Blunted arginine vasopressin secretion in individuals experiencing a major depressive episode with comorbid post-traumatic stress disorder: Results from an exploratory study using copeptin as a surrogate marker.

People with both major depression and post-traumatic stress disorder (PTSD) have lower baseline levels of copeptin, a stable marker of vasopressin secretion, and a blunted reduction in copeptin after a single low-dose ketamine infusion compared to those with depression alone. Copeptin levels were unrelated to depression diagnosis or symptom severity of depression, anxiety, PTSD, anhedonia, suicidal ideation, or childhood trauma, but higher copeptin was linked to verbal aggression, an association weakened by PTSD. These findings point to a possible biological subtype of reduced vasopressin activity in co-occurring depression and PTSD, suggesting copeptin may serve as a peripheral biomarker for central vasopressin-driven circuits in neuropsychiatric disorders.

Study at a glance

Abstract

Arginine vasopressin (AVP) modulates stress responsivity and social-affective behaviors, but its role in mood and trauma-related disorders remains poorly defined due to challenges in peripheral measurement. This study used copeptin, a stable, reliable, and well-validated 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-traumatic stress disorder (PTSD), as well as healthy volunteers (HVs). Baseline levels of copeptin, corticotropin-releasing 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-pituitary-adrenal axis markers following a single subanesthetic-dose ketamine infusion were also investigated in a subset of patients. Participants with MDE + PTSD exhibited significantly lower baseline copeptin levels and a blunted reduction in copeptin levels post-ketamine compared to MDE-only participants. Copeptin was unrelated to primary mood diagnosis and to symptom severity of depression, anxiety, post-traumatic 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-occurring 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-driven circuits in the study of neuropsychiatric disorders. Future studies integrating the temporal dynamics of copeptin with neuroimaging, genetic, and stress-challenge paradigms are needed to delineate the potential neural pathways through which AVP contributes to the pathophysiology and treatment responsiveness of mood and trauma-related disorders. Clinical Trial Registration: www.clinicaltrials.gov (NCT02543983).