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Neurotoxicity induced by chemotherapeutic agents affects peripheral nerves, dorsal root ganglia, and supporting structures, contributing to persistent pain and neurological dysfunction. This systematic review evaluated the efficacy and safety of antidepressants, particularly duloxetine and amitriptyline, in the management of CIPN\u2010related pain. Following PRISMA guidelines and registration in PROSPERO (CRD42024608551), a systematic search of PubMed, Scopus, and Web of Science was conducted for studies published between November 2019 and October 2025. This time frame was selected to capture contemporary evidence and recent developments in multimodal treatment strategies, while acknowledging that foundational studies establishing the efficacy of duloxetine predate this period. Clinical and observational studies involving adult patients with CIPN were included. Of 892 records identified, 11 studies met the eligibility criteria. Duloxetine demonstrated clinically meaningful reductions in neuropathic pain, as assessed by VAS, NRS, and CTCAE measures. Topical amitriptyline also showed promising analgesic effects, although the available evidence remains limited. Combination therapies involving duloxetine and agents such as tapentadol, pregabalin, mirogabalin, or amitriptyline were associated with additional reductions in pain intensity; however, current evidence remains insufficient to establish additive or synergistic effects. Overall, antidepressant therapy was generally well tolerated, with predominantly mild and manageable adverse events. Current evidence supports antidepressants, particularly duloxetine, associated with reductions in pain intensity in heterogeneous studies, whereas evidence for CIPN prevention remains inconclusive. These findings support their continued use in clinical practice and highlight the need for larger, well\u2010designed randomized controlled trials to optimize treatment strategies and further define the role of combination therapies in CIPN management.<\/jats:p>","DOI":"10.1002\/prp2.70327","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T06:42:21Z","timestamp":1789713741000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Role of the Antidepressants in Managing Chemotherapy\u2010Induced Neuropathic Pain: A Systematic Review"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9071-6226","authenticated-orcid":false,"given":"Rosamaria","family":"Caminiti","sequence":"first","affiliation":[{"name":"Department of Health Sciences Institute of Research for Food Safety and Health (IRC\u2010FSH), University \u201cMagna Graecia\u201d of Catanzaro  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