Novel Therapeutics in Posttraumatic Stress Disorder (PTSD): A Randomized Clinical Trial of Mifepristone

Posttraumatic stress disorder (PTSD) is a common and disabling psychiatric disorder for Veterans. Left untreated or under-treated, it can become a chronic condition associated with significant distress, depression, aggression, family disruption, substance abuse and an increased risk of morbidity and mortality. Considerable advances were made in the treatment of PTSD in recent years; however, psychopharmacological treatments have been shown to be largely ineffective for Veterans with PTSD. To address this gap, this proposal seeks to test an innovative treatment approach in PTSD - pharmacological manipulation of the body's 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. There is also 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). The purpose of the study is to examine the effects of mifepristone to determine if it is efficacious in improving PTSD symptoms and associated clinical outcomes. To achieve these objectives, the investigators propose to conduct a Phase IIa, multi-site, double-blind, placebo controlled trial of mifepristone in male Veteran outpatients with chronic PTSD through the VA's Cooperative Clinical Trial Award program. The investigators propose to enroll 90 subjects at multiple VA sites based on an estimated attrition rate of 20%. Eligible Veterans will be randomly assigned to the treatment of mifepristone (600 mg/day) or placebo for one week and followed for up to th