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Brexpiprazole
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Brexpiprazole
Clinical data
Pronunciation/brɛkˈspɪprəzoʊl/ brek-SPIP-rə-zohl
Trade namesRexulti, Rxulti, others
Other namesOPC-34712
AHFS/Drugs.comMonograph
MedlinePlusa615046
License data
Pregnancy
category
Routes of
administration		By mouth
Drug classAtypical antipsychotic
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability95% (Tmax = 4 hours)[10]
Protein binding>99%
MetabolismLiver (mainly mediated by CYP3A4 and CYP2D6)
Elimination half-life91 hours (brexpiprazole), 86 hours (major metabolite)
ExcretionFeces (46%), urine (25%)
Identifiers
  • 7-[4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy]quinolin-2(1H)-one
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.242.305 Edit this at Wikidata
Chemical and physical data
FormulaC25H27N3O2S
Molar mass433.57 g·mol−1
3D model (JSmol)
  • O=C5/C=C\c4ccc(OCCCCN3CCN(c1cccc2sccc12)CC3)cc4N5
  • InChI=1S/C25H27N3O2S/c29-25-9-7-19-6-8-20(18-22(19)26-25)30-16-2-1-11-27-12-14-28(15-13-27)23-4-3-5-24-21(23)10-17-31-24/h3-10,17-18H,1-2,11-16H2,(H,26,29)
  • Key:ZKIAIYBUSXZPLP-UHFFFAOYSA-N

Brexpiprazole, sold under the brand name Rexulti among others, is an atypical antipsychotic medication used for the treatment of major depressive disorder, schizophrenia, and agitation associated with dementia due to Alzheimer's disease.[10][12][13]

The most common side effects include akathisia (a constant urge to move) and weight gain.[11] The most common side effects among people with agitation associated with dementia due to Alzheimer's disease include headache, dizziness, urinary tract infection, nasopharyngitis, and sleep disturbances (both somnolence and insomnia).[12]

Brexpiprazole was developed by Otsuka and Lundbeck, and is considered to be a successor to aripiprazole (Abilify).[14] It was approved for medical use in the United States in July 2015.[15][16] A generic version was approved in August 2022.[17] Brexpiprazole is the first treatment approved by the US Food and Drug Administration (FDA) for agitation associated with dementia due to Alzheimer's disease.[12]

Medical uses

[edit]
brexpiprazole blister pack

In the United States and Canada, brexpiprazole is indicated as an adjunctive therapy to antidepressants for the treatment of major depressive disorder and for the treatment of schizophrenia.[7][10][18][19] In May 2023, the indication for brexpiprazole was expanded in the US to include the treatment of agitation associated with dementia due to Alzheimer's disease.[12]

In Australia and the European Union, brexpiprazole is indicated for the treatment of schizophrenia.[2][11]

In 2020, it was approved in Brazil only as an adjunctive to the treatment of major depressive disorder.[20][21]

Side effects

[edit]

The most common adverse events associated with brexpiprazole (all doses of brexpiprazole cumulatively greater than or equal to 5% vs. placebo) were upper respiratory tract infection (6.9% vs. 4.8%), akathisia (6.6% vs. 3.2%), weight gain (6.3% vs. 0.8%), and nasopharyngitis (5.0% vs. 1.6%).[22] Brexpiprazole can cause impulse control disorders.[23]

Pharmacology

[edit]

Pharmacodynamics

[edit]
See also: Atypical antipsychotic § Pharmacodynamics, and Antipsychotic § Comparison of medications

It exerts its pharmacodynamic actions mainly by modulating signaling of multiple serotonin, dopamine and noradrenaline receptors.

Brexpiprazole[24][25][26][27]
Site Human Ki (nM) IA (%) Action Ref
SERTTooltip Serotonin transporter 65% at 10 μM Blocker [25]
NETTooltip Norepinephrine transporter 0% at 10 μM Blocker [25]
DATTooltip Dopamine transporter 90% at 10 μM Blocker [25]
5-HT1A 0.12 ~60% Partial agonist [25]
5-HT1B 32 ND [25]
5-HT2A 0.47 Antagonist [25]
5-HT2B 1.9 Antagonist [25]
5-HT2C 34 Antagonist [25]
5-HT5A 140 ND [25]
5-HT6 58 Antagonist [25]
5-HT7 3.7 Antagonist [25]
D1 160 ND [25]
D2L 0.30 ~45% Partial agonist [25]
D3 1.1 ~15% Partial agonist [25]
D4 6.3 ND [25]
D5 66% at 1 μM ND ND
α1A 3.8 Antagonist [25]
α1B 0.17 Antagonist [25]
α1D 2.6 Antagonist [25]
α2A 15 Antagonist [25]
α2B 17 Antagonist [25]
α2C 0.59 Antagonist [25]
β1 59 Antagonist [25]
β2 67 Antagonist [25]
β3 >10,000 ND [25]
H1 19 Antagonist [25]
H2 >10,000 ND [25]
H3 >10,000 ND [25]
mAChTooltip Muscarinic acetylcholine receptor 52% at 10 μM ND [25]
  M1 67% at 10 μM ND [25]
  M2 >10,000 ND [25]
σ 96% at 10 μM ND [25]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site. Most or all data are for human cloned proteins.

