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



Kargar A1, 2 ; Fetratjoo DH2, 3 ; Moattar R2 ; Tarki A2, 4 ; Golsokhan A5, 6 ; Pouyan N7, 8 ; Amjadigoojgi Z2 ; Mostafaei H5 ; Kakeri F5 ; Zendehbad AS9 ; Lima BS10 ; Esmaily H1 ; Noroozian M2
Authors
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Authors Affiliations
  1. 1. Department of Clinical Pharmacy (AK, HE), School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  2. 2. Cognitive Neurology (AK, DHF, RM, AT, ZAG, MN), Dementia, and Neuropsychiatry Research Center, Tehran University of Medical Sciences, Tehran, Iran
  3. 3. School of Pharmacy (DHF), Tehran University of Medical Sciences, Tehran, Iran
  4. 4. Department of Health Psychology (AT), Karaj Branch, Islamic Azad University, Karaj, Iran
  5. 5. Yaadmaan Institute for Brain (AG, HM, FK), Cognition, and Memory Studies, Tehran, Iran
  6. 6. Department of Psychology (AG), Faculty of Psychology and Educational Sciences, Islamic Azad University, Karaj Branch, Karaj, Iran
  7. 7. Department of Anesthesiology (NP), University of Michigan Medical School, Ann Arbor, MI, United States
  8. 8. Neuroscience Graduate Program (NP), University of Michigan, Ann Arbor, MI, United States
  9. 9. Department of Geriatric Health (ASZ), Science and Research Branch, Islamic Azad University, Tehran, Iran
  10. 10. Department of Neurology (BSL), School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

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
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