title: Evaluation of a corticotropin releasing hormone type 1 receptor antagonist in women with posttraumatic stress disorder: study protocol for a randomized controlled trial.
abstract: BACKGROUND
  Pharmacologic treatment options for posttraumatic stress disorder (PTSD) are limited in number and effectiveness. Medications currently in use to treat PTSD were originally approved based on their efficacy in other disorders, such as major depression. Substantial research in PTSD suggests that increased activity of corticotropin releasing hormone (CRH)-containing circuits are involved in the pathophysiology of the disease. This Phase II trial aims to evaluate the efficacy of a CRH type 1 receptor (CRHR1) antagonist in the treatment of PTSD.
  
  
  METHODS
  Currently untreated adult women, ages 18 to 65 years, with a primary psychiatric diagnosis of PTSD of at least 3 months' duration, are being enrolled in a parallel-group, double-blind, placebo-controlled, randomized clinical trial evaluating the efficacy and safety of GSK561679, a novel CRHR1 receptor antagonist. GSK561679 (or matching placebo) is prescribed at a fixed dose of 350 mg nightly for six weeks. The primary trial hypothesis is that GSK561679 will reduce symptoms of PTSD, as measured by the Clinician-Administered PTSD Scale (CAPS), significantly more than placebo after six weeks of treatment. Putative biological markers of PTSD which may influence treatment response are measured prior to randomization and after five weeks' exposure to the study medication, including: fear conditioning and extinction using psychophysiological measures; variants of stress-related genes and gene expression profiles; and indices of HPA axis reactivity. In addition, the impact of PTSD and treatment on neuropsychological performance and functional capacity are assessed at baseline and after the fifth week of study medication. After completion of the six-week double blind treatment period, subjects enter a one-month follow-up period to monitor for sustained response and resolution of any adverse effects.
  
  
  CONCLUSIONS
  Considerable preclinical and human research supports the hypothesis that alterations in central nervous system CRH neuronal activity are a potential mediator of PTSD symptoms. This study is the first to assess the efficacy of a specific antagonist of a CRH receptor in the treatment of PTSD. Furthermore, the biological and neuropsychological measures included in this trial will substantially inform our understanding of the mechanisms of PTSD.
  
  
  BACKGROUND
  Clinicaltrials.gov Identifier: NCT01018992.Registered 6 November 2009. First patient randomized 14 January 2010.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 12 Executive Park Drive NE, 3rd Floor, Atlanta, GA, USA. bdunlop@emory.edu.
authors.forename: Boadie W
authors.initials: BW
authors.lastname: Dunlop
authors.forename: Barbara O
authors.initials: BO
authors.lastname: Rothbaum
authors.forename: Elisabeth B
authors.initials: EB
authors.lastname: Binder
authors.forename: Erica
authors.initials: E
authors.lastname: Duncan
authors.forename: Philip D
authors.initials: PD
authors.lastname: Harvey
authors.forename: Tanja
authors.initials: T
authors.lastname: Jovanovic
authors.forename: Mary E
authors.initials: ME
authors.lastname: Kelley
authors.forename: Becky
authors.initials: B
authors.lastname: Kinkead
authors.forename: Michael
authors.initials: M
authors.lastname: Kutner
authors.forename: Dan V
authors.initials: DV
authors.lastname: Iosifescu
authors.forename: Sanjay J
authors.initials: SJ
authors.lastname: Mathew
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Neylan
authors.forename: Clinton D
authors.initials: CD
authors.lastname: Kilts
authors.forename: Charles B
authors.initials: CB
authors.lastname: Nemeroff
authors.forename: Helen S
authors.initials: HS
authors.lastname: Mayberg
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D053961:Azabicyclo Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D002985:Clinical Protocols; D003213:Conditioning, Psychological / Q000187:drug effects; D003940:Diagnostic Techniques, Endocrine; D004311:Double-Blind Method; D005108:Extinction, Psychological / Q000187:drug effects; D005239:Fear / Q000187:drug effects; D005260:Female; D020869:Gene Expression Profiling; D006727:Hormone Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D008875:Middle Aged; D010069:Oxadiazoles / Q000009:adverse effects / Q000627:therapeutic use*; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D011569:Psychiatric Status Rating Scales; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012107:Research Design; D013313:Stress Disorders, Post-Traumatic / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000523:psychology; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States; D055815:Young Adult; D000099052:CRF Receptor, Type 1
chemical_list: D053961:Azabicyclo Compounds; D006727:Hormone Antagonists; C556497:NBI 77860; D010069:Oxadiazoles; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1