Brexpiprazole Guide: Pharmacology, Indications, Dosing Guidelines and Adverse Effects

In a nutshell

Brexpiprazole is a second-generation antipsychotic and dopamine partial agonist. Consider it after akathisia or activation on aripiprazole, when a partial agonist is still the goal: brexpiprazole activates D2 less, so less of both is possible, not proven. In schizophrenia and depression, aripiprazole usually comes first when it has not been tried, given its ranking in recent network meta-analyses and its generic price ^[1–8]

Unlike aripiprazole, brexpiprazole is FDA-approved for agitation in Alzheimer’s dementia, with a small average benefit. In schizophrenia trials it was neither activating nor sedating ^[2,9–12]

The trade-offs are modest efficacy, dose-related akathisia in depression, weight gain of about 2 to 3 kg over a year in open-label studies, and a brand-only US price near $18,000 a year ^{[5,8,9,12–16]}

• When to consider brexpiprazole:
  • Akathisia or activation on aripiprazole, when the goal is to stay on a partial agonist ^[1,2]
    • Less akathisia than aripiprazole is possible, not proven (see Side effects) ^[5,6]
  • Agitation in Alzheimer’s dementia that persists after non-pharmacologic approaches ^[9,17,18]
    • Aim for 2 mg and allow up to 12 weeks to judge the response ^[9,14]
    • Discuss the boxed mortality warning with the family ^[9]
  • MDD with inadequate response to antidepressants, as a first-line add-on in the 2023 CANMAT update, as is aripiprazole ^[9,19]
  • Schizophrenia, as one of several options when tolerability is the priority, including adolescents from 13 (see Indications › Clinical positioning) ^[5,9,20]
• Consider alternatives when:
  • Aripiprazole has not been tried
    • In depression, aripiprazole ranked higher on response and acceptability in a 2026 network meta-analysis, on point estimates ^[7]
    • In schizophrenia, aripiprazole had mid-range efficacy in a 2026 network meta-analysis, while brexpiprazole fell in the low-efficacy group ^[5]
  • Akathisia already limits treatment and a partial agonist is not essential
    • Akathisia is one of the most common adverse reactions in adjunctive depression, where it rose with dose ^[9]
  • A larger effect on acute psychotic symptoms is the priority: olanzapine, risperidone, or amisulpride (where available) may be preferred ^[5]
  • Weight gain would be a problem: in schizophrenia trials, aripiprazole, cariprazine and lurasidone gained less weight than brexpiprazole, short and long term, on point estimates with overlapping intervals ^[5,21]
  • Cost or formulary access is decisive: brand only in practice in the US ^[8]

Pharmacodynamics and mechanism of action

• Brexpiprazole is a partial agonist at dopamine D2 and serotonin 5-HT1A receptors, and an antagonist at serotonin 5-HT2A receptors and at alpha-1B and alpha-2C adrenergic receptors ^[3,9]
  • The label suggests efficacy could come from D2 and 5-HT1A partial agonism with 5-HT2A antagonism ^[9]
  • It has higher 5-HT1A and 5-HT2A affinity than aripiprazole ^[4,9,10]
    • These actions are proposed to offset akathisia and extrapyramidal symptoms ^[4]
    • On PET, though, 5-HT1A occupancy was negligible (see below) ^[22]

• Lower D2 intrinsic activity and akathisia
  • Brexpiprazole activates D2 less than aripiprazole ^[3,4]
    • This is expected to generate less activation and less akathisia ^[4]
    • In humans this remains unproven (see Side effects) ^[5,6]
• Receptor profile ^{[3–5,9,22,23]}
  • On PET at steady state in patients with schizophrenia, occupancy was high at D2 (64% at 1 mg/day and 80% at 4 mg/day), moderate at 5-HT2A (28% and 45%) and negligible at 5-HT1A (under 5% at 4 mg), in a small industry-funded study ^[22]

