Development of CRF1 receptor antagonists as antidepressants and anxiolytics: progress to date.
ABSTRACT Depression and anxiety disorders are highly prevalent forms of mental illness that are considered to be stress-related disorders because some form of stressful life event often triggers their symptoms. Corticotropin-releasing factor (CRF) is a 41-amino-acid neuropeptide involved in mediating neuroendocrine, autonomic and behavioural responses to stress, and clinical studies provide evidence for the role of CRF in the development of depression and anxiety disorders. Two CRF receptor subtypes have been identified to date - the CRF(1) receptor and the CRF(2) receptor. Preclinical models provide evidence of a role for CRF(1) receptors in the activation of the stress response. Data from these experiments suggest that antagonism of CRF(1) receptor activity may provide an effective pharmacological treatment for stress-related psychiatric disorders. This review highlights progress to date with the development of CRF(1) receptor antagonists as potential pharmacotherapies for depression and anxiety disorders. Although additional research is needed to fully investigate the efficacy and safety profiles of CRF(1) receptor antagonists as candidate medications for these disorders, the results of preclinical experiments and clinical trials are encouraging. Further development of these compounds is warranted.
SourceAvailable from: Christian Grillon[Show abstract] [Hide abstract]
ABSTRACT: Fear to predictable threat and anxiety to unpredictable threat reflect distinct processes mediated by different brain structures, the central nucleus of the amygdala and the bed nucleus of the stria terminalis (BNST), respectively. The present study tested the hypothesis that the corticotropin releasing factor (CRF1) antagonist GSK561679 differentially reduces anxiety but increases fear in humans. Thirty one healthy females received each of four treatments, placebo, 50 mg GSK561679 (low-GSK), 400 mg GSK561679 (high-GSK), and 1 mg alprazolam in a crossover design. Participants were exposed to three conditions during each of the four treatments. The three conditions included one in which predictable aversive shocks were signaled by a cue, a second during which shocks were administered unpredictably, and a third condition without shock. Fear and anxiety were assessed using the acoustic startle reflex. High-GSK had no effect on startle potentiation during unpredictable threat (anxiety) but increased startle potentiation during the predictable condition (fear). Low-GSK did not affect startle potentiation across conditions. Consistent with previous findings, alprazolam reduced startle potentiation during unpredictable threat but not during predictable threat. The increased fear by high-GSK replicates animal findings and suggests a lift of the inhibitory effect of the bed nucleus of the stria terminalis (BNST) on the amygdala by the CRF1 antagonist.Neuropsychopharmacology accepted article preview online, 28 November 2014. doi:10.1038/npp.2014.316.Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 11/2014; 40(5). DOI:10.1038/npp.2014.316 · 7.83 Impact Factor