Brexpiprazole

Brexpiprazole is a second-generation antipsychotic and dopamine partial agonist, used for schizophrenia, as an adjunct in major depression and, in some regions, agitation in Alzheimer dementia. It resembles aripiprazole with less akathisia but more weight gain. Availability is limited in many regions.

Classification. Second-generation antipsychotic, serotonin-dopamine activity modulator.

Mechanism. Partial agonism at dopamine D2 and 5-HT1A receptors, with antagonism at 5-HT2A and noradrenergic alpha-1B/2C receptors.

Pharmacokinetics. Oral bioavailability about 95%, unaffected by food. Metabolised by CYP3A4 and CYP2D6. Half-life about 91 hours (metabolite 86 hours); steady state in 10 to 12 days.

All regimens are oral with no loading dose.

Schizophrenia, adults.

• Days 1 to 4: 1 mg once daily; days 5 to 7: 2 mg once daily; from day 8: 4 mg once daily.
• Target 2 to 4 mg daily. Maximum 4 mg daily.
• Duration: at least 12 months after a first episode.

Adjunct in major depression, adults. Start 0.5 mg or 1 mg once daily; increase at weekly intervals to a target of 2 mg daily; maximum 3 mg daily.

Agitation in Alzheimer dementia (licensed in some regions). Start 0.5 mg daily for 7 days, then 1 mg daily for 7 days, then 2 mg daily; maximum 3 mg daily.

Dose limits. CYP2D6 poor metabolisers, or strong CYP2D6 or CYP3A4 inhibitors: halve the dose; give a quarter of the dose with both. Strong CYP3A4 inducers (rifampicin, carbamazepine): double the dose over 1 to 2 weeks. Creatinine clearance under 60 mL/min or moderate to severe liver impairment: maximum 3 mg daily (2 mg for depression).

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. Neuroleptic malignant syndrome, tardive dyskinesia, impulse-control disorders, orthostatic hypotension, seizures, hyperglycaemia, dyslipidaemia, leucopenia (rare).

Common adverse effects. Akathisia, weight gain, somnolence, headache, nasopharyngitis, dizziness.

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

Common prescribing errors. Not adjusting for CYP2D6 inhibitors or kidney impairment; titrating too fast; missing weight gain.

Special groups.

• Pregnancy: limited data; use only if benefit outweighs risk; third-trimester exposure can cause neonatal extrapyramidal symptoms and withdrawal.
• Breastfeeding: limited data; avoid unless benefit is clear.
• Children: limited data; licensed from 13 years for schizophrenia in some regions.
• Older adults: start low; mortality risk in dementia.
• Kidney impairment: maximum 3 mg daily when creatinine clearance is under 60 mL/min.
• Liver impairment: maximum 3 mg daily in moderate to severe impairment.

Formulations. Tablets 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg and 4 mg. 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.

Stopping. Reduce gradually over several weeks.

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