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 type 1 (CRF1) antagonist in adult women with PTSD. The trial randomized 128 participants, of whom 96 completed the six-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 SNP rs110402 found 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 antagonist for the treatment of PTSD, combined with other negative trials of CRF1 antagonists for major depressive disorder, generalized anxiety disorder, and Dunlop social anxiety disorder, suggest that CRF1 antagonists lack efficacy as monotherapy agents for these conditions.
ClinicialTrials.gov
Evaluation of GSK561679 in Women With Post-Traumatic Stress Disorder; https://clinicaltrials.gov/ct2/show/NCT01018992?term=NCT01018992&rank=1; NCT01018992