The role of corticotropin-releasing factor in the pathophysiology of depression: Implications for antidepressant mechanisms of action

An overwhelming and ever-growing literature support the hypothesis that the CRF-ergic neurons, including extrahypothalamic as well as HPA axis components, represent a seminal stress-response system, which plays a causal role in the etiology of affective and anxiety disorders. Data have also demonstrated a role for CRF-ergic circuitry in the mechanism of action of current antidepressant therapies. The temporal sequence of symptom improvement during treatment with these agents more closely matches normalization of CRF-ergic signaling and HPA axis functioning than their primary effects on monoaminergic systems. Moreover, CRF₁ antagonists are known to possess antidepressant and anxiolytic properties and likely represent a novel class of antidepressants/anxiolytics that may be used both in monotherapy as well as in combination with currently available treatments.