IA = Intrinsic Activity

Brexpiprazole acts as a partial agonist of the serotonin 5-HT1A receptor and the dopamine D2 and D3 receptors.[25] Brexpiprazole is a less stimulating partial agonist of the dopamine receptors than its predecessor, aripiprazole, potentially decreasing its risk for agitation and restlessness.[25] Brexpiprazole has a high affinity for the 5-HT1A receptor, acting as a potent antagonist at 5-HT2A receptors, and a potent partial agonist at dopamine D2 receptors with lower intrinsic activity compared to aripiprazole.[28][29] In vivo characterization of brexpiprazole shows that it may act as a near-full agonist of the 5-HT1A receptor. This may further underlie a lower potential than aripiprazole to cause treatment-emergent, movement-related disorders such as akathisia due to the downstream dopamine release that is triggered by 5-HT1A receptor agonism. It is also an antagonist of the serotonin 5-HT2A, 5-HT2B, and 5-HT7 receptors, which may contribute to antidepressant effect. It also binds to and blocks the α1A-, α1B-, α1D-, and α2C-adrenergic receptors.[25] The drug has negligible affinity for the muscarinic acetylcholine receptors, and hence has no anticholinergic effects.[25] Although brexpiprazole has less affinity for H1 compared to aripiprazole, weight gain can occur.[30]

History

[edit]

Clinical trials

[edit]

Brexpiprazole was in clinical trials for adjunctive treatment of major depressive disorder, adult attention deficit hyperactivity disorder, bipolar disorder,[31] schizophrenia,[32] and agitation associated with dementia due to Alzheimer's disease.[12]

Major depressive disorder

[edit]
Phase II
[edit]

The phase II multicenter, double-blind, placebo-controlled study randomized 429 adult MDD patients who exhibited an inadequate response to one to three approved antidepressant treatments (ADTs) in the current episode. The study was designed to assess the efficacy and safety of brexpiprazole as an adjunctive treatment to standard antidepressant treatment. The antidepressants included in the study were desvenlafaxine, escitalopram, fluoxetine, paroxetine, sertraline, and venlafaxine.[33]

Phase III
[edit]

A phase III study was in the recruiting stage: "Study of the Safety and Efficacy of Two Fixed Doses of OPC-34712 as Adjunctive Therapy in the Treatment of Adults With Major Depressive Disorder (the Polaris Trial)".[34] Its goal is "to compare the effect of brexpiprazole to the effect of placebo (an inactive substance) as add on treatment to an assigned FDA approved antidepressant treatment (ADT) in patients with major depressive disorder who demonstrate an incomplete response to a prospective trial of the same assigned FDA approved ADT". Estimated enrollment was 1250 volunteers.

Adult attention deficit hyperactivity disorder

[edit]
  • Attention Deficit/Hyperactivity Disorder (STEP-A)[35]

Schizophrenia

[edit]
Phase I
[edit]
  • Trial to Evaluate the Effects of OPC-34712 (brexpiprazole) on QT/QTc in Subjects With Schizophrenia or Schizoaffective Disorder[36]
Phase II
[edit]
  • A Dose-finding Trial of OPC-34712 in Patients With Schizophrenia[37]
Phase III
[edit]
  • Efficacy Study of OPC-34712 in Adults With Acute Schizophrenia (BEACON)[38][39]
  • Study of the Effectiveness of Three Different Doses of OPC-34712 in the Treatment of Adults With Acute Schizophrenia (VECTOR)[40]
  • A Long-term Trial of OPC-34712 in Patients With Schizophrenia[41]

Agitation associated with dementia due to Alzheimer's disease

[edit]

The effectiveness of brexpiprazole for the treatment of agitation associated with dementia due to Alzheimer's disease was determined through two 12-week, randomized, double-blind, placebo-controlled, fixed-dose studies.[12] In these studies, participants were required to have a probable diagnosis of Alzheimer's dementia; have a score between 5 and 22 on the Mini-Mental State Examination, a test that detects whether a person is experiencing cognitive impairment; and exhibit the type, frequency, and severity of agitation behaviors that require medication.[12] Trial participants ranged between 51 and 90 years of age.[12]

Society and culture

[edit]
[edit]

In January 2018, it was approved for the treatment of schizophrenia in Japan.[42]

Economics

[edit]

In November 2011, Otsuka Pharmaceutical and Lundbeck announced a global alliance.[43]

Patents

[edit]

Research

[edit]

Brexpiprazole was under development for the treatment of attention deficit hyperactivity disorder (ADHD) as an adjunct to stimulants, but was discontinued for this indication.[45][46][47] It reached phase II clinical trials for this use prior to discontinuation.[47]

Brexpiprazole has shown promise in clinical trials for the treatment of borderline personality disorder.[48]

References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Brexpiprazole

View on Grokipedia
from Grokipedia
Brexpiprazole is an medication approved for the treatment of in adults and adolescents aged 13 years and older, as an adjunctive therapy to antidepressants for in adults, and for the treatment of agitation associated with due to . It is marketed under the brand name Rexulti and is available in oral tablet form in strengths of 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg. Brexpiprazole functions as a serotonin- activity modulator, exhibiting activity at D2 and D3 receptors as well as serotonin 5-HT1A receptors, while acting as an at serotonin 5-HT2A, 5-HT2B, 5-HT7, and α1-adrenergic receptors. This pharmacological profile contributes to its efficacy in managing positive and negative symptoms of , depressive symptoms when added to standard antidepressants, and agitation in Alzheimer's-related , with a lower risk of extrapyramidal side effects compared to some other antipsychotics due to its D2 receptor affinity (Ki = 0.30 nM). The drug is highly bound to plasma proteins (>99%) and primarily metabolized by and enzymes, with an elimination of approximately 91 hours. Developed jointly by and , brexpiprazole received initial FDA approval on July 10, 2015, for and , with the indication for Alzheimer's agitation approved in May 2023. Common adverse effects include , , and , and it carries boxed warnings for increased mortality in elderly patients with dementia-related and suicidal thoughts and behaviors in children, adolescents, and young adults, as well as warnings for risks of cerebrovascular events, , and . Brexpiprazole is contraindicated in patients with known to the drug or its components and requires dosage adjustments in cases of hepatic or renal impairment or when co-administered with or inhibitors/inducers.

