Brexpiprazole (Rexulti®): A Comprehensive Pharmacological and Clinical Review

[Section 1: Executive Summary & Introduction]

1.1 Overview

Brexpiprazole is a second-generation, or atypical, antipsychotic agent developed through a collaboration between Otsuka Pharmaceutical Co., Ltd. and H. Lundbeck A/S.[1] It is pharmacologically classified as a Serotonin-Dopamine Activity Modulator (SDAM), a designation that reflects its unique and complex mechanism of action involving partial agonism and antagonism at key neurotransmitter receptors.[4] Administered as a once-daily oral tablet, brexpiprazole represents a significant therapeutic option in the management of several complex psychiatric disorders.[8]

1.2 Clinical Context and Positioning

Brexpiprazole is a structural analogue of aripiprazole and is widely considered its therapeutic successor.[10] Its development was a deliberate effort in medicinal chemistry to refine the pharmacodynamic profile of aripiprazole, with the specific goal of potentially improving tolerability while maintaining or enhancing efficacy.[4] The key molecular modifications were intended to reduce intrinsic activity at the dopamine D₂ receptor and increase affinity and antagonism at serotonin 5-HT₂ₐ receptors.[4] This refined pharmacology was hypothesized to mitigate the risk of certain adverse effects, most notably akathisia, a common and distressing side effect associated with D₂ partial agonism.[4]

However, the translation from preclinical design to clinical reality presents a more complex picture. While the pharmacological rationale for improved tolerability is sound, clinical trial data and post-marketing surveillance consistently identify akathisia as one of the most common treatment-emergent adverse events associated with brexpiprazole use.[10] This observation underscores a critical disconnect between theoretical molecular action and the integrated physiological response in patients. It suggests that while the risk of akathisia may be mitigated compared to its predecessor, it is by no means eliminated. This nuanced outcome challenges a simplistic interpretation of the "designed successor" narrative and highlights that akathisia remains a primary clinical concern that requires vigilant monitoring by clinicians.

Beyond its relationship to aripiprazole, brexpiprazole has carved out a distinct and significant place in the therapeutic landscape through its regulatory approvals. Most notably, it achieved landmark status as the first and, to date, only pharmacological agent approved by the U.S. Food and Drug Administration (FDA) for the treatment of agitation associated with dementia due to Alzheimer's disease (AADAD), addressing a major unmet medical need in a vulnerable patient population.[10]

1.3 Synopsis of Indications and Safety

Brexpiprazole has secured three core FDA-approved indications:

1. Adjunctive therapy for the treatment of Major Depressive Disorder (MDD) in adults who have not responded adequately to antidepressant monotherapy.[4]
2. Treatment of schizophrenia in adults and in pediatric patients aged 13 years and older.[4]
3. Treatment of agitation associated with dementia due to Alzheimer's disease in adults.[4]

The use of brexpiprazole is governed by critical safety considerations, encapsulated in two FDA Boxed Warnings. The first is a class-wide warning for all atypical antipsychotics regarding an increased risk of mortality in elderly patients with dementia-related psychosis. The second is a class-wide warning for antidepressant medications concerning an increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults (up to age 24).[2] These warnings necessitate careful risk-benefit analysis and rigorous patient monitoring.

[Section 2: Chemical Identity and Physicochemical Properties]

2.1 Identification

The unambiguous identification of a pharmaceutical substance is fundamental to research, clinical practice, and regulatory oversight. Brexpiprazole is known by several names and unique identifiers across various chemical and drug databases.

• Generic Name: Brexpiprazole [4]
• Brand/Trade Names: The most common brand name is Rexulti®, used in the United States, Canada, Australia, and Japan. In the European Union, it is marketed as Rxulti®.[4]
• Developmental Code: During its development phase, brexpiprazole was referred to as OPC-34712.[5]
• DrugBank Accession Number: DB09128 [4]
• CAS (Chemical Abstracts Service) Number: 913611-97-9 [4]
• Other Key Identifiers:
• FDA UNII: 2J3YBM1K8C [4]
• PubChem CID: 11978813 [10]
• ChEMBL ID: CHEMBL2105760 [10]
• ATC Code: N05AX16 [6]
• European Community (EC) Number: 811-628-7 [4]

2.2 Chemical Structure and Formula

Brexpiprazole is a complex heterocyclic molecule, classified as a quinolinone derivative.[11]

• IUPAC Name: 7-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy]-1H-quinolin-2-one.[4] Minor variations in nomenclature, such as quinolin-2(1H)-one or benzo[b]thiophen-4-yl, exist but refer to the same structure.[6]
• Molecular Formula: C25​H27​N3​O2​S [5]
• Molecular Weight: 433.57 g/mol (often rounded to 433.58 g/mol) [5]
• Chemical Structure Representations (for computational use):
• SMILES: C1CN(CCN1CCCCOC2=CC3=C(C=C2)C=CC(=O)N3)C4=C5C=CSC5=CC=C4 [4]
• InChIKey: ZKIAIYBUSXZPLP-UHFFFAOYSA-N [4]

2.3 Physicochemical and Formulation Properties

The physical and chemical properties of brexpiprazole influence its formulation, stability, and laboratory handling.

• Appearance: Brexpiprazole is a solid substance, typically described as a white to off-white or yellowish powder or solid.[25]
• Solubility: It is poorly soluble in aqueous media, a characteristic common to many oral drugs designed for systemic absorption. It is reported as being soluble in dimethyl sulfoxide (DMSO) and slightly soluble in organic solvents like dichloromethane, chloroform, and methanol, but insoluble in water.[5] This lipophilicity is consistent with its ability to cross the blood-brain barrier.
• Melting Point: The melting point is reported to be in the range of 179–181°C.[6]
• Storage and Stability: For long-term preservation, brexpiprazole should be stored under refrigerated conditions (0–8°C) in a dry, dark environment. However, it is stable enough for shipment at ambient temperatures.[5] Under appropriate storage, its chemical stability is maintained for at least four years.[23]
• Formulation for Clinical Use: Brexpiprazole is commercially available as film-coated tablets for oral administration, in various strengths to allow for precise dose titration.[4]

