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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.
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Lesiones Traumáticas del Encéfalo , Trastornos por Estrés Postraumático , Veteranos , Estados Unidos , Humanos , Masculino , Adulto , Femenino , Mifepristona/efectos adversos , Trastornos por Estrés Postraumático/tratamiento farmacológico , Ceguera , GalopamiloAsunto(s)
Trastorno Bipolar , Trastorno Depresivo Mayor , Trastornos Psicóticos , Depresión , Humanos , MifepristonaRESUMEN
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.
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Depresión/tratamiento farmacológico , Fatiga/tratamiento farmacológico , Mifepristona/uso terapéutico , Trastornos por Estrés Postraumático/tratamiento farmacológico , Veteranos/psicología , Adulto , Enfermedad Crónica , Cognición/efectos de los fármacos , Estudios Cruzados , Depresión/complicaciones , Dexametasona/farmacología , Método Doble Ciego , Fatiga/complicaciones , Femenino , Guerra del Golfo , Estado de Salud , Humanos , Hidrocortisona/metabolismo , Masculino , Persona de Mediana Edad , Pruebas de Función Adreno-Hipofisaria , Receptores de Glucocorticoides/metabolismo , Trastornos por Estrés Postraumático/complicacionesRESUMEN
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.
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Encéfalo/fisiopatología , Trastornos por Estrés Postraumático/fisiopatología , Veteranos , Sustancia Blanca/fisiopatología , Adulto , Imagen de Difusión Tensora , Guerra del Golfo , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Proyectos PilotoRESUMEN
Studies have demonstrated altered sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis to its direct regulators in veterans with posttraumatic stress disorder (PTSD), but little is known about the adrenal response to hormonal stimulation in PTSD. An increased cortisol response to synthetic corticotropin-releasing factor (CRF) was recently found to be associated with war-zone deployment and not PTSD specifically. To more accurately assess whether there is altered adrenocortical responsivity to hormonal stimulation in relation to war-zone deployment or PTSD, we performed the low-dose cosyntropin stimulation test in a sample of 45 male veterans: 13 war-zone exposed veterans with chronic PTSD (PTSD+), 22 war-zone exposed veterans without chronic PTSD (PTSD-), and 10 veterans not exposed to a war-zone and without chronic PTSD (non-exposed). Plasma cortisol and ACTH were measured at baseline and at intervals over a one hour period following intravenous administration of 1µg of cosyntropin. A significant main effect of group (PTSD+, PTSD-, non-exposed) on the cortisol response to cosyntropin was observed. Cosyntropin-stimulated plasma cortisol levels were significantly higher in the PTSD+ and PTSD- groups compared to the non-exposed group. A significant main effect of group was also observed on peak cortisol levels. These findings suggest that war-zone exposure itself has persistent effects on adrenocortical activity.
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Cosintropina/farmacología , Hidrocortisona/sangre , Trastornos por Estrés Postraumático/sangre , Veteranos , Hormona Adrenocorticotrópica/sangre , Adulto , Hormona Liberadora de Corticotropina/sangre , Cosintropina/administración & dosificación , Deshidroepiandrosterona/sangre , Humanos , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/metabolismo , Masculino , Persona de Mediana Edad , Personal Militar , Pruebas de Función Adreno-Hipofisaria , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/metabolismo , Factores Socioeconómicos , Veteranos/psicologíaRESUMEN
Endocannabinoid (eCB) signaling has been identified as a modulator of adaptation to stress, and is integral to basal and stress-induced glucocorticoid regulation. Furthermore, interactions between eCBs and glucocorticoids have been shown to be necessary for the regulation of emotional memories, suggesting that eCB function may relate to the development of post-traumatic stress disorder (PTSD). To examine this, plasma eCBs were measured in a sample (n=46) drawn from a population-based cohort selected for physical proximity to the World Trade Center (WTC) at the time of the 9/11 attacks. Participants received a structured diagnostic interview and were grouped according to whether they met diagnostic criteria for PTSD (no PTSD, n=22; lifetime diagnosis of PTSD=24). eCB content (2-arachidonoylglycerol (2-AG) and anandamide (AEA)) and cortisol were measured from 8 a.m. plasma samples. Circulating 2-AG content was significantly reduced among individuals meeting diagnostic criteria for PTSD. The effect of reduced 2-AG content in PTSD remained significant after controlling for the stress of exposure to the WTC collapse, gender, depression and alcohol abuse. There were no significant group differences for AEA or cortisol levels; however, across the whole sample AEA levels positively correlated with circulating cortisol, and AEA levels exhibited a negative relationship with the degree of intrusive symptoms within the PTSD sample. This report shows that PTSD is associated with a reduction in circulating levels of the eCB 2-AG. Given the role of 2-AG in the regulation of the stress response, these data support the hypothesis that deficient eCB signaling may be a component of the glucocorticoid dysregulation associated with PTSD. The negative association between AEA levels and intrusive symptoms is consistent with animal data indicating that reductions in AEA promote retention of aversive emotional memories. Future work will aim to replicate these findings and extend their relevance to clinical pathophysiology, as well as to neuroendocrine and molecular markers of PTSD.
