CRF1 receptor antagonists have elicited activity in animal models of anxiety and depression. CRF receptor antagonists have been tested in many different paradigms, including the elevated plus maze, foot shock, restraint stress, and defensive withdrawal. Pretreatment with CRF receptor antagonists decreases measures of anxiety induced by stressors. There is also some evidence that CRF receptor antagonists may reduce the effects of drug withdrawal and stress-induced relapse to drug seeking in rats.47,72-74 Based on this premise, newly developed CRF1 receptor antagonists represent a novel putative class of antidepressants. Such compounds show activity in nearly every preclinical screening test for antidepressants and anxiolytics.
Despite the rich preclinical and clinical literature supporting a potential role for CRF1 receptor antagonists, there has only been 1 published study investigating the effects of a CRF1 receptor antagonist in humans. A small open-label study examining the effectiveness of R121919, a CRF1 receptor antagonist, in major depression was completed more than 5 years ago.75 This study of 20 patients showed that R121919 (5 to 40 mg/d or 40 to 80 mg/d for 30 days) was well tolerated by patients and did not significantly affect plasma ACTH or cortisol concentrations at baseline or following CRF challenge. It is important that the use of any potential CRF antagonist not lead to complete HPA axis blockade and adrenal insufficiency, which can, of course, result in a severe medical emergency. Hamilton Depression Rating Scale and Hamilton Anxiety Scale severity scores were both significantly reduced following 30-day treatment with this drug. Although this small open-label study does not provide unequivocal proof, it does provide further evidence that a selec- tive CRF-receptor antagonist may provide antidepressant and antianxiety properties in humans.75 Although this drug is no longer in clinical development because of hepatotoxicity, several novel CRF1 antagonists are currently under investigation.
Conclusions and future directions
Since the discovery of CRF more than 25 years ago, evidence has accumulated indicating a preeminent role for this peptide in the pathophysiology of depression and anxiety. The recent introduction of small-molecule CRF receptor antagonists as a novel class of antidepressant and anxiolytic drugs remains very promising. These compounds block the actions of exogenous and endogenous CRF in a variety of in vivo models, supporting a putative role for these agents in the treatment of stress and/or anxiety and affective disorders. The promising clinical results in patients with depression in the completed open trial of R121919 is of great interest and the results of further studies are eagerly awaited.As we await the results of additional clinical trials examining the efficacy of CRF1 receptor antagonists in anxiety and mood disorders, it should be pointed out that these compounds may be beneficial in a broad array of neuropsychiatric disorders (including eating disorders, child abuse, and drug abuse), as well as irritable bowel syndrome and inflammatory diseases. Whether these drugs will be effective as monotherapy or whether they represent an important class of augmenting agents remains to be determined. Furthermore, the development of single photon emission CT and positron emission tomography ligands from these lead compounds for use in neuroimaging studies are likely to be useful in furthering our understanding of the pathophysiology of these mood and anxiety disorders.76,77
Drugs mentioned in this article:Amitriptyline(Drug information on amitriptyline) (Limbitrol)
Desipramine (Norpramin, Pertofrane)
Fluoxetine(Drug information on fluoxetine) (Prozac, Serafem)
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