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This review sought to provide a mechanism\u2010based framework for managing cancer\u2010related depression by exploring its unique pathophysiology and evaluating promising pharmacotherapies based on their alignment with these biological pathways. This narrative review synthesized evidence on promising pharmacotherapies based on their ability to target the core biological mechanisms of cancer\u2010related depression, including pro\u2010inflammatory cytokine activity, hypothalamic\u2013pituitary\u2013adrenal axis hyperactivity, serotonin pathway disruption via indolamine\u20102,3\u2010dioxygenase activation, and glutamate excitotoxicity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Recent Findings<\/jats:title>\n                    <jats:p>Interventions directly targeting inflammation (e.g., celecoxib) and glutamate modulation (e.g., ketamine) demonstrated encouraging early evidence. The effect of ketamine can also be due to its anti\u2010inflammatory properties. Atypical antidepressants, such as mirtazapine, and the serotonergic psychedelic psilocybin also showed promising but preliminary benefits. In contrast, conventional selective serotonin reuptake inhibitors and tricyclic antidepressants yielded conflicting results. Other agents, including the psychostimulant methylphenidate, showed utility for specific symptoms like fatigue.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>A personalized, mechanism\u2010informed approach targeting the core pathophysiological cascade of inflammation, hypothalamic\u2013pituitary\u2013adrenal axis hyperactivity, and glutamate excitotoxicity is essential for effectively managing depression in patients with cancer. This represents a necessary paradigm shift away from a one\u2010size\u2010fits\u2010all treatment model.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cnr2.70587","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T01:53:46Z","timestamp":1779674026000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pharmacotherapeutic Management of Depression in Patients With Cancer: A Review of Mechanistic and Clinical Evidence"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0393-1196","authenticated-orcid":false,"given":"Sepideh","family":"Hajivalizadeh","sequence":"first","affiliation":[{"name":"Osteoporosis Research Center Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences  Tehran 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