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

J Psychiatr Res. May-Jun 1999;33(3):181-214. doi: 10.1016/s0022-3956(98)90056-5.

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 CRH1 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 CRH1 receptor antagonist.

Publication types

  • Review

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology
  • Antidepressive Agents / therapeutic use
  • Anxiety Disorders / drug therapy*
  • Anxiety Disorders / physiopathology
  • Corticotropin-Releasing Hormone / biosynthesis
  • Corticotropin-Releasing Hormone / drug effects
  • Depressive Disorder / drug therapy*
  • Depressive Disorder / physiopathology
  • Female
  • Humans
  • Hypothalamo-Hypophyseal System / drug effects
  • Hypothalamo-Hypophyseal System / physiopathology
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Models, Neurological
  • Pituitary-Adrenal System / drug effects
  • Pituitary-Adrenal System / physiopathology
  • Psychopharmacology / trends*
  • Pyrimidines / pharmacology
  • Pyrroles / pharmacology
  • Rats
  • Receptors, Corticotropin-Releasing Hormone / antagonists & inhibitors*

Substances

  • Antidepressive Agents
  • CP 154526
  • Pyrimidines
  • Pyrroles
  • Receptors, Corticotropin-Releasing Hormone
  • Corticotropin-Releasing Hormone