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Pathophysiology of hypercortisolism in depression

Authors

  • B. J. Carroll,

    1. Pacific Behavioral Research Foundation, Carmel, CA
    2. Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC
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  • F. Cassidy,

    1. Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC
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  • D. Naftolowitz,

    1. Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC
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  • N. E. Tatham,

    1. Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC
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  • W. H. Wilson,

    1. Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC
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  • A. Iranmanesh,

    1. Endocrine Section, Medical Service, Salem Veterans Affairs Medical Center, Salem, VA
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  • P. Y. Liu,

    1. Endocrine Research Unit, Mayo Medical and Graduate School of Medicine, General Clinical Research Center, Mayo Clinic, Rochester, MN, USA Prof. Cassidy has received funding from Concept, Organor and Pfizer. All remaining authors declare no conflict of interests.
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  • J. D. Veldhuis

    1. Endocrine Research Unit, Mayo Medical and Graduate School of Medicine, General Clinical Research Center, Mayo Clinic, Rochester, MN, USA Prof. Cassidy has received funding from Concept, Organor and Pfizer. All remaining authors declare no conflict of interests.
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  • Presented at the Conference: ‘Melancholia: Beyond DSM, Beyond Neurotransmitters’, May 2–4, 2006, Copenhagen, Denmark.

Bernard J. Carroll, P.O. Box 223040, Carmel, CA 93922-3040, USA.
E-mail: bcarroll@redshift.com

Abstract

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.

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