Brexpiprazole for Agitation in Patients with Alzheimer&rsquo;s Dementia with and without Co-Occurring Psychosis: Post Hoc Analysis of Short- and Long-Term Trials

Pierre N Tariot; Sanjeda R Chumki; David Wang; Pedro Such; Anton M Palma; Zhen Zhang; C Brendan Montano

doi:10.2147/NDT.S586701

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Short Report

Brexpiprazole for Agitation in Patients with Alzheimer’s Dementia with and without Co-Occurring Psychosis: Post Hoc Analysis of Short- and Long-Term Trials

Authors Tariot PN, Chumki SR, Wang D, Such P, Palma AM, Zhang Z , Montano CB

Received 5 December 2025

Accepted for publication 1 April 2026

Published 21 April 2026 Volume 2026:22 586701

DOI https://doi.org/10.2147/NDT.S586701

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3

Editor who approved publication: Dr Roger Pinder

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Pierre N Tariot,^1,² Sanjeda R Chumki,³ David Wang,⁴ Pedro Such,⁵ Anton M Palma,⁶ Zhen Zhang,⁶ C Brendan Montano⁷

¹Banner Alzheimer’s Institute, Phoenix, AZ, USA; ²Department of Psychiatry, University of Arizona College of Medicine, Phoenix, AZ, USA; ³Global Medical Affairs, Otsuka Pharmaceutical Development & Commercialization Inc., Princeton, NJ, USA; ⁴Medical Affairs, Lundbeck LLC, Deerfield, IL, USA; ⁵Medical Affairs, H. Lundbeck A/S, Valby, Denmark; ⁶Medical and Real-World Data Analytics, Otsuka Pharmaceutical Development & Commercialization Inc., Princeton, NJ, USA; ⁷Connecticut Clinical Research, Cromwell, CT, USA

Correspondence: Sanjeda R Chumki, Otsuka Pharmaceutical Development & Commercialization Inc., 508 Carnegie Center Drive, Princeton, NJ, 08540, USA, Email [email protected]

Purpose: Patients with Alzheimer’s dementia may experience co-occurring agitation and psychosis symptoms. This exploratory post hoc analysis aimed to analyze the efficacy and safety of brexpiprazole for agitation in patients with Alzheimer’s dementia with and without co-occurring psychosis.
Participants and Methods: Data were pooled from two Phase 3, 12-week, randomized, double-blind, placebo-controlled, fixed-dose trials of brexpiprazole versus placebo in participants with Alzheimer’s dementia and agitation, conducted in Europe, Russia, and the US (ClinicalTrials.gov identifiers: NCT01862640, NCT03548584). Post hoc, participants were stratified into subgroups with or without co-occurring psychosis at baseline, defined as a score ≥ 4 on the Neuropsychiatric Inventory Delusions domain, Hallucinations domain, or both. Efficacy was assessed by the Cohen-Mansfield Agitation Inventory Total score. Safety was assessed by treatment-emergent adverse events (TEAEs).
Results: 142/607 participants (23.4%) had co-occurring psychosis at baseline. Brexpiprazole 2 or 3 mg/day was associated with greater improvement in agitation compared with placebo in participants with co-occurring psychosis (least squares mean difference at Week 12, − 9.18 [95% confidence interval − 15.2 to − 3.12]; P=0.004; Cohen’s d=0.52) and in participants without co-occurring psychosis (− 4.22 [− 6.91 to − 1.54]; P=0.002; Cohen’s d=0.29). In participants with co-occurring psychosis, for brexpiprazole and placebo respectively, 52.9% and 40.0% had TEAEs, and 3.4% and 9.1% discontinued due to TEAEs. No deaths occurred among participants with co-occurring psychosis. In participants without co-occurring psychosis, for brexpiprazole and placebo respectively, 49.3% and 38.2% had TEAEs, and 5.5% and 2.6% discontinued due to TEAEs. Two participants without co-occurring psychosis died; neither death was considered related to brexpiprazole treatment.
Conclusion: In this post hoc analysis, brexpiprazole improved agitation and was generally well tolerated in patients with Alzheimer’s dementia with and without co-occurring psychosis. These exploratory data suggest that brexpiprazole may be of value to patients with Alzheimer’s dementia who present with agitation and psychosis in clinical practice.

