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

Boadie W. Dunlop, Elisabeth B. Binder, Dan Iosifescu, Sanjay J. Mathew, Thomas C. Neylan, Julius C. Pape, Tania Carrillo-Roa, Charles Green, Becky Kinkead, Dimitri Grigoriadis, Barbara O. Rothbaum, Charles B. Nemeroff, Helen S. Mayberg

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)866-874
Number of pages9
JournalBiological Psychiatry
Volume82
Issue number12
DOIs
StatePublished - Dec 15 2017

Keywords

  • Adrenocorticotropic hormone
  • Child abuse
  • Clinical trial
  • Dexamethasone
  • Pharmacogenetics

ASJC Scopus subject areas

  • Biological Psychiatry

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