TY - JOUR
T1 - Pathophysiology of hypercortisolism in depression
T2 - Pituitary and adrenal responses to low glucocorticoid feedback
AU - Carroll, B. J.
AU - Iranmanesh, A.
AU - Keenan, D. M.
AU - Cassidy, F.
AU - Wilson, W. H.
AU - Veldhuis, J. D.
PY - 2012/6
Y1 - 2012/6
N2 - 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.
AB - 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.
KW - Adrenocorticotropic hormone
KW - Approximate entropy
KW - Cortisol
KW - Deconvolution
KW - Depressive disorder, major
KW - Feedback, physiological
KW - Metyrapone
UR - http://www.scopus.com/inward/record.url?scp=84860839843&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84860839843&partnerID=8YFLogxK
U2 - 10.1111/j.1600-0447.2011.01821.x
DO - 10.1111/j.1600-0447.2011.01821.x
M3 - Article
C2 - 22211368
AN - SCOPUS:84860839843
SN - 0001-690X
VL - 125
SP - 478
EP - 491
JO - Acta Psychiatrica Scandinavica
JF - Acta Psychiatrica Scandinavica
IS - 6
ER -