Adverse drug events and toxicological mechanisms of esketamine: a study based on US Food and Drug Administration Adverse Event Reporting System and network toxicology analysis.

Esketamine is a novel antidepressant approved by the US Food and Drug Administration (FDA) in 2019, but comprehensive studies on the post-marketing safety evaluation of esketamine across age groups remain limited. The objective of this study is to provide the age-based pharmacovigilance profile of esketamine and the potential toxicological mechanisms, which may provide insights to inform the development of rational and personalized drug use. In our study, age-related differences in adverse drug event (ADE) reporting were explored through data mining of the FDA Adverse Event Reporting System (FAERS), and the potential mechanism of esketamine-related ADE was explored through network toxicology analysis. A total of 7804 cases are extracted between the first quarter of 2019 and the second quarter of 2024. The disproportionality analysis determined 8754 ADEs involving 223 preferred terms (PTs) and 19 system organ classes (SOCs) overall. Three subgroups are identified by the age of ADEs occurrence. Eight general PT signals were identified across all subgroups. Some important age-specific ADEs are highlighted and analyzed. The time-to-onset analysis reveals that most of the ADEs are reported within 30 days from the start of treatment. And the time exhibits a trend of prolongation as age increases. The potential underlying mechanisms of ADEs of esketamine may involve multiple and complex signaling pathways, such as the calcium signaling pathway, lipid and atherosclerosis, and the PI3K/Akt signaling pathway. The results indicate differential reporting of esketamine-related ADEs based on age. Accordingly, the hypothesis-generating suggestions for implementing the personalized ADE monitoring and health care based on age in esketamine treatment are discussed.