Efficacy and Safety of Mifepristone in the Treatment of Male US Veterans With Posttraumatic Stress Disorder: A Phase 2a Randomized Clinical Trial.

Importance: To date, no psychopharmacologic treatment has been found to be uniformly effective in veterans with posttraumatic stress disorder (PTSD); novel targets and approaches are needed to treat this disabling disorder. Objective: To examine whether treatment with the glucocorticoid receptor antagonist mifepristone yields a signal for clinical efficacy in male veterans with PTSD. Design, Setting, and Participants: This phase 2a, double-blind, parallel-group randomized clinical trial was conducted from November 19, 2012 (accrual started), through November 16, 2016 (final follow-up), within the US Department of Veterans Affairs. Participants were male veterans with chronic PTSD and a screening Clinician-Administered PTSD Scale score of 50 or higher. A total of 181 veterans consented to participation. Statistical analysis was conducted between August 2014 and May 2017. Interventions: Participants were randomized in a 1:1 ratio to mifepristone (600 mg) or matched placebo taken orally for 7 days. Main Outcomes and Measures: The clinical outcome was whether a veteran achieved a clinical response status (a reduction of ≥30% of total Clinician-Administered PTSD Scale score from baseline) at 4- and 12-week follow-up. On the basis of a binary statistical selection rule, a difference in the proportion of treatment vs control group responders of 15% would be a clinically relevant difference. Self-report measures of PTSD and associated symptoms were also obtained. Neuroendocrine outcomes and plasma levels of mifepristone were measured. Safety was assessed throughout the study. The primary analysis was based on a multiple imputation technique to address missing outcome data; thus, some participant numbers may not appear as whole numbers. Results: A total of 81 veterans were enrolled and randomized. Excluding 1 participant randomized in error, 80 were included in the modified intention-to-treat analysis (41 randomized to mifepristone and 39 to placebo). The mean (SD) age was 43.1 (13.7) years. A total of 15.6 (38.1%) in the mifepristone group and 12.1 (31.1%) in the placebo group were clinical responders at 4 weeks in the analysis using the multiple imputation technique. The group difference in the proportion of clinical responders (7.0%) was less than the predefined margin of 15% indicating signal for clinical efficacy. In an exploratory analysis, the difference in response to mifepristone vs placebo in the subgroup with no lifetime history of traumatic brain injury (TBI) (7.0 [50.0%] vs 3.0 [27.3%]; difference, 22.7%) exceeded the efficacy margin at 4 weeks and was sustained at 12 weeks. In contrast, in veterans with PTSD and lifetime TBI, the response rate to mifepristone was lower than placebo at 12 weeks (7.4 [27.4%] vs 13.5 [48.3%]; difference, -20.9%). Conclusions and Relevance: This study did not detect a signal for efficacy for mifepristone at 600 mg/d for 1 week in male veterans with chronic PTSD. Thus, this study does not support a phase 3 trial in this population. Future studies of mifepristone for the treatment of PTSD may be of interest in those without a history of TBI or in samples with a low base rate of lifetime head trauma. Trial Registration: ClinicalTrials.gov Identifier: NCT01946685.

A common language for Gulf War Illness (GWI) research studies: GWI common data elements.

AIMS: The Gulf War Illness programs (GWI) of the United States Department of Veteran Affairs and the Department of Defense Congressionally Directed Medical Research Program collaborated with experts to develop Common Data Elements (CDEs) to standardize and systematically collect, analyze, and share data across the (GWI) research community. MAIN METHODS: A collective working group of GWI advocates, Veterans, clinicians, and researchers convened to provide consensus on instruments, case report forms, and guidelines for GWI research. A similar initiative, supported by the National Institute of Neurologic Disorders and Stroke (NINDS) was completed for a comparative illness, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), and provided the foundation for this undertaking. The GWI working group divided into two sub-groups (symptoms and systems assessment). Both groups reviewed the applicability of instruments and forms recommended by the NINDS ME/CFS CDE to GWI research within specific domains and selected assessments of deployment exposures. The GWI CDE recommendations were finalized in March 2018 after soliciting public comments. KEY FINDINGS: GWI CDE recommendations are organized in 12 domains that include instruments, case report forms, and guidelines. Recommendations were categorized as core (essential), supplemental-highly recommended (essential for specified conditions, study types, or designs), supplemental (commonly collected, but not required), and exploratory (reasonable to use, but require further validation). Recommendations will continually be updated as GWI research progresses. SIGNIFICANCE: The GWI CDEs reflect the consensus recommendations of GWI research community stakeholders and will allow studies to standardize data collection, enhance data quality, and facilitate data sharing.