Medical uses

Schizophrenia

Brexpiprazole was approved by the U.S. in July 2015 as a monotherapy for the treatment of in , specifically to address both positive symptoms such as hallucinations and delusions, and negative symptoms such as social withdrawal and blunted affect. In January 2022, the approval was expanded to include adolescents aged 13 years and older, with in this population established through from data, supported by pharmacokinetic bridging and pediatric studies. As a serotonin-dopamine activity modulator that acts as a at dopamine D2 receptors, it provides stabilization of activity to alleviate these core symptoms of the disorder. The recommended starting dose for in adults is 1 mg orally once daily for the first four days, followed by to 2 mg once daily from days 5 to 7, and then to 4 mg once daily starting on day 8, based on clinical response and tolerability. For adolescents aged 13 to 17 years, the starting dose is 0.5 mg once daily on days 1 to 4, increasing to 1 mg once daily on days 5 to 7, and to 2 mg once daily starting on day 8, with further increases of 1 mg at weekly intervals if needed. The ranges from 2 to 4 mg once daily for both adults and adolescents, with a maximum of 4 mg per day; dose reductions to 3 mg daily may be considered for patients with moderate to severe hepatic or renal impairment or those who are poor metabolizers of CYP2D6. Administration should occur with or without food, and the medication is available in tablet form for once-daily dosing to support adherence. Efficacy in acute schizophrenia was established in two pivotal 6-week, randomized, double-blind, -controlled Phase III trials involving adults with acute exacerbations. In these studies, brexpiprazole at 2 mg and 4 mg daily doses demonstrated statistically significant improvements in Positive and Negative Syndrome Scale (PANSS) total scores compared to , with least squares mean changes of -20.7 and -19.7 points versus -12.0 points, respectively, in one trial (p<0.01 for both doses). These improvements were observed as early as week 1 and sustained through week 6, indicating rapid and clinically meaningful reductions in overall symptom severity. For long-term management, a 52-week, randomized, double-blind, placebo-controlled maintenance trial (NCT01668797) in stable adults with schizophrenia showed that brexpiprazole (2-4 mg/day) significantly delayed time to relapse compared to placebo, with a relapse rate of 13.3% versus 38.5% (hazard ratio 0.30; p<0.0001). The median time to relapse exceeded 58 weeks for brexpiprazole-treated patients versus 24 weeks for placebo, supporting its role in preventing symptom exacerbation and promoting sustained remission over one year. Open-label extensions from short-term trials further confirmed maintenance of PANSS improvements up to 52 weeks in responders.

Major depressive disorder

Brexpiprazole is approved by the U.S. Food and Drug Administration (FDA) as an adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD) in adults who have an inadequate response to antidepressant therapy during the current episode. This approval was granted on July 10, 2015. Patient selection typically involves individuals with MDD who exhibit a partial response, defined as less than 50% improvement in symptoms after treatment with one to three adequate antidepressant regimens of sufficient duration, generally at least 6 weeks at an appropriate dose. The recommended starting dosage of brexpiprazole for adjunctive treatment of MDD is 0.5 mg or 1 mg orally once daily, administered alongside ongoing antidepressant therapy. The dose should be titrated weekly based on clinical response and tolerability, with a target of 2 mg once daily; the maximum recommended dose is 3 mg once daily. Brexpiprazole can be taken with or without food, and dosage adjustments are advised for patients with moderate to severe hepatic or renal impairment. Efficacy as adjunctive therapy was established in two multicenter, randomized, double-blind, placebo-controlled phase III trials involving adults with MDD and inadequate response to antidepressants. In these 6-week studies, the primary efficacy endpoint was the change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Adjunctive brexpiprazole at 2 mg/day resulted in a least squares mean change of -8.4 points compared to -5.2 points for placebo plus antidepressant therapy (difference: -3.2; 95% CI: -4.9 to -1.5; p < 0.001). In the second trial, 3 mg/day yielded a change of -8.3 points versus -6.3 points for placebo (difference: -2.0; 95% CI: -3.4 to -0.5; p = 0.01). These improvements were maintained across secondary endpoints, including response and remission rates. Brexpiprazole's antidepressant effects are attributed in part to its partial agonism at serotonin 5-HT1A receptors.

Bipolar I disorder

Brexpiprazole is not approved by regulatory authorities, including the FDA, for the treatment of . However, preliminary evidence from small-scale clinical studies indicates potential utility as an off-label adjunctive therapy for depressive episodes in adults with this condition, particularly when combined with mood stabilizers such as or . These investigations have explored its role in alleviating depressive symptoms without addressing acute manic or mixed episodes, emphasizing instead the control of depressive features in stable patients. A key open-label pilot study evaluated brexpiprazole in 21 adults with bipolar I or II disorder experiencing a depressive episode (baseline Montgomery-Åsberg Depression Rating Scale [MADRS] score ≥25). Participants received brexpiprazole as monotherapy or adjunctively, starting at 0.5 mg/day and titrated flexibly up to 4 mg/day based on tolerability and response, with most reaching 2-3 mg/day. Over 8 weeks, the treatment led to significant reductions in depressive symptoms, as evidenced by decreases in MADRS total scores from baseline at weeks 4 and 8 (mean change approximately -12.5 points at endpoint, p<0.001). Improvements were also observed in self-reported depressive symptoms via the Inventory of Depressive Symptomatology-Self-Report (IDS-SR30) and quality of life measures, without notable worsening of manic symptoms (Young Mania Rating Scale scores remained stable). No participants developed acute mania during the trial, supporting its potential for depressive symptom maintenance rather than acute phase intervention. Adverse effects were mild, primarily akathisia and weight gain, consistent with its partial agonist profile at dopamine D2 receptors. Larger randomized controlled trials are needed to confirm efficacy and optimal dosing (typically 1-3 mg/day in exploratory use), as current data are limited to small cohorts and off-label applications. Brexpiprazole's mood-stabilizing effects may stem from its antipsychotic properties, including modulation of serotonin and dopamine pathways, though these are detailed elsewhere.

