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 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

Psychophysiological treatment outcomes: Corticotropin‐releasing factor type 1 receptor antagonist increases inhibition of fear‐potentiated startle in PTSD patients

“…A limitation of the current study is that only women were included (Dunlop et al, ). Additionally, the conditional discrimination paradigm is sensitive to cycle effects and estradiol level (Glover et al, ), which were not controlled in the current study.…”

“…In our previous studies, we have found that this specific deficit, rather than a more broad learning deficit, is associated with higher PTSD symptoms (Jovanovic et al, ). The larger clinical trial of GSK561679 did not find therapeutic benefits of the drug in reducing PTSD symptoms (Dunlop et al, ). One of the possible interpretations of the negative results is that the effects of CRF receptor 1 antagonism may vary based on the degree of receptor binding in different brain regions.…”

“…Genetic data suggest that GSK561679 may be effective in individuals with the CRFR1 GG genotype and high levels of childhood trauma (Bradley et al, ; Dunlop et al, ). In the present study, we were not adequately powered to examine the effects of CRFR1 GG genotype and childhood trauma on fear inhibition, though we have seen genetic effects on inhibition of FPS in larger PTSD samples (Norrholm et al, ).…”

“…This experiment was part of a larger double‐blind, randomized, placebo‐controlled clinical trial of the investigational CRF1 receptor 1 antagonist GSK561679 (Clinicaltrials.gov: NCT01018992) that performed at four academic sites (Dunlop et al, ). The present study examined the FPS data from a pretreatment baseline and post‐treatment assessment of the 6‐week clinical trial.…”

Corticotropin-Releasing Factor (CRF) Neurocircuitry and Neuropharmacology in Alcohol Drinking

“…One of the first molecules tested, R121919, showed some promise in depression, but development of the drug was suspended due to elevations in liver enzymes (Zobel et al 2000). Other small molecule CRFR1 antagonists have been tested in depression, anxiety, human fear lab studies, and PTSD but all have yielded negative results (Binneman et al 2008; Coric et al 2010; Dunlop et al 2017; Grillon et al 2015). Two studies have examined the efficacy of CRFR1 antagonists for decreasing craving in anxious adults with AUD.…”