Plain Language Summary: Alzheimer’s dementia is a brain disorder in which people’s thinking and memory decline slowly over time. Many people with Alzheimer’s dementia experience agitation, which can emerge as movement symptoms (restlessness, wandering) or as spoken or physical aggression (swearing, hitting). People with Alzheimer’s dementia may also experience psychosis, which refers to fixed, false beliefs that are not based in reality, or hearing and seeing things that are not there. Agitation and psychosis can both be treated with antipsychotic medications. However, some antipsychotic medications are thought to cause serious harm, even death, in people with Alzheimer’s dementia. The antipsychotic, brexpiprazole, is the only medicine approved by the United States FDA for the treatment of agitation in people with Alzheimer’s dementia. In this report, researchers used information from previous clinical trials to explore whether brexpiprazole can safely treat agitation in people with Alzheimer’s dementia with both agitation and psychosis. The results showed that brexpiprazole improved agitation more than placebo (a dummy drug), with no new safety concerns compared with previous studies. This suggests that brexpiprazole may be able to help people with agitation and Alzheimer’s dementia, even if they also have psychosis.

Keywords: Alzheimer’s disease, antipsychotic, clinical trial, efficacy, safety

Introduction

Approximately 50% of patients with Alzheimer’s dementia and other dementias experience signs and symptoms of agitation.¹ There are multiple symptoms of agitation that can be classified into domains of excessive motor activity, verbal aggression, and physical aggression.² Agitation is a highly challenging and stressful aspect of Alzheimer’s dementia for patients and caregivers, which may influence the decision to transfer patients to long-term care.^3,4

Symptoms of psychosis (delusions and hallucinations) are also common in Alzheimer’s dementia (prevalence ~40%).⁵ Psychosis is associated with faster disease progression (even after adjustment for medication use), functional impairment, and increased caregiver burden (including distress, burnout, and depression).^6–10 Psychosis often co-occurs with agitation, particularly at more severe stages of Alzheimer’s dementia.^11,12

Treatment approaches for agitation and psychosis in Alzheimer’s dementia are similar, historically involving off-label antipsychotic medications.¹³ Benzodiazepines and antidepressants (eg, bupropion) are also used off-label,¹⁴ despite increased risk of psychosis and delirium.^15–17 In clinical trials, off-label atypical antipsychotics show minimal effect on psychosis in dementia, based on limited evidence.^18,19 Research into antipsychotics in older people with dementia is mitigated by safety concerns, including an increased risk of death attributed to cerebrovascular events, cardiovascular events, and infections.^20,21 In the US, antipsychotics carry a class boxed warning for increased risk of death in older patients with dementia-related psychosis.^20,22,23

Brexpiprazole is an atypical antipsychotic approved in the US, Canada, and other regions for the treatment of agitation associated with dementia due to Alzheimer’s disease.^24,25 The US boxed warning was amended in 2023 to state that brexpiprazole is “not approved for the treatment of patients with dementia-related psychosis without agitation associated with dementia due to Alzheimer’s disease”.^24,26 In Phase 3 clinical trials, brexpiprazole improved agitation in patients with Alzheimer’s dementia and was generally well tolerated over 12 and 24 weeks, with low risk of cerebrovascular events, cardiovascular events, and infections.^26–29

Given the safety concerns with antipsychotic use in older people with dementia-related psychosis, it is important to clarify whether brexpiprazole is a suitable treatment for agitation in this population. Preliminary analyses of Phase 3 trial data show that brexpiprazole improved agitation at Week 12 in patients with Alzheimer’s dementia with psychosis,^28,30 but longer-term data and safety analyses are lacking. This exploratory post hoc analysis aimed to comprehensively analyze the efficacy and safety of brexpiprazole for agitation in patients with and without co-occurring psychosis, over 12 and 24 weeks.

Participants and Methods

Three analyses were performed: (1) a 12-week analysis including data pooled from two similarly designed, randomized, fixed-dose trials; (2) a 12-week sensitivity analysis that included a third randomized trial with a different design (flexible dosing, low target dose); and (3) a 24-week analysis of a randomized trial with an extension. Analysis 1 is described here, whereas analyses 2 and 3 are described in Supplemental Material 1: Methods.

This post hoc analysis did not require ethics approval. The original trials were approved by ethics committees and followed good clinical practice and Declaration of Helsinki guidance. Participants and/or their legal representatives provided informed consent to participate.

