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Central CRH system in depression and anxiety--evidence from clinical studies with CRH1 receptor antagonists.
Eur J Pharmacol 2008; 583(2-3):350-7EJ

Abstract

Basic and clinical studies provide convincing evidence that altered stress hormone regulation frequently observed in depression and anxiety are caused by elevated secretion of the hypothalamic neuropeptides corticotrophin releasing hormone (CRH) and vasopressin. CRH predominantly acts through CRH(1) receptors to produce a number of anxiety- and depression-like symptoms, which resulted in extensive validation of CRH(1) receptors as potential drug target. A number of orally available nonpeptidergic small molecules capable to pass the blood-brain barrier have been discovered; only some of these compounds entered clinical development. Here, we summarize results from clinical studies of two CRH(1) receptor antagonists. In the first study originally designed as a safety and tolerability trial in major depression, it was observed that the CRH(1) receptor antagonist NBI-30775/R121919 has a clinical profile comparable to the antidepressant paroxetine. In a second study the effect of another CRH(1) receptor antagonist, NBI-34041, upon stress hormone secretion in response to a psychosocial stressor was investigated. Administration of this compound reduced the stress-elicited secretion of cortisol. Both compounds, however, did not impair the CRH-induced release of ACTH and cortisol rejecting the possibility that the peripheral stress hormone system is impaired by CRH(1) receptor antagonists. From these studies we conclude that both CRH(1) receptor antagonists have psychotropic effects unrelated to their neuroendocrine action, which is in line with behavioral data obtained from transgenic mice. The results of the clinical studies underscore that CRH(1) receptor antagonists represent promising novel therapeutics in the psychopharmacology of depression and anxiety.

Authors+Show Affiliations

Max-Planck-Institute of Psychiatry, Munich, Germany. holsboer@mpipsykl.mpg.deNo affiliation info available

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

18272149

Citation

Holsboer, Florian, and Marcus Ising. "Central CRH System in Depression and Anxiety--evidence From Clinical Studies With CRH1 Receptor Antagonists." European Journal of Pharmacology, vol. 583, no. 2-3, 2008, pp. 350-7.
Holsboer F, Ising M. Central CRH system in depression and anxiety--evidence from clinical studies with CRH1 receptor antagonists. Eur J Pharmacol. 2008;583(2-3):350-7.
Holsboer, F., & Ising, M. (2008). Central CRH system in depression and anxiety--evidence from clinical studies with CRH1 receptor antagonists. European Journal of Pharmacology, 583(2-3), pp. 350-7. doi:10.1016/j.ejphar.2007.12.032.
Holsboer F, Ising M. Central CRH System in Depression and Anxiety--evidence From Clinical Studies With CRH1 Receptor Antagonists. Eur J Pharmacol. 2008 Apr 7;583(2-3):350-7. PubMed PMID: 18272149.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Central CRH system in depression and anxiety--evidence from clinical studies with CRH1 receptor antagonists. AU - Holsboer,Florian, AU - Ising,Marcus, Y1 - 2008/01/24/ PY - 2007/08/09/received PY - 2007/11/28/revised PY - 2007/12/05/accepted PY - 2008/2/15/pubmed PY - 2008/7/23/medline PY - 2008/2/15/entrez SP - 350 EP - 7 JF - European journal of pharmacology JO - Eur. J. Pharmacol. VL - 583 IS - 2-3 N2 - Basic and clinical studies provide convincing evidence that altered stress hormone regulation frequently observed in depression and anxiety are caused by elevated secretion of the hypothalamic neuropeptides corticotrophin releasing hormone (CRH) and vasopressin. CRH predominantly acts through CRH(1) receptors to produce a number of anxiety- and depression-like symptoms, which resulted in extensive validation of CRH(1) receptors as potential drug target. A number of orally available nonpeptidergic small molecules capable to pass the blood-brain barrier have been discovered; only some of these compounds entered clinical development. Here, we summarize results from clinical studies of two CRH(1) receptor antagonists. In the first study originally designed as a safety and tolerability trial in major depression, it was observed that the CRH(1) receptor antagonist NBI-30775/R121919 has a clinical profile comparable to the antidepressant paroxetine. In a second study the effect of another CRH(1) receptor antagonist, NBI-34041, upon stress hormone secretion in response to a psychosocial stressor was investigated. Administration of this compound reduced the stress-elicited secretion of cortisol. Both compounds, however, did not impair the CRH-induced release of ACTH and cortisol rejecting the possibility that the peripheral stress hormone system is impaired by CRH(1) receptor antagonists. From these studies we conclude that both CRH(1) receptor antagonists have psychotropic effects unrelated to their neuroendocrine action, which is in line with behavioral data obtained from transgenic mice. The results of the clinical studies underscore that CRH(1) receptor antagonists represent promising novel therapeutics in the psychopharmacology of depression and anxiety. SN - 0014-2999 UR - https://www.unboundmedicine.com/medline/citation/18272149/Central_CRH_system_in_depression_and_anxiety__evidence_from_clinical_studies_with_CRH1_receptor_antagonists_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(08)00029-0 DB - PRIME DP - Unbound Medicine ER -