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Endocannabinoides/sangre , Trastornos por Estrés Postraumático/sangre , Trastornos por Estrés Postraumático/psicología , Terrorismo , Anciano , Alcoholismo/sangre , Alcoholismo/psicología , Amidas , Ácidos Araquidónicos/sangre , Etanolaminas/sangre , Etnicidad , Femenino , Glicéridos/sangre , Humanos , Hidrocortisona/sangre , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Ácidos Oléicos/sangre , Ácidos Palmíticos/sangre , Alcamidas Poliinsaturadas/sangre , Escalas de Valoración Psiquiátrica , Caracteres SexualesRESUMEN
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.
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BACKGROUND: Alterations in hypothalamic-pituitary-adrenal (HPA) axis activity have been observed in Gulf War veterans with posttraumatic stress disorder (PTSD) which differ from those observed in other veteran groups, raising the possibility that there is a unique neuroendocrine profile in this group of veterans. This study seeks to further characterize the effects of PTSD, military cohort (Vietnam, 1991 Gulf War, Operations Enduring Freedom/Iraqi Freedom (OEF/OIF)), and their interaction on the neuroendocrine response to synthetic corticotrophin-releasing factor (CRF) stimulation. METHODS: 51 male veterans were studied consisting of 21 from the Vietnam era, 16 from the Gulf War era, and 14 from the OEF/OIF era. 16 of these veterans were deployed to a war zone and had chronic PTSD (PTSD+), 25 were deployed to a war zone and did not have chronic PTSD (PTSD-), and 10 were not deployed to a war zone and did not have PTSD (non-exposed). The participants underwent the CRF stimulation test in the afternoon (approximately 2:00 p.m.), which measures the integrity and sensitivity of the pituitary-adrenal axis. Plasma cortisol and adrenocorticotropic hormone (ACTH) were measured at baseline and at intervals over a 2h period following intravenous administration of 1 µg/kg of ovine CRF (o-CRF, max 100 µg). In a small subset of participants, dehydroepiandrosterone (DHEA) and cortisol binding globulin (CBG) were also assessed. RESULTS: There was a significant group by era interaction in the response of ACTH to CRF, in addition to a main effect of group (PTSD+, PTSD-, non-exposed). The interaction reflected that group differences were only evident in the Gulf War cohort; among Gulf War era veterans, the PTSD+ group had higher elevations in ACTH levels following CRF than the PTSD- group and the non-exposed group. Additionally, the peak change in ACTH was associated with a self-reported environmental exposure (pyridostigmine bromide ingestion) which has been found to be linked to the excess morbidity found in Gulf War veterans. Self-reported childhood trauma was greater in veterans of the Gulf War than Vietnam or OEF/OIF, but did not account for the observed differences. There was a significant effect of group on the cortisol response to CRF, reflecting greater responsivity in both of the deployed groups (PTSD+ and PTSD-) compared to the non-exposed group which could be accounted for by baseline differences in cortisol levels; unlike the ACTH response, the cortisol response did not differ by era. There were no effects of group, era, or their interaction on the DHEA and CBG response to CRF. CONCLUSIONS: A uniform pattern of PTSD-related alterations in the response to intravenous CRF was not found. Rather, PTSD-related alterations were found only in veterans of the 1991 Gulf War, and were characterized by an enhanced pituitary response to CRF which may reflect increased sensitivity of pituitary corticotrophs or CRF hyposecretion. Together with previous neuroendocrine findings, the data suggest the HPA axis is dysregulated in Gulf War veterans in unique ways which may reflect the long-term effects of environmental exposures in addition to disease effects. Further work is needed to characterize these effects and their impact on long-term psychological and medical outcomes.