Table 1: Brexpiprazole Identification and Chemical Properties

Parameter	Value	Source(s)
Generic Name	Brexpiprazole	4
Brand Name (US)	Rexulti®	10
CAS Number	913611-97-9	4
DrugBank ID	DB09128	4
Developmental Code	OPC-34712	5
ATC Code	N05AX16	8
IUPAC Name	7-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy]-1H-quinolin-2-one	4
Molecular Formula	C25​H27​N3​O2​S	5
Molecular Weight	433.57 g/mol	5
Appearance	White to off-white solid	28
Melting Point	179-181°C	6
Solubility	Soluble in DMSO; not soluble in water	5
Formulation	Oral, film-coated tablet	4

[Section 3: Comprehensive Pharmacology]

The clinical effects of brexpiprazole are a direct consequence of its complex interactions with multiple neurotransmitter systems in the central nervous system. A thorough understanding of its pharmacodynamics (what the drug does to the body) and pharmacokinetics (what the body does to the drug) is essential for its safe and effective use.

3.1 Pharmacodynamics (Mechanism of Action)

3.1.1 Core Mechanism

The precise mechanism of action of brexpiprazole in treating psychiatric disorders has not been fully elucidated. However, its therapeutic efficacy is believed to be mediated through a unique combination of activities at key monoaminergic receptors, defining its classification as a Serotonin-Dopamine Activity Modulator (SDAM).[4] The core mechanism is attributed to a synergistic profile of:

• Partial agonist activity at serotonin 5-HT₁ₐ and dopamine D₂ receptors.
• Antagonist activity at serotonin 5-HT₂ₐ receptors.[1]

This multi-faceted action allows brexpiprazole to modulate neuronal circuits implicated in the pathophysiology of schizophrenia, depression, and agitation.[18]

3.1.2 Receptor Binding Profile

Brexpiprazole's broad spectrum of activity is rooted in its high affinity for several receptor subtypes, quantified by the inhibition constant (Ki​), where a lower value indicates a stronger binding affinity. It demonstrates subnanomolar affinity for its primary targets.

• Serotonin Receptors: Brexpiprazole binds with high affinity to multiple serotonin receptors.
• 5-HT₁ₐ: Ki​ = 0.12 nM [4]
• 5-HT₂ₐ: Ki​ = 0.47 nM [4]
• 5-HT₂ₑ: Ki​ = 1.9 nM [4]
• 5-HT₇: Ki​ = 3.7 nM [4]
• Dopamine Receptors: It shows high affinity for both D₂ and D₃ receptor subtypes.
• D₂: Ki​ = 0.30 nM [4]
• D₃: Ki​ = 1.1 nM [4]
• Adrenergic Receptors: It is a potent ligand at several noradrenergic alpha receptors.
• α₁ₑ: Ki​ = 0.17 nM [4]
• α₂₋: Ki​ = 0.59 nM [4]
• α₁ₒ: Ki​ = 2.6 nM [4]
• α₁ₐ: Ki​ = 3.8 nM [4]
• Histamine and Muscarinic Receptors:
• It has moderate affinity for the histamine H₁ receptor (Ki​ = 19 nM), which may contribute to potential side effects like sedation and weight gain.[6]
• It demonstrates very low affinity for muscarinic M₁ acetylcholine receptors, suggesting a minimal risk of anticholinergic side effects (e.g., dry mouth, blurred vision, constipation, cognitive dulling) that are common with other antipsychotic agents.[1]

This binding profile reveals that brexpiprazole does not act on a single "master" receptor. Instead, it engages multiple critical neurotransmitter systems—dopamine, serotonin, and norepinephrine—with similarly high potency. This suggests that its clinical effect arises from the simultaneous and balanced modulation of these interconnected pathways rather than a singular action.[31] This "multi-key" pharmacological approach may explain its efficacy in complex neuropsychiatric syndromes that involve widespread dysregulation. It also provides a framework for understanding its multifaceted side-effect profile, where distinct adverse events can be linked to its activity at different receptors: akathisia to D₂ partial agonism, sedation to H₁ antagonism, and orthostatic hypotension to α₁ antagonism.

3.1.3 Functional Activity and the SDAM Concept

Beyond simply binding to a receptor, a drug's functional activity—whether it stimulates (agonist), blocks (antagonist), or partially stimulates (partial agonist)—determines its ultimate physiological effect.

• Partial Agonism: Brexpiprazole acts as a partial agonist at 5-HT₁ₐ, D₂, and D₃ receptors.[1] This is the cornerstone of the "modulator" concept. In a state of low neurotransmitter tone (e.g., low dopamine in the prefrontal cortex, thought to be associated with negative and cognitive symptoms of schizophrenia), a partial agonist provides a stimulatory signal. Conversely, in a state of high neurotransmitter tone (e.g., excess dopamine in the mesolimbic pathway, linked to positive symptoms), it competes with the endogenous neurotransmitter and provides a weaker signal, effectively acting as a functional antagonist. This dual action is thought to stabilize the system, reducing psychosis without causing the profound receptor blockade that can lead to severe side effects.
• Antagonism: It functions as a potent antagonist at serotonin 5-HT₂ₐ, 5-HT₂ₑ, and 5-HT₇ receptors, as well as at multiple α-adrenergic receptors (α₁ₐ, α₁ₑ, α₁ₒ, α₂₋).[1] The potent 5-HT₂ₐ antagonism is particularly important; it is believed to enhance dopamine release in the prefrontal cortex, potentially improving negative and cognitive symptoms, and to mitigate the risk of extrapyramidal symptoms (EPS) that can arise from D₂ receptor blockade in the nigrostriatal pathway. Its antagonism at α₁-adrenergic receptors is the primary mechanism underlying the risk of orthostatic hypotension.

3.1.4 Comparison with Aripiprazole

The clinical profile of brexpiprazole is best understood in comparison to its parent compound, aripiprazole. The modifications in its receptor interactions were intentional and have significant clinical implications.

