Brexpiprazole for agitation in alzheimer's disease: A systematic review and meta-analysis of randomized controlled trials

Abstract

Background: Agitation in Alzheimer's disease (AD) severely affects patients and caregivers. Brexpiprazole, a serotonin-dopamine modulator, is the potential treatment; however, recent trials and variations in dosing have raised questions about its optimal efficacy and safety.

Aim: To evaluate the efficacy and safety of brexpiprazole in the treatment of agitation associated with AD, with a focus on dose-specific outcomes.

Methods: A systematic search was conducted in PubMed, Embase, and the Cochrane Library for Randomized Controlled Trials (RCT) comparing brexpiprazole with placebo in AD-related agitation. Primary efficacy outcomes included changes in the Cohen-Mansfield Agitation Inventory (CMAI) and Clinical Global Impression-Severity (CGI-S) scores. Safety outcomes encompassed treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and mortality. Meta-analyses were performed using a random-effects model, with mean differences (MD) and odds ratios (OR) reported with 95% confidence intervals (CI).

Results: Four RCTs with 1,710 participants were included. Brexpiprazole 2 mg significantly reduced CMAI scores (MD: -5.618; 95% CI: -7.884, -3.351; P < 0.001) and CGI-S scores (MD: -0.513; 95% CI: -0.890, -0.135; P = 0.008) compared to placebo. Lower doses (0.5-1 mg) demonstrated limited efficacy. TEAEs were more frequent with brexpiprazole 2 mg (OR: 1.554; 95% CI: 1.045, 2.312; P = 0.030), while SAEs (OR: 1.389; P = 0.384) and mortality (OR: 2.189; P = 0.301) did not significantly differ from placebo.

Conclusion: Brexpiprazole 2 mg is effective in reducing agitation symptoms in AD with an acceptable safety profile.

Keywords: Agitation; Alzheimer’s disease; brexpiprazole; meta-analysis; randomized controlled trials.

Figure 1

PRISMA flowchart

Figure 2

Forest Plot of CMAI Total Score Within 12 weeks. Forest plots showing the effect of brexpiprazole on agitation symptoms, measured by the Cohen-Mansfield Agitation Inventory (CMAI) total score within 12 weeks. (a): All brexpiprazole doses combined versus placebo. (b): Brexpiprazole 2 mg versus placebo. (c): Brexpiprazole 0.5–1 mg versus placebo

Figure 3

Forest Plot of CGI-S Score Related to Agitation Within 12 Weeks. Forest plots illustrating the effect of brexpiprazole on Clinical Global Impression – Severity of illness (CGI-S) scores related to agitation within 12 weeks. (a): All brexpiprazole doses combined versus placebo. (b): Brexpiprazole 2 mg versus placebo. (c): Brexpiprazole 0.5–1 mg versus placebo

Figure 4

Forest plot of simpson-angus scale within 12 weeks

Figure 5

Forest Plot of all-cause mortality

Figure 6

Forest Plot of At Least One TEAE. Forest plots showing the incidence of patients experiencing at least one treatment-emergent adverse event (TEAE) within 12 weeks of treatment. (a): All brexpiprazole doses combined versus placebo. (b): Brexpiprazole 2 mg versus placebo. (c): Brexpiprazole 0.5–1 mg versus placebo

Figure 7

Forest plot of patients with serious TEAEs in all dosages

Figure 8

Forest Plot of Patients with Discontinuation of Study Treatment Due To TEAEs. Forest plots illustrating the proportion of patients who discontinued study treatment due to treatment-emergent adverse events (TEAEs) within 12 weeks. (a): All brexpiprazole doses combined versus placebo. (b): Brexpiprazole 2 mg versus placebo. (c): Brexpiprazole 0.5–1 mg versus placebo

Figure 9

Risk of bias assessment