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.
| Original language | English |
|---|---|
| Article number | 240 |
| Journal | Trials |
| Volume | 15 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jun 21 2014 |
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Keywords
- Anxiety disorders
- Clinical Research Protocol
- CRH
- Drugs
- Fear conditioning
- Fear-potentiated startle
- HPA Axis
- Investigational
- Neuropsychological tests
- Placebo
- Psychophysiology
ASJC Scopus subject areas
- Medicine (miscellaneous)
- Pharmacology (medical)
Cite this
Evaluation of a corticotropin releasing hormone type 1 receptor antagonist in women with posttraumatic stress disorder : Study protocol for a randomized controlled trial. / Dunlop, Boadie W.; Rothbaum, Barbara O.; Binder, Elisabeth B.; Duncan, Erica; Harvey, Philip D; Jovanovic, Tanja; Kelley, Mary E.; Kinkead, Becky; Kutner, Michael; Iosifescu, Dan V.; Mathew, Sanjay J.; Neylan, Thomas C.; Kilts, Clinton D.; Nemeroff, Charles; Mayberg, Helen S.
In: Trials, Vol. 15, No. 1, 240, 21.06.2014.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Evaluation of a corticotropin releasing hormone type 1 receptor antagonist in women with posttraumatic stress disorder
T2 - Study protocol for a randomized controlled trial
AU - Dunlop, Boadie W.
AU - Rothbaum, Barbara O.
AU - Binder, Elisabeth B.
AU - Duncan, Erica
AU - Harvey, Philip D
AU - Jovanovic, Tanja
AU - Kelley, Mary E.
AU - Kinkead, Becky
AU - Kutner, Michael
AU - Iosifescu, Dan V.
AU - Mathew, Sanjay J.
AU - Neylan, Thomas C.
AU - Kilts, Clinton D.
AU - Nemeroff, Charles
AU - Mayberg, Helen S.
PY - 2014/6/21
Y1 - 2014/6/21
N2 - 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.
AB - 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.
KW - Anxiety disorders
KW - Clinical Research Protocol
KW - CRH
KW - Drugs
KW - Fear conditioning
KW - Fear-potentiated startle
KW - HPA Axis
KW - Investigational
KW - Neuropsychological tests
KW - Placebo
KW - Psychophysiology
UR - http://www.scopus.com/inward/record.url?scp=84902702355&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84902702355&partnerID=8YFLogxK
U2 - 10.1186/1745-6215-15-240
DO - 10.1186/1745-6215-15-240
M3 - Article
C2 - 24950747
AN - SCOPUS:84902702355
VL - 15
JO - Trials
JF - Trials
SN - 1745-6215
IS - 1
M1 - 240
ER -