 To address this gap, this proposal seeks to test an innovative treatment approach in PTSD - pharmacological manipulation of the bodys major stress system the hypothalamic-pituitary-adrenal HPA axis with mifepristone. At high doses mifepristone is a glucocorticoid receptor GR antagonist with peripheral and central nervous system effects, making it a compound of interest in the treatment of stress related disorders. There is abundant evidence of enhanced GR sensitivity in veterans with PTSD which is thought to underlie some of the symptoms of PTSD and associated disturbances in mood and cognition. Thus, blockade of the GR receptor with mifepristone may target unique aspects of PTSD and lead to clinically meaningful improvement in symptoms and cognition. There is preliminary evidence that short-term mifepristone treatment has sustained beneficial effects on mood, cognition and sleep disturbance in some neuropsychiatric conditions major depression, bipolar disorder, primary insomnia. That there can be sustained clinical and neuropsychological effects of mifepristone and normalization of basal HPA axis activity after drug discontinuation in these disorders, has led to the view that mifepristones actions include recalibration of a dysregulated HPA axis. Accordingly, we propose to study the effects of mifepristone in veterans with chronic PTSD to determine if it is efficacious in improving PTSD symptoms and associated clinical outcomes. To better understand the mechanism of action of mifepristone we propose to assess the effects of mifepristone on HPA axis activity and their relationship to treatment outcome and clinical response. 