Agitation in Alzheimer's disease

In May 2023, the U.S. Food and Drug Administration (FDA) approved brexpiprazole (Rexulti) as the first medication specifically for the treatment of agitation associated with dementia due to in adults. This supplemental approval addresses a significant unmet need in managing behavioral symptoms that affect patient safety, caregiver burden, and quality of life in this population. The recommended dosing regimen begins with 0.5 mg once daily for the first 7 days, followed by an increase to 1 mg once daily for days 8 through 14, and then to a target dose of 2 mg once daily starting on day 15. Dosage adjustments of 0.5 mg increments or decrements can be made at intervals of at least 14 days based on clinical response and tolerability, with a maximum daily dose of 3 mg. This flexible approach allows for individualized titration to balance efficacy and side effects in elderly patients. Approval was supported by results from the pivotal phase 3 trial (NCT03548584), a 12-week, randomized, double-blind, placebo-controlled study involving 345 patients aged 55 to 90 years with probable Alzheimer's disease and moderate-to-severe agitation unresponsive to non-pharmacological interventions. In this trial, brexpiprazole at 2 mg or 3 mg daily led to a 32% reduction in Cohen-Mansfield Agitation Inventory (CMAI) total scores from baseline, compared to a 19% reduction with placebo, demonstrating statistically significant improvement (least-squares mean difference: -5.32 points; P = .003). Patient selection emphasized those with agitation behaviors meeting International Psychogeriatric Association criteria, including physical or verbal aggression, and a Mini-Mental State Examination score of 5 to 22 indicating moderate to severe cognitive impairment. Brexpiprazole also showed a lower risk of extrapyramidal symptoms compared to other antipsychotics, with an incidence of 3.5% versus 0% for placebo.

Adverse effects

Common adverse effects

The most common adverse effects of brexpiprazole, defined as those occurring in more than 5% of patients in clinical trials, include , weight gain, somnolence, and headache. Akathisia, characterized by subjective feelings of restlessness, has an incidence of 4-14% across doses in patients with major depressive disorder (MDD) as adjunctive therapy, with a dose-dependent pattern (4% at 1 mg, 7% at 2 mg, and 14% at 3 mg versus 2% placebo). In schizophrenia trials, akathisia occurred in 6% of patients versus 5% with placebo. Weight gain is frequently reported, with mean increases of 1.1-1.5 kg over 6 weeks in short-term MDD and schizophrenia studies, compared to 0.2-0.3 kg with placebo; the incidence of clinically significant weight increase (≥7%) was approximately 4% versus 2% placebo in MDD adjunctive therapy. Somnolence occurs in approximately 5% of patients versus 1-3% with placebo in MDD and schizophrenia populations. Headache is also common, with incidences of 7% versus 6% placebo in MDD. These effects are generally mild to moderate and dose-related, with management often involving dose reduction or supportive measures to improve tolerability.

Pediatric use

In adolescents aged 13-17 years with schizophrenia, common adverse effects include extrapyramidal symptoms (6% vs. 3% placebo), weight gain (mean +3.8 kg long-term), nausea (6% vs. 4%), and headache (6% vs. 5%). Monitoring for growth, metabolic changes, and movement disorders is recommended.

Serious adverse effects

Brexpiprazole carries several serious adverse effects, primarily related to its antipsychotic properties, which necessitate careful monitoring in clinical practice. The most critical risk is increased mortality among elderly patients with dementia-related psychosis, as highlighted by a black box warning from the U.S. Food and Drug Administration (FDA). In pooled analyses of 17 placebo-controlled trials with various atypical antipsychotics, including brexpiprazole, the mortality rate was 4.5% in treated elderly patients compared to 2.6% with placebo, representing a 1.6- to 1.7-fold increased risk, often due to cardiovascular events or infections. Brexpiprazole is not approved for dementia-related psychosis except in cases of agitation associated with , and prescribers must weigh this risk against potential benefits in vulnerable populations. Tardive dyskinesia (TD), a potentially irreversible movement disorder characterized by involuntary movements of the face, tongue, or extremities, is another serious concern with brexpiprazole use. The risk of TD increases with treatment duration, cumulative dose, and patient factors such as advanced age, particularly in elderly women, though it remains relatively low compared to first-generation antipsychotics. In long-term studies, the incidence of TD with brexpiprazole has been reported as approximately 0.1% to 0.2% per year, with only rare cases observed in clinical trials (e.g., one moderately severe case in a 52-week open-label extension involving 1,072 patients). Discontinuation or dose reduction is recommended if TD develops, and patients should be monitored for early signs using scales like the Abnormal Involuntary Movement Scale (AIMS). Metabolic changes represent a significant class effect of atypical antipsychotics like brexpiprazole, potentially leading to hyperglycemia, dyslipidemia, weight gain, and increased risk of type 2 diabetes. These effects can exacerbate cardiovascular risks, particularly in patients with predisposing factors such as obesity or family history of diabetes. Clinical trials have shown shifts to high fasting glucose (≥126 mg/dL) similar to placebo in short-term studies, but in long-term MDD studies, 9% of patients with normal or borderline baseline shifted to high; mean weight gains ranged from 1.0 kg in short-term schizophrenia studies to 3.1 kg in long-term major depressive disorder trials. Monitoring includes baseline and periodic assessments of fasting glucose, lipid profiles (e.g., triglycerides elevated in 17% of long-term users in MDD), and body weight to detect and manage these changes early. As an adjunctive treatment for major depressive disorder, brexpiprazole shares the black box warning for suicidality associated with antidepressants, particularly in younger patients. Pooled analyses indicate an increased risk of suicidal thoughts and behaviors in individuals aged 18 to 24 years, with a need for close observation during initial treatment and dose adjustments. Patients and caregivers should be informed of warning signs, such as worsening mood or emergent suicidal ideation, and monitoring is essential across all age groups, though the risk diminishes in those over 65. Post-marketing surveillance has identified rare impulse control disorders with brexpiprazole, including pathological gambling, compulsive sexual behavior, excessive shopping, and binge eating, akin to risks seen with dopamine agonists. These behaviors may emerge or intensify during treatment and typically resolve upon dose reduction or discontinuation, underscoring the importance of patient education and periodic assessment for such changes.

