title: A randomized, double-blind, placebo-controlled, crossover trial of mifepristone in Gulf War veterans with chronic multisymptom illness.
abstract: No pharmacological treatments have been demonstrated to effectively treat chronic multisymptom illness (CMI) in Gulf War veterans (GWV). This study assessed the effect of the glucocorticoid receptor antagonist mifepristone in GWV with CMI. A randomized, double-blind, cross-over trial of mifepristone, with two six-week treatment phases separated by a one-month washout period, was conducted at a Veterans Affairs (VA) hospital between 2008 and 2011. Participants were randomized to receive either 200mg of mifepristone per day or matched placebo first. The primary clinical outcome measure was change in self-reported physical health. Neurocognitive functioning and self-reported measures of depression, PTSD, and fatigue were secondary outcomes. Sixty-five participants enrolled, of whom 36 were randomized and 32 (mean age, 49.1 (7.2) years) completed the study. Physical and mental health status and neurocognitive functioning were poor at baseline. Mifepristone treatment was not associated with improvement in self-reported physical health (p=0.838) or in other self-reported measures of mental health. Mifepristone treatment was significantly associated with improvements in verbal learning (p=0.008, d=0.508), in the absence of improvement in other cognitive measures (working memory (p=0.914), visual learning (p=0.643) and a global composite measure (p=0.937). Baseline morning cortisol levels and lysozyme IC50-DEX, a measure of peripheral glucocorticoid sensitivity, displayed a significant relationship with endpoint verbal learning scores (p=0.012 and p=0.007, respectively). The magnitude of cortisol change during treatment mediated the improvement in verbal learning. This study was negative for the primary and secondary clinical outcomes. However, the data suggest a moderate dose of mifepristone may have circumscribed cognitive-enhancing effects in CMI. Further study is warranted to determine whether and through which mechanisms mifepristone treatment can yield clinically meaningful improvement in cognitive function in CMI or other neuropsychiatric conditions associated with HPA axis dysregulation.
authors.affiliation: James J. Peters VA Medical Center, OOMH-526, 130 West Kingsbridge Road, Bronx, NY 10468, United States; Psychiatry Department, Icahn School of Medicine at Mount Sinai, 1428 Madison Ave, New York, NY 10029, United States. Electronic address: julia.golier@va.gov.
authors.forename: Julia A
authors.initials: JA
authors.lastname: Golier
authors.affiliation: James J. Peters VA Medical Center, OOMH-526, 130 West Kingsbridge Road, Bronx, NY 10468, United States.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Caramanica
authors.affiliation: James J. Peters VA Medical Center, OOMH-526, 130 West Kingsbridge Road, Bronx, NY 10468, United States.
authors.forename: Andreas C
authors.initials: AC
authors.lastname: Michaelides
authors.affiliation: James J. Peters VA Medical Center, OOMH-526, 130 West Kingsbridge Road, Bronx, NY 10468, United States; Psychiatry Department, Icahn School of Medicine at Mount Sinai, 1428 Madison Ave, New York, NY 10029, United States.
authors.forename: Iouri
authors.initials: I
authors.lastname: Makotkine
authors.affiliation: Psychiatry Department, Icahn School of Medicine at Mount Sinai, 1428 Madison Ave, New York, NY 10029, United States.
authors.forename: James
authors.initials: J
authors.lastname: Schmeidler
authors.affiliation: Miller School of Medicine, University of Miami, 1600 NW 10th Ave #1140, Miami, FL 33136, United States.
authors.forename: Philip D
authors.initials: PD
authors.lastname: Harvey
authors.affiliation: James J. Peters VA Medical Center, OOMH-526, 130 West Kingsbridge Road, Bronx, NY 10468, United States; Psychiatry Department, Icahn School of Medicine at Mount Sinai, 1428 Madison Ave, New York, NY 10029, United States.
authors.forename: Rachel
authors.initials: R
authors.lastname: Yehuda
mesh_terms: D000328:Adult; D002908:Chronic Disease; D003071:Cognition / Q000187:drug effects; D018592:Cross-Over Studies; D003863:Depression / Q000150:complications / Q000188:drug therapy*; D003907:Dexamethasone / Q000494:pharmacology; D004311:Double-Blind Method; D005221:Fatigue / Q000150:complications / Q000188:drug therapy*; D005260:Female; D047830:Gulf War; D006304:Health Status; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015735:Mifepristone / Q000627:therapeutic use*; D010912:Pituitary-Adrenal Function Tests; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D013313:Stress Disorders, Post-Traumatic / Q000150:complications / Q000188:drug therapy*; D014728:Veterans / Q000523:psychology*
chemical_list: D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D003907:Dexamethasone; D006854:Hydrocortisone
keywords: ACTH; CMI; Cortisol; Dexamethasone; Gulf War; Mifepristone; Verbal learning