Pathophysiology of hypercortisolism in depression: Pituitary and adrenal responses to low glucocorticoid feedback

B. J. Carroll, A. Iranmanesh, D. M. Keenan, F. Cassidy, W. H. Wilson, J. D. Veldhuis

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


Objective: To test three theories of hypercortisolemia in depression-hypothalamic overdrive, impaired glucocorticoid feedback, or autonomous cortisol production. Method: We applied an overnight low-cortisol feedback strategy by administering metyrapone to hypercortisolemic depressed in-patients and control subjects. Results: Under metyrapone, the increases of plasma adrenocorticotropic hormone (ACTH) concentrations and of basal and pulsatile ACTH secretion were not exaggerated in hypercortisolemic depressed patients compared with control subjects. ACTH approximate entropy (ApEn) did not differ at baseline or under metyrapone. Thus, neither hypothalamic overdrive nor irregular ACTH secretion was seen. We did not detect impaired cortisol feedback: the ACTH response was not reduced, and ApEn measures that are sensitive to feedback changes were comparable in both groups. Metyrapone disrupted cortisol secretory regularity in depressed and control subjects. On the baseline day, basal cortisol secretion was significantly increased and was highly irregular (high ApEn), and ACTH-cortisol cross-ApEn was markedly elevated in high-cortisol patients. Conclusion: Classical feed-forward overdrive and impaired feedback theories of hypercortisolemia in depression were not supported. Depressive hypercortisolemia may result from alternative pathophysiological mechanisms involving irregular basal hypersecretion of cortisol, associated with adrenal enlargement, possibly through splanchnic sympathetic activation of the adrenal cortex.

Original languageEnglish (US)
Pages (from-to)478-491
Number of pages14
JournalActa Psychiatrica Scandinavica
Issue number6
StatePublished - Jun 2012


  • Adrenocorticotropic hormone
  • Approximate entropy
  • Cortisol
  • Deconvolution
  • Depressive disorder, major
  • Feedback, physiological
  • Metyrapone

ASJC Scopus subject areas

  • Psychiatry and Mental health


Dive into the research topics of 'Pathophysiology of hypercortisolism in depression: Pituitary and adrenal responses to low glucocorticoid feedback'. Together they form a unique fingerprint.

Cite this