Hydrocortisone responsiveness in Gulf War veterans with PTSD: effects on ACTH, declarative memory hippocampal [(18)F]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 [(18)F]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 [(18)F]FDG uptake at baseline, but only the PTSD- group had an Hcort-associated decrease in hippocampal [(18)F]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.

Changes in relative glucose metabolic rate following cortisol administration in aging veterans with posttraumatic stress disorder: an FDG-PET neuroimaging study.

The authors aimed to examine central glucocorticoids effects by measuring relative glucose metabolic rate (rGMR) in the hippocampus, amygdala, and anterior cingulate cortex (ACC) and the relationship between amygdala and ACC activity. The participants were male combat veterans with and without PTSD, 52 to 81 years old. The authors utilized randomized, double-blind, placebo-controlled examinations of the rGMR response to 17.5 mg hydrocortisone (HCORT) using 2-Deoxy-2-[(18)F]fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) neuroimaging. Group differences in hemispheric laterality of rGMR were observed following placebo administration, reflecting lower rGMR in the right hippocampus and ventral amygdala, and higher rGMR in the left ventral amygdala in the PTSD+ group compared to the PTSD- group. HCORT reduced these group differences in laterality. The net effect of HCORT was to restore a normal inverse association between the ACC and amygdala in the PTSD+ group, but disrupt this neural network in the PTSD- group. The magnitude of improvement in working memory correlated with greater hemispheric laterality in the dorsal amygdala following HCORT in both groups. The restorative effects of HCORT on metabolism and working memory provide a rationale for examining the therapeutic benefits of glucocorticoid manipulation in aging PTSD patients.

Twenty-four hour plasma cortisol and adrenocorticotropic hormone in Gulf War veterans: relationships to posttraumatic stress disorder and health symptoms.

BACKGROUND: We aim to characterize the baseline functioning of the hypothalamic-pituitary-adrenal (HPA) axis in Gulf War veterans (GWV) and examine the extent to which posttraumatic stress disorder (PTSD) and unexplained health symptoms-which commonly co-occur-have similar or different biological correlates. METHODS: Thirty-one GWV, 20 with current PTSD and 11 without current or lifetime PTSD, and 16 healthy nondeployed subjects not exposed to the Gulf War theater underwent medical and psychiatric examination followed by blood sampling every half-hour over 24 hours for the measurement of cortisol and adrenocorticotropic hormone (ACTH). RESULTS: Gulf War veterans without PTSD or another psychiatric disorder had significantly lower 24-hour plasma ACTH levels, a significantly higher cortisol:ACTH ratio, and no difference in cortisol levels compared to nondeployed subjects and to GWV with PTSD, controlling for body mass index (BMI). Among GWV, health symptoms (mood and cognitive symptoms) were positively associated with, and hyperarousal symptoms were negatively associated with, the cortisol:ACTH ratio. Additionally, the self-reported acute effects of pesticides and of pyridostigmine bromide during deployment were associated with lower ACTH levels, controlling for BMI and PTSD. CONCLUSIONS: The data provide evidence of HPA axis dysregulation in Gulf War veterans, which may be related to Gulf War deployment exposures. Despite the overlap of chronic unexplained health symptoms and PTSD in GWV, these symptom constellations appear to be biologically distinct.

Hippocampal volume in aging combat veterans with and without post-traumatic stress disorder: relation to risk and resilience factors.

OBJECTIVE: To examine whether there are post-traumatic stress disorder (PTSD) related differences in hippocampal volume in middle-aged and elderly veterans and to examine the relationship of neuroendocrine activity, memory performance, and measures of risk and resilience for PTSD to hippocampal volume in this cohort. METHODS: Seventeen veterans with chronic PTSD and 16 veterans without chronic PTSD received an MRI scan followed by neuroendocrine assessment (24-h urinary cortisol excretion and the lysozyme IC(50-DEX), a measure of glucocorticoid receptor (GR) responsiveness), and cognitive testing. RESULTS: Veterans with PTSD did not differ from those without PTSD in hippocampal volume, but they did show significantly lower urinary cortisol levels, and poorer memory performance on the Wechsler Logical Memory test and Digit Span test. Smaller left hippocampal volumes were observed in veterans who developed PTSD in response to their first reported traumatic exposure, compared to veterans who had first experienced a traumatic event to which they did not develop PTSD, prior to experiencing a subsequent event that led to PTSD. In contrast, the two neuroendocrine measures were associated with risk factors related to early trauma exposure. CONCLUSION: Although hippocampal volume was not found to differ between subjects with and without PTSD, smaller hippocampal volumes in PTSD may be associated with specific risk and resilience factors. These may be distinct from vulnerability markers associated with increased responsiveness to glucocorticoids and/or other neuroendocrine measures that have been observed in combat-related PTSD.

