Hyperactivity of CRH neuronal circuits as a target for therapeutic interventions in affective disorders

Increasing evidence suggests that the neuroendocrine changes seen in psychi atric patients, especially in those suffering from affective disorders, may be causally related to the psychopathology and course of these clinical co nditions. The most robustly confirmed neuroendocrine finding among psychiat ric patients with affective disorders is hyperactivity of the hypothalamic- pituitary-adrenocortical (HPA) system. resulting from hyperactive hypothala mic corticotropin-releasing hormone (CRH) neurons. A large body of preclini cal and clinical evidence suggests that both genetic and environmental fact ors contribute to the development of these HPA system abnormalities. Furthe r, normalization of HPA system regulation was shown to be a prerequisite fo r favorable treatment response and stable remission among depressives. Prec linical data based on animal models including selectively bred rat lints an d mouse mutants support the notion that CRH neurons are hyperactive also in neuroanatomical regions that are involved in behavioral regulation but are located outside the neuroendocrine system. This raises the question of whe ther more direct interventions such as CRH receptor antagonists would open a new lead in the treatment of stress-related disorders such as depression, anxiety and sleep disorders. Recent clinical observations support this pos sibility. (C) 2001 Elsevier Science Inc. All rights reserved.