• D₂ Receptor Intrinsic Activity: The most critical distinction is that brexpiprazole possesses lower intrinsic activity at the D₂ receptor compared to aripiprazole.[4] This means it provides a weaker stimulatory signal at the D₂ receptor. This property was specifically designed to reduce the incidence of D₂ partial agonist-mediated adverse effects, such as akathisia, restlessness, and insomnia, which are notable tolerability challenges with aripiprazole.
• Serotonin Receptor Affinity: Brexpiprazole exhibits approximately 10-fold higher affinity and stronger antagonism at 5-HT₂ₐ receptors than aripiprazole.[4] It also has a higher affinity for 5-HT₁ₐ receptors.[11] This enhanced engagement with the serotonin system is hypothesized to contribute to more robust antidepressant, anxiolytic, and pro-cognitive effects.

Table 2: Receptor Binding and Functional Activity Profile of Brexpiprazole

Receptor	Binding Affinity (Ki​, nM)	Functional Activity	Potential Clinical Implication(s)	Source(s)
Dopamine D₂	0.30	Partial Agonist (low intrinsic activity)	Antipsychotic effect (modulation); Risk of akathisia	4
Dopamine D₃	1.1	Partial Agonist	Potential pro-cognitive and mood effects	4
Serotonin 5-HT₁ₐ	0.12	Partial Agonist	Antidepressant, anxiolytic, pro-cognitive effects	4
Serotonin 5-HT₂ₐ	0.47	Antagonist	Antidepressant effect; Mitigation of EPS	4
Serotonin 5-HT₂ₑ	1.9	Antagonist	Potential antidepressant effect	4
Serotonin 5-HT₇	3.7	Antagonist	Potential antidepressant and pro-cognitive effects	4
Adrenergic α₁ₑ	0.17	Antagonist	Risk of orthostatic hypotension, dizziness	4
Adrenergic α₂₋	0.59	Antagonist	Potential antidepressant effect	4
Histamine H₁	19	Antagonist	Risk of sedation, weight gain	6
Muscarinic M₁	Low affinity	Antagonist	Low risk of anticholinergic side effects	1

3.2 Pharmacokinetics (ADME)

The pharmacokinetic profile of brexpiprazole is characterized by high bioavailability, extensive distribution, metabolism via key cytochrome P450 enzymes, and a notably long elimination half-life.

3.2.1 Absorption

Following oral administration, brexpiprazole is well absorbed, with an absolute bioavailability of 95%, indicating that nearly the entire dose reaches systemic circulation.[8] Peak plasma concentrations (

Tmax​) are typically achieved within 4 hours of ingestion. The absorption of brexpiprazole is not significantly affected by food; administration with a high-fat meal does not meaningfully alter its peak concentration (Cmax​) or total exposure (Area Under the Curve, AUC).[8] This allows for convenient once-daily dosing without regard to meals.

3.2.2 Distribution

Brexpiprazole has a large apparent volume of distribution (Vd​) of 1.56 L/kg following intravenous administration, which signifies extensive distribution into tissues beyond the bloodstream, including the central nervous system.[8] It is highly bound to plasma proteins (>99%), primarily to serum albumin and alpha-1-acid glycoprotein.[8] This high degree of protein binding means that only a small fraction of the drug is free to exert its pharmacological effects and that it is not readily removed by hemodialysis, an important consideration in cases of overdose.[8]

3.2.3 Metabolism

Brexpiprazole undergoes extensive hepatic metabolism, with the parent drug being transformed into various metabolites.[8] This metabolic clearance is primarily mediated by two key cytochrome P450 (CYP) isoenzymes:

CYP3A4 and CYP2D6.[1] The major circulating metabolite, known as DM-3411, is pharmacologically inactive and is not believed to contribute to the drug's therapeutic effects.[8] The reliance on these two enzymes is the basis for numerous clinically significant drug-drug interactions.

3.2.4 Elimination

The elimination of brexpiprazole is characterized by a very long terminal half-life (t1/2​) of 91 hours.[8] Its inactive major metabolite, DM-3411, also has a long half-life of 86 hours. Following a single radiolabeled dose, the drug and its metabolites are eliminated from the body primarily via the feces (approximately 46%) and to a lesser extent via the urine (approximately 25%). Very little of the parent drug is excreted unchanged, with less than 1% found in urine and about 14% in feces, underscoring the completeness of its metabolism.[8]

The long half-life of 91 hours is a clinically significant pharmacokinetic parameter with dual implications. On one hand, it supports a stable drug concentration with convenient once-daily dosing and provides a degree of forgiveness if a dose is occasionally missed. On the other hand, it dictates a slow path to achieving steady-state plasma concentrations, which is the point at which the rate of drug administration equals the rate of elimination. This state is typically reached in 10 to 12 days for brexpiprazole.[8] This delay means that the full therapeutic benefits and the complete side-effect profile may not become apparent for nearly two weeks following initiation or a change in dosage. This pharmacokinetic reality can pose a challenge in clinical practice, as it may lead to a perception of "delayed efficacy and tolerability issues," as noted in American Psychiatric Association guidelines.[22] It necessitates a patient and methodical approach to dose titration and requires thorough patient education regarding the expected timeline for both therapeutic effects and potential adverse reactions. Furthermore, upon discontinuation, the drug will be cleared from the body very slowly, delaying the resolution of any persistent side effects.

[Section 4: Clinical Efficacy and Therapeutic Applications]

Brexpiprazole has been rigorously evaluated in numerous clinical trials, leading to its approval for three distinct psychiatric conditions. Its efficacy is supported by a robust body of evidence from placebo-controlled, randomized clinical trials.

