brexpiprazole

General Information

Brexpiprazole (brand Rexulti) is a second-generation (atypical) antipsychotic and dopamine-serotonin system stabilizer with lower intrinsic activity at D2 receptors than aripiprazole, designed to balance efficacy and tolerability.

This profile highlights its use in schizophrenia and in antidepressant augmentation regimens for treatment-resistant mood presentations within serious mental illness care pathways.

The contrast table can help weigh akathisia, metabolic, and sedation profiles against common alternatives, and the evidence feed can support dose adjustments and antidepressant augmentation decisions.

The schizophrenia hub can support relapse-prevention planning, and the brexpiprazole print view provides shareable counseling sheets for patients and shared-care teams.

Clinicians select brexpiprazole for once-daily dosing, relatively low akathisia rates compared with aripiprazole, and modest metabolic burden. Weight gain and akathisia remain top adverse-event drivers, but its tolerability profile supports use in outpatient schizophrenia programs and antidepressant augmentation.

Mechanism of Action

Refer to the Glossary entry on Neurotransmitters for background on receptor systems involved in serious mental illness.

Brexpiprazole modulates dopamine and serotonin signaling via partial agonism and antagonism across key receptors, combining mesolimbic dampening with mesocortical support.

Lower intrinsic activity at D2 receptors versus aripiprazole may curb akathisia, while potent 5-HT2A antagonism and 5-HT1A partial agonism contribute to antidepressant effects.

• Partial agonist at dopamine D2 and D3 receptors with low intrinsic efficacy.
• Partial agonist at serotonin 5-HT1A and antagonist at 5-HT2A/5-HT2B/5-HT7 receptors.
• Antagonist at adrenergic α1A/α1B/α2C and histamine H1 receptors.
• Minimal muscarinic receptor affinity.

Metabolism and Pharmacokinetics

• Oral bioavailability ≈95%; Tmax ~4 hours; food has minimal impact on exposure.
• Greater than 99% plasma protein bound with an apparent volume of distribution around 1.6 L/kg.
• Metabolized primarily via CYP3A4 and CYP2D6 to active metabolite DM-3411 with similar potency and half-life.
• Terminal half-life ~91 hours (brexpiprazole) and ~86 hours (DM-3411), yielding once-daily dosing and gradual washout.
• Eliminated ~25% in urine and ~46% in feces, largely as metabolites.

Dosing and Administration

• Schizophrenia (adults): titrate from 1 mg once daily (days 1–4) to 2 mg (days 5–7), then 4 mg once daily; therapeutic range 2–4 mg/day.
• Schizophrenia (adolescents 13–17): start 0.5 mg once daily, increase by 0.5–1 mg weekly to 2–4 mg/day per response and tolerability.
• Adjunctive major depressive disorder: initiate 0.5 mg once daily with antidepressant, increase to 1 mg after ≥1 week, then 2 mg/day; some patients require 3 mg/day (max 3 mg).
• Label recommends dose adjustments: halve dose with strong CYP3A4 or CYP2D6 inhibitors; quarter dose if combined inhibitors present; double dose gradually with strong CYP3A4 inducers.
• Therapeutic drug monitoring is not standard; no established serum target range.

Adverse Effects

Interactions

• Strong CYP3A4 inhibitors (ketoconazole, clarithromycin) or CYP2D6 inhibitors (fluoxetine, paroxetine, quinidine, bupropion) increase exposure; label recommends reducing brexpiprazole dose by 50% (or to 25% of usual dose if both pathways are inhibited).
• Strong CYP3A4 inducers (carbamazepine, rifampin, St. John’s wort) lower exposure; label recommends doubling the brexpiprazole dose gradually over 1–2 weeks with efficacy monitoring.
• Additive CNS depression with alcohol, benzodiazepines, opioids, or sedating antihistamines.
• May diminish response to dopamine agonists such as levodopa; this combination is often avoided in Parkinson’s disease when dopaminergic therapy is needed.

Other Useful Information

• Long half-life supports once-daily adherence but prolongs titration and discontinuation; expectation-setting about delayed onset of effect (1–2 weeks) is helpful.
• Weight, fasting glucose, and lipids are typically checked at baseline, 3 months, and annually; more frequent checks are often used in MDD augmentation where metabolic effects are amplified.
• Manage akathisia with dose adjustments, beta-blockers, or benzodiazepines; patients can be advised on early symptom recognition.
• Renal impairment (CrCl <60 mL/min) or moderate hepatic impairment warrants maximum daily dose of 3 mg for schizophrenia and 2 mg for adjunctive MDD.
• No routine ECG monitoring required, but a baseline tracing is often considered in patients with cardiac history or polypharmacy.

References

1. REXULTI (brexpiprazole) prescribing information — Otsuka Pharmaceutical Co. (2024)
2. FDA Rexulti Medr 2015
3. Efficacy AND Safety OF Brexpiprazole FOR THE Treatment OF Acute Schizophrenia: A Randomized, Double Blind, Placebo Controlled Trial — Schizophrenia Research (2015)
4. Citrome2016 Brexpiprazole Review
5. Maeda2014 Brexpiprazole Characterization
6. AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology — Pharmacopsychiatry (2018)