A Pilot Study of Mifepristone in Combat-Related PTSD

Background. We obtained pilot data to examine the clinical and neuroendocrine effects of short-term mifepristone treatment in male veterans with PTSD. Methods. Eight male veterans with military-related PTSD completed a randomized, double-blind trial of one week of treatment with mifepristone (600 mg/day) or placebo. The primary clinical outcome measures were improvement in PTSD symptoms and dichotomously defined clinical responder status as measured by the CAPS at one-month follow-up. Additional outcome measures included self-reported measures of PTSD symptom severity, CAPS-2 symptom subscale scores, and morning plasma cortisol and ACTH levels. Results. Mifepristone was associated with significant improvements in total CAPS-2 score. At one-month follow-up, all four veterans in the mifepristone group and one of four veterans in the placebo group achieved clinical response; three of four veterans in the mifepristone group and one of four veterans in the mifepristone group remitted. Mifepristone treatment was associated with acute increases in cortisol and ACTH levels and decreases in cytosolic glucocorticoid receptor number in lymphocytes. Conclusions. Further controlled trials of the effects of mifepristone and their durability are indicated in PTSD. If effective, a short-term pharmacological treatment in PTSD could have myriad uses

Memory for trauma-related information in Holocaust survivors with PTSD

The impact of trauma-related information on memory performance in aging Holocaust survivors with post-traumatic stress disorder (PTSD) was evaluated. Explicit and implicit memory for neutral and Holocaust-related words was assessed in Holocaust survivors with PTSD (PTSD +, n=31), in Holocaust survivors without PTSD (PTSD −, n=17), and in healthy Jewish adults not exposed to the Holocaust (non-exposed, n=34) using the paired associates learning and word-stem completion tests, respectively. The PTSD + group had significantly poorer paired associate recall than the PTSD − and non-exposed groups, and showed a significantly different response to the introduction of Holocaust-related words. The PTSD + group recalled significantly more words from the Holocaust-related than the neutral word pairs, whereas word type had little effect on paired associate recall in the other two groups. In contrast, there were no group differences in implicit memory performance or in the effect of Holocaust-related words on implicit memory. Among Holocaust survivors, explicit recall of Holocaust-related word pairs was associated with intrusive PTSD symptoms. These results suggest that aging Holocaust survivors with PTSD preferentially form new associations with trauma-related stimuli as compared with neutral stimuli. The presence of such a disturbance of associative learning decades after the Holocaust may underlie the persistence of psychological symptoms and, in particular, the intrusive symptoms of PTSD. This trauma-related facilitation of explicit memory, together with generally poorer explicit memory, may help to explain the bi-directional nature of the memory impairments in PTSD

A randomized, double-blind, placebo-controlled, crossover trial of mifepristone in Gulf War veterans with chronic multisymptom illness

Background : Nearly 34–65% of Gulf War veterans (GWV) continue to suffer from chronic multisymptom illness (CMI); novel pharmacological treatment approaches are needed to improve the health of these veterans. This study aims to determine whether mifepristone, a glucocorticoid receptor antagonist, can reverse the neuroendocrine alterations described in GWV and improve the physical health, mental health, and neurocognitive functioning of GWV with CMI. Methods : Sixty-five GWV were enrolled into the study; 36 eligible GWV who met criteria for CMI and did not have any exclusionary medical or psychiatric conditions were randomized to receive mifepristone (200 mg/day) or matched placebo first in this crossover study. Both treatment phases lasted 6 weeks and were separated by a 4-week wash-out period. The primary clinical outcome measure was the change from treatment baseline to treatment endpoint in the physical health component score (PCS) of the veterans SF-36 health survey. Primary neurocognitive outcome measures included change in spatial working memory and verbal declarative memory as measured by the MATRICS Consensus Cognitive Battery. Additional outcome measures included change in the mental health components score (MCS) of the SF-36 and self-reported symptoms of fatigue, depression, and PTSD. Cortisol and ACTH levels and a measure of glucocorticoid sensitivity (lysozyme IC50-DEX) were also obtained to characterize the neuroendocrine response to mifepristone in GWV with CMI. Results : Data collection is complete; results regarding the primary and secondary clinical, neuropsychological, and neuroendocrine outcome measures will be presented. Conclusion : If this study shows that mifepristone improves physical health or cognition or reduces constituent symptoms of CMI in GWV, it would suggest that mifepristone may be of therapeutic value in this population

A randomized, double-blind, placebo-controlled, crossover trial of mifepristone in Gulf War veterans with chronic multisymptom illness

