Amisulpride

Amisulpride is a second-generation (atypical) benzamide antipsychotic used for schizophrenia in oral form and, in some regions, for postoperative nausea and vomiting as an intravenous injection. It is eliminated by the kidney, causes marked prolactin elevation and dose-related QT prolongation, and has little sedation. It is not available in the United States for oral use.

Classification. Second-generation antipsychotic, substituted benzamide.

Mechanism. Selective antagonism of dopamine D2 and D3 receptors. Low doses block presynaptic autoreceptors and may help negative symptoms; higher doses block postsynaptic receptors and treat positive symptoms.

Pharmacokinetics. Oral bioavailability about 48%. Little hepatic metabolism; about 50% is excreted unchanged in urine. Half-life about 12 hours.

All regimens are oral unless stated, with no loading dose.

Acute psychosis with positive symptoms, adults.

• Start 400 to 800 mg daily; give doses over 400 mg in two divided doses.
• Maximum 1200 mg daily.
• Duration: at least 12 months after a first episode.

Predominantly negative symptoms, adults. 50 to 300 mg once daily.

Postoperative nausea and vomiting (intravenous, licensed in some regions). Prophylaxis: 5 mg slowly over 1 to 2 minutes at induction of anaesthesia. Treatment in patients who did not receive prophylaxis: 10 mg. Maximum single dose 10 mg.

Dose limits. Creatinine clearance 30 to 60 mL/min: halve the dose. Creatinine clearance 10 to 30 mL/min: one third of the dose. Under 10 mL/min: avoid. Older adults: start low; liver impairment: no adjustment.

Contraindications. Phaeochromocytoma, prolactin-dependent tumours (prolactinoma, breast cancer), known QT prolongation, bradycardia under 55 beats/minute, uncorrected hypokalaemia, use with QT-prolonging drugs or levodopa, hypersensitivity, children under 15 years. Boxed-warning-level increase in mortality in older adults with dementia-related psychosis.

Serious adverse effects. QT prolongation and torsades de pointes, neuroleptic malignant syndrome, tardive dyskinesia, seizures, marked hyperprolactinaemia, venous thromboembolism, leucopenia (rare).

Common adverse effects. Insomnia, anxiety, extrapyramidal symptoms, raised prolactin (galactorrhoea, amenorrhoea, sexual dysfunction), weight gain, constipation, drowsiness.

Interactions. QT-prolonging drugs (halofantrine, artemether-lumefantrine, quinine, chloroquine, macrolides, quinolones, methadone, ondansetron) are avoided. Diuretics causing hypokalaemia add risk. Antihypertensives add hypotension. Levodopa is antagonised. Alcohol and sedatives add effects.

Common prescribing errors. Not reducing the dose in kidney impairment; combining with antimalarials that prolong QT; ignoring hypokalaemia; missing prolactin symptoms.

Special groups.

• Pregnancy: limited data; use only if benefit outweighs risk; third-trimester exposure can cause neonatal extrapyramidal symptoms and withdrawal.
• Breastfeeding: excreted in milk; avoid.
• Children: not advised in under 18 years.
• Older adults: start low; kidney function sets the dose; mortality risk in dementia.
• Kidney impairment: halve the dose at creatinine clearance 30 to 60 mL/min and give one third at 10 to 30 mL/min.
• Liver impairment: no adjustment.

Formulations. Tablets 50 mg, 100 mg, 200 mg and 400 mg; oral solution 100 mg/mL; injection in some regions.

Baseline. ECG, potassium and magnesium, creatinine clearance, weight, BMI, waist, blood pressure, fasting glucose or HbA1c, lipids, prolactin if symptomatic, and a baseline rating of extrapyramidal symptoms.

Monitoring. Repeat the ECG after dose increases and when an interacting drug is added; reduce or stop if QTc is over 500 ms. Repeat creatinine clearance when illness reduces fluid intake. Weight, waist, glucose and lipids at baseline, 12 weeks, then annually. Measure prolactin if symptoms occur.

Stopping. Reduce gradually over several weeks.

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