Design of Randomized Trials

The two trials in the main 12-week analysis were Phase 3, randomized, double-blind, placebo-controlled, fixed-dose, parallel-arm trials conducted in Europe, Russia, and the US: Trial 283 (ClinicalTrials.gov identifier: NCT01862640) and Trial 213 (NCT03548584).^27,28 The designs and primary results are published.^27,28

Investigators at clinical trial sites enrolled participants aged 55–90 years with a diagnosis of probable Alzheimer’s disease by NINCDS-ADRDA criteria³¹ supported by magnetic resonance imaging or computed tomography scans. Cognitive impairment was indicated by a Mini-Mental State Examination³² score of 5–22, and agitation by a Neuropsychiatric Inventory (NPI) Agitation/aggression domain^33,34 score ≥4. In Trial 213, eligible participants also met agitation criteria based on the International Psychogeriatric Association definition² and the Cohen-Mansfield Agitation Inventory (CMAI) Aggressive behaviors factor.^28,35,36 Participants could be living either in a care facility or community-based setting. People with clinically significant or uncontrolled medical conditions (eg, other forms of dementia) or diagnoses of schizophrenia, schizoaffective disorder, or other psychotic disorders (not related to dementia) were excluded.

Eligible participants were randomly allocated to brexpiprazole (fixed doses of 1, 2, or 3 mg/day, depending on the trial) or placebo, for 12 weeks. Titration occurred over 2–4 weeks. Stable background medications for Alzheimer’s dementia and depression were permitted. Antipsychotics (other than brexpiprazole), mood stabilizers, and anticonvulsants were prohibited. Benzodiazepine use was restricted to the first 4 weeks.

Definition of Co-Occurring Psychosis

Post hoc, participants were stratified into two subgroups: those with co-occurring psychosis at baseline, and those without. Co-occurring psychosis was defined as a score ≥4 on the NPI Delusions domain, the NPI Hallucinations domain, or both. This cut-off of 4 points, a standard definition in clinical trials, indicates clinically significant symptoms that require intervention.³⁷

Outcome Measures

The CMAI is a questionnaire that measures how often 29 different agitation symptoms occurred over the past 2 weeks.^35,38 CMAI Total scores range from 29 (no agitation) to 203 (worst possible agitation). Further details are provided in Supplemental Material 1: Methods.

Safety was assessed by treatment-emergent adverse events (TEAEs), including serious TEAEs, discontinuation due to TEAEs, death, and TEAE categories of specific interest²⁶ (any cerebrovascular, cardiovascular, extrapyramidal symptom, akathisia, orthostatic hypotension/dizziness/syncope, falls, insomnia, and somnolence/sedation).

Statistical Analysis

This exploratory, hypothesis-generating analysis investigated brexpiprazole 2 or 3 mg/day, the US FDA-approved doses.²⁴ Participant data were pooled across the trials to create brexpiprazole and placebo groups. Participants with a CMAI assessment at baseline and at any post-baseline visit were analyzed.

Least squares (LS) mean change in CMAI Total score from baseline was calculated using a mixed model for repeated measures with fixed effects of trial, treatment, site (nested in trial), and visit week, an interaction term of treatment-by-visit week, and an interaction term of baseline score-by-visit week, with unstructured covariance, and with no imputation for missing data. P values were tested at a nominal 0.05 level (two-sided) with no correction for multiple comparisons. Analyses were performed using SAS version 9.4 (SAS Institute Inc; Cary, NC).

The 12-week sensitivity analysis and 24-week analysis are described in Supplemental Material 1: Methods.

Results

Participants

In the 12-week analysis, 621 participants were randomized, 610 had baseline and post-baseline CMAI assessments, and 607 had a baseline psychosis status. Co-occurring psychosis was present at baseline in 142/607 participants (23.4%): 87/361 (24.1%) on brexpiprazole 2 or 3 mg, and 55/246 (22.4%) on placebo. Of the 142 participants with psychosis, 128 had delusions and 50 had hallucinations.

A similar proportion of participants completed the trials in the subgroups with co-occurring psychosis (brexpiprazole, 77/87 [88.5%]; placebo, 46/55 [83.6%]) and without co-occurring psychosis (brexpiprazole, 240/274 [87.6%]; placebo, 177/191 [92.7%]).

Baseline demographic and clinical characteristics were generally similar between treatment groups, with and without co-occurring psychosis (Table 1). Co-occurring psychosis was more common in females than males and was associated with more frequent agitation at baseline (CMAI Total score) (Table 1). Participants with co-occurring psychosis were more likely to have other co-occurring neuropsychiatric symptoms, eg, depression (35.9% versus 11.2%) and anxiety (66.2% versus 40.3%), compared with those without co-occurring psychosis.

Table 1 Baseline Demographic and Clinical Characteristics (12-Week Analysis)

In the 24-week analysis, co-occurring psychosis was present at baseline in 35/157 participants (22.3%) (Supplemental Table 1).

