Corticotropin-releasing factor antagonists - Therapeutic potential in the treatment of affective disorders

Since its isolation and characterisation in 1981, corticotropin-releasing f actor (CRF) has been found to integrate not only the endocrine, but also th e autonomic, immunological and behavioural, responses of mammalian organism s to stress. Direct CNS administration of CRF to laboratory animals produce s actions similar to those observed after exposure to stress. Moreover, CNS administration of peptidergic CRF antagonists blocks, many of the behaviou ral responses to stress. Because 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 neu ronal hyperactivity in patients with affective disorders, small molecule, l ipophilic CRF antagonists have been hypothesised to possess antidepressant activity. Within the last few years, a number of pharmaceutical companies h ave developed selective, small molecule CRF1 receptor antagonists. These co mpounds block: the effects of CRF both in vitro and in vivo. There is also evidence that these agents possess anxiolytic and antidepressant activity i n animal behavioural models. Compounds that act upon the CRF system have be en hypothesised to be of value not only for certain psychiatric disorders b ut also in neurodegenerative and inflammatory disorders. Some of these CRF1 receptor antagonists are currently undergoing clinical trials to determine their efficacy and tolerability in patients with affective disorders.