Pharmacology

Pharmacodynamics

Brexpiprazole is an atypical antipsychotic characterized as a serotonin-dopamine activity modulator, primarily exerting its effects through partial agonism at dopamine D2, D3, and serotonin 5-HT1A receptors. It binds with high affinity to the D2 receptor (Ki = 0.30 nM) and displays partial agonism with an intrinsic activity of approximately 43% (Emax), allowing it to stabilize dopamine transmission in both hyper- and hypodopaminergic conditions. At the D3 receptor, it also acts as a partial agonist (Ki = 1.1 nM). At the 5-HT1A receptor, brexpiprazole acts as a partial agonist with high affinity (Ki = 0.09–0.12 nM), contributing to enhanced serotonergic modulation compared to other agents in its class. Additionally, it functions as a potent antagonist at the 5-HT2A receptor (Ki = 0.47 nM), which is implicated in its antipsychotic efficacy by reducing excessive serotonergic activity. Brexpiprazole exhibits lower affinity for other receptors, including moderate binding to the histamine H1 receptor (Ki = 19 nM) and the α1B-adrenergic receptor (Ki = 0.17 nM human), resulting in weaker antagonistic effects at these sites relative to its primary targets. This binding profile minimizes off-target adverse effects such as sedation or orthostatic hypotension, distinguishing it from typical antipsychotics with stronger histaminergic or adrenergic interactions. The balanced D2 partial agonism of brexpiprazole, with lower intrinsic activity than full agonists but sufficient to avoid receptor upregulation, reduces the risk of extrapyramidal side effects associated with complete D2 blockade in traditional antipsychotics. Downstream, this mechanism stabilizes and serotonin signaling in key pathways, such as the mesolimbic and mesocortical systems, supporting its therapeutic roles in and by normalizing imbalances without excessive disruption.

Pharmacokinetics

Brexpiprazole exhibits linear pharmacokinetics following single and multiple oral doses, with exposure (Cmax and AUC) increasing proportionally across the therapeutic dose range of 0.5 to 4 mg once daily. Steady-state plasma concentrations are achieved within 10 to 12 days of repeated dosing.

Absorption

Following , brexpiprazole is rapidly absorbed, with peak plasma concentrations (Tmax) occurring approximately 4 hours post-dose. The absolute of the tablet formulation is approximately 95%. Administration with food, including high-fat meals, has no clinically significant effect on the rate or extent of absorption, allowing brexpiprazole to be taken with or without meals.

Distribution

Brexpiprazole is highly bound to plasma proteins (>99%), primarily to and α1-acid glycoprotein. The volume of distribution at is approximately 1.56 L/kg following intravenous administration. Protein binding remains unaffected by renal or hepatic impairment, or by co-administration of , , or .

Metabolism

Brexpiprazole undergoes extensive hepatic metabolism primarily via the enzymes and , with being the major pathway. The principal , DM-3411 (7-carboxy brexpiprazole), accounts for 23% to 48% of brexpiprazole's AUC at but exhibits negligible brain penetration at therapeutic doses and does not contribute to the drug's pharmacological activity. Brexpiprazole demonstrates minimal inhibition of CYP450 isozymes.

Elimination

The terminal elimination of brexpiprazole is approximately 91 hours, while that of its major DM-3411 is about 86 hours, following multiple once-daily doses. The apparent oral clearance is 19.8 mL/h/kg. occurs primarily via (46%) and (25%), with less than 1% of unchanged brexpiprazole recovered in urine and approximately 14% in .

Chemistry

Brexpiprazole is a synthetic classified as an , featuring a molecular of \ceC25H27N3O2S\ce{C25H27N3O2S} and a of 433.57 g/mol. Its consists of a quinolinone core linked via a butoxy chain to a piperazine ring, which is further substituted with a benzothiophen-4-yl group at the para position; the systematic (IUPAC) name is 7-[4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy]-1H-quinolin-2-one. The compound presents as a white to off-white crystalline powder, non-hygroscopic in nature, with a range of 160–164 °C. Brexpiprazole exhibits low aqueous , being practically insoluble in (approximately 0.0024 mg/mL at 25 °C), though its increases at lower values due to its weakly basic character (pKa ≈ 7.8). It is freely soluble in polar organic solvents such as , , and , and soluble in and . Developed by Co., Ltd., brexpiprazole's synthesis typically proceeds through a multi-step process involving the formation of a key intermediate by coupling with 4-halobenzothiophene (e.g., 4-bromobenzo) under catalytic conditions, followed by N-alkylation of this intermediate with a 7-(4-halobutoxy)quinolin-2(1H)-one derivative to assemble the full structure. This approach emphasizes regioselective substitutions to ensure high purity of the final product. Brexpiprazole demonstrates good under accelerated stress conditions (e.g., heat, humidity, oxidation, and photolysis) and standard storage at temperatures below 30 °C, supporting a re-test period of several years. However, it requires protection from light to mitigate potential photoinstability during handling and storage, and while non-hygroscopic, it is advisable to shield from excessive moisture to maintain integrity.