Target	Affinity	Action	Clinical relevance
Dopamine D2	●●●●○	Partial agonist with low intrinsic activity	Antipsychotic effect
5-HT1A	●●●●○	Partial agonist	Part of the label’s efficacy hypothesis, though occupancy on PET was negligible
5-HT2A	●●●●○	Antagonist	Proposed to lower extrapyramidal risk, a contested theory: parkinsonism still rises with dose
Alpha-1B and alpha-2C	●●●●○	Antagonist	Orthostatic hypotension (1% or less) and orthostasis-related dizziness (2% to 3%)
Dopamine D3	●●●○○	Partial agonist	No measurable occupancy at 4 mg
5-HT2B, 5-HT7, alpha-1A and alpha-1D	●●●○○	Antagonist	Clinical relevance unknown
H1	●●○○○	Binding only	Possible contributor to the modest somnolence (see Side effects)
Muscarinic M1	●○○○○	Binding only	Low anticholinergic burden (see Side effects)

Affinity dots group the published binding affinities (Ki): ●●●●○ subnanomolar, ●●●○○ nanomolar, ●●○○○ moderate, ●○○○○ low ^[3,9]

Pharmacokinetics and Drug Interactions

Metabolism

• Brexpiprazole is metabolized mainly by CYP3A4 and CYP2D6 ^[9]

• Known CYP2D6 poor metabolizers: halve the dose, and quarter it with a strong or moderate CYP3A4 inhibitor ^[9]
  • Genotyping is not routine; in known poor metabolizers the pharmacogenetics guideline also recommends a dose reduction ^[24]

Half-life

• Half-life about 4 days (91 hours) ^[9]
• A dose change is fully reflected in plasma after about two weeks: steady state comes in 10 to 12 days ^[9]
  • Side effects can appear a week or two after an increase, a practical inference from the time to steady state ^[9]
• After stopping, the drug washes out in 1 to 2 weeks ^[25]

Absorption and food

• Once daily, with or without food (see Dosage forms) ^[9]

Drug interactions

Pharmacokinetic interactions

• Halve the dose when one pathway is blocked, quarter it when both are, double it with a strong CYP3A4 inducer ^[9]

Scenario	Brexpiprazole dose
Strong CYP2D6 inhibitor (e.g., fluoxetine, paroxetine, bupropion)	Half
Strong CYP3A4 inhibitor (e.g., nefazodone, clarithromycin, itraconazole, ketoconazole)	Half
A strong or moderate inhibitor of both CYP3A4 and CYP2D6 (e.g., fluoxetine, paroxetine or duloxetine with erythromycin, fluconazole or verapamil)	A quarter
Strong CYP3A4 inducer (e.g., carbamazepine, phenytoin, St John’s wort, rifampin)	Double over 1 to 2 weeks; back down over 1 to 2 weeks when the inducer stops
A single moderate inhibitor of either enzyme	No adjustment in the label

Doses from the US label; examples from the EU label and the FDA’s list of interacting drugs ^[9,25,26]

• When an inhibitor stops, return to the original dose ^[9]
• Adjunctive MDD: no adjustment for strong CYP2D6 inhibitors such as fluoxetine or paroxetine, because the trials did not adjust for them; still, favor 1 to 2 mg with them, a practical inference from the FDA’s review ^[9,27]
  • In that review of the depression trials, akathisia at 3 mg reached 24% with fluoxetine or paroxetine vs. 11% with other antidepressants, without more discontinuations; the reviewer advised halving the dose, and the label did not adopt it ^[9,27]
  • A known CYP2D6 poor metabolizer still takes half the dose in depression ^[9]
• Brexpiprazole as a perpetrator: other drugs need no adjustment; it had no clinically relevant effect on the substrates tested ^[9]

Pharmacodynamic interactions

• Other antipsychotics:
  • Switching to brexpiprazole: consider gradual cross-titration (see Indications › Schizophrenia) ^[25]
  • Switching away: stop brexpiprazole and start the next antipsychotic at its lowest dose; no cross-titration is needed ^[25]
• Additive orthostasis with antihypertensives: check orthostatic vital signs, especially during titration ^[9,25]
• Alcohol and other centrally acting drugs: use caution ^[25]

Dosage forms

• Tablets: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg and 4 mg ^[9]
  • The 0.25 mg and 0.5 mg strengths cover the quarter and half doses with CYP interactions (see Pharmacokinetics); 0.5 mg is also a starting dose in depression, adolescent schizophrenia and dementia agitation (see Indications) ^[9]
  • Every strength costs the same, about $49.50 a tablet (about $18,000 a year), so a lower dose saves nothing ^[8]
    • Brand cariprazine costs about the same; generic aripiprazole standard tablets cost 12 to 18 cents each ^[8]
• Formulation considerations
  • Take once daily, with or without food ^[9]
  • Tablets are unscored; a half or quarter of a 3 mg dose takes two tablets (1 mg plus 0.5 mg, or 0.5 mg plus 0.25 mg) ^[9]