4.1 Adjunctive Treatment of Major Depressive Disorder (MDD)

• Indication: Brexpiprazole is approved as an adjunctive therapy to be used alongside a primary antidepressant for the treatment of MDD in adult patients who have demonstrated an inadequate response to one to three prior courses of antidepressant treatment (ADT).[4] This positions it as a second-line or augmentation strategy for treatment-resistant depression.
• Pivotal Trials: Its efficacy for this indication was established in two large, 6-week, randomized, double-blind, fixed-dose, placebo-controlled Phase 3 studies (including NCT01360632, known as the Polaris trial).[12] The patient population consisted of adults with MDD who had a documented history of inadequate response to ADTs and who remained symptomatic despite an 8-week prospective treatment phase with a standard antidepressant.[12] Pooled analyses of four Phase 3 studies have further corroborated these findings.[14]
• Primary Endpoint: The primary measure of efficacy in these trials was the change from baseline to week 6 in the total score on the Montgomery-Åsberg Depression Rating Scale (MADRS), a standard clinician-rated scale for assessing the severity of depressive symptoms.[12]
• Efficacy Results: In the pivotal trials, adjunctive brexpiprazole at doses of 2 mg/day and 3 mg/day demonstrated a statistically significant and clinically meaningful reduction in MADRS total scores compared to adjunctive placebo. In one representative study, the mean change from baseline in MADRS score was -8.36 for the brexpiprazole 2 mg group versus -5.15 for the placebo group, a highly significant difference (p=0.0002).[12] A pooled analysis of studies showed a similar benefit for brexpiprazole 2-3 mg/day, with a least squares mean difference of -2.15 points versus placebo ( p<0.0001) and a Cohen's d effect size of 0.33, indicating a small to medium treatment effect.[14] Improvements were also seen in secondary measures, such as functional impairment as measured by the Sheehan Disability Scale (SDS).[12]
• Safety in MDD Trials: In the context of adjunctive MDD treatment, the most frequently reported treatment-emergent adverse events (TEAEs) with an incidence greater than placebo were weight gain and akathisia.[12]

4.2 Treatment of Schizophrenia

• Indication: Brexpiprazole is indicated for the acute and maintenance treatment of schizophrenia in adults, and for the acute treatment of schizophrenia in pediatric patients aged 13 to 17 years.[4]
• Pivotal Trials (Adults): Efficacy in adults with an acute exacerbation of schizophrenia was established in two 6-week, multicenter, randomized, fixed-dose, placebo-controlled Phase 3 studies.[15] Maintenance efficacy was demonstrated in a long-term, randomized-withdrawal study where stable patients were randomized to either continue brexpiprazole or switch to placebo.[37]
• Primary Endpoint: The primary efficacy outcome for the acute treatment trials was the change from baseline in the total score of the Positive and Negative Syndrome Scale (PANSS), a comprehensive scale for assessing the severity of psychotic symptoms.[15] For the maintenance trial, the primary endpoint was the time to impending relapse.[37]
• Efficacy Results (Adults): In the acute trials, brexpiprazole at doses of 2 mg/day and 4 mg/day resulted in statistically significant improvements in PANSS total scores compared to placebo. At week 6, the treatment differences versus placebo were -8.72 for the 2 mg dose and -7.64 for the 4 mg dose in one key study.[15] In the long-term maintenance trial, brexpiprazole demonstrated superior efficacy in preventing relapse; the proportion of patients who experienced impending relapse was significantly lower in the brexpiprazole group (13.5%) compared to the placebo group (38.5%).[37]
• Pediatric Data (Adolescents 13-17): The approval for adolescents was not based on a new placebo-controlled trial but on an extrapolation analysis. This analysis leveraged pharmacokinetic data from both adult and pediatric trials, efficacy data from adult studies, and safety data from an ongoing 6-month open-label study in adolescents (NCT03198078).[36] The safety profile in adolescents was found to be generally consistent with that in adults, although with some observed differences in the incidence of metabolic side effects, such as weight gain.[40]
• Safety in Schizophrenia Trials: For adults, the most common TEAE was weight increased. In the adolescent population, the most common TEAEs (≥5% incidence) were weight increased, somnolence, headache, akathisia, and nasopharyngitis.[15]

4.3 Treatment of Agitation Associated with Dementia due to Alzheimer's Disease (AADAD)

• Indication: Brexpiprazole holds the distinction of being the first and only medication to receive FDA approval specifically for the treatment of agitation associated with dementia due to Alzheimer's disease.[4] The prescribing information explicitly states that it is not intended for "as-needed" (prn) use and requires consistent daily administration for its effect.[2]
• Pivotal Trials: The efficacy for this novel indication was established in three 12-week, randomized, double-blind, placebo-controlled Phase 3 studies conducted in patients aged 55-90 with a diagnosis of probable Alzheimer's disease and clinically significant agitation.[32]
• Primary Endpoint: The primary efficacy measure across these trials was the change from baseline to week 12 in the total score of the Cohen-Mansfield Agitation Inventory (CMAI), a standard, validated scale for assessing the frequency and severity of agitated behaviors in elderly individuals.[41]
• Efficacy Results: The trials consistently demonstrated that brexpiprazole, at flexible doses of 2 mg/day to 3 mg/day, produced a statistically significant and clinically meaningful improvement in CMAI total scores compared to placebo. In one pivotal trial, patients receiving brexpiprazole (2 or 3 mg) had a mean change from baseline of -22.6 points on the CMAI, compared to a mean change of -17.0 for placebo.[42] Post-hoc analyses have further supported these findings, showing efficacy across various patient subgroups, including different levels of baseline dementia severity and different care settings (e.g., institutional vs. community).[32]
• Safety in AADAD Trials: Brexpiprazole was generally well-tolerated in this vulnerable, elderly population. The most common adverse reactions occurring at a rate of ≥4% and at least twice the rate of placebo were nasopharyngitis and dizziness.[10] Notably, the rates of discontinuation due to adverse events were similar between the brexpiprazole and placebo groups, suggesting good overall tolerability.[42]

The approval of brexpiprazole for AADAD represents a significant regulatory and clinical paradox. The drug carries a class-wide black box warning regarding an increased risk of mortality in elderly patients with dementia-related psychosis.[2] This warning is based on older studies of atypical antipsychotics in broad dementia populations. Yet, the FDA granted approval for a specific symptom—agitation—within a specific type of dementia—Alzheimer's disease. This decision reflects a nuanced understanding that agitation and psychosis, while often co-occurring, are distinct syndromes. The pivotal trials for brexpiprazole specifically recruited and measured outcomes for agitation using the CMAI.[41] The FDA's action implies that for patients with documented, significant agitation, the demonstrated benefits of treatment may outweigh the class-associated risks. The drug's label explicitly clarifies this distinction, stating it is "not approved for the treatment of patients with dementia-related psychosis without agitation associated with dementia due to Alzheimer's disease".[32] This creates a critical imperative for clinicians to perform a precise diagnosis, carefully documenting the presence and severity of agitation to justify treatment, and to engage in a thorough risk-benefit discussion with patients and their caregivers. This landmark approval signals a shift toward more targeted, symptom-based indications in neuropsychiatric drug development.

