Schizophrenia, adults (oral).

• Start 20 mg twice daily with food.
• Titration: increase no sooner than every 2 days, to 40 to 80 mg twice daily.
• Usual 40 to 80 mg twice daily. Maximum 160 mg daily.
• Duration: at least 12 months after a first episode.

Bipolar mania, adults. 40 mg twice daily with food on day 1, then 60 to 80 mg twice daily from day 2. Maximum 160 mg daily.

Acute agitation in schizophrenia (intramuscular). 10 mg every 2 hours or 20 mg every 4 hours. Maximum 40 mg in 24 hours. Use for no more than 3 consecutive days, and change to oral treatment as soon as possible.

Dose limits. Liver impairment: caution and use lower doses. Kidney impairment: no adjustment for oral use; caution with the injection. Strong CYP3A4 inhibitors raise levels modestly; carbamazepine lowers levels by about one third.

Contraindications. Known QT prolongation or congenital long QT syndrome, recent myocardial infarction, uncompensated heart failure, arrhythmia treated with QT-prolonging drugs, use with other QT-prolonging drugs, hypersensitivity. Boxed-warning-level increase in mortality in older adults with dementia-related psychosis.

Serious adverse effects. QT prolongation and torsades de pointes, drug reaction with eosinophilia and systemic symptoms, neuroleptic malignant syndrome, tardive dyskinesia, severe cutaneous reactions, orthostatic hypotension, seizures, priapism.

Common adverse effects. Somnolence, akathisia, nausea, dizziness, headache, extrapyramidal symptoms, dry mouth, injection site pain.

Interactions. QT-prolonging drugs (macrolides, quinolones, quinine, artemether-lumefantrine, chloroquine, methadone, ondansetron, citalopram, other antipsychotics) are avoided. Carbamazepine lowers and ketoconazole raises levels. Diuretics that cause hypokalaemia or hypomagnesaemia add risk. Antihypertensives add hypotension.

Common prescribing errors. Giving on an empty stomach; combining with other QT-prolonging drugs; not checking potassium and magnesium; using the injection beyond 3 days.

Special groups.

• Pregnancy: limited data; use only if benefit outweighs risk; third-trimester exposure can cause neonatal extrapyramidal symptoms and withdrawal.
• Breastfeeding: avoid; limited data.
• Children: not advised.
• Older adults: start low; QT and mortality risk in dementia.
• Kidney impairment: no adjustment for oral use.
• Liver impairment: use lower doses.

Formulations. Capsules 20 mg, 40 mg, 60 mg and 80 mg; injection 20 mg/mL (reconstitute with water for injection). Swallow capsules whole with a meal of at least 500 kcal.

Baseline. ECG, potassium and magnesium, weight, blood pressure, fasting glucose or HbA1c, lipids, and a baseline rating of extrapyramidal symptoms. Avoid starting if QTc is over 450 ms in men or 470 ms in women.

Monitoring. Repeat the ECG after dose increases and when an interacting drug is added; stop the drug if QTc stays over 500 ms. Check potassium and magnesium if vomiting, diarrhoea or diuretics. Weight, glucose and lipids at baseline, 12 weeks, then annually. Check extrapyramidal symptoms at each review.

Stopping. Reduce gradually over several weeks.

Referral and escalation. Refer to psychiatry for first-episode psychosis or treatment resistance. Syncope, palpitations, rash with fever, or QTc over 500 ms needs emergency care.