Brexpiprazole
Rexulti (brand name)
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Major depressive disorder | Adults | Adjunctive to antidepressants | FDA Approved |
| Schizophrenia | Adults and pediatric patients ≥13 years | Monotherapy | FDA Approved |
| Agitation associated with dementia due to Alzheimer’s disease | Adults | Monotherapy | FDA Approved |
Brexpiprazole was first approved in 2015 for MDD adjunctive therapy and schizophrenia, followed by the Alzheimer’s disease agitation indication in 2023, making it the first and currently only atypical antipsychotic with a specific FDA approval for agitation associated with Alzheimer’s dementia. It is structurally related to aripiprazole but was designed to have lower intrinsic activity at D2 receptors, which may account for its lower incidence of akathisia and activation-related adverse effects in schizophrenia trials compared to its predecessor. Brexpiprazole is not indicated as an as-needed (PRN) treatment for Alzheimer’s agitation and is not approved for dementia-related psychosis without the specific Alzheimer’s agitation indication.
PTSD — Investigated in clinical trials; not yet FDA-approved. Evidence quality: Moderate (clinical trial data available).
Bipolar disorder — Studied in bipolar mania trials but not approved. Evidence quality: Low.
Behavioural disturbances in non-Alzheimer’s dementia — Clinical data limited; use is extrapolated from the Alzheimer’s agitation indication. Evidence quality: Low.
Dosing
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| MDD — adjunct to antidepressant | 0.5 or 1 mg QD | 2 mg QD (target) | 3 mg/day | Titrate at weekly intervals: 0.5/1 mg → 1 mg → 2 mg CYP2D6 inhibitor dose adjustment NOT required in MDD (already factored into trial dosing) |
| Schizophrenia — adult | 1 mg QD (Days 1–4) | 2–4 mg QD (target) | 4 mg/day | Titrate to 2 mg Days 5–7; may increase to 4 mg on Day 8 |
| Alzheimer’s agitation | 0.5 mg QD (Days 1–7) | 2 mg QD (target; Day 15) | 3 mg/day | 1 mg Days 8–14, then 2 mg Day 15; may increase to 3 mg after ≥14 additional days NOT indicated as PRN therapy |
Paediatric Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Schizophrenia — adolescent (13–17 years) | 0.5 mg QD (Days 1–4) | 2–4 mg QD (target) | 4 mg/day | Titrate to 1 mg Days 5–7, then 2 mg Day 8; weekly increases in 1 mg increments thereafter |
Dose Adjustments for Special Populations
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Moderate-severe hepatic impairment (Child-Pugh ≥7) | Standard titration | 2 mg (MDD/Alzheimer’s); 3 mg (schizo) | Reduced maximum dose | |
| Renal impairment (CrCl <60 mL/min) | Standard titration | 2 mg (MDD/Alzheimer’s); 3 mg (schizo) | Reduced maximum dose | |
| CYP2D6 poor metaboliser | Half the recommended dose | ~8% of Caucasians; 3–8% of Black/African Americans | ||
| Strong CYP3A4 or CYP2D6 inhibitor | Half the recommended dose | Exception: no adjustment for CYP2D6 inhibitors in MDD (paroxetine/fluoxetine already used in trials) | ||
| Both CYP2D6 + CYP3A4 inhibitors (or CYP2D6 PM + CYP3A4 inhibitor) | Quarter the recommended dose | Most restrictive dose reduction | ||
| Strong CYP3A4 inducer | Double the recommended dose over 1–2 weeks | If inducer discontinued, reduce to original dose over 1–2 weeks | ||
A unique feature of brexpiprazole prescribing is that dose adjustment for strong CYP2D6 inhibitors (e.g. paroxetine, fluoxetine) is not required when used for MDD. This is because the pivotal MDD clinical trials did not adjust brexpiprazole doses for patients taking these CYP2D6 inhibitors as their background antidepressant, so the MDD dosing recommendations already incorporate this exposure. However, CYP2D6 inhibitor dose adjustments still apply for the schizophrenia and Alzheimer’s agitation indications.