Longitudinal assessment of cognitive performance in Holocaust survivors with and without PTSD.

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

Effect of sertraline on glucocorticoid sensitivity of mononuclear leukocytes in post-traumatic stress disorder.

This study examined the effects of sertraline (SER) on glucocorticoid sensitivity in mononuclear leukocytes (MNL) from eight subjects with current post-traumatic stress disorder (PTSD) and nine comparison subjects. In all, 60 ml of blood was withdrawn by venipuncture at 0800, and MNL were isolated from blood and divided into two portions: the first contained live cells incubated with a series of concentrations of dexamethasone (DEX); the second contained cells incubated with similar concentrations of DEX+2 muM SER. Group difference in the concentrations of DEX required to inhibit lysozyme activity by 50% were evaluated under conditions of DEX-only and DEX+SER using analysis of covariance (ANCOVA). A significant Group x Condition interaction reflected that SER altered the lysozyme IC(50-DEX) in the direction of decreasing sensitivity to glucocorticoids in PTSD while having no uniform effect in cells from comparison subjects. The data provide support for the idea that glucocorticoid receptors might be more responsive to antidepressants in PTSD than in persons without PTSD. Insofar as increased sensitivity to glucocorticoids has been linked with PTSD, the actions of SER on the lysozyme IC(50-DEX) suggest that this medication may target a biologic alteration associated with PTSD pathophysiology.

Enhanced cortisol suppression to dexamethasone associated with Gulf War deployment.

OBJECTIVE: To examine whether PTSD or post-deployment health symptoms in veterans of the first Gulf War (Operation Desert Shield/Storm) are associated with enhanced suppression of the pituitary-adrenal axis to low-dose dexamethasone (DEX). METHOD: Plasma cortisol and lymphocyte glucocorticoid receptor (GR) number were measured at 08:00 h on two consecutive days, before and after administration of 0.5mg of DEX at 23:00 h in 42 male Gulf War veterans (14 without psychiatric illness, 16 with PTSD only, and 12 with both PTSD and MDD) and 12 healthy male veterans not deployed to the Gulf War or another war zone. RESULTS: In the absence of group differences in basal cortisol levels or GR number, Gulf War veterans without psychiatric illness and Gulf War veterans with PTSD only had significantly greater cortisol suppression to DEX than non-deployed veterans and Gulf War veterans with both PTSD and MDD. Gulf War deployment was associated with significantly greater cortisol suppression to DEX controlling for weight, smoking status, PTSD, and MDD; PTSD was not associated with response to DEX. Among Gulf War veterans musculoskeletal symptoms were significantly associated with cortisol suppression and those who reported taking anti-nerve gas pills (i.e., pyridostigmine bromide) during the war had significantly greater DEX-induced cortisol suppression than those who did not. CONCLUSIONS: The data demonstrate that alterations in neuroendocrine function are associated with deployment to the Gulf War and post-deployment musculoskeletal symptoms, but not PTSD. Additional studies are needed to examine the relationship of enhanced glucocorticoid responsivity to deployment exposures and chronic unexplained medical symptoms in Gulf War veterans.

Alterations in cortisol negative feedback inhibition as examined using the ACTH response to cortisol administration in PTSD.

OBJECTIVE: Studies using the dexamethasone suppression test (DST) have demonstrated an enhanced negative feedback inhibition at the pituitary in PTSD, but have not provided information about central feedback effects, since dexamethasone (DEX) does not penetrate the brain well. The authors therefore examined the change in ACTH and cortisol before and after cortisol administration, which acts at central feedback sites in addition to peripheral targets. METHOD: Blood was obtained from 31 male veterans (18 with PTSD) before, and 8, 40 and 95 min following injection of 17.5 mg cortisol and placebo. RESULTS: A greater decline in ACTH was observed after cortisol injection in PTSD. CONCLUSIONS: Central as well as peripheral negative feedback inhibition may be altered in PTSD.

The ACTH response to dexamethasone in Persian Gulf War veterans.