Interactions

Pharmacokinetic interactions

Brexpiprazole is primarily metabolized by the enzymes and , making it susceptible to pharmacokinetic interactions with inhibitors and inducers of these pathways. Strong inhibitors of , such as , increase brexpiprazole exposure approximately 2-fold, as evidenced by a 1.97-fold increase in AUC and 1.19-fold increase in Cmax in clinical studies. To mitigate this, the brexpiprazole dose should be reduced by 50% when coadministered with strong inhibitors. In contrast, strong inducers like rifampin substantially decrease brexpiprazole levels by about 70%, with studies showing a 73% reduction in AUC and 40% reduction in Cmax. In such cases, concomitant use should be avoided if possible, or the brexpiprazole dose doubled with close monitoring of clinical response. Strong inhibitors of , such as or , increase brexpiprazole exposure, and the dose should be reduced by 50% when coadministered. When a strong inhibitor is used concomitantly with a strong or moderate inhibitor, the brexpiprazole dose should be reduced to 25% of the usual dose. In individuals with poor metabolizer status, brexpiprazole exposure is approximately 1.5-fold higher compared to extensive metabolizers, based on population pharmacokinetic analyses showing about 47% greater exposure. Although routine dose adjustment is not always required, the recommended approach is to initiate with half the usual dose in known poor metabolizers to account for reduced clearance. Brexpiprazole is not a significant substrate for (P-gp), and studies indicate no clinically relevant interactions mediated by this efflux transporter. Regarding alcohol, there are no pharmacokinetic alterations to brexpiprazole exposure, though pharmacodynamic effects such as enhanced may occur.

Pharmacodynamic interactions

Brexpiprazole, as an with partial agonist activity at dopamine D₂ and serotonin 5-HT₁A receptors and antagonist activity at 5-HT₂A and α₁-adrenergic receptors, can exhibit pharmacodynamic interactions through additive effects on neurotransmitter systems or physiological responses. Concomitant use with other antipsychotics, benzodiazepines, or opioids may lead to additive (CNS) depression due to overlapping sedative properties and enhanced inhibition of and serotonergic pathways, increasing the risk of , respiratory depression, and impaired psychomotor function. Caution is advised, with dose adjustments or monitoring recommended to mitigate these effects. Brexpiprazole has minimal direct effect on prolongation at therapeutic doses, but coadministration with other QT-prolonging agents, such as certain antidepressants (e.g., ) or antiarrhythmics, may result in additive prolongation of cardiac repolarization, potentially elevating the risk of . Electrocardiographic monitoring is suggested in patients with risk factors for arrhythmias. Due to its α₁-adrenergic receptor antagonism, brexpiprazole can potentiate the hypotensive effects of antihypertensives, leading to enhanced and syncope, particularly in vulnerable populations such as the elderly or those with volume depletion. Close monitoring of , especially upon standing, is essential when combining with agents like beta-blockers or ACE inhibitors. In patients receiving dopamine agonists such as levodopa for , brexpiprazole's partial agonism at D₂ receptors may antagonize the therapeutic effects of these agents, potentially worsening psychotic symptoms or . Careful benefit-risk assessment and possible dose are warranted in such cases. Brexpiprazole's partial at 5-HT₁A receptors confers a lower risk of compared to full agonists, with no major reports of this interaction in clinical use; however, vigilance is still required when combined with potent serotonergic agents like SSRIs.

History

Development and discovery

Brexpiprazole was discovered by in the late as a successor to aripiprazole, with research initiated in 1999 to enhance serotonin system modulation while reducing intrinsic activity at the D2 receptor, thereby aiming for improved tolerability and a broader therapeutic profile combining serotonin-dopamine antagonism and stabilization features. This development focused on achieving higher affinity for 5-HT1A partial and 5-HT2A antagonism compared to aripiprazole, addressing limitations such as risk observed in earlier antipsychotics. Preclinical studies conducted primarily between 2006 and 2010 demonstrated brexpiprazole's superior balance of D2 partial agonism and 5-HT1A partial agonism in animal models of and depression, exhibiting antipsychotic-like effects by inhibiting apomorphine-induced hyperlocomotion and in rats without inducing significant , alongside antidepressant-like activity through modulation of monoamine systems in forced swim and tail suspension tests. These investigations, including binding assays and microdialysis in , confirmed high receptor occupancy at therapeutic-equivalent doses, supporting efficacy in models like phencyclidine-induced deficits in novel tasks. The initial for brexpiprazole was filed internationally in 2006 (WO 2006/112464 A1), covering its and use in disorders. An Investigational New Drug (IND) application was submitted to the U.S. Food and Drug Administration in 2009, paving the way for human trials. Non-clinical toxicology evaluations revealed no genotoxic potential in vivo, with negative results in the rat micronucleus and unscheduled DNA synthesis assays despite weak in vitro findings at cytotoxic concentrations exceeding therapeutic relevance. Reproductive toxicity was absent at therapeutic doses, though effects such as impaired female fertility and developmental delays emerged in rats at supratherapeutic exposures (≥7.3 times the maximum recommended human dose), attributed to hyperprolactinemia rather than direct teratogenicity.

