Comparative efficacy and safety of different brexpiprazole doses for agitation in Alzheimer's disease: A systematic review and network meta-analysis

BackgroundAgitation in Alzheimer's disease significantly impacts patient outcomes and caregiver burden. Brexpiprazole has emerged as a promising treatment option, but optimal dosing remains unclear.ObjectiveTo evaluate the comparative efficacy and safety of different brexpiprazole doses in treating agitation associated with Alzheimer's disease through a systematic review and network meta-analysis (NMA).MethodsFollowing PRISMA guidelines, we searched PubMed, Embase, Web of Science, and Scopus through January 2025. Four randomized controlled trials (N = 1451) comparing various brexpiprazole doses (0.5-3 mg/day) with placebo were included. Primary outcomes included changes in the Cohen-Mansfield Agitation Inventory (CMAI), the Clinical Global Impression-Severity Scale (CGI-S), and the Neuropsychiatric Inventory-Nursing Home Version (NPI-NH) scores, alongside safety measures.ResultsBrexpiprazole 2 mg demonstrated significant improvement in CMAI scores versus placebo (mean difference [MD]: -5.88; 95% CI: -8.13 to -3.63) and CGI-S scores (MD: -0.48; 95% CI: -0.95 to -0.01). Multiple doses showed significant NPI-NH improvements, with 2-3 mg showing the strongest effect (MD: -4.60; 95% CI: -7.54 to -1.66). Higher doses (2-3 mg) increased treatment-emergent adverse events (risk ratio [RR]: 1.20-1.33) but showed no significant difference in serious adverse events compared to placebo.ConclusionsBrexpiprazole 2 mg provides optimal therapeutic benefit while maintaining a favorable safety profile. The findings support initiating treatment at lower doses with careful titration to 2 mg based on individual response and tolerability. Future research should focus on long-term outcomes and real-world effectiveness.