Efficacy for Agitation

In the subgroup with co-occurring psychosis, LS mean (standard error) CMAI Total score change from baseline to Week 12 was −28.5 (1.9) for brexpiprazole and −19.4 (2.3) for placebo (Figure 1A). The LS mean difference (95% confidence interval) at Week 12 was −9.18 (−15.2 to −3.12); P=0.004; Cohen’s d=0.52.

Figure 1 Change from baseline in agitation symptoms (CMAI Total score; 12-week analysis).

Abbreviations: CMAI, Cohen-Mansfield Agitation Inventory; MMRM, mixed model for repeated measures; LS, least squares; SE, standard error.

Notes: *p<0.05, **p<0.01, ***p<0.001 versus placebo; MMRM. Mean (standard deviation) baseline score: (A) brexpiprazole, 82.4 (20.7); placebo, 84.1 (20.8); (B) brexpiprazole, 75.1 (15.6); placebo, 73.0 (16.4).

In the subgroup without co-occurring psychosis, LS mean (standard error) CMAI Total score change from baseline to Week 12 was −21.2 (0.9) for brexpiprazole and −17.0 (1.1) for placebo (Figure 1B). The LS mean difference (95% confidence interval) at Week 12 was −4.22 (−6.91 to −1.54); P=0.002; Cohen’s d=0.29.

The sensitivity analysis that included participants from the flexible-dose trial had consistent findings (Supplemental Material 2: Results).

In the 24-week analysis, agitation continued to improve in participants who took brexpiprazole with or without co-occurring psychosis (Supplemental Figure 1).

Safety

Over 12 weeks in the subgroup with co-occurring psychosis, TEAEs were reported for 46/87 participants (52.9%) on brexpiprazole and 22/55 (40.0%) on placebo.³⁰ Specific TEAEs with incidence ≥5% with brexpiprazole and greater than placebo were insomnia (5.7% compared to 3.6%) and urinary tract infection (5.7% compared to 1.8%) (Table 2). One TEAE category of interest (any extrapyramidal symptom) had incidence ≥5% with brexpiprazole and greater than placebo (6.9% compared to 1.8%) (Table 2). The proportion who discontinued due to TEAEs was lower with brexpiprazole than placebo (3.4% compared to 9.1%). No deaths occurred among participants with co-occurring psychosis.

Table 2 Summary of TEAEs (12-Week Analysis)

Over 12 weeks in the subgroup without co-occurring psychosis, TEAEs were reported for 135/274 participants (49.3%) on brexpiprazole and 73/191 (38.2%) on placebo. The only TEAE with incidence ≥5% with brexpiprazole and greater than placebo was headache (8.8% compared to 8.4%) (Table 2). The proportion who discontinued due to TEAEs was higher with brexpiprazole than placebo (5.5% compared to 2.6%). Two participants without co-occurring psychosis died during treatment with brexpiprazole; neither death was considered related to brexpiprazole treatment (as reported previously).²⁶

The 24-week safety analysis was limited by small subgroup sizes (Supplemental Table 2). The incidence of TEAEs on brexpiprazole was higher in participants without co-occurring psychosis (39.3%) than with co-occurring psychosis (31.4%). Headache was the only TEAE with incidence ≥5%, in both subgroups.

Discussion

Over 12 weeks, brexpiprazole 2 or 3 mg/day was associated with greater improvement in agitation (CMAI Total score) versus placebo in patients with Alzheimer’s dementia with and without co-occurring psychosis. Over 24 weeks, agitation continued to improve in patients with and without co-occurring psychosis taking brexpiprazole 2 or 3 mg/day.

Improvement in agitation over 12 weeks with brexpiprazole was greater in the subgroup with psychosis (Cohen’s d=0.52) than without psychosis (0.29). The study sample had frequent agitation symptoms at baseline, particularly in the subgroup with psychosis, potentially allowing more scope for improvement. Although studied predominantly in samples enriched for psychosis rather than agitation, off-label antipsychotics have shown CMAI Cohen’s d values of 0.18–0.30 versus placebo.³⁹ While the present analysis did not assess changes in psychosis, a separate analysis showed small improvements for brexpiprazole on the NPI Delusions domain in the total pooled sample,⁴⁰ which should be repeated in a sample with baseline psychosis.