No pharmacological treatments have been demonstrated to effectively treat chronic multisymptom illness (CMI) in Gulf War veterans (GWV). This study assessed the effect of the glucocorticoid receptor antagonist mifepristone in GWV with CMI. A randomized, double-blind, cross-over trial of mifepristone, with two six-week treatment phases separated by a one-month washout period, was conducted at a Veterans Affairs (VA) hospital between 2008 and 2011. Participants were randomized to receive either 200mg of mifepristone per day or matched placebo first. The primary clinical outcome measure was change in self-reported physical health. Neurocognitive functioning and self-reported measures of depression, PTSD, and fatigue were secondary outcomes. Sixty-five participants enrolled, of whom 36 were randomized and 32 (mean age, 49.1 (7.2) years) completed the study. Physical and mental health status and neurocognitive functioning were poor at baseline. Mifepristone treatment was not associated with improvement in self-reported physical health (p=0.838) or in other self-reported measures of mental health. Mifepristone treatment was significantly associated with improvements in verbal learning (p=0.008, d=0.508), in the absence of improvement in other cognitive measures (working memory (p=0.914), visual learning (p=0.643) and a global composite measure (p=0.937). Baseline morning cortisol levels and lysozyme IC50-DEX, a measure of peripheral glucocorticoid sensitivity, displayed a significant relationship with endpoint verbal learning scores (p=0.012 and p=0.007, respectively). The magnitude of cortisol change during treatment mediated the improvement in verbal learning. This study was negative for the primary and secondary clinical outcomes. However, the data suggest a moderate dose of mifepristone may have circumscribed cognitive-enhancing effects in CMI. Further study is warranted to determine whether and through which mechanisms mifepristone treatment can yield clinically meaningful improvement in cognitive function in CMI or other neuropsychiatric conditions associated with HPA axis dysregulation

Longitudinal Assessment of Cognitive Performance in Holocaust Survivors with and without PTSD

There are currently no longitudinal studies of cognitive performance in older patients with Posttraumatic Stress Disorder (PTSD). It is therefore unclear whether relationships between memory and symptoms differ over time among older persons with and without PTSD. Twenty-eight Holocaust survivors and nineteen comparison subjects were evaluated 5 years after they had received a memory assessment including paired-associates learning and the California Verbal Learning Test (CVLT). While Holocaust survivors with PTSD showed a diminution in symptom severity ( t = 2.99, df = 12, p = .011), they still manifested a decline in paired associates learning, suggesting an acceleration in age-related memory impairment (related word pairs: t = 2.87, df = 13, p = .013; unrelated word pairs: t = 2.06, df = 13, p = .060). The survivors with PTSD showed improvements on several CVLT measures over time. These improvements correlated with symptom improvements, such that group differences at the follow-up were no longer detected. The discrepancy in the pattern of performance on these two tests of memory following symptom improvement suggests possible differentiation between of aspects of memory functions associated with aging and trauma exposure and those associated with the severity of PTSD symptoms. Performance on the CVLT appeared related to clinical symptom severity while paired associate learning worsened over time in Holocaust survivors with PTSD, consistent with earlier cross-sectional findings

Learning and Memory in Aging Combat Veterans with PTSD

The California Verbal Learning Test (CVLT) was administered to examine learning and memory performance in aging combat veterans with (n=30) and without PTSD (n=20), and veterans unexposed to combat (n=15). Combat veterans with PTSD (PTSD+) showed many impairments compared to non-exposed veterans, but only long-delay free recall consistently discriminated the PTSD+ group from combat-exposed subjects without PTSD (PTSD-), when data were corrected for subscale scores on the WAIS (Vocabulary, Block Design). Alterations in total learning were associated with PTSD when controlling for substance abuse and depression. Two contrast measures, proactive interference and recognition hits, distinguished combat from noncombat veterans, and may be related to trauma exposure. Impairments in total learning are similar to what has been observed in Holocaust survivors. However, increased severity of rapid forgetting may be a specific alteration in older combat veterans, likely reflecting aspects of both combat exposure and aging. This work was supported by VA Merit Funding to RY and JG and in part by a grant (5 M01 RR00071) for the Mount Sinai General Clinical Research Centre from the National Center for Research Resources, National Institute of Health

Hydrocortisone responsiveness in Gulf War veterans with PTSD: Effects on ACTH, declarative memory hippocampal [ 18F]FDG uptake on PET

Neuroendocrine, cognitive and hippocampal alterations have been described in Gulf War (GW) veterans, but their inter-relationships and significance for posttraumatic stress disorder (PTSD) have not been described. Hydrocortisone (Hcort) was administered to GW veterans with (PTSD+ n = 12) and without (PTSD− n = 8) chronic PTSD in a randomized, placebo-controlled, double-blind challenge. Changes in plasma ACTH, memory, and hippocampal [ 18F]FDG uptake on positron emission tomography were assessed. The low-dose dexamethasone suppression test was also administered. The PTSD+ group showed greater cortisol and ACTH suppression, reflecting greater peripheral glucocorticoid receptor (GR) responsiveness, and did not show an Hcort–induced decrement in delayed recall or retention. The groups had comparable relative regional hippocampal [ 18F]FDG uptake at baseline, but only the PTSD− group had an Hcort–associated decrease in hippocampal [ 18F]FDG uptake. Asymmetry in hippocampal hemispheric volumes differed between PTSD+ and PTSD− groups. This asymmetry was associated with cortisol, ACTH, retention and functional hippocampal asymmetry before, but not after, Hcort administration. Differences in brain metabolic responses between GW veterans with and without PTSD may reflect differences in peripheral and central GR responsiveness