Brexpiprazole
Brexpiprazole
Generic Name
Brexpiprazole
Brand Names
*Rexulti*) is a third‑generation antipsychotic with a unique pharmacological profile. It serves as a partial agonist at dopamine D₂/D₃ and serotonin 5‑HT₁A receptors, with a moderate antagonist effect at 5‑HT₂A receptors. Approved by the FDA for the adjunctive and monotherapy treatment of schizophrenia and as monotherapy for depressive episodes in major depressive disorder (MDD) with adjunctive use of antidepressants.
Mechanism
- D₂/D₃ receptor partial agonism – provides antipsychotic efficacy while minimizing dopamine‑depleting side effects.
- 5‑HT₁A partial agonism – contributes to antidepressant and anxiolytic effects.
- 5‑HT₂A antagonism – reduces extrapyramidal symptoms (EPS) and contributes to cognitive benefit.
- Low affinity for histamine H₁, adrenergic α₁, and muscarinic receptors → minimal sedation, weight gain, or anticholinergic burden.
Pharmacokinetics
- Absorption: Oral bioavailability ~55 %; peak plasma concentration (Tmax) in 1‑3 h.
- Distribution: High plasma protein binding (~98 %; albumin & α1‑acid glycoprotein).
- Metabolism: Primarily hepatic via CYP2D6 (major) and CYP3A4 (minor).
- Elimination: Renal (≈30 %) and fecal (≈70 %); terminal half‑life ~90 h (steady‑state ~4–5 days).
- Drug interactions: Significant with CYP2D6 inhibitors (e.g., fluoxetine, paroxetine) and inducers (e.g., carbamazepine). Avoid concomitant use with strong CYP3A4 inhibitors (e.g., ketoconazole).
Indications
- Schizophrenia – adjunctive or monotherapy.
- Major depressive disorder – adjunctive antidepressant in adults with documented inadequate response to psychotherapy or pharmacotherapy.
- Off‑label: treatment‑resistant bipolar depression, tic disorders (off‑label; emerging data).
Contraindications
- Contraindications: hypersensitivity to brexpiprazole or any excipient; serious liver disease (Child‑Pugh B/C).
- Warnings/Precautions:
- *Extrapyramidal symptoms* – dose‑related risk, especially in elderly or Parkinsonian patients.
- *Metabolic syndrome* – modest weight gain (≈1–2 kg); monitor BMI/waist circumference.
- *Serotonin syndrome* – when combined with serotonergic agents (SSRIs, SNRIs, MAOIs).
- *Cardiovascular* – QTc prolongation (rare); avoid in patients with congenital long QT or concurrent QT‑prolonging drugs.
- *Neuroleptic malignant syndrome* – rare; advise patients of symptoms.
- *Suicidality* – monitor depressed patients closely for emergent suicidal ideation.
Dosing
| Condition | Starting Dose | Target Dose | Titration Schedule | Max Dose |
| Schizophrenia | 1 mg PO daily | 2–4 mg PO daily | Increase by 1 mg every 1–2 weeks | 6 mg |
| MDD adjunctive | 0.5 mg PO daily | 2 mg PO daily | Increase by 0.5–1 mg every 1–2 weeks | 6 mg |
• Initiate at the lowest dose; titrate slowly to minimize EPS.
• Administer with or without food; food increases absorption slightly.
• For renal or hepatic impairment, dose adjustment is not recommended unless severe hepatic disease; monitor closely.
Adverse Effects
Common (≥10 %)
• Akathisia
• Dry mouth
• Headache
• Insomnia
• Nausea
Less common (1–10 %)
• Dizziness
• Weight gain
• Hyperglycemia
• Hyperlipidemia
Serious (≤1 %)
• Neuroleptic malignant syndrome (NMS)
• Severe EPS (rigidity, dystonia)
• Thyroid dysfunction (rare hyperthyroidism)
• Severe QT prolongation (rare)
• Suicidal ideation in susceptible populations
Patient education: report sudden movements, fever with rigidity, or any suicidal thoughts immediately.
Monitoring
| Parameter | Frequency | Rationale |
| Weight, BMI, waist circumference | Every 3–6 months | Assess metabolic effects |
| Fasting glucose, HbA1c | Baseline, 3 months, then annually | Identify hyperglycemia |
| Lipid panel | Baseline, 6–12 months | Monitor dyslipidemia |
| Liver function tests | Baseline, every 3–6 months (if impaired) | Detect hepatic toxicity |
| ECG (QTc) | Baseline for high‑risk patients; then annually | Screen for QT prolongation |
| EPS score | Baseline, then at 1, 3, and 6 months | Detect early motor side‑effects |
| Suicidality assessment | Every visit | Monitor emerging suicidal ideation |
Clinical Pearls
- Titration matters: a 0.5‑mg weekly increase is safer for a geriatric population; rapid dose jumps heighten akathisia risk.
- Metabolic vigilance: unlike other atypicals, brexpiprazole’s weight gain is usually mild, but still monitor glucose and lipids, especially in obese patients.
- Drug–drug interactions: because of CYP2D6 liability, fluoxetine can double brexpiprazole exposure—consider a 1‑mg lower starting dose if co‑administered.
- Suicidality screening: while not a major risk, include brexpiprazole on MDD monitoring charts; document baseline PHQ‑9 or equivalent.
- Pregnancy category: not recommended; avoid in pregnancy unless clear benefit outweighs risk; counsel women of childbearing potential regarding contraception.
- Elderly patients: start at 0.5 mg and consider stepping down after 2–3 months if stable to reduce EPS.
- Off‑label use in tic disorders: evidence is emerging; consider when conventional therapy fails, but weigh the benefit‑to‑risk profile carefully.
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• Brexpiprazole offers a balanced antipsychotic‑antidepressant mechanism with a favorable side‑effect profile, making it a valuable option for patients with schizophrenia and depression requiring pharmacologic augmentation.