Abstract
A substantial minority of individuals exposed to severe or traumatic stress subsequently develops long-lasting mental or physical health problems, which may severely impair daily functioning. These stress-related conditions include posttraumatic stress disorder (PTSD), major depressive disorder (MDD) and severe fatigue. Military personnel deployed to combat zones are particularly at risk
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for the development of these conditions. The working model for this PhD-thesis was that the development of these stress-related conditions is associated with vulnerability factors present prior to the stressor leading to symptom-onset. To investigate our hypothesis, we focused on identifying biological vulnerability factors, i.e. biomarkers, for development of these conditions. We assessed whether glucocorticoid receptor (GR) pathway components within peripheral blood mononuclear cells (PBMCs) predicted the subsequent development of PTSD, depressive and/or fatigue symptoms in response to military deployment. In addition, we investigated whether the capacity of peripheral blood cells to produce cytokines upon stimulation, and the reactivity of peripheral blood cells to regulation by the pro-inflammatory mediator IL-1β, predicted the development of these stress-related conditions in response to deployment. We identified several biological vulnerability factors for the development of PTSD, depressive and fatigue symptoms in response to military deployment. High glucocorticoid (GC) signalling in PBMCs, as assessed on various levels of the GR signalling pathway prior to deployment, was a vulnerability factor for development of a high level of PTSD symptoms. In contrast, low GC signalling in PBMCs, specifically in T-cells, prior to deployment was a vulnerability factor for the development of a high level of depressive symptoms. In addition, a high T-cell cytokine production capacity prior to deployment was also a vulnerability factor for development of depressive symptoms. Furthermore, we observed that low GC-sensitivity of monocytes prior to deployment was a vulnerability factor for development of severe fatigue. In addition, severely fatigued participants showed an increased reactivity of monocytes to IL-1β after deployment. Intriguingly, despite the high co-morbidity between symptoms of PTSD, MDD and severe fatigue, these identified vulnerability factors were condition-specific. This indicates that symptoms of PTSD, depression and fatigue have different biological mechanisms. Collectively, our results suggest that the biological profile prior to exposure to severe stress or trauma predicts the subsequent development of mental and physical health problems. Moreover, our results indicate that the biological profile may not only determine whether an individual has an increased risk of developing a stress-related condition, but also which specific stress-related condition is most likely to develop. We convincingly showed that performing prospective, longitudinal studies in groups at risk for stress- and trauma exposure is a promising and fruitful approach to identify biological vulnerability factors for development of stress-related conditions. This is likely to be valuable for individuals in jobs with a high risk for stress- and trauma exposure, such as the military. If optimal cut-offs for our vulnerability factors can be identified, in the future vulnerable individuals may be identified via screening prior to stress- and trauma-exposure. This could lead to targeted interventions that could potentially prevent the development or aggravation of symptoms
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