Journal Article Systematic Review Ahead of print
PubMed: 40886227 DOI: 10.1007/s40263-025-01219-y
Brexpiprazole for the Treatment of Agitation in Older Adults with Alzheimer's Disease: A Systematic Review, Bayesian Meta-analysis, and Meta-regression.
CNS Drugs
Authors: 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
Affiliations
- Department of Physiology and Pharmacology, Federal University of Pernambuco, Recife, PE, Brazil.
- Department of Medicine, Bahiana School of Medicine and Public Health, Salvador, BA, Brazil.
- Department of Medicine, Federal University of Piauí, Teresina, PI, Brazil.
- Department of Medicine, Barão de Mauá University Center, Ribeirão Preto, SP, Brazil.
- Department of Medicine, Institute of Medical Education, Angra dos Reis, RJ, Brazil.
- Department of Medicine, University of São Paulo, São Paulo, SP, Brazil.
- Department of Medicine, Medical University of Silesia, Katowice, Poland.
- Department of Medicine, Federal Fluminense University, Niterói, RJ, Brazil.
- Department of Neurology, Centro de Cognição Paulista (CECOP), Santa Casa of São Paulo, São Paulo, SP, Brazil.
- Center for Medical Sciences, Graduate Program in Translational Health, Federal University of Pernambuco, Recife, PE, Brazil.
- Department of Physiology and Pharmacology, Federal University of Pernambuco, Recife, PE, Brazil.
Abstract
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.
MeSH
Safety, Alzheimer Disease, Signs And Symptoms, Therapeutics