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Atypical Antipsychotic — D2/5-HT1A Partial Agonist (Schizophrenia / Adjunct MDD) Pregnancy: Avoid unless essential — risk of neonatal extrapyramidal symptoms and withdrawal in third trimester (class effect). Discuss individual risk-benefit with specialist and patient.

Brexpiprazole

Brand names: Rxulti, Rexulti

Adult dose

Dose: Schizophrenia: 2–4 mg once daily. Adjunct MDD: 0.5–3 mg once daily (starting 0.5 mg, titrate weekly)
Route: Oral
Frequency: Once daily
Max: 4 mg/day (schizophrenia); 3 mg/day (MDD adjunct)
Schizophrenia: start 1 mg on days 1–4, 2 mg on days 5–7, then 4 mg from day 8. Adjunct to antidepressants in major depressive disorder: start 0.5 mg once daily, increase weekly to response. Take with or without food. Similar aripiprazole mechanism but different receptor binding ratios. Source: BNF 90; MHRA SPC Rxulti.

Paediatric dose

Dose: Not licensed under 18 years N/A/kg
Route: N/A
Frequency: N/A
Max: N/A
Not licensed for paediatric use in the UK.

Dose adjustments

Renal

Severe renal impairment (eGFR <30 mL/min): reduce maximum dose to 3 mg/day (schizophrenia) or 2 mg/day (MDD adjunct).

Hepatic

Severe hepatic impairment (Child-Pugh C): reduce maximum dose to 3 mg/day (schizophrenia) or 2 mg/day (MDD adjunct).

Paediatric weight-based calculator

Not licensed for paediatric use in the UK.

Clinical pearls

  • Serotonin-dopamine activity modulator (SDAM) class: brexpiprazole and cariprazine represent the third generation of atypical antipsychotics after first-generation dopamine antagonists and second-generation partial agonists (aripiprazole). Brexpiprazole has lower intrinsic activity at D2 receptors than aripiprazole — less akathisia and activation, at the cost of slightly more sedation.
  • Adjunct MDD use: after 2 antidepressant failures, adding brexpiprazole to an SSRI/SNRI (augmentation) is an evidence-based strategy. VECTOR and BEACON trials demonstrated 34–50% response rates with brexpiprazole augmentation vs placebo augmentation — similar to aripiprazole augmentation. NICE NG222 acknowledges augmentation strategies for treatment-resistant depression.
  • Lower akathisia than aripiprazole: the partial agonism profile of brexpiprazole has lower intrinsic D2 activity (partial agonist efficacy ~0.71× vs aripiprazole ~0.88×) → less activation-driven akathisia. Clinically, patients who experienced akathisia on aripiprazole may tolerate brexpiprazole better.
  • ARROW trial (dementia agitation): brexpiprazole is in late-stage development for Alzheimer's-related agitation. FDA approved in 2023 for this indication (US) — first pharmacological treatment approved for this indication. Relevant for geriatric psychiatry.
  • CYP2D6 poor metabolisers: 7–10% of European population are CYP2D6 poor metabolisers — brexpiprazole levels will be significantly higher. Patients with known poor metaboliser status should start at lowest dose and titrate cautiously. Source: BNF 90; Thase et al. J Clin Psychiatry 2015 (VECTOR/BEACON); MHRA SPC Rxulti.

Contraindications

  • Hypersensitivity to brexpiprazole
  • Strong CYP3A4 + CYP2D6 inhibitor combination (significantly increases exposure — dose reduce)
  • Children under 18 years

Side effects

  • Weight gain (moderate — less than olanzapine but more than ziprasidone)
  • Akathisia (dose-dependent — lower risk than aripiprazole at lower doses)
  • Somnolence, fatigue
  • Nasopharyngitis, headache
  • Increased appetite, dyslipidaemia
  • Tardive dyskinesia (long-term use — class effect; lower risk than FGAs)

Interactions

  • Strong CYP2D6 inhibitors (paroxetine, fluoxetine): increase brexpiprazole AUC 2-fold — reduce dose by 50%
  • Strong CYP3A4 inhibitors (clarithromycin, itraconazole): increase brexpiprazole — reduce dose by 50%
  • Both CYP2D6 + CYP3A4 inhibitors together: reduce dose by 75%
  • Strong CYP3A4 inducers (rifampicin): reduce brexpiprazole levels — increase dose
  • Alcohol, CNS depressants: additive sedation

Monitoring

  • Weight and BMI at baseline, 4 weeks, 3 months, then every 6 months
  • Fasting glucose and lipid profile at baseline and annually
  • Extrapyramidal symptoms (akathisia, tardive dyskinesia screening — AIMS scale every 6 months)
  • Blood pressure and pulse
  • Mental state examination — depression and psychosis rating scales
  • Prolactin level if galactorrhoea, sexual dysfunction, or gynaecomastia reported

Reference: BNFc; BNF 90; Thase et al. J Clin Psychiatry 2015 (VECTOR/BEACON MDD trials); Citrome et al. Schizophr Res 2014; MHRA SPC Rxulti. Verify against your local formulary and the latest BNF before prescribing.

Related

Curated clinical cross-links plus same-class fallbacks.

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