LAY ABSTRACTThere has been an increase in cases of sick leave due to stress in several European countries in recent decades. Chronic stress-induced exhaustion disorder is linked with physiological and neurobiological changes, which may add to cognitive problems and long-term exhaustion. This narrative review summarizes the published evidence about the effectiveness of different interventions for the rehabilitation of patients with chronic stress-induced exhaustion disorder. Cognitive behavioural interventions and multimodal interventions reduce symptoms. Workplace interventions often improve return to work. Better sleep is associated with improvement of symptoms and return to work. Interventions for improving sleep might therefore be important. For improving cognitive function, which is a main complaint among patients with chronic stress-induced exhaustion disorder, aerobic and cognitive training may have some effect. Most interventions for the rehabilitation of chronic stress-induced exhaustion disorder have only marginal effects. Therefore, it is important to prevent the onset of this disorder. Objective: An increase in numbers of cases of sick leave due to stress have been reported from several European countries during recent decades. Chronic stress-induced exhaustion disorder is associated with physiological and neurobiological perturbations that may contribute to cognitive problems and longterm exhaustion. Rehabilitation of patients with chronic stress-induced exhaustion disorder is therefore challenging. This narrative review summarizes the evidence regarding the effectiveness of different interventions for the rehabilitation of patients with chronic stress-induced exhaustion disorder. Methods: Both structured and unstructured searches of research studies and reports were performed in order to find knowledge sources. The structured search had 2 predefined inclusion criteria: (i) chronic stress-induced exhaustion/clinical burnout/severe burnout/stress-induced exhaustion; and (ii) rehabilitation with improvement of symptoms and/or return to work as outcomes. Results: Cognitive behavioural interventions and multimodal interventions seem to reduce symptoms. Workplace interventions, either work-focused cognitive behavioural or workplace dialogue, seem to improve return to work. Sleep is important for both symptom improvement and return to work, and interventions for improving sleep might therefore be important. For improvement of cognitive function, which is a main complaint among patients with chronic stress-induced exhaustion disorder, aerobic and cognitive training may have some effect. Conclusion: In summary, the few studies of highquality that examine interventions for rehabilitation of chronic stress-induced exhaustion disorder show only marginal effects. Thus, it is important to prevent the onset of chronic stress-induced exhaustion disorder.

Patients with stress-induced exhaustion disorder (SED) demonstrate cognitive dysfunction similar to patients with minor traumatic brain injury (TBI). We have previously detected elevated concentrations of astrocyte-derived extracellular vesicles (EVs) in patients with TBI. As such, we hypothesized that astrocyte-derived EVs could be higher in patients with SED than in patients with major depressive disorder (MDD) and healthy controls. Patients with SED (n = 31), MDD (n = 31), and healthy matched controls (n = 61) were included. Astrocyte-derived EVs (previously known as microparticles) were measured in plasma with flow cytometry and labeled against glial fibrillary acidic protein (GFAP) and aquaporin 4 (AQP4). In addition, platelet EVs and their CD40 ligand expression were measured. Patients with SED had significantly higher concentrations of AQP4 and GFAP-positive EVs and EVs co-expressing AQP4/GFAP than patients with MDD and healthy controls. Patients with MDD had significantly higher concentrations of GFAP-positive EVs and EVs co-expressing AQP4/GFAP than healthy controls. Platelet EVs did not differ between groups. CD40 ligand expression was significantly higher in patients with SED and MDD than in controls. In conclusion, the present study suggests that patients with SED, and to some extent, patients with MDD, have increased leakage of astrocyte-derived EVs through the blood–brain barrier.

BackgroundVascular endothelial growth factor (VEGF), epidermal growth factor (EGF) and monocyte chemotactic protein-1 (MCP-1) have previously been suggested to be potential biomarkers for chronic stress induced exhaustion. The knowledge about VEGF has increased during the last decades and supports the contention that VEGF plays an important role in stress and depression. There is scarce knowledge on the possible relationship of EGF and MCP-1 in chronic stress and depression. This study further examines the role of VEGF, EGF and MCP-1 in women with chronic stress induced exhaustion and healthy women during a follow-up period of two years.Methods and FindingsBlood samples were collected from 105 women with chronic stress induced exhaustion on at least 50% sick leave for at least three months, at inclusion (T0), after 12 months (T12) and after 24 months (T24). Blood samples were collected at inclusion (T0) in 116 physically and psychiatrically healthy women. The plasma levels of VEGF, EGF and MCP-1 were analyzed using Biochip Array Technology. Women with chronic stress induced exhaustion had significantly higher plasma levels of VEGF and EGF compared to healthy women at baseline, T12 and at T24. There was no significant difference in plasma levels of MCP-1. Plasma levels of VEGF and EGF decreased significantly in women with chronic stress induced exhaustion during the two years follow-up.ConclusionsThe replicated findings of elevated levels of VEGF and EGF in women with chronic stress induced exhaustion and decreasing plasma levels of VEGF and EGF during the two years follow-up add important knowledge to the pathophysiology of chronic stress induced exhaustion.