Differences in psychiatric comorbidity patterns in patients diagnosed with chronic stress-induced exhaustion disorder and depression - A cohort study in the total population of Region Stockholm.

The high prevalence of stress-related disorders and depression underscores the urgent need to unravel their impact on individual well-being. This study aim to investigate common psychiatric and stress-related diagnoses, along with postviral fatigue, in individuals with prior stress-induced exhaustion disorder (SED) and prior depression compared to those without prior SED or depression, and to study whether the psychiatric comorbidity patterns differ. The study includes individuals in Region Stockholm who, in 2011, did not have a diagnosis of SED or depression. ICD-10 diagnosis of SED, depression, or both, recorded in 2012-2013, were compared to individuals without prior SED or depression in a cohort (n = 1,362,886), aged 18 to 65. Odds ratios (OR) with 99 % confidence intervals, adjusted for age and neighborhood socioeconomic status, were calculated for psychiatric disorders and post-viral fatigue in 2014-2022. Patients with prior SED showed associations primarily with stress related diagnoses, including acute stress reaction, reaction to severe stress, as well as post-COVID-19 and post-viral fatigue syndrome. These ORs were all larger for SED than depression. Depression was primarily associated with post-traumatic stress disorder (PTSD), alcohol related and substance use disorders, schizophrenia, schizotypal disorders, delusional disorders, manic episode, bipolar affective disorder, persistent mood disorder, neurotic disorder, borderline personality disorder, autistic disorder, Asperger's syndrome, attention -deficit hyperactivity disorder, attention-deficit disorders ADHD/ADD), and suicide attempt. These ORs were all higher for depression, although autistic disorders, ADHD/ADD and PTSD were also highly associated with prior SED (OR > 3.5). The divergent psychiatric comorbidity patterns suggest different underlying mechanisms and clinical prognosis.

Stress, depression, and risk of dementia - a cohort study in the total population between 18 and 65 years old in Region Stockholm.

BACKGROUND: Chronic stress and depression are potential risk factors for mild cognitive impairment and dementia, including Alzheimer disease. The aim was to investigate whether any such risk is additive. METHODS: Cohort study including 1 362 548 people (665 997 women, 696 551 men) with records in the Region Stockholm administrative healthcare database (VAL). Exposure was a recorded ICD-10 diagnosis of chronic stress, depression, or both, recorded in 2012 or 2013. Outcome was a diagnosis of Alzheimer disease, other dementia, or mild cognitive impairment recorded from 2014 through 2022. Odds ratios with 99% confidence intervals (CI) adjusted for age, sex, neighborhood socioeconomic status, diabetes, and cardiovascular disorders were calculated. RESULTS: During the exposure period, 4 346 patients were diagnosed with chronic stress, 40 101 with depression, and 1 898 with both. The average age at baseline was around 40 years in all groups. In the fully adjusted model, the odds ratio of Alzheimer disease was 2.45 (99% CI 1.22-4.91) in patients with chronic stress, 2.32 (99% CI 1.85-2.90) in patients with depression, and 4.00 (99% CI 1.67-9.58) in patients with chronic stress and depression. The odds ratio of mild cognitive impairment was 1.87 (99% CI 1.20-2.91) in patients with chronic stress, 2.85 (99% CI 2.53-3.22) in patients with depression, and 3.87 (99% CI 2.39-6.27) in patients with both. When other dementia was analyzed, the odds ratio was significant only in patients with depression, 2.39 (99% CI 1.92-2.96). CONCLUSIONS: Documented chronic stress increased the risk of mild cognitive impairment and Alzheimer disease. The same was seen with depression. The novel finding is the potential additive effect of chronic stress to depression, on risk of MCI and AD.

Plasma levels of S100B and neurofilament light chain protein in stress-related mental disorders.

The pathophysiological changes underlying stress-related mental disorders remain unclear. However, research suggests that alterations in astrocytes and neurons may be involved. This study examined potential peripheral markers of such alterations, including S100B and neurofilament light chain (NF-L). We compared plasma levels of S100B and NF-L in patients with chronic stress-induced exhaustion disorder (SED), patients with major depressive disorder (MDD), and healthy controls. We also investigated whether levels of S100B and NF-L correlated with levels of astrocyte-derived extracellular vesicles (EVs that indicate astrocyte activation or apoptosis) and with symptom severity. Only women had measurable levels of S100B. Women with SED had higher plasma levels of S100B than women with MDD (P < 0.001) and healthy controls (P < 0.001). Self-rated symptoms of cognitive failures were positively correlated with levels of S100B (rs = 0.434, P = 0.005) as were depressive symptoms (rs = 0.319, P < 0.001). Plasma levels of astrocyte-derived EVs were correlated with levels of S100B (rs = 0.464, P < 0.001). Plasma levels of NF-L did not differ between the groups and were not correlated with symptom severity or EV levels. Thus, long-term stress without sufficient recovery and SED may be associated with raised plasma levels of S100B, which may be evidence of pathophysiological changes in astrocytes. The findings also support the hypothesis that plasma levels of S100B are associated with cognitive dysfunction.

Isoforms of soluble vascular endothelial growth factor in stress-related mental disorders: a cross-sectional study.

Vascular endothelial growth factor (VEGF) has been implicated in the pathophysiology of stress-related mental disorders. However, VEGF levels have seldom been compared across mental disorders and never by isoforms. Pathophysiological processes involving leakage of astrocyte-derived extracellular vesicles (EVs) across the blood-brain barrier could be associated with VEGF levels in patients with stress-related mental disorders. This cross-sectional study compared plasma levels of VEGF121, VEGF165, and VEGF121 + VEGF165 (VEGFtotal) in patients with stress-induced exhaustion disorder (SED) (n = 31), patients with major depressive disorder (MDD) (n = 31), and healthy controls (n = 61). It also analyzed the correlation between VEGF and astrocyte-derived EVs in plasma. An enzyme-linked immunosorbent assay (ELISA) was used to measure VEGF121 and VEGF165 in citrate plasma, and flow cytometry was used to measure astrocyte-derived EVs in plasma. The mean concentration of soluble VEGF121 (sVEGF121) was significantly higher in patients with SED than healthy controls (P = 0.043). Mean sVEGF165 was significantly lower in patients with MDD than patients with SED (P = 0.004) or healthy controls (P = 0.037). Mean sVEGFtotal was significantly higher in patients with SED than in patients with MDD (P = 0.021) and also higher in patients with SED than healthy controls (P = 0.040). Levels of sVEGF121 were positively correlated with levels of astrocyte-derived EVs only in patients with SED (P = 0.0128). The same was true of levels of sVEGFtotal and astrocyte-derived EVs (P = 0.0046). Differing levels of VEGF isoforms may reflect different pathophysiological mechanisms in SED and MDD. Further research is needed to better understand the potential roles of VEGF isoforms and astrocyte-derived EVs in mental disorders.

Leakage of astrocyte-derived extracellular vesicles in stress-induced exhaustion disorder: a cross-sectional study.

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.

Role of rehabilitation in chronic stress-induced exhaustion disorder: A narrative review.

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 long-term 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) rehabil-itation 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 high-quality 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.

Possible Biomarkers of Chronic Stress Induced Exhaustion - A Longitudinal Study.

BACKGROUND: Vascular 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 FINDINGS: Blood 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. CONCLUSIONS: The 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.