Risk of drug-related aggression in pediatric populations: a pharmacovigilance analysis using the FAERS database

Background Aggression in pediatric populations poses significant risks to mental health and development, and drug-associated aggression may either exacerbate pre-existing behavioral problems or arise de novo following medication exposure. Existing studies, primarily based on randomized controlled trials (RCTs) and cohort designs, often underestimate real-world incidence. This study used the FDA Adverse Event Reporting System (FAERS) to systematically identify drugs associated with pediatric aggression, examining age/sex-specific differences and time-to-onset (TTO) patterns. Methods We conducted a retrospective disproportionality analysis of FAERS data (2004 Q1–2025 Q2) for patients 18 years. Aggression was defined using Standardized MedDRA Queries (SMQ code: 10001488). Signals were detected using four consensus algorithms (ROR, PRR, MGPS, and BCPNN). Drugs were categorized by Anatomical Therapeutic Chemical (ATC) classification. Subgroup analyses and multivariable logistic regression were used to calculate adjusted reporting odds ratios (aRORs), and TTO was evaluated to characterize temporal patterns. Results Among 7,959 reports (67.75% male; median age: 9 years), 31 drugs exhibited positive signals, primarily nervous system (45.16%) and respiratory (32.26%) agents. Signals for tezacaftor, elexacaftor, macrogol, desloratadine, and ebastine were identified despite absent FDA label warnings. The strongest signals were for ebastine (ROR: 23.40) and perampanel (17.41), while montelukast had the highest case volume ( N = 1,392). Most drugs showed the highest aRORs in early childhood, except levetiracetam, which peaked in adolescence. Females generally showed higher risks across most agents. Median TTO ranged from rapid (anti-infectives: 2–3 days) to delayed (montelukast: 133 days; macrogol: 129 days). Conclusion This study identifies robust signals linking multiple drugs to pediatric aggression, with elevated risks observed particularly in younger children and females. These findings underscore the need for heightened clinical vigilance, consideration of demographic-specific risks, and updated regulatory labeling to improve pediatric drug safety.