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.

Keywords: Adrenocorticotropic hormone; Child abuse; Clinical trial; Dexamethasone; Pharmacogenetics.