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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\u2013protein 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 \u201camphetamine addiction\u201d and \u201cdopaminergic synapse\u201d. Five core genes (monoamine oxidase (MAO)-A, MAO-B, glycogen synthase kinase-3\u03b2, 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.<\/jats:p>","DOI":"10.31083\/ap56752","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T12:23:51Z","timestamp":1788438231000},"source":"Crossref","is-referenced-by-count":0,"title":["Network Pharmacology Reveals the Potential Mechanism of Ketamine in Improving Cognitive Impairment in Patients With Depression"],"prefix":"10.31083","volume":"27","author":[{"given":"Lei","family":"Yang","sequence":"first","affiliation":[{"name":"Computational Biology and Animal Imaging Center (CBAC), Tianjin Anding Hospital, Nankai University Affiliated Tianjin Anding Hospital, Tianjin Medical University Affiliated Tianjin Anding Hospital, Tianjin Medical University Affiliated Tianjin Mental Health Center, 300222 Tianjin, China"},{"name":"Laboratory of Psychiatric-Neuroimaging-Genetic and Co-morbidity (PNGC_Lab), Tianjin Anding Hospital, Tianjin Mental Health Center of Tianjin Medical University, 300222 Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Computational Biology and Animal Imaging Center (CBAC), Tianjin Anding Hospital, Nankai University Affiliated Tianjin Anding Hospital, Tianjin Medical University Affiliated Tianjin Anding Hospital, Tianjin Medical University Affiliated Tianjin Mental Health Center, 300222 Tianjin, China"},{"name":"Laboratory of Psychiatric-Neuroimaging-Genetic and Co-morbidity (PNGC_Lab), Tianjin Anding Hospital, Tianjin Mental Health Center of Tianjin Medical University, 300222 Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zhang","sequence":"additional","affiliation":[{"name":"Computational Biology and Animal Imaging Center (CBAC), Tianjin Anding Hospital, Nankai University Affiliated Tianjin Anding Hospital, Tianjin Medical University Affiliated Tianjin Anding Hospital, Tianjin Medical University Affiliated Tianjin Mental Health Center, 300222 Tianjin, China"},{"name":"Laboratory of Psychiatric-Neuroimaging-Genetic and Co-morbidity (PNGC_Lab), Tianjin Anding Hospital, Tianjin Mental Health Center of Tianjin Medical University, 300222 Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaifang","family":"Yao","sequence":"additional","affiliation":[{"name":"Computational Biology and Animal Imaging Center (CBAC), Tianjin Anding Hospital, Nankai University Affiliated Tianjin Anding Hospital, Tianjin Medical University Affiliated Tianjin Anding Hospital, Tianjin Medical University Affiliated Tianjin Mental Health Center, 300222 Tianjin, China"},{"name":"Laboratory of Psychiatric-Neuroimaging-Genetic and Co-morbidity (PNGC_Lab), Tianjin Anding Hospital, Tianjin Mental Health Center of Tianjin Medical University, 300222 Tianjin, China"},{"name":"Department of Psychiatry, Tianjin Fourth Center Hospital, Nankai University Affiliated Tianjin Fourth Center Hospital, 300140 Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ximing","family":"Chen","sequence":"additional","affiliation":[{"name":"Computational Biology and Animal Imaging Center (CBAC), Tianjin Anding Hospital, Nankai University Affiliated Tianjin Anding Hospital, Tianjin Medical University Affiliated Tianjin Anding Hospital, Tianjin Medical University Affiliated Tianjin Mental Health Center, 300222 Tianjin, China"},{"name":"Laboratory of Psychiatric-Neuroimaging-Genetic and Co-morbidity (PNGC_Lab), Tianjin Anding Hospital, Tianjin Mental Health Center of Tianjin Medical University, 300222 Tianjin, China"},{"name":"Department of Psychiatry, Tianjin Fourth Center Hospital, Nankai University Affiliated Tianjin Fourth Center Hospital, 300140 Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongjun","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Tianjin Fourth Center Hospital, Nankai University Affiliated Tianjin Fourth Center Hospital, 300140 Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6163-5235","authenticated-orcid":true,"given":"Chuanjun","family":"Zhuo","sequence":"additional","affiliation":[{"name":"Computational Biology and Animal Imaging Center (CBAC), Tianjin Anding Hospital, Nankai University Affiliated Tianjin Anding Hospital, Tianjin Medical University Affiliated Tianjin Anding Hospital, Tianjin Medical University Affiliated Tianjin Mental Health Center, 300222 Tianjin, China"},{"name":"Laboratory of Psychiatric-Neuroimaging-Genetic and Co-morbidity (PNGC_Lab), Tianjin Anding Hospital, Tianjin Mental Health Center of Tianjin Medical University, 300222 Tianjin, 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