Clinical trials

Brexpiprazole's efficacy in was evaluated in five short-term, -controlled phase II/III trials involving over 2,000 patients, demonstrating consistent improvements in (PANSS) total scores at doses of 2 mg and 4 mg compared to . In these studies, brexpiprazole 2 mg and 4 mg showed statistically significant reductions in PANSS scores, with effect sizes indicating clinically meaningful activity, particularly in positive and negative symptoms. Pooled analyses confirmed robust efficacy across diverse patient subgroups, including those with prominent negative symptoms or first-episode . As an adjunctive therapy to antidepressants in major depressive disorder (MDD), brexpiprazole was assessed in four randomized, -controlled trials, where it produced significant reductions in Montgomery-Åsberg Depression Rating Scale (MADRS) total scores at doses of 2 mg and 3 mg. These trials enrolled patients with inadequate response to ongoing therapy, and brexpiprazole augmentation led to greater improvements in core depressive symptoms over 6 weeks compared to plus alone. Post-hoc analyses from these studies further highlighted benefits in secondary outcomes, including reductions in anxiety symptoms and improvements in sleep quality and severity. For agitation associated with Alzheimer's disease dementia, two phase III, 12-week, fixed-dose trials conducted between 2021 and 2023 evaluated brexpiprazole at 2 mg and 3 mg versus , enrolling patients with moderate-to-severe agitation. Both trials met their primary endpoint, showing significant reductions in Cohen-Mansfield Agitation Inventory (CMAI) total scores for brexpiprazole compared to , with effect sizes indicating clinically relevant decreases in agitation frequency and severity. A long-term extension study following these trials supported sustained efficacy and tolerability over 52 weeks, with continued CMAI improvements and low rates of symptom recurrence. Across these clinical trials for , MDD, and Alzheimer's agitation, brexpiprazole exhibited a favorable overall profile, with being the most common treatment-emergent leading to discontinuation, occurring in 3-5% of patients at therapeutic doses. Other discontinuations were primarily due to consent withdrawal or lack of , and no new signals emerged in long-term extensions.

Regulatory approvals

Brexpiprazole, marketed as Rexulti in the United States, received initial approval from the (FDA) on July 10, 2015, for the treatment of in adults and as an adjunctive therapy to for (MDD) in adults. This approval was based on clinical trials demonstrating efficacy in reducing symptoms and augmenting response in MDD. In the , brexpiprazole, marketed as Rxulti, was granted marketing authorization by the (EMA) on July 26, 2018, for the treatment of in adults. The authorization was extended on March 13, 2025, to include adolescents aged 13 years and older with . The FDA expanded approvals for brexpiprazole on January 6, 2022, to include treatment of in pediatric patients aged 13 to 17 years. A further supplemental approval was granted on May 11, 2023, for the treatment of agitation associated with due to in adults, marking it as the first FDA-approved drug specifically for this indication. As of November 2025, pediatric approvals remain limited to in adolescents aged 13 and older, with ongoing investigations for other indications such as adjunctive MDD treatment in youth showing no additional approvals. Post-marketing requirements include a for increased mortality risk in elderly patients with dementia-related , though brexpiprazole is not approved for dementia-related without agitation. No Risk Evaluation and Mitigation Strategy (REMS) program is required.

Society and culture

Brexpiprazole is not classified as a under the , as it demonstrates no potential for abuse or dependence in preclinical studies where animals did not self-administer the drug. Similarly, it is not scheduled under the conventions on psychotropic substances. In the , , and , brexpiprazole is available only by prescription due to its classification as an requiring medical supervision. The U.S. assigns brexpiprazole a C, indicating that animal reproduction studies have shown adverse effects on the fetus, but there are no adequate and well-controlled studies in humans, and potential benefits may warrant use despite the risks. Exposure during the third trimester may increase the risk of or withdrawal in neonates. As of 2025, brexpiprazole has been approved for use in more than 60 countries worldwide, including indications for and , with no changes to its legal status following the 2023 U.S. approval for agitation associated with due to . In regions where it is not approved for dementia-related agitation, such as much of the and Asia beyond select markets, for symptoms remains restricted or cautioned against due to regulatory warnings on increased mortality risks in elderly patients with dementia-related .

Brand names and availability

Brexpiprazole is marketed under the brand name Rexulti in the United States and , developed and distributed by in collaboration with . In the European Union, it is sold as Rxulti, also by Otsuka and Lundbeck. The drug is available in other regions, including and , primarily under the Rexulti brand name. It is formulated exclusively as oral film-coated tablets in strengths of 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg, allowing for flexible dosing based on clinical needs. Rexulti was first launched in the United States in August 2015 following FDA approval earlier that month. In the , Rxulti became available in select markets during the first half of 2019 after authorization in July 2018. In , Rexulti launched in April 2018 subsequent to approval by the Ministry of Health, Labour and Welfare for treatment. The medication remains actively marketed worldwide without discontinuations in any approved regions, and shortages have been rare, with no widespread supply disruptions reported as of late 2025. Generic versions of brexpiprazole received FDA approval in early 2025, but market entry is anticipated after the primary U.S. expiration in April 2033, due to ongoing exclusivity protections.

Economics and

In the , the annual cost for brexpiprazole at a standard dose of 2 mg per day is approximately $15,000 to $20,000 based on 2025 wholesale pricing, though out-of-pocket expenses can vary significantly with coverage and assistance programs. This pricing reflects its positioning as a branded , with list prices for a 30-tablet supply of 2 mg tablets exceeding $1,400 monthly before discounts. Global sales of brexpiprazole, marketed as Rexulti by and , totaled approximately $1.2 billion in 2024, largely propelled by demand for its approved indications in (MDD) as an adjunctive therapy and . These revenues underscore its commercial success in key markets like the and , contributing to Otsuka's overall pharmaceutical segment growth amid competition in the antipsychotic category. Intellectual property protection for brexpiprazole is anchored by key US patents, including US Patent 8,461,154 covering its , which is scheduled to expire in 2031. Additional patent term extensions, including up to six months via pediatric exclusivity granted for studies in adolescent , could prolong market exclusivity until 2036. Other listed patents in the FDA Orange Book, such as those for and methods of use, provide layered protection with base expirations around 2026 but effective extensions aligning with the 2031-2036 window. There has been no major litigation history disrupting brexpiprazole's market exclusivity, though isolated suits against generic challengers like Teva have occurred without significant outcomes altering availability. Generic entry and associated challenges are anticipated post-2030 as core patents near expiration, potentially increasing competition and reducing costs. In 2025, a proposal was submitted to the World Health Organization for inclusion of brexpiprazole tablets on the Essential Medicines List as an adjunctive treatment for MDD in adults, highlighting its potential role in global mental health access strategies. This initiative, supported by clinical evidence of efficacy in treatment-resistant cases, aims to address gaps in affordable options for depression management worldwide.

