Efficacy of Add-On Agomelatine on Agitation, Aggression, and Neuroprotection in Alzheimer's Disease: A Randomized, Blinded, Controlled Trial Publisher



Kargar A^{1, 2} ; Fetratjoo DH^{2, 3} ; Moattar R² ; Tarki A^{2, 4} ; Golsokhan A^{5, 6} ; Pouyan N^{7, 8} ; Amjadigoojgi Z² ; Mostafaei H⁵ ; Kakeri F⁵ ; Zendehbad AS⁹ ; Lima BS¹⁰ ; Esmaily H¹ ; Noroozian M²
Source: American Journal of Geriatric Psychiatry Published:2025

Abstract

Background: Agitation and aggression are challenging behavioral and psychological symptoms of dementia (BPSD) in Alzheimer's disease (AD), which is diagnosed based on NINCDS-ADRDA criteria. Limited efficacy and safety of existing pharmacotherapies complicate treatment. Agomelatine, a melatonergic agonist and serotonergic antagonist, may provide a safer and more effective alternative. Objectives: The primary outcome is to evaluate the efficacy of agomelatine as an add-on therapy to nonpharmacological treatment in reducing agitation and aggression in patients with AD, with secondary outcomes assessing its safety and potential neuroprotective effects. Methods: In a randomized, triple-blind, placebo-controlled trial, 56 patients with AD (aged ≥65) experiencing agitation and aggression received 12.5 mg agomelatine (n = 28) or placebo (n = 28) daily for 6 weeks. The primary outcome was the Cohen-Mansfield Agitation Inventory (CMAI) score change. Secondary outcomes included serum brain-derived neurotrophic factor (BDNF) levels and safety. Results: At 6 weeks, the agomelatine group showed a greater reduction in CMAI scores than placebo (mean difference: –12.39, 95% CI: –19.37 to –5.42; p = 0.001). No significant BDNF changes were detected (p = 0.848). Total adverse events (AEs) were more common in the agomelatine group (50.0% vs. 21.4%, p = 0.050), but no serious AEs or liver enzyme abnormalities were reported. Conclusion: A daily dose of 12.5 mg agomelatine may effectively and safely reduce agitation and aggression in patients with AD when used as an add-on therapy. However, further studies with larger samples and extended durations are needed to definitively confirm agomelatine's role in managing BPSD in AD. © 2025 American Association for Geriatric Psychiatry