Indications

Clinical positioning

• Efficacy is modest in all three indications, and the main trade-offs are akathisia in depression and weight gain over the first year (see Side effects) ^[5,13–16]
• Adjunctive MDD: first-line in the 2023 CANMAT update, as is aripiprazole ^[19]
  • The US Veterans Affairs guideline lists augmentation with a second-generation antipsychotic among four unranked options after partial or no response ^[28]
• Schizophrenia: one of several options, as the APA guideline favors no antipsychotic over another, clozapine possibly aside ^[20]
• Agitation in Alzheimer’s dementia: only after non-pharmacologic approaches; the Canadian label also limits it to aggressive behavior ^[29,30]
  • The Beers criteria advise avoiding antipsychotics for behavioral problems of dementia unless documented non-pharmacologic options have failed or the patient threatens substantial harm to self or others ^[18]
• Most reasonable when:
  • Akathisia or activation on aripiprazole is the reason to switch, and the goal is to stay on a partial agonist ^[1,2]
    • Less akathisia or activation than aripiprazole is possible, not proven (see Side effects) ^[2,5,6]
  • Tolerability is the priority over maximal efficacy in schizophrenia ^[5]
  • Agitation in Alzheimer’s dementia persists after non-drug approaches, and the family accepts a small average benefit and the mortality warning ^[9,17]
• Prefer alternatives:
  • When a larger effect on acute psychotic symptoms is the priority (olanzapine, risperidone, or amisulpride where available) ^[5]
  • When tolerability is the priority in schizophrenia and aripiprazole has not been tried
    • The 2026 network meta-analysis suggests aripiprazole, which keeps mid-range efficacy ^[5]
    • The 2025 INTEGRATE guidelines point the same way: with first-episode psychosis and no patient preference, they recommend a drug with a lower side-effect burden, such as a D2 partial agonist (e.g., aripiprazole), and their dosing table includes brexpiprazole ^[31]
  • When augmentation with aripiprazole has not been tried
    • Same CANMAT tier, and aripiprazole ranked higher on response and acceptability in a 2026 network meta-analysis, with overlapping intervals ^[7,19]
  • When weight gain is unacceptable
    • Aripiprazole, cariprazine, lurasidone and ziprasidone gained less weight than brexpiprazole in short-term schizophrenia trials, on point estimates ^[5]
    • All four had lower point estimates than brexpiprazole in schizophrenia trials longer than 13 weeks, with overlapping intervals (see Side effects) ^[21]
  • When an antipsychotic is not acceptable for agitation in dementia
    • Dextromethorphan-bupropion has the same indication without an antipsychotic’s mortality warning ^[32]
  • When cost or access is decisive: generic aripiprazole costs cents a tablet, and brexpiprazole is brand only (see Dosage forms) ^[8]

FDA-Approved Indications

Major depressive disorder, adjunctive to antidepressants (adults)

• Approved as adjunctive therapy to antidepressants for MDD in adults ^[9]
  • Trial patients had failed one to three antidepressant courses in the current episode and then an 8-week prospective antidepressant course ^[9]
  • Efficacy rests on four positive 6-week trials ^[9,33–36]
    • Effect size: small, a standardized mean difference of 0.20 vs. placebo at week 6 in a meta-analysis ^[13]
    • 1 mg did not separate, and functioning did not separate in the later trials ^[9,35,36]
    • Number needed to treat for response: 12 in the two label trials, and 17 in a meta-analysis that also included unpublished trials ^[13,37]
    • Patients with anxious distress responded at least as well, in a prespecified subgroup of one trial and in two sponsor-funded post hoc analyses ^[35,38,39]
  • A 24-week trial missed its remission endpoint and did not separate on MADRS at week 6; longer-term data are open-label ^[16,40]
• How it compares with the other approved add-ons
  • CANMAT lists akathisia and weight gain as common to brexpiprazole and aripiprazole ^[19]
  • In a 2026 network meta-analysis of the approved adjunctive antipsychotics ^[7]
    • Response: third, behind lumateperone and aripiprazole, with overlapping intervals
    • Acceptability: third, behind aripiprazole and cariprazine, and more patients stopped treatment than on placebo
• Dosing ^[9]
  • Starting dose: 0.5 mg or 1 mg once daily, added to the antidepressant; prefer 0.5 mg when akathisia is a concern ^[41]
  • Titration: 1 mg, then 2 mg, at weekly intervals
  • Target dose: 2 mg once daily
  • Maximum dose: 3 mg/day
  • Dose tip: stay at 2 mg; efficacy peaked around 2 mg in a dose-response meta-analysis, and 3 mg doubled akathisia in the label’s pooled fixed-dose trials (14% vs. 7%, arms from different trials) ^[9,42]