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Hormona Liberadora de Corticotropina/análogos & derivados , Sistema Hipotálamo-Hipofisario/fisiopatología , Sistema Hipófiso-Suprarrenal/fisiopatología , Trastornos por Estrés Postraumático/fisiopatología , Veteranos/psicología , Hormona Adrenocorticotrópica/sangre , Adulto , Campaña Afgana 2001- , Proteínas Portadoras/sangre , Deshidroepiandrosterona/sangre , Humanos , Hidrocortisona/sangre , Masculino , Pruebas de Función Adreno-Hipofisaria/métodos , Pruebas de Función Adreno-Hipofisaria/psicología , Trastornos por Estrés Postraumático/sangre , Veteranos/estadística & datos numéricos , Guerra de VietnamRESUMEN
We have previously reported the differential expression of 17 probe sets in survivors of the 9/11 attacks with current posttraumatic stress disorder (PTSD) compared to similarly exposed survivors with no lifetime PTSD. The current study presents an expanded analysis of these subjects, including genotype at FKBP5, a modulator of glucocorticoid receptor (GR) sensitivity. It includes data from additional subjects who developed PTSD following 9/11 but then recovered, distinguishing expression profiles associated with risk for developing PTSD, resilience, and symptom recovery. 40 Caucasians (20 with and 20 without PTSD, matched for exposure, age, and gender) were selected from a population-representative sample of persons exposed to the 9/11 attacks from which longitudinal data had been collected in four previous waves. Whole blood gene expression and cortisol levels were obtained and genome-wide gene expression was analyzed. 25 probe sets were differentially expressed in PTSD. Identified genes were generally involved in hypothalamic-pituitary-adrenal axis, signal transduction, or in brain and immune cell function. STAT5B, a direct inhibitor of GR, and nuclear factor I/A, both showed reduced expression in PTSD. Comparison of lifetime versus current PTSD identified overlapping genes with altered expression suggesting enduring markers, while some markers present only in current PTSD may reflect state measures. As a follow-up, direct comparisons of expression in current PTSD, lifetime-only PTSD, and control groups identified FKBP5 and MHC Class II as state markers, and also identified several trait markers. An analysis of indirect effects revealed that homozygosity for any of 4 PTSD risk-related polymorphisms at FKBP5 predicted FKBP5 expression, which mediated indirect effects of genotype on plasma cortisol and PTSD severity.
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Resiliencia Psicológica , Ataques Terroristas del 11 de Septiembre/psicología , Trastornos por Estrés Postraumático/genética , Sobrevivientes/psicología , Proteínas de Unión a Tacrolimus/genética , Adulto , Anciano , Femenino , Perfilación de la Expresión Génica , Genes MHC Clase II , Marcadores Genéticos , Genotipo , Humanos , Hidrocortisona/sangre , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Biosíntesis de Proteínas , Factores de Riesgo , Índice de Severidad de la Enfermedad , Trastornos por Estrés Postraumático/epidemiología , Trastornos por Estrés Postraumático/psicología , Proteínas de Unión a Tacrolimus/metabolismoRESUMEN
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.
