Pathophysiology of hypercortisolism in depression: pituitary and adrenal responses to low glucocorticoid feedback
Article first published online: 30 DEC 2011
© 2011 John Wiley & Sons A/S
Acta Psychiatrica Scandinavica
Volume 125, Issue 6, pages 478–491, June 2012
How to Cite
Carroll, B. J., Iranmanesh, A., Keenan, D. M., Cassidy, F., Wilson, W. H. and Veldhuis, J. D. (2012), Pathophysiology of hypercortisolism in depression: pituitary and adrenal responses to low glucocorticoid feedback. Acta Psychiatrica Scandinavica, 125: 478–491. doi: 10.1111/j.1600-0447.2011.01821.x
- Issue published online: 10 MAY 2012
- Article first published online: 30 DEC 2011
- Accepted for publication November 28, 2011
- adrenocorticotropic hormone;
- approximate entropy;
- depressive disorder, major;
- feedback, physiological;
Carroll BJ, Iranmanesh A, Keenan DM, Cassidy F, Wilson WH, Veldhuis JD. Pathophysiology of hypercortisolism in depression: pituitary and adrenal responses to low glucocorticoid feedback.
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.