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Open Access Study protocol

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

Boadie W Dunlop1*, Barbara O Rothbaum1, Elisabeth B Binder12, Erica Duncan13, Philip D Harvey4, Tanja Jovanovic1, Mary E Kelley5, Becky Kinkead1, Michael Kutner5, Dan V Iosifescu6, Sanjay J Mathew7, Thomas C Neylan8, Clinton D Kilts9, Charles B Nemeroff4 and Helen S Mayberg1

Author Affiliations

1 Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 12 Executive Park Drive NE, 3rd Floor, Atlanta, GA, USA

2 Max Planck Institute of Psychiatry, Munich, Germany

3 Atlanta Veterans Affairs Medical Center, Decatur, GA, USA

4 Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, USA

5 Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA, USA

6 Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA

7 Menninger Department of Psychiatry & Behavioral Sciences, Mental Health Care Line, Michael E Debakey VA Medical Center Baylor College of Medicine, Houston, TX, USA

8 Department of Psychiatry, University of California, San Francisco & the San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA

9 Psychiatric Research Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA

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Trials 2014, 15:240  doi:10.1186/1745-6215-15-240

Published: 21 June 2014

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.

Trial registration

Clinicaltrials.gov Identifier: NCT01018992.

Registered 6 November 2009. First patient randomized 14 January 2010.

Keywords:
Clinical Research Protocol; Drugs; Investigational; HPA Axis; Anxiety disorders; Fear-potentiated startle; Fear conditioning; Neuropsychological tests; Placebo; Psychophysiology; CRH