The basis of postdeployment health symptoms in Gulf War veterans remains poorly understood. Alterations in the feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis have been demonstrated in posttraumatic stress disorder (PTSD) and other bodily disorders related to stress. The objective of this article was to examine whether similar HPA axis alterations are related to Gulf War deployment, postdeployment health symptoms, or PTSD. Plasma adrenocorticotropic hormone (ACTH) was measured on consecutive mornings at 08:00 h before and after a low dose of oral dexamethasone (DEX) at 23:00 h in Gulf War veterans with PTSD (n = 14), Gulf War veterans without PTSD (n = 11), and healthy veterans never deployed to a war zone (n = 12). Both Gulf War veterans with PTSD and Gulf War veterans without PTSD had significantly lower post-DEX ACTH levels than the nonexposed veterans, in the absence of group differences in basal ACTH or DEX levels. Among Gulf War veterans, post-DEX ACTH levels were significantly associated with musculoskeletal symptoms. Gulf War deployment and postdeployment health symptoms appear to be associated with alterations in feedback regulation of the pituitary gland that suggests a possible common link between postdeployment health symptoms and other chronic stress-related conditions.

Memory performance in older trauma survivors: implications for the longitudinal course of PTSD.

Impaired declarative memory performance and smaller hippocampal volume have been observed in young and middle-aged adults with chronic posttraumatic stress disorder (PTSD). These alterations may put trauma survivors with PTSD at greater risk for cognitive decline in later life. This article focuses on the emerging literature on neuropsychological impairment in aging trauma survivors, in particular, elderly combat veterans and survivors of the Holocaust. In veterans and in Holocaust survivors, PTSD was associated with substantial impairments in learning, free and cued recall, and recognition memory compared to the respective nonexposed subjects; however, in neither group was PTSD associated with impaired retention or "rapid forgetting." Additionally, PTSD was not associated with smaller right or left hippocampal volume in either cohort. PTSD is associated with considerable cognitive burden with age. Longitudinal studies of older subjects are warranted to examine whether PTSD is associated with accelerated aging or progressive memory loss.

Cognitive effects of intravenous hydrocortisone in subjects with PTSD and healthy control subjects.

On the basis of peripheral (nonbrain) neuroendocrine findings in subjects with posttraumatic stress disorder (PTSD), it has been hypothesized that these individuals also have a greater central (brain) sensitivity to glucocorticoids. In nonpsychiatric subjects, it has been found that working and declarative memory performance is selectively impaired by acute glucocorticoid administration. We hypothesized that subjects with PTSD, as compared to nonpsychiatric controls, would show greater impairments in verbal declarative memory and working memory, but not attention, following exogenous glucocorticoid administration. These data are part of a larger study using functional neuroimaging and peripheral HPA axis measures in these same subjects. Subjects underwent a 0.5-mg dexamethasone suppression test and measurement of basal cortisol, basal plasma lymphocyte glucocorticoid receptor number, and postdexamethasone cortisol on a separate day. Under double-blind randomized crossover conditions, 17-mg hydrocortisone or placebo was administered by intravenous (i.v.) bolus to 15 medication-free PTSD subjects (4 female) and 12 nonpsychiatric control subjects (4 female) matched by age, sex, and education level. Participants then underwent positron emission tomography (PET) scanning and 90 min after the initial drug/placebo administration, cognitive testing was then performed. By repeated measures ANCOVA (covaried for baseline performance on that neuropsychological test), neither attention tasks of digit span forward nor backward showed significant change. However, there were significant drug (F = 17.644, df = 1,25 P < 0.001), group (F = 4.383, df = 1,25 P = 0.048), and drug by group interactions (F = 4.756, df = 1,25 P = 0.040) for verbal declarative memory. By t-test, there was not a difference in baseline performance on this measure between subject groups. The subject group with PTSD experienced a greater decline in verbal declarative memory performance following hydrocortisone administration. For working memory, there were significant group (F = 6.048, df = 1,25 P = 0.022) and drug by group interactions (F = 6.048, df = 1,25 P = 0.022) for verbal declarative memory. By t-test, there was not a difference in baseline performance on this measure between subject groups. The hydrocortisone administration led to impairment in working memory in the group of subjects with PTSD, but not in the control subject group. Exploratory correlations between percent cortisol suppression following dexamethasone and baseline plasma lymphocyte glucocorticoid receptor number with declarative and working memory measures among subject groups separately and in a combined way revealed a negative correlation between lymphocyte glucocorticoid receptor density and working memory (r = -0.54, df = 25, P = 0.008). Brain sensitivity to glucocorticoids appears to be greater in subjects with PTSD. Heightened vulnerability of declarative memory in subjects with PTSD may indicate hippocampal involvement, whereas working memory vulnerability suggests additional brain regions (prefrontal, cingulate, temporal, and parietal cortices) and neurotransmitter systems (dopamine and serotonin) particularly sensitive to glucocorticoids in persons with PTSD.

