Lymphocyte glucocorticoid receptor expression level and hormone-binding properties differ between war trauma-exposed men with and without PTSD

Matić, Gordana; Milutinović, Danijela Vojnović; Nestorov, Jelena; Elaković, Ivana; Jovanović, Snežana; Perisic, Tatjana; Dunđerski, Jadranka; Damjanović, Svetozar; Knežević, Goran; Spiric, Z.; Vermetten, Eric; Savić, D

doi:10.1016/j.pnpbp.2013.01.005

Cited by 41 publications

(17 citation statements)

References 55 publications

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“…CRH hypersensitivity has been particularly associated with survivors of childhood trauma (de Kloet et al, 2008a; Heim et al, 2008), as is very common in our cohort. Increased concentrations of CRH also occur in individuals with PTSD (Baker et al, 2005; de Kloet et al, 2008b) in tandem with augmented GR levels (Matic et al, 2013) and lower levels of the GR co-chaperone FKBP5 (Yehuda et al, 2009a) that can facilitate augmented glucocorticoid sensitivity in PTSD (Yehuda et al, 2004a). Our current findings suggest that dexamethasone-mediated stabilization of HPA hyperactivity at multiple levels may contribute to the decreased fear and enhanced extinction effects.…”

Section: Discussionmentioning

confidence: 99%

“…While studies characterizing basal cortisol levels in PTSD have been equivocal (Meewisse et al, 2007), enhanced glucocorticoid negative feedback inhibition of the HPA axis in response to a dexamethasone suppression test has been repeatedly described in PTSD (Yehuda et al, 2004a). This enhanced suppression of endogenous cortisol in response to dexamethasone administration in individuals with PTSD occurs in tandem with lower levels of the GR co-chaperone FKBP5 (Yehuda et al, 2009a), and increased concentrations of corticotropin-releasing hormone (CRH) (Baker et al, 2005; de Kloet et al, 2008b) and glucocorticoid receptors (GRs, (Matic et al, 2013)) that can facilitate augmented glucocorticoid sensitivity (Yehuda et al, 2004a). Importantly, dexamethasone administration and the resulting suppression of cortisol in individuals with PTSD also results in a reduction of heightened fear responses that is characteristic of the PTSD (Jovanovic et al, 2010; Jovanovic et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Dexamethasone facilitates fear extinction and safety discrimination in PTSD: A placebo-controlled, double-blind study

Michopoulos

Norrholm

Stevens

et al. 2017

Psychoneuroendocrinology

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Psychophysiological hallmarks of posttraumatic stress disorder (PTSD) include exaggerated fear responses, impaired inhibition and extinction of conditioned fear, and decreased discrimination between safety and fear cues. This increased fear load associated with PTSD can be a barrier to effective therapy thus indicating the need for new treatments to reduce fear expression in people with PTSD. One potential biological target for reducing fear expression in PTSD is the hypothalamic-pituitary-adrenal (HPA) axis, which is dysregulated in PTSD. Recent translational rodent studies and cross-sectional clinical studies have shown that dexamethasone administration and the resulting suppression of cortisol in individuals with PTSD leads to a decrease in the fear responses characteristic of PTSD. These data, taken together, suggest that dexamethasone may serve as a novel pharmacologic intervention for heightened fear responses in PTSD. We conducted a double-blind, placebo-controlled trial to test our hypothesis that dexamethasone administration and the concomitant suppression of HPA axis hyperactivity would attenuate fear expression and enhance fear extinction in individuals with PTSD. Study participants (n=62) were recruited from Grady Memorial Hospital in Atlanta, GA. Participants were randomized to receive dexamethasone or placebo prior to fear conditioning and extinction, in a counterbalanced design (treatments separated by a week). Both PTSD− (n=37) and PTSD+ (n=25) participants showed significant startle increases in the presence of the danger signal during placebo and dexamethasone treatments (all p<0.05). However, only PTSD− control participants showed decreases in fear-potentiated startle across extinction blocks during both conditions (p’s≤ 0.001), with PTSD+ participants showing deficits in fear extinction and safety discrimination in the placebo condition. Notably, extinction and discrimination deficits in PTSD+ subjects were markedly reversed with dexamethasone (p<0.001). These data suggest that dexamethasone may serve as a pharmacological agent with which to facilitate fear extinction and discrimination in individuals with PTSD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Dexamethasone facilitates fear extinction and safety discrimination in PTSD: A placebo-controlled, double-blind study

Michopoulos

Norrholm

Stevens

et al. 2017

Psychoneuroendocrinology

View full text Add to dashboard Cite

show abstract

“…This suggests a more active HPA axis and potentially a more metabolically labile system. Furthermore, individuals with PTSD are reported to exhibit elevated GR levels (Matic et al, 2013) and enhanced glucocorticoid sensitivity (Yehuda et al, 2004) both of which would theoretically lead to enhanced GR-mediated gene transcription.…”

Section: The Hpa Axis and Metabolic Alterations In Ptsdmentioning

confidence: 99%

Posttraumatic stress disorder: A metabolic disorder in disguise?