Schizophrenia

• Approved for the treatment of schizophrenia in adults and in adolescents from 13 years ^[9]
  • Adolescents: approved in 2021 by extrapolation from adult data ^[43,44]
    • A later 6-week trial was positive at 2 to 4 mg ^[9,45]
• How it compares with other antipsychotics in schizophrenia
  • Efficacy: in the low-efficacy group of a 2026 network meta-analysis of 24 antipsychotics, with lumateperone, iloperidone, cariprazine and lurasidone ^[5]
  • Tolerability: the same analysis found the partial agonists, brexpiprazole included, better tolerated overall than dopamine antagonists ^[5]
  • Versus aripiprazole
    • Head to head, reported non-inferior on symptoms at 6 weeks, with similar adverse events, in one Otsuka-sponsored, double-blind trial in China ^[46,47]
    • An earlier network meta-analysis of short-term trials found no significant difference on any outcome in its primary analysis ^[6]
    • Less akathisia is possible, not proven (see Side effects) ^[5,6]
• Dosing in adults ^[9]
  • Starting dose: 1 mg once daily on days 1 to 4
  • Titration: 2 mg on days 5 to 7, then up to 4 mg from day 8
  • Target dose: 2 to 4 mg once daily
  • Maximum dose: 4 mg/day
  • Dose tip: reach 2 mg, and go to 4 mg if response falls short and tolerability allows ^[9,48–50]
• Dosing in adolescents (13 to 17 years) ^[9]
  • Starting dose: 0.5 mg once daily on days 1 to 4
  • Titration: 1 mg on days 5 to 7, 2 mg on day 8, then weekly steps of 1 mg
  • Target dose: 2 to 4 mg once daily
  • Maximum dose: 4 mg/day
• Switching to brexpiprazole:
  • Consider a gradual cross-titration over about 4 weeks ^[25,51]
  • Switches from aripiprazole rarely failed, while switches from olanzapine need more care, as serious adverse events led to stopping, in a sponsor-authored post hoc analysis ^[52]

• A 2025 systematic review found no randomized comparison of switching strategies for brexpiprazole ^[53]

  • Gradual: fewer adverse events than faster switches, with similar improvement, in one sponsor-authored post hoc analysis ^[51]
  • Plateau: about one in ten stopped for adverse events when switching from olanzapine, risperidone or paliperidone, in a single-arm, open-label study ^[54]

• Patients with treatment-resistant schizophrenia failed the switch more often, in a retrospective series ^[55]

• Switching from brexpiprazole:

  • Stop it and start the new antipsychotic at its lowest dose; no cross-titration is needed, as brexpiprazole washes out in 1 to 2 weeks ^[25]

Agitation associated with dementia due to Alzheimer’s disease

• Approved in May 2023 as the first drug for this indication ^[56]
  • Carries the class boxed warning on mortality: deaths were more frequent than on placebo in the 12-week trials, an excess the FDA judged consistent with the class (see Side effects) ^[9,57]
• What the benefit means in practice
  • Expect a small average improvement: 3 to 6 points on the 29 to 203 agitation scale across two meta-analyses, and a new trial could plausibly show none ^[9,11,12]
  • Weigh it against slightly worse parkinsonism ratings and the mortality warning (see Side effects) ^[9,11]
  • The balance is debated
    • A consumer group argued the benefit does not outweigh the risk ^[58]
    • The joint advisory committee voted 9 to 1 that the data identify a population in whom benefits outweigh risks ^[59]
  • A larger benefit with co-occurring psychotic symptoms remains a hypothesis: 9.2 vs. 4.2 points over placebo, with overlapping intervals, in a sponsor-authored exploratory post hoc analysis; dementia-related psychosis without agitation is not an approved use ^[9,60]
• Dosing ^[9]
  • Starting dose: 0.5 mg once daily on days 1 to 7
  • Titration: 1 mg on days 8 to 14, then 2 mg from day 15
  • Target dose: 2 mg once daily
  • Maximum dose: 3 mg/day, only after at least 14 days at 2 mg
  • Dose tip:
    • Do not settle at 1 mg: it did not separate from placebo in the US label’s trial and is not approved in the US ^[9]
    • Allow up to 12 weeks before judging response: separation from placebo took 6 to 12 weeks, and the optimal length of a trial is unknown ^[14]
    • Give it daily; it is not for as-needed use

