Network Pharmacology Reveals the Potential Mechanism of Ketamine in Improving Cognitive Impairment in Patients With Depression

Background: Ketamine may have antidepressant and anti-suicidal effects. However, the mechanism underlying ketamine-mediated improvement in cognitive impairment in patients with depression remains unclear. To improve patient cognition in depression using molecular docking and network pharmacology, we examined ketamine's key targets and identified its molecular mechanisms. Methods: To gain target information about cognitive impairment (1983) and depression (1874), we used three databases, including Online Mendelian Inheritance in Man, GeneCards, and DisGENET. Information on ketamine targets (63) was retrieved from public databases. To locate signaling pathways and core targets, we conducted bioinformatics analysis, including an enrichment analysis and protein–protein interaction (PPI) network analysis. To assess the interaction between core targets and ketamine, we carried out molecular docking. Results: We identified 20 ketamine target proteins of ketamine related to depression and cognitive impairment. Enrichment analyses revealed that ketamine influenced depression and cognitive function through multiple pathways, targets, and overall synergy. The important signaling pathways identified were “amphetamine addiction” and “dopaminergic synapse”. Five core genes (monoamine oxidase (MAO)-A, MAO-B, glycogen synthase kinase-3β, sirtuin-1, epidermal growth factor receptor) were identified through PPI-network analyses. Our molecular docking results showed that binding was strong between these core genes and ketamine. Conclusions: The antidepressant and cognitive-enhancing effects of ketamine are primarily mediated through targets associated with inflammation, neural signaling, tumors, and neurodegeneration, as well as pathways such as amphetamine addiction, dopaminergic synapse, and the cyclic adenosine monophosphate (cAMP) signaling pathway. The findings provide theoretical support and guidance for optimizing clinical application strategies of ketamine and for designing new drugs.