Risperidone

Risperidone is a second-generation (atypical) antipsychotic used for schizophrenia, bipolar mania, irritability in autism and, in short courses, severe aggression in dementia. It comes as tablets, oral solution, orally disintegrating tablets and long-acting injections. It causes dose-related extrapyramidal symptoms, marked prolactin elevation and weight gain.

Classification. Second-generation antipsychotic, benzisoxazole derivative.

Mechanism. Potent antagonism of 5-HT2A and dopamine D2 receptors, with alpha-1 and histamine H1 blockade. The active metabolite 9-hydroxyrisperidone (paliperidone) has similar activity.

Pharmacokinetics. Oral bioavailability about 70%, unaffected by food. Metabolised by CYP2D6 to 9-hydroxyrisperidone. Half-life about 3 hours for the parent drug in extensive metabolisers and about 20 hours for the active moiety.

Schizophrenia, adults (oral).

• Start 2 mg daily in one or two doses (1 mg twice daily).
• Titration: increase by 1 to 2 mg daily at intervals of at least 24 hours to 4 to 6 mg daily.
• Usual 4 to 6 mg daily; doses over 6 mg add extrapyramidal effects without added benefit. Maximum 16 mg daily.

Bipolar mania, adults. Start 2 to 3 mg once daily; adjust by 1 mg daily; usual 1 to 6 mg daily.

Older adults. Start 0.5 mg twice daily; increase by 0.5 mg twice daily to 1 to 2 mg twice daily.

Persistent aggression in dementia (short term, specialist use). 0.25 mg twice daily, increase by 0.25 mg twice daily on alternate days; usual 0.5 mg twice daily; maximum 1 mg twice daily; review at 6 weeks.

Irritability in autism, aged 5 to 17 years. Under 20 kg: start 0.25 mg daily, increase after at least 4 days to 0.5 mg. 20 kg or more: start 0.5 mg daily, increase after at least 4 days to 1 mg. Maximum 3 mg daily.

Long-acting injection (microspheres, intramuscular). After oral tolerance, 25 mg every 2 weeks; increase to 37.5 mg or 50 mg every 2 weeks if needed. Maximum 50 mg every 2 weeks. Continue oral risperidone for 3 weeks after the first injection.

Dose limits. Creatinine clearance under 30 mL/min and liver impairment: start 0.5 mg twice daily, increasing by 0.5 mg twice daily to 1 to 2 mg twice daily; long-acting injection start 12.5 to 25 mg after oral tolerance.

Contraindications. Hypersensitivity to risperidone or paliperidone. Boxed-warning-level increase in mortality in older adults with dementia-related psychosis. Caution in Parkinson disease, Lewy body dementia, cardiac disease, QT risk and stroke risk.

Serious adverse effects. Neuroleptic malignant syndrome, tardive dyskinesia, stroke in older adults with dementia, QT prolongation, orthostatic hypotension, hyperglycaemia and diabetes, marked hyperprolactinaemia, priapism, seizures, neutropenia (rare), venous thromboembolism.

Common adverse effects. Extrapyramidal symptoms (dose-related), weight gain, sedation, dizziness, raised prolactin (galactorrhoea, amenorrhoea, sexual dysfunction), tachycardia, rhinitis, raised lipids.

Interactions. Fluoxetine, paroxetine and bupropion raise active moiety levels. Carbamazepine, phenytoin and rifampicin lower levels. Clozapine and ritonavir raise levels. Antihypertensives add hypotension. Levodopa is antagonised. QT-prolonging drugs add risk.

Common prescribing errors. Using doses over 6 mg daily; failing to reduce the dose in kidney impairment; ignoring prolactin symptoms; prescribing for dementia without time limit.

Special groups.

• Pregnancy: use only if benefit outweighs risk; third-trimester exposure can cause neonatal extrapyramidal symptoms and withdrawal.
• Breastfeeding: excreted in milk at low to moderate levels; monitor the infant for sedation and extrapyramidal symptoms.
• Children: used for autism irritability from 5 years and for schizophrenia from 13 years (start 0.5 mg daily, target 3 mg, range 1 to 6 mg).
• Older adults: start 0.5 mg twice daily; stroke and mortality risk in dementia.
• Kidney impairment: when creatinine clearance is under 30 mL/min start 0.5 mg twice daily and increase by 0.5 mg twice daily to 1 to 2 mg twice daily.
• Liver impairment: start 0.5 mg twice daily and increase slowly to 1 to 2 mg twice daily.

Formulations. Tablets 0.5 mg, 1 mg, 2 mg, 3 mg and 4 mg; oral solution 1 mg/mL (do not mix with cola or tea); orally disintegrating tablets; microsphere injection 25 mg, 37.5 mg and 50 mg. Give with or without food. Reconstitute the injection with the supplied diluent and give deep gluteal or deltoid.

Baseline. Weight, BMI, waist, blood pressure, fasting glucose or HbA1c, lipids, prolactin if symptomatic, ECG if cardiac risk, and a baseline rating of extrapyramidal symptoms.

Monitoring. 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 and rate abnormal movements every 6 to 12 months. Measure prolactin if symptoms of hyperprolactinaemia occur. Check blood pressure lying and standing after dose changes.

Stopping. Reduce gradually over several weeks to limit relapse and withdrawal dyskinesia.

Referral and escalation. Refer to psychiatry for first-episode psychosis or treatment resistance after two adequate antipsychotic courses. Fever with rigidity, priapism or syncope needs emergency care.