Off-label and emerging uses

• Post-traumatic stress disorder: not approved, and with efficacy not established, not a reasonable off-label choice ^[61,62]
  • The FDA declined to approve brexpiprazole started together with sertraline after its advisory committee voted 10 to 1, in July 2025, that efficacy had not been established ^[61,62]
  • Two of three trials were positive (about 5 CAPS-5 points over sertraline alone); a meta-analysis of four trials pooled 3.8 points, with no difference on the clinician’s global severity rating and 1.5 kg of weight gain ^[63–66]
• Other studied uses, all negative or preliminary
  • Bipolar I mania: two phase 3 trials negative ^[67]
  • Borderline personality disorder: a phase 2 trial missed its primary endpoint, with akathisia in 14% vs. 1%; a small academic trial separated only at week 12, with heavy dropout ^[68,69]
  • Irritability in autism spectrum disorder: effectiveness not shown, with more somnolence and weight gain ^[9,70]

Side effects

In schizophrenia trials, brexpiprazole was neither activating nor sedating ^[2]

Weight gain over the first year is larger than the short-term trials suggest (open-label data): in depression most of it comes in the first 6 months, and in schizophrenia it continues through the year ^[9,15,16]

Akathisia is one of the most common adverse reactions in adjunctive depression, where it rose with dose ^[9,37]

Most common side effects

Akathisia

• Dose-related in adjunctive depression: 4%, 7% and 14% at 1, 2 and 3 mg vs. 2% on placebo; restlessness rose with dose too ^[9]
• Close to placebo in the other indications (schizophrenia 4% to 7% vs. 5%; dementia agitation 1% vs. 0%; adolescents 4% vs. 3%) ^[9,37]
• Long-term rates differed between studies ^[16,71]
• With fluoxetine or paroxetine, watch for akathisia as the dose rises (see Pharmacokinetics) ^[27]
• Management
  • Step down the dose first ^[72]
  • In depression, start at 0.5 mg rather than 1 mg (less akathisia in a cross-trial comparison) ^[41]
  • Adjunctive treatment: mirtazapine (15 mg once daily) or propranolol (10 to 30 mg two to three times daily) are the usual add-ons, with low confidence and no evidence of long-term efficacy ^[31,72,73]
    • Choose by profile: mirtazapine is sedating, and propranolol needs blood pressure checks as the dose rises ^[20,72]
    • A short course of a benzodiazepine, or high-dose vitamin B6, might also help, with very low confidence ^[72,73]
    • Anticholinergics are not routinely recommended, and they add cognitive and anticholinergic effects ^[72]
• Versus the other partial agonists: less akathisia than aripiprazole is possible, not proven ^[5,6]
  • In acute schizophrenia:
    • A 2026 network meta-analysis placed brexpiprazole in the lower-risk group, and aripiprazole and cariprazine in the higher one ^[5]
    • Direct comparisons with aripiprazole pointed the same way, without reaching significance ^[5]
  • In depression, the data are mixed and all indirect ^[2,41,74]

Extrapyramidal symptoms other than akathisia

• Slightly above placebo in each adult indication (depression 6% vs. 3%; schizophrenia 5% vs. 4%; dementia agitation 3% vs. 2%) ^[9]
• Tremor (depression 4% vs. 2%) ^[9]
• In older adults with dementia, parkinsonism ratings worsened slightly in two meta-analyses ^[11,75]

Psychiatric

• Somnolence (depression 4% vs. 1%; schizophrenia 5% vs. 3%; dementia agitation 3% vs. 1%) ^[9]
  • Among the least sedating antipsychotics in acute schizophrenia, with cariprazine, aripiprazole and lurasidone ^[5]
• Insomnia (dementia agitation 4% vs. 3%; 9% over a year of open-label treatment in schizophrenia) ^[9,15]

