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Background <p>Agitation is a common and distressing neuropsychiatric symptom in Alzheimer’s disease (AD), affecting up to half of patients and contributing to faster cognitive decline and caregiver burden. Brexpiprazole, a serotonin–dopamine modulator, has been evaluated for this indication, but uncertainties remain regarding its efficacy, safety, and appropriate use in older adults.</p> Objective <p>We aimed to assess the efficacy and safety of brexpiprazole for the treatment of agitation in older adults with AD through a systematic review and meta-analysis of randomized controlled trials (RCTs).</p> Methods <p>Following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020 guidelines and the Cochrane Handbook, we included RCTs comparing brexpiprazole (0.5–3&#xa0;mg/day) with placebo in older adults with a clinical diagnosis of AD. Primary outcomes were agitation severity (measured using the Cohen–Mansfield Agitation Inventory [CMAI]), clinical impression (clinical global impression–severity scale [CGI-S]), neuropsychiatric symptoms (Neuropsychiatric Inventory [NPI]), and adverse events. Risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI) were pooled using a random-effects model. Random-effects meta-analyses were performed using frequentist and Bayesian models in R (version 4.3.0).</p> Results <p>A total of five RCTs (<i>N</i>&#xa0;=&#xa0;1770) met the inclusion criteria. Brexpiprazole was associated with a modest reduction in agitation CMAI (MD −&#xa0;5.79; 95% CI −&#xa0;9.55 to −&#xa0;2.04; prediction interval: −&#xa0;14.07 to 2.49) and improved CGI-S scores (MD −&#xa0;0.23; 95% CI −&#xa0;0.32 to −&#xa0;0.13; prediction interval: −&#xa0;0.39 to −&#xa0;0.06). No significant differences were found in NPI scores. Adverse events such as extrapyramidal symptoms and daytime somnolence occurred more frequently with brexpiprazole but with wide and nonsignificant intervals. Meta-regression did not identify dose or duration as effect modifiers.</p> Conclusions <p>Brexpiprazole may offer modest short-term benefits for agitation in AD without cognitive worsening, but safety signals remain imprecise. However, prediction intervals indicate considerable uncertainty, and its use should be individualized and closely monitored. Future trials should prioritize long-term outcomes and patient-centered measures.</p> Registration PROSPERO Protocol Number <p>CRD 42025646060.</p>

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Brexpiprazole for the Treatment of Agitation in Older Adults with Alzheimer’s Disease: A Systematic Review, Bayesian Meta-analysis, and Meta-regression

  • 期刊论文

  • 发表日期：

    2025年8月31日

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  • Anderson Matheus Pereira da Silva,
  • Luciano Falcão,
  • Ocilio Ribeiro Gonçalves,
  • Filipe Virgilio Ribeiro,
  • Pedro Lucas Machado Magalhães,
  • Mariana Lee Han,
  • Paweł Łajczak,
  • Mariana Letícia de Bastos Maximiano,
  • Henrique Cal,
  • Eryvelton de Souza Franco,
  • Maria Bernadete de Sousa Maia

摘要

Background

Agitation is a common and distressing neuropsychiatric symptom in Alzheimer’s disease (AD), affecting up to half of patients and contributing to faster cognitive decline and caregiver burden. Brexpiprazole, a serotonin–dopamine modulator, has been evaluated for this indication, but uncertainties remain regarding its efficacy, safety, and appropriate use in older adults.

Objective

We aimed to assess the efficacy and safety of brexpiprazole for the treatment of agitation in older adults with AD through a systematic review and meta-analysis of randomized controlled trials (RCTs).

Methods

Following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020 guidelines and the Cochrane Handbook, we included RCTs comparing brexpiprazole (0.5–3 mg/day) with placebo in older adults with a clinical diagnosis of AD. Primary outcomes were agitation severity (measured using the Cohen–Mansfield Agitation Inventory [CMAI]), clinical impression (clinical global impression–severity scale [CGI-S]), neuropsychiatric symptoms (Neuropsychiatric Inventory [NPI]), and adverse events. Risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI) were pooled using a random-effects model. Random-effects meta-analyses were performed using frequentist and Bayesian models in R (version 4.3.0).

Results

A total of five RCTs (N = 1770) met the inclusion criteria. Brexpiprazole was associated with a modest reduction in agitation CMAI (MD − 5.79; 95% CI − 9.55 to − 2.04; prediction interval: − 14.07 to 2.49) and improved CGI-S scores (MD − 0.23; 95% CI − 0.32 to − 0.13; prediction interval: − 0.39 to − 0.06). No significant differences were found in NPI scores. Adverse events such as extrapyramidal symptoms and daytime somnolence occurred more frequently with brexpiprazole but with wide and nonsignificant intervals. Meta-regression did not identify dose or duration as effect modifiers.

Conclusions

Brexpiprazole may offer modest short-term benefits for agitation in AD without cognitive worsening, but safety signals remain imprecise. However, prediction intervals indicate considerable uncertainty, and its use should be individualized and closely monitored. Future trials should prioritize long-term outcomes and patient-centered measures.

Registration PROSPERO Protocol Number

CRD 42025646060.