Table 3: Summary of Pivotal Clinical Trials for Agitation in Alzheimer's Dementia

Trial Identifier	Study Design	Patient Population	Doses Studied	Primary Endpoint	Key Efficacy Result	Key Safety Findings	Source(s)
NCT01862640	Phase 3, 12-week, randomized, double-blind, placebo-controlled	55-90 years, probable AD with agitation	1 mg/day, 2 mg/day	Change in CMAI total score at Week 12	2 mg dose showed statistically significant improvement vs. placebo.	Generally well-tolerated. Most common AEs were headache, urinary tract infection.	41
NCT03107070 (Trial 331-12-283)	Phase 3, 12-week, randomized, double-blind, placebo-controlled	55-90 years, probable AD with agitation	2 mg/day, 3 mg/day (flexibly dosed)	Change in CMAI total score at Week 12	Brexpiprazole showed statistically significant improvement vs. placebo (mean change -22.6 vs -17.0).	No AE with incidence ≥5% and > placebo. Discontinuation due to AEs similar to placebo.	42
NCT03620981 (Japan)	Phase 2/3, 10-week, randomized, double-blind, placebo-controlled	Hospitalized or care facility patients with AD and agitation	1 mg/day, 2 mg/day	Change in CMAI total score at Week 10	To evaluate superiority of brexpiprazole over placebo.	Safety and tolerability were primary objectives.	43

4.4 Investigational and Off-Label Uses

Beyond its approved indications, brexpiprazole has been explored for other psychiatric conditions, with mixed results.

• Post-Traumatic Stress Disorder (PTSD): Brexpiprazole has been investigated as a potential treatment for PTSD, but the outcomes of these clinical trials have not yet led to an approved indication.[1]
• Bipolar Disorder: While its predecessor, aripiprazole, is approved for bipolar mania, brexpiprazole has not demonstrated similar efficacy. Clinical trials in patients with acute bipolar mania failed to show a significant difference between brexpiprazole and placebo in reducing symptoms, representing a key point of clinical differentiation from aripiprazole.[10]
• Attention Deficit Hyperactivity Disorder (ADHD): Brexpiprazole was studied for the treatment of adult ADHD but failed to meet its endpoints in Phase II clinical trials, and development for this indication was discontinued.[5]
• Borderline Personality Disorder (BPD): There is some preliminary evidence and off-label use suggesting that brexpiprazole may be beneficial in managing symptoms of mood instability and impulsivity in patients with BPD, although this is not supported by large-scale, controlled trials.[17]
• Treatment-Resistant Depression (TRD) with Ketamine: A Phase 4 clinical trial (NCT03149991) was conducted to investigate the efficacy and safety of brexpiprazole in combination with ketamine for patients with TRD, exploring novel combination strategies for this difficult-to-treat population.[47]

[Section 5: Safety Profile and Tolerability]

The safety and tolerability profile of brexpiprazole is a critical component of its clinical utility. While designed for improved tolerability, it shares many of the class-wide risks of atypical antipsychotics, including two major FDA Boxed Warnings.

5.1 FDA Boxed Warnings

Brexpiprazole's label includes two prominent boxed warnings that highlight its most serious potential risks.

• Increased Mortality in Elderly Patients with Dementia-Related Psychosis: This is a class-wide warning for all atypical antipsychotic drugs. Analyses of placebo-controlled trials have consistently shown that elderly patients with dementia-related psychosis treated with these agents have a higher risk of death compared to placebo. The causes of death are varied but are often cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. It is crucial to reiterate that brexpiprazole is not approved for the treatment of dementia-related psychosis in the absence of diagnosed agitation associated with Alzheimer's disease.[2]
• Suicidal Thoughts and Actions: This is a class-wide warning for all drugs with antidepressant activity. Pooled analyses of short-term placebo-controlled trials of antidepressants showed an increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults (ages 18-24). This risk must be balanced against the clinical need. All patients, particularly those in the younger age groups, who are started on brexpiprazole (especially for the adjunctive MDD indication) must be closely monitored for clinical worsening, suicidality, or unusual changes in behavior, particularly during the initial months of therapy or following dose adjustments.[2]

5.2 Common Adverse Events Profile

The incidence of common adverse events varies by indication and patient population, reflecting differences in dosing and underlying patient vulnerabilities.

• Adjunctive MDD: In adult patients, the most common TEAEs (≥5% and at least twice the rate of placebo) were akathisia, somnolence, and weight increased.[12]
• Schizophrenia (Adults): The most common TEAEs (≥5% incidence) included weight increased, akathisia, headache, somnolence, and insomnia.[10]
• Schizophrenia (Pediatric): In adolescents (ages 13-17), the most common TEAEs (≥5% incidence) were weight increased, somnolence, headache, akathisia, and nasopharyngitis.[20]
• Agitation in Alzheimer's Dementia: In this elderly population, the safety profile was notably benign compared to other indications. The most common adverse reactions (≥4% and at least twice the rate of placebo) were nasopharyngitis and dizziness.[10]
• Hepatic Effects: During clinical trials, brexpiprazole has been associated with a low rate of transient serum aminotransferase elevations, but it has not been convincingly linked to cases of clinically apparent acute liver injury.[4]

Table 4: Incidence of Common Adverse Events (≥5% and >Placebo) by Indication

Adverse Event	Adjunctive MDD (Adults)	Schizophrenia (Adults)	Schizophrenia (Adolescents)	Agitation in AD (Adults)
	Brexpiprazole (%)	Placebo (%)	Brexpiprazole (%)	Placebo (%)
Akathisia	7.4	1.0	6.6	3.2
Weight Increased	8.0	3.1	6.3	0.8
Somnolence	≥5	<5	≥5	<5
Headache	<5	<5	≥5	<5
Insomnia	<5	<5	≥5	<5
Nasopharyngitis	<5	<5	5.0	1.6
Dizziness	<5	<5	<5	<5

Note: Data compiled and synthesized from multiple sources.[10] Exact percentages may vary slightly between individual trials. This table represents a consolidated overview of the most frequently cited common adverse events.