Gastrointestinal

• Nausea, dyspepsia, diarrhea, constipation, increased appetite and dry mouth, all slightly above placebo ^[9]

Cardiovascular

• Orthostatic hypotension 1% or less and syncope 0.1% to 0.2%, at or near placebo ^[9]
  • The risk is greatest during titration, so check orthostatic vital signs in vulnerable patients
• Dizziness (depression 3% vs. 1%; dementia agitation 3% vs. 2%) ^[9]
• QTc: no clinically relevant prolongation at 3 to 4 times the maximum dose ^[9]
  • Among the antipsychotics with the smallest QTc effect in the 2026 network meta-analysis ^[5]

Severe or rare side effects

Metabolic changes

• Weight gain: modest at first, larger over a year
  • At 6 weeks: +1.0 to +1.6 kg vs. +0.2 to +0.3 kg on placebo; almost none in older adults with dementia over 12 weeks ^[9,37,76]
  • Over a year, in open-label studies: about +2 to +3 kg, with 19% to 30% of patients gaining 7% or more; fewer than half completed the year ^[9,15,16]
  • Adolescents: track weight against expected growth ^[9]
• Versus aripiprazole and cariprazine: more gain on point estimates in schizophrenia trials, short and long term (figures below) ^[5,21]
  • Short term: +1.0 kg over placebo vs. +0.6 kg for both in a 2026 network meta-analysis; in another, brexpiprazole gained weight over placebo while aripiprazole and cariprazine did not ^[5,77]
  • Long term: +1.9 kg vs. +0.4 kg and +0.6 kg in trials longer than 13 weeks, with a wide interval for brexpiprazole that crossed zero ^[21]

• Glucose and lipids:
  • Short-term shifts close to placebo, except slightly more triglyceride rises ^[9]
    • Among the five most benign metabolic profiles in a short-term network meta-analysis, with no worsening of mean values ^[77]
  • Shifts to high values in long-term open-label studies, with no comparison group ^[9]
    • Fasting glucose: 9% to 10% of those normal or borderline at baseline (20% in a 12-week dementia extension)
    • Triglycerides: 13% to 17% of those normal at baseline
• Monitoring per label: fasting glucose and lipids at baseline and periodically; weight at baseline and often ^[9]

Prolactin

• Small rises, mainly in women ^[78]
• In adolescents: in a 6-week trial, 29% of girls and 21% of boys shifted above the normal range vs. 5% and 7% on placebo ^[9]
  • In the long-term open-label adolescent study, the FDA noted a high incidence of abnormal prolactin values, with no comparison group ^[43]
• Sexual-function scores improved over a year of open-label adjunctive treatment in depression, in observed cases (fewer than half completed) and with no comparison group ^[16]

Impulse-control disorders

• The label warns of new intense urges (gambling, sexual urges, shopping, binge eating):
  • Ask patients and caregivers from the first follow-up
  • Reports with a recorded onset cluster early (median 8 days) ^[79]
  • Consider reducing or stopping the drug if they appear ^[9]

Mortality in older adults with dementia

• The agitation indication did not remove the boxed warning: discuss the mortality risk with the family and weigh it against the small benefit (see Indications) ^[9]

Tardive dyskinesia and other class warnings

• Class warnings apply, including tardive dyskinesia (rare in a year-long trial), neuroleptic malignant syndrome, seizures, dysphagia and body-temperature dysregulation ^[9,15]

Other rare reactions

• Hematologic: leukopenia and neutropenia as for the class ^[9]
  • With a low white-cell or neutrophil count before treatment, or a history of drug-induced leukopenia or neutropenia, check the blood count often during the first few months, as the label advises ^[9]
  • Stop if the absolute neutrophil count falls below 1000/mm³ ^[9]
• Suicidal thoughts and behaviors: as a treatment for depression, it carries the antidepressant boxed warning for patients aged 24 and younger; monitor closely at the start and after dose changes ^[9]
• Hypersensitivity is the only contraindication in the US label; reactions have included rash, facial swelling, urticaria and anaphylaxis ^[9]

