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Author Notes:

Corresponding Author: Boadie W. Dunlop, MD, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 12 Executive Park Drive NE, 3rd Floor, Atlanta, GA, 30329, bdunlop@emory.edu, Phone: 404-727-8474, Fax: 404-727-3700.

See publication for full list of disclosures.

Subjects:

Research Funding:

Funding for the study was provided from a grant from the National Institute of Mental Health, U19 MH069056 (BWD, HM).

Additional support was received from K23 MH086690 (BWD) and VA CSRD Project ID 09S-NIMH-002 (TCN).

The GSK561679 compound was currently licensed by Neurocrine Biosciences.

GlaxoSmithKline contributed the study medication and matching placebo, as well as funds to support subject recruitment and laboratory testing, and Neurocrine Biosciences conducted the pharmacokinetic analyses.

GlaxoSmithKline and Neurocrine Biosciences were not involved in the data collection, data analysis or interpretation of findings.

This work was supported with resources and the use of facilities at the Michael E DeBakey VA Medical Center, Houston, TX.

Disclaimer: the views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Neurosciences
  • Psychiatry
  • Neurosciences & Neurology
  • Adrenocorticotropic hormone
  • Child abuse
  • Clinical trial
  • Dexamethasone
  • Pharmacogenetics
  • MESSENGER-RNA LEVELS
  • LOCUS-COERULEUS
  • HORMONE
  • DEPRESSION
  • ANXIETY
  • PTSD
  • PLACEBO
  • SYSTEMS
  • FEAR
  • NOREPINEPHRINE

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

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Journal Title:

Biological Psychiatry

Volume:

Volume 82, Number 12

Publisher:

, Pages 866-874

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

© 2017 Society of Biological Psychiatry

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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