The steroid could be more effective for veterans with post-traumatic stress disorder who do not have a history of traumatic brain injury.
Mifepristone (600 mg daily) was not an effective treatment for chronic post-traumatic stress disorder (PTSD) in male veterans, according to the results of a recent 2a trial study published in JAMA Network Open. Therefore, the study investigators do not support a phase 3 clinical trial for this patient population.
The signal for clinical efficacy was a 15% difference in the proportion of treatment versus control group responders at 4 weeks. Although more patients responded to mifepristone (38.1%) compared to placebo (31.1%), it is a 7% difference that is not clinically relevant.
Most veterans in the Veterans Administration (VA) who have PTSD—a common and disabling psychiatric disorder—are treated with psychotropics such as selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs), trazodone, prazosin, benzodiazepines, and antipsychotics.
Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is associated with stress-related psychiatric disorders. Investigators hypothesized that mifepristone, an FDA-approved steroid with antiglucocorticoid and antiprogesterone properties, could reset the HPA axis in veterans with PTSD. It is currently indicated for Cushing disease and medical abortion.
Investigators conducted a 12-week, double-blind, placebo-controlled, parallel-group randomized phase 2a clinical trial, including 80 veterans in the modified intention-to-treat analysis. Of those enrolled in the trial, 41 individuals received mifepristone at 600 mg/d for 7 days and 39 received placebo, to evaluate whether mifepristone is clinically effective for male veterans with PTSD.
The primary endpoint was mifepristone 600 mg/d compared to placebo in male veterans with PTSD at 4 and 12 weeks. Clinical response was the 15% signal that justifies testing mifepristone at 600 mg/d for 1 week in a phase 3 trial. Secondary endpoints included effects on associated clinical (depression, sleep quality, and anger) and laboratory (cortisol, adrenocorticotropic hormone [ACTH], and mifepristone levels) parameters.
Mifepristone was shown to produce short-term increases in cortisol and ACTH—these mediate stress response—but its positive effect was not significantly different between responders and non-responders over 12 weeks. In addition, treatment did not improve continuous or longitudinal symptoms of PTSD.
Investigators also conducted an exploratory analysis of mifepristone versus placebo in a subgroup of patients with no lifetime history of traumatic brain injury (TBI). While response rates were similar between those with lifetime TBI and placebo at 4 weeks, those without lifetime history of TBI had a 22.7% greater response to mifepristone than placebo at 4 weeks.
The study only included men, which is a limiting factor. Other limitations included that the efficacy and safety profile look different than it would for women who are able to have an abortion. The study was restricted to a single 600 mg dose and a shorter timeframe, and the study population is not generalizable to all veterans.
Generally, the treatment was well tolerated and could be researched in future studies to treat PTSD in patients with or without a history of TBI, or in populations who have a low base rate of lifetime head trauma, according to the study authors.
Golier J, Li X, Bizien M, et al. Efficacy and Safety of Mifepristone in the Treatment of Male US Veterans With Posttraumatic Stress Disorder. JAMA Netw Open. 2023. doi:10.1001/jamanetworkopen.2023.10223