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Previous studies on the neuroendocrine stress response in youth with MDD are scarce, limited to cortisol, and rarely considered sex differences. Due to puberty\u2010associated neuroendocrine transitions increasing the risk for MDD onset in adolescence, this study aimed to investigate sex\u2010specific stress responses of stress and sex hormones as well as of neuropeptides.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In 103 pubertal youths with MDD and 72 healthy controls (HCs; 62% females, 12\u201318\u2009years), psychological stress as well as salivary cortisol, testosterone, and oxytocin reactivity to a standardized psychosocial stress test (Trier Social Stress Test, TSST) were assessed. Effects of group and sex, and their interactions were analyzed using hierarchical linear models, while controlling for potentially confounding factors (such as age and pubertal status).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Females and males with MDD showed a stronger psychological stress response than HCs. In contrast, both female and male youth with MDD showed blunted cortisol, testosterone, and oxytocin stress responses compared to HCs. In addition, baseline testosterone was elevated in MDD compared to HCs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Results indicate a discrepant stress reactivity in youth with MDD, with increased psychological, but decreased neuroendocrine responses to psychosocial stress. Blunted neuroendocrine stress responses in youth with MDD were found across different neuroendocrine systems and in both females and males with MDD. These novel findings point to a fundamentally changed stress response in youth with MDD irrespective of sex, which may influence successful stress regulation in the affected adolescents.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jcpp.14168","type":"journal-article","created":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T02:42:05Z","timestamp":1742784125000},"page":"1563-1576","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Psychoneuroendocrine stress response in female and male youth with major depressive disorder"],"prefix":"10.1111","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8864-1360","authenticated-orcid":false,"given":"Anka","family":"Bernhard","sequence":"first","affiliation":[{"name":"Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy University Hospital Frankfurt am Main, Goethe University  Frankfurt am Main Germany"},{"name":"Department of Child and Adolescent Psychiatry and Psychotherapy Faculty of Medicine, Technische Universit\u00e4t Dresden, German Center for Child and Adolescent Health (DZKJ), Partner Site Leipzig\/Dresden  Dresden Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikola","family":"Fann","sequence":"additional","affiliation":[{"name":"Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy University Hospital Frankfurt am Main, Goethe University  Frankfurt am Main Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas G.","family":"Chiocchetti","sequence":"additional","affiliation":[{"name":"Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy University Hospital Frankfurt am Main, Goethe University  Frankfurt am Main Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Ackermann","sequence":"additional","affiliation":[{"name":"Department of Child and Adolescent 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