Pharmacology
Mechanism of Action
Brexpiprazole is a serotonin-dopamine activity modulator that acts as a partial agonist at 5-HT1A and D2 receptors and an antagonist at 5-HT2A receptors. It is structurally and mechanistically related to aripiprazole but has key pharmacological differences: brexpiprazole displays lower intrinsic activity (greater functional antagonism) at D2 receptors, higher affinity for 5-HT1A receptors (Ki 0.12 nM), and more potent antagonism at 5-HT2A receptors (Ki 0.47 nM) and noradrenergic alpha-1B/alpha-2C receptors. This receptor profile may explain its lower propensity for akathisia and activation-type side effects compared to aripiprazole in schizophrenia populations, while maintaining meaningful antidepressant augmentation and antipsychotic efficacy. Brexpiprazole does not significantly prolong the QTc interval at clinically relevant doses.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Tmax ~4 h; absolute bioavailability 95%; food does not significantly affect Cmax or AUC; dose-proportional PK across dose range | Exceptionally high oral bioavailability for an antipsychotic; can be taken with or without food with no impact on exposure |
| Distribution | Vd = 1.56 L/kg; >99% protein-bound | Extensive extravascular distribution; high protein binding unlikely to produce displacement interactions |
| Metabolism | CYP3A4 and CYP2D6 (both contribute significantly); major metabolite DM-3411 (inactive at D2 in clinically relevant concentrations); not a substrate of P-gp or BCRP | Dual CYP dependence creates a complex interaction profile requiring dose adjustments for inhibitors of either pathway and further reduction when both are inhibited; CYP2D6 PM status requires dose halving |
| Elimination | t½ ~91 h (brexpiprazole), ~86 h (DM-3411); steady state 10–12 days; apparent oral clearance 19.8 mL/h/kg; excretion ~25% urine, ~46% faeces | Very long half-life supports once-daily dosing and provides some protection against relapse from missed doses; effects persist for days after discontinuation |
Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Akathisia (MDD adjunct) | 9% vs 2% placebo | Dose-related; the most clinically significant AE in MDD adjunctive use; incidence increases with higher doses and faster titration |
| Weight increased (MDD adjunct) | 7% vs 2% placebo | Mean +1.3 to +1.6 kg at 6 weeks; long-term: +2.9 kg at 26 weeks, +3.1 kg at 52 weeks; 30% had ≥7% gain long-term |
| Somnolence (MDD adjunct) | 5% vs 0.5% placebo | Includes sedation and hypersomnia; more prominent than in schizophrenia trials |
| Weight increased (schizophrenia adults) | 10–11% (≥7% gain) vs 4% placebo | Mean +1.0 to +1.2 kg at 6 weeks; the only AE meeting the ≥4%/twice-placebo threshold in adult schizophrenia |
| EPS (schizophrenia pediatric) | ≥5% and 2× placebo | Non-akathisia EPS was the primary AE meeting the threshold in adolescent schizophrenia trials |
| Somnolence (schizophrenia pediatric) | 16% vs 5% placebo | Substantially higher rate in adolescents than in adults (5% vs 3%); requires careful monitoring in paediatric use |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Akathisia (schizophrenia adults) | 6% vs 5% placebo | Notably close to placebo rate — a key differentiator from aripiprazole; marketed advantage of brexpiprazole |
| EPS (MDD adjunct) | 6% vs 3% placebo | Non-akathisia EPS including tremor, parkinsonism |
| Headache | 5–9% | Common across indications; often similar to or slightly below placebo rate |
| Insomnia | 3–7% | More prominent in schizophrenia trials |
| Nasopharyngitis | 4–5% (Alzheimer’s agitation) | One of only two AEs meeting 4%/twice-placebo threshold in Alzheimer’s agitation trials |
| Dizziness | 4–5% (Alzheimer’s agitation) | Second AE meeting threshold in Alzheimer’s agitation trials; related to alpha-1 antagonism |
| Restlessness (MDD) | 4% vs 2% | Related to akathisia spectrum but distinguished as separate term |
| Constipation | 2–4% | Across indications; generally mild |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Neuroleptic malignant syndrome | Very rare | Days to weeks | Immediate discontinuation; ICU supportive care |
| Tardive dyskinesia | Rare | Months to years | Consider discontinuation; screen with AIMS periodically |
| Pathological gambling / Compulsive behaviours | Rare | Any time during treatment | Ask patients about new urges; consider dose reduction or discontinuation |
| Suicidal thoughts/behaviours (MDD) | See boxed warning | Early weeks or dose changes | Close monitoring in patients <25 years; not approved for paediatric MDD |
| Leukopenia / Neutropenia | Rare | First months | Monitor CBC in patients with pre-existing low WBC; discontinue if ANC <1000/mm³ |
| Cerebrovascular events (elderly with dementia) | Increased risk (class effect) | Any time | Not approved for dementia-related psychosis without Alzheimer’s agitation indication |
While short-term weight gain with brexpiprazole is moderate (mean +1.0 to +1.6 kg at 6 weeks), long-term data reveal substantial cumulative weight gain: +2.9 kg at 26 weeks and +3.1 kg at 52 weeks in MDD, with 30% of patients experiencing ≥7% body weight increase. In schizophrenia, long-term gain is +1.3 kg at 26 weeks and +2.0 kg at 52 weeks with 20% having ≥7% increase. Proactive dietary counselling and exercise recommendations should accompany prescribing, particularly in MDD augmentation where patients may already have metabolic risk factors.
