Corticotropin-releasing factor antagonists in affective disorders

Abstract

Following a search lasting nearly three decades, corticotropin-releasing factor (CRF), a 41 amino acid-containing peptide, was isolated and characterised in 1981. In the preceding 18 years, a concatenation was developed that appears to show that CRF integrates not only the endocrine, but also the autonomic, immunologic and behavioural responses of mammalian organisms to stress. Direct CNS administration of CRF to laboratory animals produces actions similar to those observed after exposure to stress. Moreover, CNS administration of peptidergic CRF antagonists blocks many of the behavioural responses to stress. Since both early untoward life events as well as recently experienced stress have been implicated in the pathophysiology of affective disorders, and because there is substantial evidence for CRF neuronal hyperactivity in patients with affective disorders, small molecule, lipophilic CRF antagonists have been hypothesised to possess antidepressant and/or anxiolytic activity. Within the last few years, a number of pharmaceutical companies have developed selective, small molecule CRF(1) receptor antagonists. These compounds block the effects of CRF both in vitro and in vivo. There is also evidence that these agents possess anxiolytic and antidepressant activity in animal behavioural models. Compounds that act upon the CRF system have been hypothesised to be of value not only for certain psychiatric disorders, but also in neurodegenerative and inflammatory disorders. Some of these CRF(1) receptor antagonists are currently undergoing clinical trials to determine their efficacy and tolerability in patients with mood and anxiety disorders.