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.

Circadian rhythm of salivary cortisol in Holocaust survivors with and without PTSD.

OBJECTIVE: The authors' goal was to determine whether cortisol circadian rhythm alterations observed in younger subjects with posttraumatic stress disorder (PTSD) are also present in geriatric trauma survivors with PTSD. METHOD: Salivary cortisol levels were measured at six intervals from awakening until bedtime in 23 Holocaust survivors with PTSD, 19 Holocaust survivors without PTSD, and 25 subjects who had not been exposed to the Holocaust. Thirty-three of the subjects were men, and 34 were women. RESULTS: Cortisol levels were significantly lower at awakening, at 8:00 a.m., and at 8:00 p.m. in Holocaust survivors with PTSD than in nonexposed subjects, resulting in a flatter circadian rhythm, similar to what has been observed in aging but different from what has been reported in younger subjects with PTSD. CONCLUSIONS: These data provide evidence of differential neuroendocrine alterations in geriatric PTSD.

Relationship between cortisol and age-related memory impairments in Holocaust survivors with PTSD.

RATIONALE: Holocaust survivors with PTSD appear to show an accelerated aging effect as evidenced by their performance on tests of explicit memory, and also show more exaggerated patterns on age-related alterations in cortisol release over the diurnal cycle than Holocaust survivors without PTSD and nonexposed subjects. To investigate the implications of age-related HPA axis alterations on cognition, we examined correlations between parameters reflecting circadian cortisol release and implicit and explicit memory performance. METHODS: Nineteen Holocaust survivors with PTSD (7 men, 12 women), 16 Holocaust survivors without PTSD (7 men, 9 women), and 28 non-exposed healthy comparison subjects (13 men, 15 women) collected salivary samples at six times over the diurnal cycle, and were tested with Paired Associates and Word Stem Completion Tests. RESULTS: Negative correlations were observed between several measures of salivary cortisol concentrations and explicit memory in Holocaust survivors with PTSD after adjusting for IQ, years of education and current age reflecting poorer performance in association with higher cortisol levels. This relationship was absent in Holocaust survivors without PTSD and in demographically-comparable subjects who were not exposed to the Holocaust or other extremely traumatic events. CONCLUSION: The significantly different relationship between cortisol and memory performance in these groups suggests that the neuropsychological impairments observed in Holocaust survivors with PTSD may reflect an interaction of PTSD and aging effects.

Absence of hippocampal volume differences in survivors of the Nazi Holocaust with and without posttraumatic stress disorder.

It remains unclear whether smaller hippocampal volume is a consistent feature of chronic posttraumatic stress disorder (PTSD) and whether it accounts for the associated memory deficits observed in this illness. Hippocampal volume, comparison regions and memory performance were examined in Holocaust survivors with PTSD (PTSD+: n=14; 5 men, 9 women) and without PTSD (PTSD-: n=13; 6 men, 7 women) and a non-exposed control group of healthy Jewish adults (n=20; 13 men, 7 women). The subjects had medical examinations, high-resolution magnetic resonance imaging, and memory testing. PTSD+ subjects had poorer memory performance than non-exposed subjects and PTSD- subjects, but they did not differ from either group in right or left hippocampal volume when gender and head size were taken into account. Older age and smaller left hippocampal volume were more strongly associated in the PTSD+ group than in the PTSD- groups. Holocaust survivors had larger superior temporal gyral and lateral temporal lobe volumes bilaterally than non-exposed subjects. Smaller hippocampal volume is not invariably associated with chronic PTSD and does not explain the substantial explicit memory impairment observed in Holocaust survivors with this disorder. Larger temporal lobe volumes may be associated with early traumatization and survival or may reflect some other characteristic of Holocaust survivors.

White matter abnormalities in Gulf War veterans with posttraumatic stress disorder: A pilot study.