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Hormona Adrenocorticotrópica/sangre , Hipocampo/efectos de los fármacos , Hidrocortisona/administración & dosificación , Memoria/efectos de los fármacos , Trastornos por Estrés Postraumático/fisiopatología , Veteranos , Adulto , Análisis de Varianza , Método Doble Ciego , Ensayo de Inmunoadsorción Enzimática , Guerra del Golfo , Hipocampo/diagnóstico por imagen , Hipocampo/metabolismo , Humanos , Hidrocortisona/sangre , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Cintigrafía , Trastornos por Estrés Postraumático/diagnóstico por imagen , Trastornos por Estrés Postraumático/metabolismoRESUMEN
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.
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Glucosa/metabolismo , Hidrocortisona/administración & dosificación , Tomografía de Emisión de Positrones , Trastornos por Estrés Postraumático/diagnóstico por imagen , Trastornos por Estrés Postraumático/metabolismo , Veteranos , Factores de Edad , Anciano , Anciano de 80 o más Años , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Estudios de Cohortes , Trastornos de Combate/diagnóstico por imagen , Trastornos de Combate/tratamiento farmacológico , Trastornos de Combate/metabolismo , Método Doble Ciego , Metabolismo Energético/efectos de los fármacos , Metabolismo Energético/fisiología , Fluorodesoxiglucosa F18/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones/métodos , Trastornos por Estrés Postraumático/tratamiento farmacológico , Veteranos/psicologíaRESUMEN
OBJECTIVE: Gulf War deployment has been associated with a distinct neuroendocrine profile characterized by low 24h basal ACTH levels and enhanced cortisol and ACTH suppression to low-dose dexamethasone. The metyrapone stimulation test was performed to further characterize hypothalamic-pituitary activity in Gulf War veterans (GWV) and its relationship to unexplained medical symptoms and post-traumatic stress disorder (PTSD). METHOD: Eleven GWV without PTSD, 18 GWV with PTSD and 15 healthy subjects not exposed to the Gulf War theater (non-exposed) underwent the metyrapone stimulation test, which inhibits cortisol synthesis, impairs cortisol-mediated negative feedback inhibition and in turn increases levels of ACTH and 11-deoxycortisol, a cortisol precursor. These hormones were measured at baseline (7:00 a.m.) and at intervals (from 8:00 a.m. to 4:00 p.m.) following the administration of metyrapone 750mg orally at 7:05 a.m. and at 10:05 a.m. RESULTS: There were group differences in the ACTH response despite similar cortisol and 11-deoxycortisol responses to metyrapone. GWV without PTSD had a significantly attenuated ACTH response compared to non-exposed subjects; GWV with PTSD had a significantly higher ACTH response than GWV without PTSD but did not differ from non-exposed subjects. Among GWV, unexplained medical health symptoms (e.g., neurological, musculoskeletal, cardiac, and pulmonary symptoms) and PTSD symptoms were significantly positively associated with the ACTH response to metyrapone. CONCLUSION: Gulf War deployment is associated with a substantially lower ACTH response to metyrapone. In contrast, unexplained health symptoms and PTSD in Gulf War veterans are associated with relatively greater hypothalamic-pituitary activity which may reflect increased CRF activity and is evident only in consideration of deployment effects. This pattern of differences suggests either that Gulf War deployment and its associated exposures results in enduring changes in pituitary function or that reduced hypothalamic-pituitary activity protects against the development of PTSD and other deployment-related health problems.
