Are CRF receptor antagonists potential antidepressants?

Corticotropin-releasing factor (CRF) is the major regulator of the hypothal amic-pituitary-adrenal (HPA) axis, and plays a key role in coordinating the endocrine, as well as autonomic and behavioral responses of an organism to stress. Direct CNS administration of CRF to laboratory animals produces an aggregate of effects that mimic the mammalian stress response. Impeding CR F function with CNS administration of a peptidergic CRF antagonist can bloc k these manifestations of the stress response whether produced by exogenous CRF or occurring naturally in response to a stressor. A role for hypersecr etion of CRF in the pathophysiology of depression is suggested by the findi ng that CNS administration of CRF mirrors many of the signs and symptoms ut ilized as diagnostic criteria for major depression. in addition, a large bo dy of clinical evidence points to excess hypothalamic secretion of CRF and an accompanying HPA axis hyperactivity in patients with major depression. T he recent development of selective, small molecule CRF1 receptor antagonist s, which block the effects of CRF both in vitro and in vivo, suggest that t hese compounds may be effective in the treatment of affective and anxiety d isorders. Early evidence indicates that these agents possess anxiolytic and antidepressant activity in animal behavioral models. Copyright (C) 2001 Jo hn Wiley & Sons, Ltd.