Real-world pharmacovigilance analysis of adverse events associated with selective serotonin reuptake inhibitor antidepressants in children and adolescents
Abstract
BackgroundDepressive 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.MethodsWe 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.ResultsA 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.ConclusionThis 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.
Related
- Selective serotonin reuptake inhibitors and tricyclic antidepressants differentially affect heart failure risk in patients with kidney failure.
- Comparative Effectiveness of Tricyclic Antidepressants, Serotonin–Norepinephrine Reuptake Inhibitors, and Anticonvulsants for Diabetic Painful Neuropathy: A Systematic Review and Meta-Analysis
- Selective Serotonin Reuptake Inhibitor-Associated Bruxism: Neuropharmacologic Mechanisms and Clinical Implications
- Drug–drug Interaction Signals for Sexual Dysfunction with Antidepressants and Antipsychotics: A Pharmacovigilance–pharmacodynamic Study
- Aripiprazole versus Bupropion Augmentation in Patients with Anxious Depression Resistant to Selective Serotonin Reuptake Inhibitors: A Randomized, Prospective, Open-label, Multicenter Study
BibTeX
@article{yuan2026realworld,
title = {{Real-world pharmacovigilance analysis of adverse events associated with selective serotonin reuptake inhibitor antidepressants in children and adolescents}},
author = {Wenjun Yuan and Fu Zhang and Kexin Sun and Xiaotong Guo and Jingxi Yao and Xing Wei and Zhenggang Shi and Jing Shang},
journal = {Frontiers in Pharmacology},
year = {2026},
month = nov,
doi = {10.3389/fphar.2026.2002544},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.2002544},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Real-world pharmacovigilance analysis of adverse events associated with selective serotonin reuptake inhibitor antidepressants in children and adolescents
AU - Wenjun Yuan
AU - Fu Zhang
AU - Kexin Sun
AU - Xiaotong Guo
AU - Jingxi Yao
AU - Xing Wei
AU - Zhenggang Shi
AU - Jing Shang
PY - 2026
DA - 2026/11/02
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.2002544
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.2002544
AB - BackgroundDepressive 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.MethodsWe 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.ResultsA 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.ConclusionThis 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.
SN - 1663-9812
ER -