The rationale for corticotropin-releasing hormone receptor (CRH-R) antagonists to treat depression and anxiety

The rationale for corticotropin-releasing hormone receptor (CRH-R) antagonists to treat... Neuroendocrine studies strongly suggest that dysregulation of the hypothalamic–pituitary–adrenocortical (HPA) system plays a causal role in the development and course of depression. Whereas the initial mechanism resulting in HPA hyperdrive remains to be elucidated, evidence has emerged that corticosteroid receptor function is impaired in many patients with depression and in many healthy individuals at increased genetic risk for an depressive disorder. Assuming such impaired receptor function, then central secretion of CRH would be enhanced in many brain areas, which would account for a variety of depressive symptoms. As shown in rats and also in transgenic mice with impaired glucocorticoid receptor function, antidepressants enhance the signaling through corticosteroid receptors. This mechanism of action can be amplified through blocking central mechanisms that drive the HPA system. Animal experiments using antisense oligodeoxynucleotides directed against the mRNA of both CRH receptor subtypes identified the CRH 1 receptor as the mediator of the anxiogenic effects of CRH. Studies in mouse mutants in which this receptor subtype had been deleted extended these findings as the animals were less anxious than wild-type mice when experimentally stressed. Thus, patients with clinical conditions that are causally related to HPA hyperactivity may profit from treatment with a CRH 1 receptor antagonist. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Psychiatric Research Elsevier

The rationale for corticotropin-releasing hormone receptor (CRH-R) antagonists to treat depression and anxiety

Journal of Psychiatric Research, Volume 33 (3) – May 1, 1999

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Publisher
Elsevier
Copyright
Copyright © 1999 Elsevier Science B.V.
ISSN
0022-3956
DOI
10.1016/S0022-3956(98)90056-5
Publisher site
See Article on Publisher Site

Abstract

Neuroendocrine studies strongly suggest that dysregulation of the hypothalamic–pituitary–adrenocortical (HPA) system plays a causal role in the development and course of depression. Whereas the initial mechanism resulting in HPA hyperdrive remains to be elucidated, evidence has emerged that corticosteroid receptor function is impaired in many patients with depression and in many healthy individuals at increased genetic risk for an depressive disorder. Assuming such impaired receptor function, then central secretion of CRH would be enhanced in many brain areas, which would account for a variety of depressive symptoms. As shown in rats and also in transgenic mice with impaired glucocorticoid receptor function, antidepressants enhance the signaling through corticosteroid receptors. This mechanism of action can be amplified through blocking central mechanisms that drive the HPA system. Animal experiments using antisense oligodeoxynucleotides directed against the mRNA of both CRH receptor subtypes identified the CRH 1 receptor as the mediator of the anxiogenic effects of CRH. Studies in mouse mutants in which this receptor subtype had been deleted extended these findings as the animals were less anxious than wild-type mice when experimentally stressed. Thus, patients with clinical conditions that are causally related to HPA hyperactivity may profit from treatment with a CRH 1 receptor antagonist.

Journal

Journal of Psychiatric ResearchElsevier

Published: May 1, 1999

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