CRH-sub-1 receptor antagonists for the treatment of depression and anxiety

From basic and clinical studies, ample evidence has emerged that abnormalities of stress hormone regulation observed in depression and anxiety are caused by elevated secretion of hypothalamic corticotropin-releasing hormone (CRH). This neuropeptide acts through CRH1 receptors to produce a number of anxiety- and depression-like symptoms, which has resulted in extensive validation of CRH1 receptors as a potential drug target. A number of orally available nonpeptidergic small molecules that are able to pass the blood-brain barrier have been discovered. Some of these compounds have entered clinical development. The authors summarize results from clinical studies of 2 CRH1 antagonists. One study designed as a safety and tolerability study also monitored amelioration of depression under 2 dose-escalation regimens. The compound studied, NBI-30775/R121919, was found to have a clinical profile comparable to that of paroxetine. In a second study the effect of another CRH1 antagonist, NBI-34041, on stress hormone secretion in response to a psychosocial stressor was investigated. Administration of this compound to healthy controls was found to reduce the stress-elicited secretion of stress hormones. However, neither compound impaired the CRH-induced release of adrenocorticotropic hormone and cortisol, rejecting the possibility that the stress hormone system is impaired by CRH1 antagonists. From these studies the authors conclude that both CRH1 antagonists have psychotropic effects unrelated to their neuroendocrine action, in line with behavioral data obtained from transgenic mice with CRH1 gene deletions. The psychotropic effects observed in the clinical studies underscore that CRH1 antagonists constitute a novel treatment of depression and anxiety but may also serve to prevent negative sequelae of severe stressors.