Research

Approved indications expansions

Following its approval in May 2023 for the treatment of agitation associated with due to , brexpiprazole has been supported by post-approval data from long-term extensions of pivotal phase 3 trials, demonstrating sustained efficacy. In a 12-week open-label extension (NCT03594123) to the initial , patients who continued brexpiprazole at 2 or 3 mg/day exhibited further reductions in agitation symptoms, as measured by the Cohen-Mansfield Agitation Inventory, with mean changes from baseline indicating ongoing improvement up to 24 weeks and no new safety signals emerging. This extension supports label expansion for longer-term use in this indication, highlighting brexpiprazole's role in maintaining symptom control beyond the initial 12-week period without increased risk of adverse events like or falls. For its approved use as an adjunctive therapy in (MDD), a 2024 post-hoc analysis of pooled data from three randomized, -controlled phase 3 trials confirmed brexpiprazole's specific benefits in patients with anxious depression subtypes, defined by high scores on the Montgomery-Åsberg Depression Rating Scale anxious distress specifier. Adjunctive brexpiprazole (2-3 mg/day) led to significantly greater reductions in core depressive symptoms, including psychic anxiety and somatic symptoms, compared to , with effect sizes indicating enhanced response rates in this subgroup (up to 15% higher remission). These findings bolster expansion of the MDD label to emphasize efficacy in comorbid anxiety, where traditional antidepressants alone may be less effective, while maintaining a favorable tolerability profile with low rates of . In schizophrenia, real-world evidence from a 2024 retrospective involving over 200 patients highlighted brexpiprazole's advantages in treatment adherence and remission rates post-approval. Switching to brexpiprazole monotherapy resulted in 70% persistence at 6 months, surpassing rates for other atypicals, correlated with reduced hospitalizations and improved symptom stability. Functional remission, assessed via the Personal and Social Performance scale, was achieved in 25% of patients after 12 months, supporting label expansions for maintenance therapy in diverse real-world populations, including those with prior non-adherence.

Investigational uses

Brexpiprazole is under investigation for the adjunctive treatment of (PTSD) in adults, particularly in combination with sertraline. A phase 3, double-blind, randomized, parallel-group (NCT04124614) conducted from 2019 to 2023 at 86 U.S. sites enrolled 416 participants (mean age 37.4 years, 74.5% female) who were randomized 1:1 to brexpiprazole (2–3 mg/day) plus sertraline (up to 150 mg/day) or sertraline plus for 11 weeks following a 1-week placebo run-in. The primary endpoint was the change in Clinician-Administered PTSD Scale for (CAPS-5) total score from baseline to week 12, showing a least-squares mean change of −19.2 (SE 1.2) for the combination versus −13.6 (SE 1.2) for sertraline alone, with a least-squares mean difference of −5.59 (95% CI, −8.79 to −2.38; P < .001). Secondary outcomes, including Clinical Global Impressions-Severity (CGI-S) and Brief Inventory of Psychosocial Functioning (B-IPF) scores, also favored the combination, with response rates of 68.5% versus 48.2% (P < .001). Based on these results, a supplemental (sNDA) for brexpiprazole plus sertraline was submitted to the FDA in and accepted for review in June 2024; however, in September 2025, the FDA issued a complete response letter citing insufficient evidence of effectiveness and requesting additional data. Research into brexpiprazole as an adjunct to s for treatment-resistant attention-deficit/hyperactivity disorder (ADHD) in adults has yielded mixed findings, with no ongoing development reported. A phase 2 trial (NCT01074294) evaluated brexpiprazole added to in adults with ADHD, but results indicated no significant improvement on ADHD severity scores compared to , though some analyses suggested potential benefits in . Stimulant-naïve participants showed no adjunctive benefit from brexpiprazole. These outcomes have not led to further pursuit of this indication. For (BPD), a phase 2, randomized, double-blind, -controlled assessed brexpiprazole's effects on and overall symptoms, but the study failed to meet the primary endpoint. The targeted reduction but observed only preliminary efficacy signals, such as improvements in and certain subscales, without statistical separation from on the main measure at the predefined time point. No phase 3 development has followed. Post-hoc analyses of phase 3 trials in have explored brexpiprazole's potential to alleviate comorbid anxiety symptoms without exacerbating . A pooled analysis of data from four short-term, -controlled studies (n=2,200+ patients) examined anxiety via the (HAM-A) and (PANSS) anxiety item, revealing significant reductions in HAM-A total scores (mean change −4.2 vs. −2.1 for ; P < .05) and PANSS anxiety/depression subscale scores at doses of 2–4 mg/day, alongside improvements in functioning and patient engagement. These effects were attributed to brexpiprazole's partial agonism at serotonin 5-HT1A receptors, supporting its role in anxiety management within , though dedicated trials are needed. Early-phase investigations into brexpiprazole for associated with autism spectrum disorder (ASD) in pediatric patients (ages 5–17) are ongoing as of 2025, focusing on safety and preliminary efficacy. An open-label extension study (NCT04258839) following a completed phase 3 (NCT04174365) continues to evaluate long-term tolerability, with initial data indicating no new safety signals beyond those in adult populations, though the prior efficacy did not meet its primary endpoint for irritability reduction. Further phase 2 data collection is planned to inform potential advancement.

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