Evaluation of a corticotropin releasing hormone type 1 receptor antagonist in women with posttraumatic stress disorder: study protocol for a randomized controlled trial

• Type of Material: Article
• Authors: Boadie W Dunlop, Emory University; Barbara O Rothbaum, Emory University; Elisabeth B. Binder, Emory University; Erica Duncan, Emory University; Philip D Harvey, University of Miami; Tanja Jovanovic, Emory University; Mary Kelley, Emory University; Becky Kinkead, Emory University; Michael Kutner, Emory University; Dan V Iosifescu, Mount Sinai School of Medicine; Sanjay J Mathew, Baylor College of Medicine; Thomas C Neylan, University of California; Clinton D Kilts, University of Arkansas; Charles B Nemeroff, University of Miami; Helen S Mayberg, Emory University
• Language: English
• Date: 2014
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: © 2014 Dunlop et al.; licensee BioMed Central Ltd.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://www.trialsjournal.com/content/15/1/240
• Title of Journal or Parent Work: Trials
• ISSN: 1745-6215
• Volume: 15
• Issue: 240
• Grant/Funding Information: GSK561679 compound is currently licensed by Neurocrine Biosciences, which will also perform pharmacokinetic analyses.; Additional support was received from K23 MH086690 (BWD) and VA CSRD Project ID 09S-NIMH-002 (TCN).; Funding for the study is provided from a grant from the National Institute of Mental Health, U19 MH069056 (BWD, HM).; GlaxoSmithKline contributed the study medication and matching placebo, as well as funds to support subject recruitment and laboratory testing. GSK is uninvolved in the data collection, data analysis (excepting some pharmacokinetic analysis), or interpretation of findings.
• Keywords: Fear conditioning; Investigational; Fear-potentiated startle; HPA Axis; Neuropsychological tests; Clinical Research Protocol; Psychophysiology; Drugs; Anxiety disorders; Placebo; CRH
• Research Categories: Psychology, Behavioral; Health Sciences, General

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/design 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. Discussion 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.