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Their concurrent manifestation is rare but clinically significant due to overlapping pathophysiological mechanisms. This report describes the fatal outcome of a 30-year-old female who presented to the Emergency Department with agitation following self-administration of duloxetine 60\u2009mg, in addition to ongoing amitriptyline therapy and possible L-tryptophan supplementation. During hospitalization, she was treated with intravenous chlorphenamine for a suspected allergic reaction. Subsequently, she developed severe neurological deterioration, malignant arrhythmia, and profound acute hyponatremia (serum sodium 114\u2009mmol\/L), culminating in brain death within 48\u2009h. The synergistic pharmacodynamic and pharmacokinetic interactions between duloxetine, amitriptyline, and chlorphenamine\u2014three agents with serotonin reuptake inhibition properties\u2014were implicated in precipitating SS and syndrome of inappropriate antidiuresis (SIAD)-induced hyponatremia. This combination resulted in extensive cerebral edema and cardiopulmonary arrest. The case highlights the diagnostic challenge posed by overlapping SS and hyponatremia manifestations, particularly when compounded by incomplete pharmacological histories and inappropriate drug administration. Clinicians should maintain high vigilance for SS and hyponatremia in patients receiving serotonergic agents, especially when multiple such drugs are co-administered. Comprehensive medication anamnesis, prompt electrolyte monitoring, and avoidance of pharmacodynamic duplication are essential to prevent similar outcomes.<\/jats:p>","DOI":"10.1177\/20451253251406044","type":"journal-article","created":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T11:12:21Z","timestamp":1771585941000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":2,"title":["The interplay between serotonin syndrome and syndrome of inappropriate antidiuresis: a fatal case of acute hyponatremia during treatment with duloxetine, chlorphenamine, amitriptyline, and L-tryptophan"],"prefix":"10.1177","volume":"16","author":[{"given":"Donato","family":"Morena","sequence":"first","affiliation":[{"name":"Department of Anatomical, Histological, Forensic and Orthopedic Science, Sapienza University of Rome, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore Silvio","family":"Colonna","sequence":"additional","affiliation":[{"name":"Intensive Care Anesthetist, Lecce, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Santurro","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Dentistry \u201cSchola Medica Salernitana,\u201d University of Salerno, Baronissi, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Scopetti","sequence":"additional","affiliation":[{"name":"Department of Medical Surgical Sciences and Translational Medicine, Sapienza University of Rome, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Tortorella","sequence":"additional","affiliation":[{"name":"Forensic Pathologist, Lecce, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1686-3236","authenticated-orcid":false,"given":"Vittorio","family":"Fineschi","sequence":"additional","affiliation":[{"name":"Department of Anatomical, Histological, Forensic and Orthopedic Science, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,2,20]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra041867"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.3949\/ccjm.83a.15129"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1097\/00005792-200007000-00001"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1080\/15563650.2022.2151455"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1080\/15563650.2021.1993242"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cpem.2005.04.009"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1080\/15563650.2020.1839662"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2007.07.009"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/qjmed\/hcg109"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12883-016-0616-1"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-13-1020"},{"issue":"5","key":"e_1_3_4_13_2","first-page":"519","article-title":"Hyponatremia and the syndrome of inappropriate secretion of antidiuretic hormone associated with the use of selective serotonin reuptake inhibitors: a review of spontaneous reports","volume":"155","author":"Liu BA","year":"1996","unstructured":"Liu BA, Mittmann N, Knowles SR, et al. 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