BACKGROUND: Gulf War veterans were exposed to environmental toxins not present in other combat theaters resulting in a unique biological signature that only partially resembles that seen in other combat veterans with PTSD. Thus it is important to determine if brain abnormalities seen in non-Gulf War veterans with PTSD are also present in Gulf War veterans. In this pilot study, diffusion tensor imaging (DTI) tractography was used to assess the ultra-structural integrity of fronto-limbic white matter connections in Gulf War veterans with and without PTSD. The effects of chronic multisymptom illness on DTI measures was also evaluated. METHODS: Subjects were 20 previously studied Gulf War veterans on whom MRIs had been obtained. Mean diffusivity (MD) and fractional anisotropy (FA) were determined for left and right cingulum bundle by DTI tractography and compared in separate analyses for 12 veterans with, and 8 without PTSD. The effect of chronic multisymptom illness and it's interaction with PTSD, were similarly investigated using multivariate ACOVA. Partial correlations were used to test the associations of both DTI indices with PTSD severity and plasma cortisol, controlling for whole brain volume. RESULTS: Significantly lower MD was demonstrated in the right cingulum bundle among Gulf War veterans with PTSD. There were no significant differences in MD or FA in the left cingulum bundle. The presence of chronic multisymptom illness significantly attenuated the PTSD associated decrement in right cingulum MD. Clinician and self-rated PTSD symptom severity scores were significantly associated with reduced MD and increased FA in the right cingulum. Similar associations were observed for 8am plasma cortisol in a subset of participants. CONCLUSIONS: The preliminary findings indicate increased structural integrity - supporting enhanced connectivity - between right amygdala and anterior cingulate cortex in PTSD. This effect was strongest among Gulf War veterans without chronic multisymptom illness. The association of both MD and FA in the right cingulum with PTSD severity, and with heightened glucocorticoid responsivity, suggests that these DTI findings are a reflection of current PTSD illness expression. Although based on a small sample, these microstructural observations are consistent with a functional model suggesting increased amygdala responsivity in association with anterior cingulate modulation in PTSD.

Enhanced sensitivity to glucocorticoids in peripheral mononuclear leukocytes in posttraumatic stress disorder.

BACKGROUND: The aim of this study was to determine whether there is increased responsiveness to corticosteroids in posttraumatic stress disorder (PTSD) by examining the differential effects of dexamethasone (DEX) on the inhibition of lysozyme activity. METHODS: 60 mL of blood was withdrawn at 8:00 am, and mononuclear leukocytes were isolated from the blood of 26 men with, and 18 men without, PTSD. An aliquot of live cells was incubated with a series of concentrations of DEX to determine the rate of inhibition of lysozyme activity; a portion of cells was frozen for the determination of glucocorticoid receptors (GR). RESULTS: Subjects with PTSD showed evidence of a greater sensitivity to glucocorticoids as reflected by a significantly lower mean concentration (nmol/L) of dexamethasone at which 50% of lysozyme activity is inhibited (IC(50-DEX)) (PTSD+ = 4.9 +/-.53; PTSD- group = 7.2 +/-.64). The lysozyme IC(50-DEX) was significantly correlated with age at exposure to the first traumatic event in subjects with PTSD (r =.44, n = 26, p =.025). The number of cytosolic glucocorticoid receptors was also correlated with age at exposure to the focal traumatic event (r = -.44, n = 25, p =.03) in PTSD. CONCLUSIONS: This is the first in vitro demonstration of an alteration in target tissue sensitivity to glucocorticoids in PTSD. The lower lysozyme IC(50-DEX) might be related to the risk factor of prior exposure to trauma.

Learning and memory in Holocaust survivors with posttraumatic stress disorder.

BACKGROUND: Impairments in explicit memory have been observed in Holocaust survivors with posttraumatic stress disorder. METHODS: To evaluate which memory components are preferentially affected, the California Verbal Learning Test was administered to Holocaust survivors with (n = 36) and without (n = 26) posttraumatic stress disorder, and subjects not exposed to the Holocaust (n = 40). RESULTS: Posttraumatic stress disorder subjects showed impairments in learning and short-term and delayed retention compared to nonexposed subjects; survivors without posttraumatic stress disorder did not. Impairments in learning, but not retention, were retained after controlling for intelligence quotient. Older age was associated with poorer learning and memory performance in the posttraumatic stress disorder group only. CONCLUSIONS: The most robust impairment observed in posttraumatic stress disorder was in verbal learning, which may be a risk factor for or consequence of chronic posttraumatic stress disorder. The negative association between performance and age may reflect accelerated cognitive decline in posttraumatic stress disorder.