Differences in baseline and dynamic plasma/saliva endocrine and linear/non-linear heart measures between patients with major depression and closely-matched healthy subjects: A 3-day combined overnight dexamethasone/metyrapone challenge study

• Published in: Journal of psychiatric research Vol. 187; pp. 192 - 199
• Main Authors: Agorastos, Agorastos, Stiedl, Oliver, Heinig, Alexandra, Sommer, Anne, Hager, Torben, Wiedemann, Klaus, Demiralay, Cüneyt
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.07.2025
• Subjects: Adrenocorticotropic Hormone - blood; Adrenocorticotropic Hormone - metabolism; Adult; Autonomic nervous system; Autonomic Nervous System - drug effects; Autonomic Nervous System - physiopathology; Depressive Disorder, Major - blood; Depressive Disorder, Major - drug therapy; Depressive Disorder, Major - metabolism; Depressive Disorder, Major - physiopathology; Dexamethasone; Dexamethasone - administration & dosage; Dexamethasone - pharmacology; Female; Heart Rate - drug effects; Heart Rate - physiology; Heart rate variability; Humans; Hydrocortisone - blood; Hydrocortisone - metabolism; Hypothalamo-Hypophyseal System - drug effects; Hypothalamo-Hypophyseal System - metabolism; Hypothalamo-Hypophyseal System - physiopathology; Hypothalamus-pituitary-adrenal axis (HPA axis); Major depressive disorder; Male; Metyrapone; Metyrapone - administration & dosage; Metyrapone - pharmacology; Middle Aged; Pituitary-Adrenal System - drug effects; Pituitary-Adrenal System - metabolism; Pituitary-Adrenal System - physiopathology; Saliva - drug effects; Saliva - metabolism; Young Adult; Dexamethasone; Autonomic nervous system; Heart rate variability; Major depressive disorder; Hypothalamus-pituitary-adrenal axis (HPA axis); Metyrapone
• ISSN: 0022-3956; 1879-1379; 1879-1379
• DOI: 10.1016/j.jpsychires.2025.05.020

Major depressive disorder (MDD) has been consistently associated with hypothalamic-pituitary-adrenal (HPA)-axis and autonomic nervous system (ANS) (re-)activity abnormalities, however, often with conflicting results. This study offers a concurrent multi-measure assessment of both HPA-axis and ANS activity and reactivity over 3 days to better characterize baseline and dynamic neuroendocrine alterations in MDD accounting for multiple individual factors. We therefore investigated group differences between 20 unmedicated MDD patients and 20 carefully-matched healthy controls (HC) by simultaneously assessing morning plasma (CORT, ACTH, copeptin) and awakening response saliva (CORT, DHEA, DHEA-s) endocrine measures, as well as multiple linear and non-linear measures of resting heart rate (HR) and its variability (HRV), before (baseline, day 1) and after a successive overnight metyrapone (HPA-axis stimulation, day 2) and dexamethasone (HPA-axis suppression, day 3) pharmaco-endocrine challenge, controlling for childhood trauma (CT) history. Statistically significant group differences emerged only for baseline plasma CORT and ACTH levels (MDD > HC) and resting HR in all 3 days. No differences were found in dynamic plasma levels and all saliva endocrine measures, as well as all HRV measures. Baseline HR was the only significant predictor for MDD diagnosis. Our detailed baseline and dynamic neuroendocrine comparison using closely matched HC indicates fewer neuroendocrine alterations in MDD than expected. These results challenge prior findings and support the importance of exact matching when investigating neuroendocrine biomarkers, as previously reported findings may rely on unaccounted individual but not group differences. •First study on detailed & simultaneous neuroendocrine MDD vs. HC dynamic differences.•No differences in baseline/dynamic saliva endocrine levels or multiple HRV parameters.•No group differences in dynamic plasma CORT, ACTH and copeptin levels.•Significant group differences only in baseline plasma CORT, ACTH and heart rate.•MDD prediction only through baseline HR, but no endocrine parameter.