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Corticotropin-Releasing Factor Receptor 1 Antagonism Is Ineffective for Women With Posttraumatic Stress Disorder.

ABSTRACT: BACKGROUND:Medication and psychotherapy treatments for posttraumatic stress disorder (PTSD) provide insufficient benefit for many patients. Substantial preclinical and clinical data indicate abnormalities in the hypothalamic-pituitary-adrenal axis, including signaling by corticotropin-releasing factor, in the pathophysiology of PTSD. METHODS:We conducted a double-blind, placebo-controlled, randomized, fixed-dose clinical trial evaluating the efficacy of GSK561679, a corticotropin-releasing factor receptor 1 (CRF1 receptor) antagonist in adult women with PTSD. The trial randomized 128 participants, of whom 96 completed the 6-week treatment period. RESULTS:In both the intent-to-treat and completer samples, GSK561679 failed to show superiority over placebo on the primary outcome of change in Clinician-Administered PTSD Scale total score. Adverse event frequencies did not significantly differ between GSK561679- and placebo-treated subjects. Exploration of the CRF1 receptor single nucleotide polymorphism rs110402 found that response to GSK561679 and placebo did not significantly differ by genotype alone. However, subjects who had experienced a moderate or severe history of childhood abuse and who were also GG homozygotes for rs110402 showed significant improvement after treatment with GSK561679 (n = 6) but not with placebo (n = 7) on the PTSD Symptom Scale-Self-Report. CONCLUSIONS:The results of this trial, the first evaluating a CRF1 receptor antagonist for the treatment of PTSD, combined with other negative trials of CRF1 receptor antagonists for major depressive disorder, generalized anxiety disorder, and social anxiety disorder, suggest that CRF1 receptor antagonists lack efficacy as monotherapy agents for these conditions.

SUBMITTER: Dunlop BW

PROVIDER: S-EPMC5683912 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Corticotropin-Releasing Factor Receptor 1 Antagonism Is Ineffective for Women With Posttraumatic Stress Disorder.

Dunlop Boadie W BW Binder Elisabeth B EB Iosifescu Dan D Mathew Sanjay J SJ Neylan Thomas C TC Pape Julius C JC Carrillo-Roa Tania T Green Charles C Kinkead Becky B Grigoriadis Dimitri D Rothbaum Barbara O BO Nemeroff Charles B CB Mayberg Helen S HS

Biological psychiatry 20170704 12

<h4>Background</h4>Medication and psychotherapy treatments for posttraumatic stress disorder (PTSD) provide insufficient benefit for many patients. Substantial preclinical and clinical data indicate abnormalities in the hypothalamic-pituitary-adrenal axis, including signaling by corticotropin-releasing factor, in the pathophysiology of PTSD.<h4>Methods</h4>We conducted a double-blind, placebo-controlled, randomized, fixed-dose clinical trial evaluating the efficacy of GSK561679, a corticotropin- ...[more]

PMID: 28793974

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Project description: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.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.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.Clinicaltrials.gov Identifier: NCT01018992.Registered 6 November 2009. First patient randomized 14 January 2010.

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Corticotropin-Releasing Factor Receptor 1 Antagonism Is Ineffective for Women With Posttraumatic Stress Disorder.

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Corticotropin-Releasing Factor Receptor 1 Antagonism Is Ineffective for Women With Posttraumatic Stress Disorder.

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