Background: In our ongoing work in Gulf War veterans (GWV), we have described distinct biological alterations associated with deployment to the 1991 Gulf War and the development of chronic multisymptom illness (CMI) that could be reflective of disturbances in central processes that regulate neuroendocrine systems (Golier et al., 2006a; Golier et al., 2006b; Golier et al., 2007). In particular, enhanced negative feedback inhibition of the hypothalamic pituitary-adrenal (HPA) axis and lower 24-hour plasma ACTH levels are associated with Gulf War deployment and CMI. Enhanced negative feedback inhibition has also been found in chronic fatigue syndrome, fibromyalgia, and post-traumatic stress disorder, all of which can co-occur with CMI. Since dysregulation of the HPA axis can have deleterious effects on multiple systems including the immune system, the autonomic nervous system, and the central nervous system, this system may be a useful target of treatment in CMI. Accordingly, we seek to determine whether mifepristone, a glucocorticoid receptor antagonist, can reverse the neuroendocrine alterations described in GWV, by reducing glucocorticoid sensitivity, and in so doing, improve the health of these veterans. Mifepristone has previously been safely used to treat physical symptoms and disturbances of memory and mood in other medical and neuropsychiatric disorders associated with disturbances in the HPA axis. Accordingly, we propose to conduct a pilot, placebo-controlled trial of mifepristone in CMI to examine its effects on physical health and cognitive functioning.

Objective: To test whether mifepristone, a safe and tolerable glucocorticoid receptor antagonist, improves the health and functioning of GWV with CMI.

Specific Aims: (1) To determine the efficacy of mifepristone on physical health in GWV with CMI; (2) To determine the efficacy of mifepristone on cognitive functioning in GWV with CMI; (3) To determine whether mifepristone is effective in reducing other symptoms characteristic of or associated with CMI; (4) To determine whether screening levels of HPA axis activity (glucocorticoid sensitivity, cortisol level, and ACTH level) or changes in HPA axis activity associated with mifepristone treatment predict outcome.

Study Design: Forty GWV with CMI will be studied in an 8-week randomized double-blind placebo-controlled crossover trial of mifepristone (400 mg/day) with a 4-week follow-up. The two treatment phases will include 21 days of medication separated by a 7-day wash-out period to avoid crossover effects. The primary outcome measure will be improvement in physical health as measured by the Veterans Rand 36-item health survey. Secondary outcomes will include improvement in objective cognitive functioning (using a standardized neuropsychological test battery especially designed for use in clinical trials), subjective cognitive functioning, and symptoms characteristic of or associated with CMI (e.g., pain, fatigue, depression, symptoms of post-traumatic stress). Furthermore, HPA axis activity will be measured at baseline and longitudinally to characterize the neuroendocrine response to mifepristone in GWV and determine whether pre-treatment HPA axis measures or changes in HPA activity predict clinical outcome.

Impact: This study is designed to examine whether enhanced glucocorticoid sensitivity is a potential treatment target in symptomatic GWV and whether mifepristone, in particular, could improve physical health, cognitive functioning, or other symptoms in GWV with CMI.