5.3 Clinically Significant Risks and Management

Beyond the most common side effects, brexpiprazole carries several other clinically significant risks that require careful management and patient counseling.

• Neuroleptic Malignant Syndrome (NMS): A rare but life-threatening neurological emergency associated with antipsychotic use. It is characterized by a symptom complex of hyperthermia, severe muscle rigidity ("lead pipe" rigidity), autonomic dysfunction (tachycardia, labile blood pressure, diaphoresis), and altered mental status. If NMS is suspected, brexpiprazole must be discontinued immediately, and intensive supportive care must be initiated.[8]
• Tardive Dyskinesia (TD): A syndrome of potentially irreversible, involuntary, dyskinetic movements that can develop with long-term antipsychotic treatment. Symptoms include orofacial movements (e.g., lip-smacking, tongue protrusion) and choreoathetoid movements of the limbs and trunk. The risk appears to increase with the cumulative dose and duration of therapy. Patients should be monitored regularly for signs of TD, and discontinuation should be considered if it emerges.[8]
• Metabolic Changes: This is a well-established risk for the atypical antipsychotic class.
• Weight Gain: Brexpiprazole is consistently associated with weight gain, which can be significant and may contribute to non-adherence and long-term health complications. Baseline weight and frequent monitoring throughout treatment are essential.[8]
• Dyslipidemia: The drug can cause adverse changes in lipid profiles, including elevated triglycerides and cholesterol. A fasting lipid panel is recommended at baseline and periodically during treatment.[8]
• Hyperglycemia and Diabetes Mellitus: Atypical antipsychotics can impair glucose regulation, leading to hyperglycemia and, in rare cases, diabetic ketoacidosis or hyperosmolar coma. Patients with diabetes or risk factors for diabetes require regular monitoring of fasting blood glucose.[8]
• Pathological Gambling and Other Compulsive Behaviors: Post-marketing reports have identified cases of patients developing intense and uncontrollable urges, particularly for gambling, but also including compulsive shopping, binge eating, and hypersexuality. These urges often resolve upon dose reduction or discontinuation of the drug. It is imperative to warn patients and their families about this potential side effect.[8]
• Other Significant Risks:
• Orthostatic Hypotension and Syncope: Due to its α₁-adrenergic blocking properties, brexpiprazole can cause a drop in blood pressure upon standing, leading to dizziness, lightheadedness, and falls. This risk is highest during initial dose titration.[8]
• Leukopenia, Neutropenia, and Agranulocytosis: A temporary decrease in white blood cell count has been reported with antipsychotics. Patients with a pre-existing low WBC or a history of drug-induced neutropenia should be monitored closely.[8]
• Seizures: Brexpiprazole may lower the seizure threshold and should be used with caution in patients with a history of seizures.[8]
• Body Temperature Dysregulation: Antipsychotics can disrupt the body's ability to regulate core temperature. Caution is advised in situations that can lead to overheating, such as strenuous exercise or exposure to extreme heat.[8]
• Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic use. Caution is warranted in patients at risk for aspiration pneumonia.[8]

[Section 6: Dosing, Administration, and Special Populations]

The effective use of brexpiprazole requires adherence to specific dosing and titration schedules that are tailored to the indication and patient characteristics.

6.1 Formulations and Recommended Dosing

• Available Formulations: Brexpiprazole is supplied as oral tablets in a wide range of strengths to facilitate gradual dose titration: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg.[8]
• Administration: The tablets are administered orally once per day and can be taken with or without food.[8]
• Titration Schedules: A slow and steady titration is recommended for all indications to optimize tolerability, particularly given the drug's long half-life.

Table 5: Dosing and Administration Summary by Indication

Indication (Population)	Starting Dose	Titration Schedule	Recommended Target Dose	Maximum Daily Dose	Source(s)
Adjunctive MDD (Adults)	0.5 mg or 1 mg once daily	Increase at weekly intervals to 1 mg, then to the target dose.	2 mg once daily	3 mg once daily	8
Schizophrenia (Adults)	1 mg once daily	Days 1-4: 1 mg/day. Days 5-7: 2 mg/day. Day 8 onwards: May increase to 4 mg/day.	2 mg to 4 mg once daily	4 mg once daily	8
Schizophrenia (Adolescents 13-17)	0.5 mg once daily	Days 1-4: 0.5 mg/day. Days 5-7: 1 mg/day. Day 8 onwards: Increase to 2 mg/day. May titrate further weekly.	2 mg to 4 mg once daily	4 mg once daily	17
Agitation in AD (Adults)	0.5 mg once daily	Days 1-7: 0.5 mg/day. Days 8-14: 1 mg/day. Day 15 onwards: Increase to 2 mg/day.	2 mg once daily	3 mg once daily	17

6.2 Dosage Adjustments for Special Populations

Dosage modifications are necessary for patients with certain physiological conditions or genetic variations that affect drug metabolism.

• Hepatic Impairment: For patients with moderate to severe hepatic impairment (Child-Pugh score ≥7), the maximum recommended daily dose should be reduced. For MDD or AADAD, the maximum dose is 2 mg. For schizophrenia, the maximum dose is 3 mg.[8]
• Renal Impairment: For patients with moderate, severe, or end-stage renal disease (Creatinine Clearance, CrCl <60 mL/minute), the maximum recommended daily dose should also be reduced. The maximum dose is 2 mg for MDD or AADAD and 3 mg for schizophrenia.[8]
• CYP2D6 Poor Metabolizers: Individuals with a known genetic deficiency in CYP2D6 enzyme activity will have higher plasma concentrations of brexpiprazole. For these patients, the recommended dosage should be reduced by 50% (i.e., administered at half the usual dose).[2]
• Geriatric Patients: While no specific dose adjustment is mandated, cautious dosage selection is recommended. Treatment should generally be initiated at the lower end of the dosing range, with slow titration, to account for the higher likelihood of decreased renal, hepatic, or cardiac function and the presence of comorbidities and concomitant medications in this population.[8]

[Section 7: Significant Drug-Drug Interactions]

Brexpiprazole's metabolism via CYP3A4 and CYP2D6 makes it susceptible to a variety of clinically significant drug-drug interactions. These interactions can be pharmacokinetic (affecting drug levels) or pharmacodynamic (affecting drug effects).