TEAE analysis revealed no new safety concerns for patients with co-occurring psychosis taking brexpiprazole 2 or 3 mg/day over 12 or 24 weeks, compared with prior analyses.^26,29 TEAE categories associated with off-label atypical antipsychotics (including cerebrovascular, cardiovascular, and somnolence)^19,41 had incidence <5% with brexpiprazole, except extrapyramidal symptoms in the co-occurring psychosis subgroup (6.9%). There were no deaths among patients with dementia-related psychosis taking brexpiprazole over 12 or 24 weeks. This supports the amended US boxed warning, allowing brexpiprazole use in patients with dementia-related psychosis provided they have agitation associated with dementia due to Alzheimer’s disease.²⁴ Across the entire clinical program, six deaths were reported on brexpiprazole.²⁶ None were attributed to brexpiprazole (intracranial hemorrhage, meningoencephalitis, pneumonia, obstructive airways disorder [choked on food], end-stage Alzheimer’s dementia, and cardiac failure).²⁶

Strengths of this analysis include addressing a clinically relevant question, and pooling of data from two similarly designed trials to increase the sample size to investigate subgroups. Considering limitations, small subgroup sizes limit the interpretation of results and reduce the opportunity to observe less common adverse events. Trial 213 (only) enriched for the CMAI Aggressive behaviors factor, which enhanced signal detection in this trial.²⁸ There was no correction for multiplicity, and the trials were powered for analyses of the full sample, not co-occurring psychosis subgroups. The 24-week analysis had no comparator and a sample (patients who rolled over) that may be biased towards better tolerability and response. Post hoc analyses are exploratory and hypothesis generating, and prospective studies are needed to confirm these findings.

Conclusion

In this post hoc analysis, brexpiprazole improved agitation and was generally well tolerated in patients with Alzheimer’s dementia with and without co-occurring psychosis. These exploratory data support the US approval of brexpiprazole for the treatment of agitation in patients with Alzheimer’s dementia-related psychosis. In clinical practice, brexpiprazole may be of value to patients with agitation associated with dementia due to Alzheimer’s disease, presenting with or without psychosis.

Abbreviations

CMAI, Cohen-Mansfield Agitation Inventory; LS, least squares; NPI, Neuropsychiatric Inventory; TEAE, treatment-emergent adverse event.

Data Sharing Statement

To submit inquiries related to Otsuka clinical research, or to request access to individual participant data (IPD) associated with any Otsuka clinical trial, please visit https://clinical-trials.otsuka.com/. For all approved IPD access requests, Otsuka will share anonymized IPD on a remotely accessible data sharing platform.

Acknowledgments

Writing support was provided by Chris Watling, PhD, and colleagues of the Prime Group of Companies (Knutsford, UK), funded by Otsuka Pharmaceutical Development & Commercialization Inc. and H. Lundbeck A/S.

Parts of this work were presented as a poster at the Psych Congress; September 6–10, 2023; Nashville, TN and the American Association for Geriatric Psychiatry (AAGP) Annual Meeting; March 15–18, 2024; Atlanta, GA.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; have agreed on the journal to which the article has been submitted; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.

Funding

This work was supported by Otsuka Pharmaceutical Development & Commercialization Inc. (Princeton, NJ, USA) and H. Lundbeck A/S (Valby, Denmark). The sponsors were involved in the design of the research, the analysis and interpretation of data, the writing and reviewing of this article, and the decision to submit the article for publication. The sponsors thank the patients and their families who participated in these studies. The academic authors were not compensated for this work.

Disclosure

PNT reports consulting fees from AbbVie, Acadia Pharmaceuticals, AC Immune, Athira Pharma, Axsome Therapeutics, Bristol Myers Squibb, Cognition Therapeutics, Cognito, Corium, CuraSen Therapeutics, EMA Wellness, Eisai, Genentech, ImmunoBrain, Janssen, Lundbeck, MapLight, Merck & Co., Novartis, Novo Nordisk, ONO Pharma, Otsuka/Astex Pharmaceuticals, Roche, and T3D Therapeutics, and honoraria from Novo Nordisk and Lundbeck.

SRC, AMP, and ZZ are full-time employees of Otsuka Pharmaceutical Development & Commercialization Inc.

DW is a full-time employee of Lundbeck LLC.

PS is a full-time employee of H. Lundbeck A/S.

CBM has received consulting fees from AbbVie, Acadia Pharmaceuticals, Alkermes, Arbor, Eisai, Neos, Novo Nordisk, Otsuka, Sunovion, Supernus, and Takeda, and has received payment/honoraria from AbbVie, Arbor, Eisai, Otsuka, and Takeda.

The authors report no other conflicts of interest in this work.

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