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This study used copeptin, a stable, reliable, and well\u2010validated surrogate marker of AVP secretion, to assess vasopressinergic function in a transdiagnostic sample of individuals experiencing a major depressive episode (MDE) with and without post\u2010traumatic stress disorder (PTSD), as well as healthy volunteers (HVs). Baseline levels of copeptin, corticotropin\u2010releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and urine cortisol were compared across groups and examined in relation to clinical symptoms and behavioral traits. Acute changes in copeptin and other hypothalamic\u2013pituitary\u2013adrenal axis markers following a single subanesthetic\u2010dose ketamine infusion were also investigated in a subset of patients. Participants with MDE\u2009+\u2009PTSD exhibited significantly lower baseline copeptin levels and a blunted reduction in copeptin levels post\u2010ketamine compared to MDE\u2010only participants. Copeptin was unrelated to primary mood diagnosis and to symptom severity of depression, anxiety, post\u2010traumatic stress, anhedonia, suicidal ideation, childhood trauma history, or behavioral traits other than aggression. Higher baseline copeptin levels were associated with verbal aggression, and PTSD comorbidity attenuated these associations. Collectively, these findings suggest a possible biological subtype of attenuated AVP secretion in the dual diagnostic subgroup of co\u2010occurring MDE and PTSD that is independent of symptom burden. Plasma copeptin might therefore serve not only as a peripheral biomarker but also as a proxy for central neuromodulatory changes relevant to AVP\u2010driven circuits in the study of neuropsychiatric disorders. Future studies integrating the temporal dynamics of copeptin with neuroimaging, genetic, and stress\u2010challenge paradigms are needed to delineate the potential neural pathways through which AVP contributes to the pathophysiology and treatment responsiveness of mood and trauma\u2010related disorders. Clinical Trial Registration:\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.clinicaltrials.gov\">www.clinicaltrials.gov<\/jats:ext-link>\n                    (NCT02543983).\n                  <\/jats:p>","DOI":"10.1111\/jne.70133","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T07:38:27Z","timestamp":1768894707000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Blunted arginine vasopressin secretion in individuals experiencing a major depressive episode with comorbid post\u2010traumatic stress disorder: Results from an exploratory study using copeptin as a surrogate marker"],"prefix":"10.1111","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1587-2736","authenticated-orcid":false,"given":"Hiroe","family":"Hu","sequence":"first","affiliation":[{"name":"Experimental Therapeutics and Pathophysiology 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