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Metirapona/farmacología , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Trastornos por Estrés Postraumático/sangre , Veteranos/psicología , Hormona Adrenocorticotrópica/sangre , Adulto , Cortodoxona/sangre , Guerra del Golfo , Estado de Salud , Humanos , Hidrocortisona/sangre , MasculinoRESUMEN
BACKGROUND: Although genetic risk factors for posttraumatic stress disorder (PTSD) in similarly traumatized cohorts can be confounded with risk for type of exposure, the primary risk for exposure to the 9/11 attack on New York City was proximity, allowing study of PTSD risk in a sample that is not confounded by exposure-related risk. METHODS: Thirty-five Caucasians (15 with PTSD, stratified for exposure, age, and gender) were selected from a population-representative sample of persons exposed to the attack from which longitudinal data had been collected in four previous waves. Whole blood gene expression and cortisol levels were obtained. RESULTS: Seventeen probe sets were differentially expressed in PTSD. Identified genes were generally involved in hypothalamic-pituitary-adrenal (HPA) axis, signal transduction, or brain and immune cell function. FKBP5, a modulator of glucocorticoid receptor (GR) sensitivity, showed reduced expression in PTSD, consistent with enhanced GR responsiveness. FKBP5 expression was predicted by cortisol when entered with PTSD severity in regression analysis. Quantitative polymerase chain reaction confirmed significant reductions in FKBP5. Also less expressed in PTSD were STAT5B, a direct inhibitor of GR, and major histocompatibility complex (MHC) Class II. CONCLUSIONS: Consistent with observations of HPA axis dysfunction in PTSD, several genes involved in glucocorticoid signaling are differentially expressed among those with current PTSD.
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Regulación de la Expresión Génica/fisiología , Ataques Terroristas del 11 de Septiembre , Trastornos por Estrés Postraumático/metabolismo , Trastornos por Estrés Postraumático/fisiopatología , Adulto , Anciano , Análisis de Varianza , Femenino , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase II/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Factor de Transcripción STAT5/genética , Factor de Transcripción STAT5/metabolismo , Proteínas de Unión a Tacrolimus/genética , Proteínas de Unión a Tacrolimus/metabolismoRESUMEN
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.
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Hormona Adrenocorticotrópica/sangre , Hidrocortisona/sangre , Síndrome del Golfo Pérsico/sangre , Trastornos por Estrés Postraumático/sangre , Adulto , Análisis de Varianza , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Tiempo , VeteranosRESUMEN
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.
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Envejecimiento/fisiología , Hipocampo/anatomía & histología , Hipocampo/fisiopatología , Trastornos por Estrés Postraumático/fisiopatología , Trastornos por Estrés Postraumático/psicología , Veteranos/psicología , Guerra , Anciano , Anciano de 80 o más Años , Enfermedad Crónica , Femenino , Humanos , Hidrocortisona/orina , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Factores de Riesgo , Trastornos por Estrés Postraumático/diagnóstico , Escalas de WechslerRESUMEN
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.
Asunto(s)
Dexametasona/farmacología , Guerra del Golfo , Hidrocortisona/sangre , Veteranos , Adulto , Exposición a Riesgos Ambientales/estadística & datos numéricos , Humanos , Linfocitos/química , Masculino , Persona de Mediana Edad , Receptores de Glucocorticoides/análisisRESUMEN
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.
Asunto(s)
Trastornos del Conocimiento/diagnóstico , Cognición/fisiología , Holocausto/psicología , Trastornos por Estrés Postraumático/psicología , Sobrevivientes/psicología , Anciano , Análisis de Varianza , Trastornos del Conocimiento/complicaciones , Femenino , Humanos , Judíos/psicología , Acontecimientos que Cambian la Vida , Estudios Longitudinales , Masculino , Pruebas Neuropsicológicas , Valores de Referencia , Trastornos por Estrés Postraumático/complicaciones , Aprendizaje Verbal/fisiologíaRESUMEN
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.
Asunto(s)
Memoria , Trastornos por Estrés Postraumático/psicología , Sobrevivientes/psicología , Heridas y Lesiones/psicología , Anciano , Holocausto/psicología , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética , Desempeño Psicomotor/fisiología , Trastornos por Estrés Postraumático/patología , Veteranos/psicologíaRESUMEN
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.
Asunto(s)
Hormona Adrenocorticotrópica/sangre , Dexametasona , Veteranos/psicología , Adulto , Femenino , Humanos , Masculino , Estrés Psicológico/fisiopatologíaRESUMEN
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.