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.

Figure 1. Change in CAPS past-week total scores by treatment group

S.E. bars represent ± 1 S.E. CAPS, Clinician Administered PTSD Scale

Figure 2. Significant interaction effect of rs110402 and childhood abuse on percent change PSS-SR score

The boxplots describe the mean percent change of PSS total score in abused and non-abused patients treated with the GSK561679 or placebo. GG carriers are shown in light grey and AA/AG in dark grey. Higher PSS percent change corresponds to improvement (reduction) in PTSD symptoms from baseline to endpoint. rs110402 A carrier status by childhood abuse exposure showed a significant interaction effect on PSS score percent change over treatment in subjects treated with GSK561679 (s=-1.904, p=0.043) but not in subjects treated with placebo (s=0.421, p=0.68). rs110402 GG carriers exposed to child abuse displayed the highest percent change of PSS symptoms following GSK561679 treatment. PSS-SR, PTSD Symptom Scale, Self-Report

Figure 3. PSS-SR score change over time among patients treated with GSK561679 by abuse level

Mean (± SEM) PSS-SR total score at 5 time points during treatment with GSK561679 in: A) patients with a history of childhood abuse and, B) patients with mild/no childhood abuse, stratified by rs110402 carrier status (GG in light grey, AA/AG in dark grey). When treated with GSK561679, the GG genotype carriers that experienced childhood abuse showed consistently lower symptom scores over all 5 time points compared to abused AG/AA carriers while this genotype effect is not observed in the non-abused group. PSS-SR, PTSD Symptom Scale, Self-Report