Use in special populations

Pregnancy

• Discuss pregnancy plans and contraception before starting ^[80]
  • The EU does not recommend brexpiprazole during pregnancy or in women of childbearing potential not using contraception ^[25]
• Human pregnancy data on brexpiprazole are too few to estimate risk
  • Five exposed pregnancies in published case reports and series ^[81–83]
  • Spontaneous reports of pregnancy-related adverse events, which cannot show how often problems occur ^[84]
• Third-trimester exposure carries the class risk of neonatal extrapyramidal and withdrawal signs: monitor the newborn ^[9]
  • In a US registry, about a third of infants exposed to second-generation antipsychotics had at least one sign of poor neonatal adaptation, a rate similar to that after an SSRI or SNRI (preliminary data) ^[85]
• Manage by shared decision-making, weighing the risks of stopping treatment, including relapse ^[9,86]

Breastfeeding

• Prefer another agent for a patient who wants to breastfeed:
  • Stop the partial agonist during breastfeeding, or do not breastfeed if it must continue, a class review suggests; the review draws mostly on aripiprazole and calls the evidence not clear-cut ^[84]
  • If brexpiprazole continues, watch milk supply and infant weight
    • For brexpiprazole, reduced supply rests on a few pharmacovigilance reports and occasional formula supplementation in a three-infant series ^[82,84]
• No lactation study ^[9]
  • One case on three antipsychotics put the relative infant dose below 1.1%, under the 10% conventionally considered compatible; too few to establish safety ^[83,87]
  • Infant outcomes: no withdrawal or serious adverse events in the first month in a three-infant series, and normal growth to 6 months in one exclusively breastfed infant ^[81,82]
• Reassess the infant once a new dose reaches steady state (10 to 12 days), and expect exposure to persist for 1 to 2 weeks after a stop ^[9,25,87]

Hepatic impairment

• Mild (Child-Pugh A): no dose adjustment ^[9]
• Moderate or severe (Child-Pugh B or C):
  • Maximum 2 mg/day in depression and dementia agitation, 3 mg/day in schizophrenia ^[9]

Renal impairment

• Creatinine clearance below 60 mL/min:
  • Maximum 2 mg/day in depression and dementia agitation, 3 mg/day in schizophrenia ^[9]
• Dialysis: no dosing guidance in the label ^[9]

Older adults

• Start at the low end of the dosing range: only 3% of schizophrenia and depression trial patients were 65 or over ^[9]
  • Many stopped for adverse events in open-label depression studies ^[71,88]
    • 18% of older adults over 26 weeks ^[88]
    • More than half of those aged 65 or over who were new to brexpiprazole, over a year at a fixed 2 mg (18 of 31) ^[71]
• Watch for falls: assess fall risk at the start and periodically on long-term treatment when illness or other drugs add to sedation, orthostasis or unsteadiness ^[9]
• Before raising the dose for agitation, bear in mind that akathisia in an older patient can be mistaken for agitation
• Tardive dyskinesia risk is highest in older adults, especially older women ^[9]

Brand names

• US: Rexulti ^[9]
  • Brand only in practice: twelve generic applications are approved, but no generic is priced in the national acquisition-cost survey as of October 2026 ^[8,89]
    • With pediatric exclusivity, patents run to June 2029 (substance) and April 2033 (one product patent) ^[89]
• Canada: Rexulti ^[29]
• Other countries/regions: Rxulti (European Union); Rexulti (Japan, Australia, Switzerland); Rexulti, Brexil, Laplex, Brexan and Bremidan (Argentina); no UK product listed on the electronic medicines compendium (emc) ^{[25,30,90–95]}
• Practical differences among the labels checked:
  • Adjunctive depression is an indication only in the US, Canadian, Japanese and Argentine labels ^{[9,25,29,30,90–92]}
  • Agitation in Alzheimer’s dementia is approved in the US and Japan; in Canada, Australia and Switzerland only after non-drug approaches fail (Canada also requires aggressive behavior); not in the EU ^{[9,25,29,30,90,91]}
  • Like the US label, the EU and Swiss labels cover schizophrenia from 13 years; the Canadian and Australian labels, adults only ^{[9,25,29,30,91]}
  • The Japanese label doses every indication at 2 mg/day or less, half the US schizophrenia maximum of 4 mg, and uses 1 mg as the usual dose for dementia agitation ^[9,90]

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