Discussion
TBI, PTSD, head trauma
Direct manipulation of the HPA axis with mifepristone led to the anticipated short-term changes in neuroendocrine activity in this sample of veterans with PTSD and was well tolerated. However, the patterns of clinical response did not demonstrate a signal for efficacy at 4 or 12 weeks for mifepristone. Additionally, there were no mifepristone-related improvements in PTSD or associated symptoms measured continuously or longitudinally. As such, this trial did not provide a basis for a phase 3 trial of this treatment regimen in a heterogeneous population of male veterans with PTSD.Cortisol and ACTH level increased in the mifepristone group but did not differ between responders and nonresponders in the mifepristone group. However, posttreatment ACTH levels were higher in responders than nonresponders for the entire sample, including those taking placebo. These results point to a possible relationship between improvement and change in neuroendocrine activity but include changes that are not limited to direct drug effects.Lifetime TBI status was assessed in recognition of this signature injury of the wars in Iraq and Afghanistan and a contributor to postdeployment health outcomes.Only TBI emerged as a relevant subgroup. In this exploratory analysis, veterans with no TBI demonstrated an efficacy signal at 4 and 12 weeks. In contrast, in veterans with TBI, there was a signal that favored placebo at 12 weeks. Given the broad CIs and small samples in these exploratory analyses, the potential efficacy signal of the no TBI subgroup should not be overstated. However, it raises the possibility that further study of mifepristone may be warranted in this subgroup or a PTSD population with a low base rate of head trauma. Given the opposing effects of mifepristone based on this categorization, TBI clinical assessments should be included in future psychopharmacologic trials of veterans with PTSD because it may influence the outcome.