Drug Interactions
Brexpiprazole is metabolised by both CYP3A4 and CYP2D6, creating a dual-pathway interaction profile that is more complex than drugs dependent on a single CYP enzyme. The critical distinction is that both pathways contribute meaningfully, so inhibition of either pathway alone necessitates dose halving, while inhibition of both pathways simultaneously requires a quarter-dose reduction.
Monitoring
- Body Weight & BMIBaseline, monthly for 3 months, then quarterly
RoutineThe most important monitoring parameter. Long-term: 30% of MDD patients and 20% of schizophrenia patients had ≥7% weight gain. Monitor paediatric patients for weight gain vs normal growth using z-scores. - Fasting Glucose & HbA1cBaseline, 12 weeks, then annually
RoutineShort-term glucose shifts similar to placebo. Long-term: 5% (MDD) and 8% (schizo) of patients with normal baseline developed high fasting glucose. Standard APA/ADA monitoring applies. - Lipid PanelBaseline, 12 weeks, then annually
RoutineTriglycerides may shift from normal to high in 5–13% (MDD) and 8–10% (schizo) of patients. Cholesterol and LDL shifts similar to placebo in short-term trials. - EPS / AkathisiaEach visit
RoutineAkathisia notably lower in schizophrenia (6% vs 5% placebo) compared to MDD adjunctive use (9% vs 2%). AIMS every 6–12 months for tardive dyskinesia screening. - Compulsive BehavioursEach visit
RoutineAsk about new or intensified urges (gambling, shopping, eating, sexual behaviour). Consider dose reduction or discontinuation if identified. - Suicidality AssessmentWeekly for first 4 weeks, then at dose changes
Trigger-BasedRequired for patients <25 years; brexpiprazole is not approved for paediatric MDD. - Renal & Hepatic FunctionBaseline
RoutineMaximum dose is reduced in CrCl <60 mL/min and moderate-severe hepatic impairment. Re-check periodically in at-risk patients.
Contraindications & Cautions
Absolute Contraindications
- Known hypersensitivity to brexpiprazole or any component (reactions include rash, facial swelling, urticaria, and anaphylaxis)
Relative Contraindications (Specialist Input Recommended)
- Dementia-related psychosis without Alzheimer’s-specific agitation — increased mortality; not approved for this broader population
- Paediatric MDD — safety and effectiveness not established in paediatric patients with MDD
Use with Caution
- History of seizures or conditions lowering seizure threshold
- Patients at risk for falls — somnolence, orthostatic hypotension
- Patients at risk for aspiration — dysphagia has been reported
- Exposure to extreme heat — thermoregulation impairment possible
- Known CYP2D6 poor metabolisers — require dose halving
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death (4.5% vs 2.6% in placebo). Brexpiprazole is not approved for the treatment of patients with dementia-related psychosis without agitation associated with dementia due to Alzheimer’s disease.
Antidepressants increased the risk of suicidal thoughts and behaviours in paediatric and young adult patients in short-term studies. Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts. Safety and effectiveness of brexpiprazole have not been established in paediatric patients with MDD.
Patient Counselling
Purpose of Therapy
Brexpiprazole works by adjusting the balance of dopamine and serotonin activity in the brain. For depression, it is added to an existing antidepressant to boost its effect. For schizophrenia, it reduces psychotic symptoms. For Alzheimer’s-related agitation, it helps reduce distressing behavioural symptoms. Improvement may begin within 1–2 weeks, but full benefit often takes 4–6 weeks.
