Pathophysiology of hypercortisolism in depression

B. J. Carroll, F. Cassidy, D. Naftolowitz, N. E. Tatham, W. H. Wilson, A. Iranmanesh, P. Y. Liu, Johannes D Veldhuis

Research output: Contribution to journalArticlepeer-review


Objective: The mechanisms mediating hypercortisolemia in depression remain controversial. Adopting the biomarker strategy, we studied adrenocorticotropin (ACTH) and cortisol dynamics in hypercortisolemic and non-hypercortisolemic depressed in-patients, and in normal volunteers. Method: Deconvolution analysis of 24-h pulsatile secretion, approximate entropy (ApEn) estimation of secretory regularity, cross-ApEn quantitation of forward and reverse ACTH-cortisol synchrony, and cosine regression of 24-h rhythmicity. Results: Hypercortisolemia was strongly associated with melancholic and psychotic depressive subtypes. Hypercortisolemic patients had elevated ACTH and cortisol secretion, mediated chiefly by increased burst masses. Basal ACTH secretion was increased, ACTH half-life was reduced, and mean 24-h ACTH concentration was normal. Cortisol secretion was increased in a highly irregular pattern (high ApEn), with high ACTH → cortisol cross-ApEn (impaired feedforward coupling). Cortisol-mediated feedback on the secretory pattern of ACTH was normal. Hypercortisolemic depressed patients had normal programming of the central hypothalamo-pituitary-adrenal (HPA) axis pulse generator: ACTH pulse frequency, cortisol pulse frequency, circadian acrophases, and ApEn of ACTH secretion were normal. Responsiveness of the adrenal cortex to endogenous ACTH was normal. Non-hypercortisolemic patients resembled hypercortisolemic patients on ACTH regulatory parameters but had low total cortisol secretion. Conclusion: Increased ACTH secretion occurs in depressed in-patients regardless of cortisolemic status, confirming central HPA axis overdrive in severe depression. Depressive hypercortisolemia results from an additional change in the adrenal cortex that causes ACTH-independent, disorderly basal cortisol release, a sign of physiological stress in melancholic/psychotic depression.

Original languageEnglish (US)
Pages (from-to)90-103
Number of pages14
JournalActa Psychiatrica Scandinavica
Issue numberSUPPL. 433
StatePublished - Mar 2007


  • Adrenal
  • Adrenocorticotropin
  • Approximate entropy
  • Biomarker
  • Cortisol
  • Cross-ApEn
  • Depression
  • Feedback
  • Hypothalamus
  • Pituitary
  • Regulation
  • Secretion

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Neuroscience(all)


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