Region-Specific Agomelatine-Associated Hepatic Disorder Signals Using the World Health Organization VigiBase Pharmacovigilance Database

Objective: Agomelatine, an antidepressant with a unique mechanism acting on melatonin and serotonin receptors, is associated with a risk of hepatotoxicity, leading to divergent regulatory statuses and risk management strategies across countries.This study aimed to analyze the global reporting patterns of agomelatine-related hepatic adverse events (AEs) using the World Health Organization-Uppsala Monitoring Centre (WHO-UMC) VigiBase and to explore the interpretability of safety signals considering regional regulatory environments.Methods: Individual Case Safety Reports (ICSRs) reported to VigiBase between 2009 and 2024 were analyzed.Agomelatine was defined as the drug of interest, with two comparators: all other drugs (Comparator 1) and core antidepressant classes (Selective Serotonin Reuptake Inhibitors SSRIs, Serotonin-Norepinephrine Reuptake Inhibitors SNRIs, and Tricyclic Antidepressants TCAs; Comparator 2).Hepatic disorders were identified using the Standardised Medical Dictionary for Regulatory Activities (MedDRA) Query.Disproportionality analysis was performed to calculate adjusted Reporting Odds Ratios (aRORs) and 95% confidence intervals (CIs) across different regions (Europe, Western Pacific, and Others).Subgroup analyses were conducted by sex, reporting year, and the clinical presentation of liver injury, which was categorized into biochemical signals and clinical outcomes.Results: In the overall analysis, agomelatine demonstrated a substantially increased reporting odds ratio versus all other drugs (aROR 15.83, 95% CI 14.55-17.21),with comparable estimates versus other antidepressants.Disproportionality analysis revealed significantly elevated hepatic signals for agomelatine across all regions.Compared to all other drugs, the aRORs were 13.24 (11.97-14.65) in Europe, 11.72 (9.93-13.84) in the Western Pacific, and 20.30 (14.02-29.41) in other regions.Similar trends were observed when compared to other antidepressants.Subgroup analysis showed a higher aROR in females than in males.Notably, the signal strength increased over time.Conclusion: Disproportionate reporting signals for agomelatinerelated hepatic adverse events were identified across multiple regions without clear regional differences, suggesting broadly comparable reporting patterns rather than causal risk variation.These findings provide a global overview of reporting patterns and support cautious interpretation of pharmacovigilance signals within differing regional regulatory contexts.(PeRM