Brexpiprazole (Rexulti)
SGA • Last reviewed 2025-09-23
General information
Brexpiprazole is a dopamine-serotonin activity modulator approved in the United States for schizophrenia (adults) and as an adjunctive treatment for major depressive disorder (MDD) when antidepressant response is inadequate. First approved in 2015, it is marketed under the brand name REXULTI. The compound has been positioned as a successor to aripiprazole with improved tolerability, particularly regarding akathisia and insomnia, while maintaining efficacy on positive and negative symptoms of schizophrenia.
The drug is supplied as oral tablets in strengths of 0.25, 0.5, 1, 2, 3, and 4 mg. For schizophrenia the recommended starting dose is 1 mg once daily on days 1 to 4, increased to 2 mg on days 5 to 7, and adjusted to a target dose of 2 to 4 mg once daily from day 8 onward. Adjunctive MDD therapy begins at 0.5 mg or 1 mg once daily, titrated weekly up to 2 mg and, if needed, to a maximum of 3 mg daily. Dose reductions are required when coadministered with strong CYP2D6 or CYP3A4 inhibitors, and increases are needed with strong CYP3A4 inducers.
Brexpiprazole is a partial agonist at dopamine D2 and D3 receptors with lower intrinsic activity than aripiprazole, a partial agonist at 5-HT1A receptors, and an antagonist at 5-HT2A, 5-HT2B, alpha1B, and alpha2C receptors. This profile is thought to dampen dopaminergic tone without causing substantial dopamine blockade, producing antipsychotic effects with fewer extrapyramidal symptoms and prolactin changes.
The medication is metabolized primarily by CYP3A4 and CYP2D6 to active metabolites (DM-3411 and DM-3412) with pharmacologic activity similar to the parent. Peak plasma concentrations occur within 4 hours, and the terminal elimination half-life is approximately 91 hours, allowing once-daily dosing and gradual changes in plasma levels when titrating or discontinuing. Steady state is reached in 10 to 14 days.
Dosing & administration
Schizophrenia: 1 mg once daily days 1-4, 2 mg once daily days 5-7, adjust to 2-4 mg once daily from day 8 based on response and tolerability.
Adjunctive MDD: start 0.5-1 mg once daily, increase by up to 1 mg weekly; target 2 mg/day, maximum 3 mg/day.
Strong CYP2D6 or CYP3A4 inhibitors: reduce brexpiprazole dose by half; avoid exceeding 2 mg/day in schizophrenia or 1 mg/day in MDD when both pathways are inhibited.
Strong CYP3A4 inducers: double the usual dose over 1 to 2 weeks; reassess when inducer is withdrawn.
Dose adjustments
- Hepatic impairment (Child-Pugh C)
- Do not exceed 3 mg/day for schizophrenia and 2 mg/day for MDD.
- Renal impairment (CrCl <60 mL/min)
- Maximum 3 mg/day for schizophrenia and 2 mg/day for MDD.
- Strong CYP2D6 inhibitors
- Administer half the usual dose.
- Strong CYP3A4 inducers
- Increase to double the usual dose; reduce when inducer stopped.
Mechanism of action
Brexpiprazole exhibits partial agonism at D2/D3 receptors with intrinsic activity around 40% of dopamine, providing antipsychotic efficacy while limiting dopaminergic suppression in nigrostriatal pathways. The strong antagonism at 5-HT2A and 5-HT2B receptors and partial agonism at 5-HT1A receptors enhance dopaminergic transmission in prefrontal cortex, potentially benefitting mood and cognition.
Affinity for alpha1B and alpha2C receptors produces vasodilatory and noradrenergic modulation, contributing to orthostatic hypotension risk in early treatment but improving negative symptom control by dampening stress-induced catecholamine signaling.
- D2 Ki ~0.3 nM; partial agonist with low intrinsic activity.
- 5-HT1A partial agonist Ki ~0.1 nM, supporting antidepressant effects.
- 5-HT2A antagonist Ki ~0.5 nM, reducing EPS risk.
Metabolism & pharmacokinetics
Brexpiprazole displays linear pharmacokinetics across the 0.25-6 mg range. Oral bioavailability is high (~95%), and food has minimal impact on absorption. The drug is highly protein-bound (>99%).
CYP3A4 and CYP2D6 metabolism produces several metabolites; DM-3411 is active with a half-life of ~86 hours. Poor CYP2D6 metabolizers experience about 1.8-fold higher exposure, motivating lower maximum doses.
- Tmax
- ~4 h
- Terminal half-life
- ~91 h
- Protein binding
- >99%
Drug interactions
Strong CYP3A4 inhibitors (ketoconazole) and CYP2D6 inhibitors (paroxetine) increase exposure; dose reduction is required to avoid adverse effects.
Strong CYP3A4 inducers (carbamazepine, rifampin) decrease plasma levels significantly; increase dose or select an alternative.
Additive sedation may occur with CNS depressants; caution patients about impaired alertness.
| Mechanism | Agents / factors | Management |
|---|---|---|
| CYP3A4 inhibition | Ketoconazole, clarithromycin | Reduce brexpiprazole dose by 50%. |
| CYP3A4 induction | Carbamazepine, rifampin | Increase dose up to double; monitor for symptom return. |
| CYP2D6 inhibition | Fluoxetine, paroxetine, quinidine | Reduce dose by 50% and monitor for akathisia or somnolence. |
Monitoring & safety checks
Weight, BMI, fasting lipids and glucose
Baseline, 12 weeks, then annually • Modest metabolic risk relative to other SGAs but weight gain can occur.
Blood pressure and pulse
Baseline and during early titration • Monitor for orthostatic hypotension due to alpha1 blockade.
Akathisia assessment
Each visit during titration • Partial agonism can cause akathisia, especially at higher doses.
Educate patients about the long half-life; missed doses >1 week may require retitration.
Assess adherence if relapse occurs because steady-state washout takes about 14 days.
Discontinuation guidance
Gradually reduce dose over 1-2 weeks to avoid rebound insomnia, anxiety, or agitation. Because of the long half-life, dose decrements of 1 mg every few days are generally well tolerated.
If abrupt discontinuation is necessary, monitor for symptom return for at least two weeks; plasma levels decline slowly and relapse may be delayed.
Special populations
Elderly patients: titrate slowly and monitor for orthostasis and falls; efficacy in dementia-related psychosis is not established and carries increased mortality risk.
Renal impairment (CrCl <60 mL/min) or hepatic impairment (Child-Pugh C): maximum recommended dose is 3 mg/day.
Pregnancy: limited human data; third-trimester exposure may cause EPS or withdrawal in neonates; enrol in pregnancy registry when possible.
Common adverse effects
Very common (≥5%): weight gain, akathisia, nasopharyngitis, headache.
Orthostatic hypotension and somnolence are generally mild but more frequent during titration.
Prolactin elevations are uncommon compared with risperidone but can occur at higher doses.
References
- REXULTI (brexpiprazole) prescribing information — Otsuka Pharmaceutical Co. (2024)
- Brexpiprazole for the treatment of schizophrenia and major depressive disorder — Journal of Psychopharmacology (2022) DOI: 10.1177/02698811211073008
- Safety and tolerability of brexpiprazole: a pooled analysis — Journal of Clinical Psychiatry (2018) DOI: 10.4088/JCP.17m11973
Educational use only — verify details in current prescribing information and authoritative clinical guidelines before making prescribing decisions.