Michopoulos

Vester

Neigh

2016

Experimental Neurology

105

103

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Posttraumatic stress disorder (PTSD) is a heterogeneous psychiatric disorder that affects individuals exposed to trauma and is highly co-morbid with other adverse health outcomes, including cardiovascular disease and obesity. The unique pathophysiological feature of PTSD is the inability to inhibit fear responses, such that individuals suffering from PTSD re-experience traumatic memories and are unable to control psychophysiological responses to trauma-associated stimuli. However, underlying alterations in sympathetic nervous system activity, neuroendocrine systems, and metabolism associated with PTSD are similar to those present in traditional metabolic disorders, such as obesity and diabetes. The current review highlights existing clinical, translational, and preclinical data that support the notion that underneath the primary indication of impaired fear inhibition, PTSD is itself also a metabolic disorder and proposes altered function of inflammatory responses as a common underlying mechanism. The therapeutic implications of treating PTSD as a whole-body condition are significant, as targeting any underlying biological system whose activity is altered in both PTSD and metabolic disorders, (i.e. HPA axis, sympathetic nervous systems, inflammation) may elicit symptomatic relief in individuals suffering from these whole-body adverse outcomes.

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“…Low cortisol levels in PTSD have been coupled to enhanced glucocorticoid negative feedback inhibition of the HPA axis as evidenced by increased suppression of cortisol levels following a dexamethasone suppression test (39). This enhanced HPA negative feedback in PTSD is coincident with: (1) augmented levels of peripheral and central corticotropin-releasing hormone (CRH) (40, 41), (2) elevated glucocorticoid receptor (GR) levels (42), (3) increased glucocorticoid sensitivity (43), and (4) decreased levels of FKBP5 (44), a co-chaperone of GR that inhibits ligand binding and nuclear translocation of GRs. A recent prospective study indicates that augmented baseline GR levels and diminished FKBP5 mRNA levels are associated with increased risk for PTSD symptoms following trauma (45).…”

Section: Introductionmentioning

confidence: 99%

Diagnostic Biomarkers for Posttraumatic Stress Disorder: Promising Horizons from Translational Neuroscience Research

Michopoulos¹,

Norrholm²,

Jovanović³

2015

Biological Psychiatry

177

123

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Posttraumatic stress disorder (PTSD) is a heterogeneous disorder that affects individuals exposed to trauma (e.g., combat, interpersonal violence, and natural disasters). Although its diagnostic features have been recently re-classified with the emergence of the Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition (DSM-5), the disorder remains characterized by hyperarousal, intrusive reminders of the trauma, avoidance of trauma-related cues, and negative cognition and mood. This heterogeneity indicates the presence of multiple neurobiological mechanisms underlying the etiology and maintenance of PTSD. Translational research spanning the past few decades has revealed several potential avenues for the identification of diagnostic biomarkers for PTSD. These include, but are not limited to, monoaminergic transmitter systems, the hypothalamic-pituitary-adrenal (HPA) axis, metabolic hormonal pathways, inflammatory mechanisms, psychophysiological reactivity, and neural circuits. The current review provides an update to the literature with regard to the most promising putative PTSD biomarkers with specific emphasis on the interaction between neurobiological influences on disease risk and symptom progression. Such biomarkers will most likely be identified by multi-dimensional models derived from comprehensive descriptions of molecular, neurobiological, behavioral, and clinical phenotypes.

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Lymphocyte glucocorticoid receptor expression level and hormone-binding properties differ between war trauma-exposed men with and without PTSD

Cited by 41 publications

References 55 publications

Dexamethasone facilitates fear extinction and safety discrimination in PTSD: A placebo-controlled, double-blind study

Dexamethasone facilitates fear extinction and safety discrimination in PTSD: A placebo-controlled, double-blind study

Posttraumatic stress disorder: A metabolic disorder in disguise?

Diagnostic Biomarkers for Posttraumatic Stress Disorder: Promising Horizons from Translational Neuroscience Research

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