Mifepristone (RU-486) treatment for depression and psychosis: a review of the therapeutic implications

The mechanisms underlying the pathophysiology of severe psychiatric illnesses are complex, involving multiple neuronal and neurochemical pathways. A growing body of evidence indicates that alterations in hypothalamic–pituitary–adrenal (HPA) axis function may be a trait marker in both mood disorders and psychosis, and may exert significant causal and exacerbating effects on symptoms and neurocognition. At present, however, no available treatments preferentially target HPA axis abnormalities, although many drugs do increase feedback-regulation of the HPA axis at the level of the glucocorticoid receptor (GR). This action may in part underpin their therapeutic efficacy. Therapeutic interventions directly targeted at GR function may therefore have clinical benefit. The present review examines the current literature for the clinical utility of GR antagonists (specifically mifepristone) in mood disorders and psychosis. At present, most studies are at the “proof-of-concept” stage, although the results of preliminary, randomized, controlled trials are encouraging. The optimum strategy for the clinical application of GR antagonists is yet to be established, their potential role as first-line or adjunctive treatments being unclear. The therapeutic utility of such drugs will become known within the next few years following the results of larger clinical trials currently underway.