How to Take
Take brexpiprazole once daily with or without food. Swallow the tablet whole. The dose is started low and gradually increased. Do not stop taking it abruptly without discussing with your prescriber.
Sources
- Otsuka Pharmaceutical Co., Ltd. REXULTI (brexpiprazole) Prescribing Information. Revised May 2025. FDA LabelPrimary source for all dosing, indications, contraindications, adverse reaction data, weight gain tables, and CYP interaction tables in this monograph.
- Thase ME, Youakim JM, Skuban A, et al. Efficacy and safety of adjunctive brexpiprazole 2 mg in major depressive disorder: a phase 3, randomized, placebo-controlled study in patients with inadequate response to antidepressants. J Clin Psychiatry. 2015;76(9):1224-1231. doi:10.4088/JCP.14m09688Pivotal Pyxis trial supporting the MDD adjunctive indication at the 2 mg target dose.
- Thase ME, Youakim JM, Skuban A, et al. Adjunctive brexpiprazole 1 and 3 mg for patients with major depressive disorder following inadequate response to antidepressants: a phase 3, randomized, double-blind study. J Clin Psychiatry. 2015;76(9):1232-1240. doi:10.4088/JCP.14m09689Pivotal Polaris trial establishing efficacy at 3 mg and providing dose-response data for MDD.
- Correll CU, Skuban A, Ouyang J, et al. Efficacy and safety of brexpiprazole for the treatment of acute schizophrenia: a 6-week randomized, double-blind, placebo-controlled trial. Am J Psychiatry. 2015;172(9):870-880. doi:10.1176/appi.ajp.2015.14101275Pivotal Vector trial demonstrating efficacy at 2 mg and 4 mg for acute schizophrenia with safety data.
- Kane JM, Skuban A, Ouyang J, et al. A multicenter, randomized, double-blind, controlled phase 3 trial of fixed-dose brexpiprazole for the treatment of adults with acute schizophrenia. Schizophr Res. 2015;164(1-3):127-135. doi:10.1016/j.schres.2015.01.038Second pivotal schizophrenia trial providing confirmatory efficacy and safety at 1 mg, 2 mg, and 4 mg doses.
- Grossberg GT, Kohegyi E, Mergel V, et al. Efficacy and safety of brexpiprazole for the treatment of agitation in Alzheimer’s dementia: two 12-week, randomized, double-blind, placebo-controlled trials. Am J Geriatr Psychiatry. 2020;28(4):383-400. doi:10.1016/j.jagp.2019.09.009Key registration trials supporting the Alzheimer’s agitation indication approved in 2023.
- American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia, 3rd edition. Am J Psychiatry. 2021;178(suppl). doi:10.1176/appi.books.9780890424841Current APA guideline including brexpiprazole among antipsychotic options for schizophrenia.
- American Psychiatric Association. Practice guideline for the treatment of major depressive disorder, 3rd edition. Am J Psychiatry. 2010;167(suppl):1-152. doi:10.1176/appi.books.9780890423387.654001APA guideline for MDD management providing framework for antipsychotic augmentation strategies; predates brexpiprazole’s approval but contextualises the treatment approach.
- Maeda K, Sugino H, Akazawa H, et al. Brexpiprazole I: in vitro and in vivo characterization of a novel serotonin-dopamine activity modulator. J Pharmacol Exp Ther. 2014;350(3):589-604. doi:10.1124/jpet.114.213793Foundational preclinical study establishing brexpiprazole’s receptor-binding profile and lower D2 intrinsic activity compared to aripiprazole.
- Citrome L. Brexpiprazole: a new dopamine D2 receptor partial agonist for the treatment of schizophrenia and major depressive disorder. Drugs Today. 2015;51(7):397-414. doi:10.1358/dot.2015.51.7.2358605Comprehensive clinical review covering pharmacokinetics, CYP interaction profile, and number-needed-to-treat/harm analyses from pivotal trials.
- Das S, Bhattacharjee D, Bhattacharyya S. Brexpiprazole: a review of a new treatment option for schizophrenia and major depressive disorder. Health Psychol Res. 2018;6(1):5987. doi:10.4081/hpr.2018.5987Clinical review comparing akathisia and weight gain rates across pivotal MDD and schizophrenia trials with adverse effect frequency data.