7.1 Metabolically-Mediated Interactions (Pharmacokinetic)

The core principle governing these interactions is that inhibitors of CYP3A4 or CYP2D6 will decrease the metabolism of brexpiprazole, leading to increased plasma concentrations and a higher risk of adverse effects. Conversely, inducers of CYP3A4 will increase its metabolism, leading to lower plasma concentrations and a potential loss of efficacy. These predictable interactions necessitate specific dose adjustments.

• Strong CYP3A4 Inhibitors: Co-administration with potent inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin) requires that the usual brexpiprazole dose be reduced by 50% (administered at half dose).[2]
• Strong CYP2D6 Inhibitors: Co-administration with potent inhibitors of CYP2D6 (e.g., fluoxetine, paroxetine, bupropion, quinidine) also requires that the usual brexpiprazole dose be reduced by 50% (administered at half dose).[2]
• Strong CYP3A4 Inducers: When given with potent inducers of CYP3A4 (e.g., rifampin, carbamazepine, phenytoin, St. John's Wort), the usual brexpiprazole dose should be doubled (200% of the original dose) over one to two weeks to maintain therapeutic concentrations.[2]
• Complex Combination Scenarios: The most complex adjustments are required when multiple interacting drugs are used or in patients with inherent metabolic deficiencies.
• In patients taking both a strong/moderate CYP3A4 inhibitor AND a strong/moderate CYP2D6 inhibitor concurrently, the brexpiprazole dose should be reduced to 25% (one-quarter) of the usual dose.[2]
• In patients who are known CYP2D6 poor metabolizers AND are also taking a strong/moderate CYP3A4 inhibitor, the brexpiprazole dose should similarly be reduced to 25% (one-quarter) of the usual dose.[2]

Table 6: Dosage Adjustments for Key CYP-Mediated Drug Interactions

Patient Status / Concomitant Medication	Recommended Brexpiprazole Dosage Adjustment	Example Medications	Source(s)
Strong CYP3A4 Inhibitor	Administer 50% of the usual dose	Ketoconazole, Itraconazole, Clarithromycin	2
Strong CYP2D6 Inhibitor	Administer 50% of the usual dose	Fluoxetine, Paroxetine, Bupropion, Quinidine	2
Strong CYP3A4 Inducer	Double the usual dose over 1-2 weeks	Rifampin, Carbamazepine, Phenytoin, St. John's Wort	2
Strong/Moderate CYP3A4 Inhibitor + Strong/Moderate CYP2D6 Inhibitor	Administer 25% of the usual dose	e.g., Itraconazole + Paroxetine	2
Known CYP2D6 Poor Metabolizer + Strong/Moderate CYP3A4 Inhibitor	Administer 25% of the usual dose	N/A	2

7.2 Pharmacodynamic Interactions

These interactions involve the additive or opposing effects of drugs at their sites of action.

• CNS Depressants: Brexpiprazole can cause sedation and impair cognitive and motor skills. Concomitant use with other CNS depressants—such as alcohol, benzodiazepines, opioids, and sedative-hypnotics—will result in additive effects, increasing the risk of profound sedation, respiratory depression, and impairment. Caution and careful monitoring are essential.[18]
• Dopaminergic Agents: As a dopamine D₂ receptor partial agonist, brexpiprazole may antagonize the effects of full dopamine agonists used to treat Parkinson's disease (e.g., levodopa, pramipexole, ropinirole). This can lead to a worsening of motor symptoms in these patients.[9]
• Antihypertensive Agents: Due to its antagonist activity at α₁-adrenergic receptors, brexpiprazole can enhance the blood pressure-lowering effects of antihypertensive medications. This increases the risk of orthostatic hypotension, syncope, and falls.[18]
• Serotonergic Agents: Co-administration with other serotonergic drugs (e.g., SSRIs, SNRIs, triptans, tramadol) theoretically increases the risk of serotonin syndrome, a potentially life-threatening condition. However, as a partial agonist at 5-HT₁ₐ receptors, this risk may be complex. Close monitoring is advised.[18]

[Section 8: Regulatory History and Global Status]

The development and approval pathway of brexpiprazole reflects its evolving role in psychiatric pharmacotherapy, culminating in its landmark indication for AADAD.

8.1 FDA Approval Timeline (United States)

The regulatory journey of brexpiprazole in the U.S. has been marked by a series of sequential approvals that have expanded its clinical utility.

• July 10, 2015: The FDA granted initial approval for Rexulti® for two indications: as an adjunctive therapy for adults with MDD and as a treatment for adults with schizophrenia. This was based on a clinical program involving over 4,300 subjects in Phase II and III trials.[1]
• September 23, 2016: The label was updated to include an indication for the maintenance treatment of schizophrenia in adults, based on data from a long-term relapse prevention study.[35]
• January 6, 2022: The FDA approved a supplemental New Drug Application (sNDA) to expand the schizophrenia indication to include pediatric patients aged 13 to 17 years. This application was granted Priority Review.[35]
• August 2022: A generic version of brexpiprazole received FDA approval, increasing market competition and potential access.[10]
• May 10, 2023: In a landmark decision, the FDA approved an sNDA for Rexulti® for the treatment of agitation associated with dementia due to Alzheimer's disease. This made it the first and only pharmacological treatment approved in the U.S. for this specific indication.[10]

8.2 Global Regulatory Status

Brexpiprazole has also been approved for use in numerous other countries, although the specific indications may vary.

• European Union (EMA): Marketed as Rxulti®, it is approved for the treatment of schizophrenia in adults.[4]
• Canada (Health Canada): Approved for the treatment of schizophrenia (2017) and as an adjunctive therapy for MDD (2019).[16]
• Japan (PMDA): Approved and marketed as Rexulti®.[4]
• Other Regions: Approvals have also been granted in Australia for schizophrenia and in Brazil as an adjunctive treatment for MDD, among other nations.[10]

[Section 9: Ancillary Research and Future Directions]

While the primary clinical focus of brexpiprazole is in neuropsychiatry, intriguing preclinical research has suggested potential activity in other therapeutic areas, most notably oncology.

