Real-world pharmacovigilance analysis of adverse events associated with selective serotonin reuptake inhibitor antidepressants in children and adolescents

Background Depressive disorders are common in children and adolescents, with major depression affecting 3.7% of youth and subclinical symptoms affecting over one-fifth. Selective serotonin reuptake inhibitors (SSRIs), including fluoxetine, sertraline, and fluvoxamine, are prescribed for moderate-to-severe pediatric depression. However, real-world safety signals for specific SSRIs remain incompletely characterized because evidence derives mainly from randomized controlled trials with restrictive inclusion criteria, observational studies affected by prescribing bias, and spontaneous reporting systems without reliable exposure denominators. Methods We extracted reports from the U.S. Food and Drug Administration Adverse Event Reporting System through the second quarter of 2026 for depressed children and adolescents aged 6–18 years receiving fluoxetine, sertraline, or fluvoxamine. Disproportionality analyses used reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker to detect signals at system organ class and preferred term levels. Weibull models assessed time to onset, and network toxicology approaches explored candidate targets and pathways underlying the shared rhabdomyolysis signal. Results A total of 2,614 reports were included: 1,260 for fluoxetine, 1,278 for sertraline, and 76 for fluvoxamine. Psychiatric and nervous system disorders were the most frequently reported system organ classes for all three drugs. Fluoxetine showed prominent signals for serotonin syndrome, neuroleptic malignant syndrome, rhabdomyolysis, blood creatine phosphokinase increase, and acute kidney injury; sertraline showed strong signals for serotonin syndrome, urinary retention, intentional self-injury, rhabdomyolysis, hepatocellular injury, and respiratory failure. Rhabdomyolysis was reported in 39 fluoxetine cases (ROR = 4.26, 95% CI: 2.81–6.45) and 26 sertraline cases (ROR = 2.69, 95% CI: 1.71–4.24). Time-to-onset analyses revealed an early-failure Weibull pattern for both drugs, with median onsets of 24 and 30 days, respectively. Network toxicology analysis identified shared candidate targets including CYP3A4, CYP2D6, SLC6A4, MAOA, DRD1, DRD2, NOS2, and KCNH2, with enrichment in serotonergic synapse, oxidative stress, and hypoxia response pathways. Conclusion This study provides evidence to prioritize symptoms, organ systems, and high-risk monitoring windows in pediatric SSRI prescribing. It offers the first systematic report of SSRI-associated rhabdomyolysis in children and adolescents and translates real-world pharmacovigilance signals into guidance for baseline risk assessment, early monitoring, family education, and symptom-driven laboratory testing.