Aripiprazole

Aripiprazole is a second-generation antipsychotic with partial dopamine D2 agonist activity, used for schizophrenia, bipolar mania, adjunctive treatment in major depression and irritability in autism. It causes little sedation, weight gain, prolactin elevation or QT prolongation, but akathisia, insomnia and impulse-control problems are important.

Classification. Second-generation antipsychotic, dopamine partial agonist, quinolinone derivative.

Mechanism. Partial agonism at dopamine D2 and 5-HT1A receptors, with antagonism at 5-HT2A receptors. It stabilises dopamine signalling rather than blocking it.

Pharmacokinetics. Oral bioavailability about 87%, unaffected by food. Metabolised by CYP2D6 and CYP3A4 to dehydro-aripiprazole (active). Half-life about 75 hours (94 hours for the metabolite); steady state takes about 2 weeks.

Schizophrenia, adults (oral).

• Start 10 to 15 mg once daily.
• Titration: do not increase faster than every 2 weeks.
• Usual 10 to 30 mg daily. Maximum 30 mg daily.

Bipolar mania, adults. Start 15 mg once daily (30 mg if rapid control is needed); maximum 30 mg daily.

Adjunct in major depression. Start 2 to 5 mg once daily; adjust by 5 mg at intervals of at least 1 week; usual 5 to 10 mg; maximum 15 mg daily.

Acute agitation (intramuscular). 9.75 mg; range 5.25 to 15 mg; repeat after at least 2 hours; maximum 30 mg daily in all forms.

Long-acting injection (monohydrate, intramuscular). Confirm oral tolerance first. 400 mg once monthly (not sooner than 26 days after the last dose); give oral aripiprazole 10 to 20 mg daily for the first 14 days. Reduce to 300 mg monthly for adverse effects.

Adolescents aged 13 to 17 years with schizophrenia. Start 2 mg daily for 2 days, then 5 mg for 2 days, then 10 mg daily (target); maximum 30 mg daily.

Dose limits. Strong CYP2D6 inhibitors (paroxetine, fluoxetine, quinidine) or strong CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir): halve the dose; give a quarter of the dose with both. CYP2D6 poor metabolisers: halve the dose. Strong inducers (carbamazepine, rifampicin): double the dose. Kidney and liver impairment: no adjustment.

Contraindications. Hypersensitivity. Boxed-warning-level increase in mortality in older adults with dementia-related psychosis, and suicidal thinking in under 25 years for depression.

Serious adverse effects. Akathisia, neuroleptic malignant syndrome, tardive dyskinesia, impulse-control disorders (pathological gambling, compulsive shopping, binge eating, hypersexuality), orthostatic hypotension, seizures, hyperglycaemia, leucopenia (rare), dysphagia.

Common adverse effects. Akathisia, restlessness, insomnia, nausea, headache, anxiety, dizziness, somnolence (less than other antipsychotics).

Interactions. CYP2D6 and CYP3A4 inhibitors raise levels; carbamazepine and rifampicin lower them. Alcohol and sedatives add effects. Antihypertensives add hypotension. Levodopa is antagonised.

Common prescribing errors. Not adjusting for CYP inhibitors; titrating faster than every 2 weeks; mistaking akathisia for agitation and increasing the dose; not asking about gambling or compulsive behaviours.

Special groups.

• Pregnancy: limited data; use only if benefit outweighs risk; third-trimester exposure can cause neonatal extrapyramidal symptoms and withdrawal.
• Breastfeeding: avoid; it can suppress milk production and is excreted in milk.
• Children: licensed from 13 years for schizophrenia and 10 years for bipolar disorder in some regions.
• Older adults: start low; mortality risk in dementia.
• Kidney and liver impairment: no adjustment.

Formulations. Tablets 5 mg, 10 mg, 15 mg and 30 mg; orally disintegrating tablets; oral solution 1 mg/mL; injection 9.75 mg/1.3 mL; monthly depot. Give once daily with or without food.

Baseline. Weight, BMI, waist, blood pressure, fasting glucose or HbA1c, lipids, and a baseline rating of extrapyramidal symptoms and akathisia.

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 for akathisia and extrapyramidal symptoms at each review; rate abnormal movements every 6 to 12 months. Ask about impulse-control symptoms at each review.

Stopping. Reduce gradually over several weeks; the long half-life limits rebound symptoms.

Referral and escalation. Refer to psychiatry for first-episode psychosis, treatment resistance or severe akathisia. Fever with rigidity or seizures needs emergency care.