9.1 Preclinical Anti-Tumor Activity

A 2019 study published in Oncotarget explored the effects of brexpiprazole on cancer cells, yielding provocative results that, while highly preliminary, suggest a potential off-target biological activity.[5]

• In Vitro Findings: The study treated several human cancer cell lines (A549 lung cancer, PANC-1 and PSN-1 pancreatic cancer) with brexpiprazole. The drug was found to induce cell death and inhibit cell growth in these lines. More significantly, it demonstrated similar cytotoxic and growth-inhibitory effects against cancer stem-like cells (CSLCs) derived from these lines. CSLCs are a subpopulation of tumor cells thought to be responsible for tumor initiation, metastasis, and resistance to therapy. Crucially, at the concentrations effective against cancer cells, brexpiprazole showed no toxicity to non-cancerous cells, including normal human fibroblasts (IMR-90) and rat cortical stem cells.[5]
• In Vivo Findings: The researchers then evaluated these effects in an animal model. Mice were subcutaneously transplanted with PANC-1 pancreatic CSLCs to form tumors. Subsequent treatment with brexpiprazole resulted in a significant suppression of tumor growth compared to control animals. This anti-tumor effect was achieved without causing weight loss or other observable adverse effects in the mice. Analysis of the tumors showed that brexpiprazole treatment reduced the expression of key stemness and survival markers, Sox2 and survivin.[5]

It is essential to contextualize these findings with scientific rigor and clinical caution. This research represents a single, preclinical study. The history of drug development is replete with compounds that show promising anti-cancer activity in cell cultures and animal models but fail to translate into effective human cancer therapies. The mechanisms underlying this observed effect are not well understood and are likely unrelated to brexpiprazole's primary action on neurotransmitter receptors. This information is scientifically interesting and may provide a foundation for future hypothesis-driven research by oncologists and pharmacologists. However, it holds no current clinical relevance for patients or prescribers using brexpiprazole for its approved psychiatric indications. Any discussion of brexpiprazole as an "anti-cancer drug" is premature and unsupported by clinical evidence. This research should be viewed as an example of potential drug repurposing that requires extensive, independent investigation far removed from its established role in psychiatry.

[Section 10: Expert Synthesis and Concluding Remarks]

10.1 Integrated Clinical Profile

Brexpiprazole has established itself as a significant second-generation antipsychotic, representing an incremental but clinically meaningful evolution of the Serotonin-Dopamine Activity Modulator (SDAM) class. It is not a revolutionary agent that redefines the treatment of psychosis or depression, but rather a thoughtfully "version 2.0" molecule, refined from its predecessor, aripiprazole. Its distinct pharmacodynamic profile—characterized by lower intrinsic activity at D₂ receptors and more potent antagonism at 5-HT₂ₐ receptors—translates into a unique clinical balance of efficacy and tolerability. This profile, combined with its long half-life and complex metabolism, demands a high degree of clinical sophistication for optimal use.

10.2 Risk-Benefit Assessment

The clinical utility of any medication rests on a careful weighing of its benefits against its risks. For brexpiprazole, this assessment is particularly nuanced and indication-specific.

The primary and most impactful benefit of brexpiprazole is its novel, evidence-based indication for the treatment of agitation associated with dementia due to Alzheimer's disease (AADAD). This approval addressed a major unmet medical need and provided the first FDA-sanctioned pharmacological tool for a distressing and difficult-to-manage syndrome.

This substantial benefit must be balanced against a profile of significant risks, many of which are shared across the atypical antipsychotic class. The most prominent of these are the metabolic liabilities: brexpiprazole is consistently associated with weight gain and has the potential to cause dyslipidemia and hyperglycemia. These risks necessitate baseline and ongoing metabolic monitoring. Furthermore, despite its design, the risk of akathisia persists and remains one of its most common dose-limiting side effects. The central paradox of its clinical profile is the juxtaposition of its AADAD approval with the class-wide black box warning for increased mortality in elderly patients with dementia-related psychosis. This requires clinicians to navigate a fine diagnostic and ethical line, justifying its use for documented agitation while avoiding it for psychosis alone in the same vulnerable population.

10.3 Place in Therapy

Based on the totality of evidence, brexpiprazole's place in therapy can be clearly defined:

• For Major Depressive Disorder: It is a valuable and evidence-based adjunctive or second-line agent for patients who have failed to respond to antidepressant monotherapy. The choice to use it over other augmentation strategies will depend on the individual patient's tolerability profile and the clinician's assessment of the risk-benefit ratio, particularly concerning weight gain and akathisia.
• For Schizophrenia: It is a viable first- or second-line agent for both acute and maintenance treatment in adults and adolescents. Its specific side-effect profile—with a potentially lower risk of hyperprolactinemia and a moderate risk of metabolic issues and akathisia—will guide its selection for specific patients.
• For Agitation in Alzheimer's Dementia: It is now established as a first-line, evidence-based pharmacological option. Its use, however, is predicated on a confirmed diagnosis of Alzheimer's disease with significant, documented agitation. Its application in this setting demands extreme caution, slow titration, and a thorough discussion of the risks, including the black box warning, with caregivers.

10.4 Final Conclusion

Brexpiprazole is a sophisticated pharmacological agent that has successfully leveraged a refined molecular design to achieve a distinct clinical profile. While it did not fully escape the tolerability limitations of its predecessor, it has demonstrated robust efficacy across three challenging psychiatric conditions. Its landmark approval for agitation in Alzheimer's dementia has cemented its importance in the psychiatric armamentarium. The safe and effective use of brexpiprazole is not straightforward; it requires a deep understanding of its complex pharmacology, a patient approach to its slow titration, diligent management of its metabolic and extrapyramidal risks, and careful navigation of its nuanced indications and warnings. For the well-informed clinician, brexpiprazole offers a valuable and differentiated therapeutic tool for managing some of the most difficult-to-treat neuropsychiatric symptoms.

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