Esketamine, a drug used for treatment-resistant depression, is associated with a range of adverse drug events, including psychiatric, neurological, and cardiovascular effects. Analysis of reports from the US Food and Drug Administration Adverse Event Reporting System identified the most common adverse events as dissociation, sedation, and increased blood pressure. Network toxicology analysis suggested that esketamine may interact with multiple biological targets and pathways, potentially explaining its toxicological mechanisms. The findings indicate that while esketamine is effective, careful monitoring for specific adverse events is warranted.
Repeated esketamine exposure during early postnatal development in mice led to significant hippocampal injury, including downregulation of glutamatergic neuronal markers and persistent cognitive dysfunction in adolescence. These adverse outcomes were strongly associated with elevated expression of Kcnq2 in the hippocampus. Both pharmacological blockade and genetic knockdown of Kcnq2 mitigated the cognitive deficits. Mechanistically, activation of Kcnq2 drove dephosphorylation of key signaling molecules within the Akt1/GSK-3β pathway. The findings identify Kcnq2 as a novel therapeutic target for preventing anesthesia-related cognitive deficits in pediatric populations.