Showing papers by "Clemens Kirschbaum published in 2022"

Depressive symptoms are negatively associated with hair N-arachidonoylethanolamine (anandamide) levels: A cross-lagged panel analysis of four annual assessment waves examining hair endocannabinoids and cortisol

Abstract: The endocannabinoid system (ECS) is increasingly being recognized as key regulatory system coupled with the glucocorticoid system implicated in the pathophysiology of major depressive disorder (MDD). However, prior studies examining the ECS in MDD have been inconclusive, of small sample size or of cross-sectional nature limiting interpretation of causal inferences or time-dependent effects.In a prospective community-based cohort study including 128 individuals (women: 108), depressive symptoms (PHQ-9) as well as hair cortisol and endocannabinoids were measured annually over four years (T1-T4). Cortisol, N-arachidonoylethanolamine (AEA), and 2-arachidonoyl-sn-glycerol/1-arachidonoyl-sn-glycerol (2-AG/1-AG) were extracted from 3 cm hair segments reflecting cumulative concentrations of the last three months prior sampling.Cross-sectional group comparisons at baseline revealed reduced AEA and cortisol levels in the group with a positive MDD screening compared to individuals with low depressive symptomatology (both p < .05). Cross-lagged panel models showed that AEA levels at T2 were negatively associated with depressive symptoms at T3 (p < .05). Also, depressive symptoms at T3 were negatively associated with AEA levels at T4 (p < .01). The direction of association was reversed for 2-AG/1-AG, as 2-AG/1-AG levels at T1 were positively associated with depressive symptoms at T2 (p < .01).While cross-sectional analyses suggest higher depressive symptomatology to be associated with reduced AEA and cortisol release, longitudinal analyses reveal that primarily AEA levels are negatively associated with depressive symptoms. These longitudinal associations elucidate time-dependent relationships between depressive symptomatology and the ECS and further highlight AEA as potential treatment target in MDD.

Cerebrospinal Fluid Cortisol and Dehydroepiandrosterone Sulfate, Alzheimer’s Disease Pathology, and Cognitive Decline

Abstract: Introduction Elevated cortisol levels have been reported in Alzheimer’s disease (AD) and may accelerate the development of brain pathology and cognitive decline. Dehydroepiandrosterone sulfate (DHEAS) has anti-glucocorticoid effects and it may be involved in the AD pathophysiology. Objectives To investigate associations of cerebrospinal fluid (CSF) cortisol and DHEAS levels with (1) cognitive performance at baseline; (2) CSF biomarkers of amyloid pathology (as assessed by CSF Aβ levels), neuronal injury (as assessed by CSF tau), and tau hyperphosphorylation (as assessed by CSF p-tau); (3) regional brain volumes; and (4) clinical disease progression. Materials and Methods Individuals between 49 and 88 years (n = 145) with mild cognitive impairment or dementia or with normal cognition were included. Clinical scores, AD biomarkers, brain MRI volumetry along with CSF cortisol and DHEAS were obtained at baseline. Cognitive and functional performance was re-assessed at 18 and 36 months from baseline. We also assessed the following covariates: apolipoprotein E (APOE) genotype, BMI, and education. We used linear regression and mixed models to address associations of interest. Results Higher CSF cortisol was associated with poorer global cognitive performance and higher disease severity at baseline. Cortisol and cortisol/DHEAS ratio were positively associated with tau and p-tau CSF levels, and negatively associated with the amygdala and insula volumes at baseline. Higher CSF cortisol predicted more pronounced cognitive decline and clinical disease progression over 36 months. Higher CSF DHEAS predicted more pronounced disease progression over 36 months. Conclusion Increased cortisol in the CNS is associated with tau pathology and neurodegeneration, and with decreased insula and amygdala volume. Both CSF cortisol and DHEAS levels predict faster clinical disease progression. These results have implications for the identification of patients at risk of rapid decline as well as for the development of interventions targeting both neurodegeneration and clinical manifestations of AD.

Cue-induced cocaine craving enhances psychosocial stress and vice versa in chronic cocaine users

Abstract: Stress and craving, it has been found, contribute to the development and maintenance of and relapse in cocaine use disorder. Chronic cocaine users (CU), previous research has shown, display altered physiological responses to psychosocial stress and increased vegetative responding to substance-related cues. However, how psychosocial stress and cue-induced craving interact in relation to the CU's physiological responses remains largely unknown. We thus investigated the interaction between acute psychosocial stress and cocaine-cue-related reactivity in 47 CU and 38 controls. In a crossed and balanced design, the participants were randomly exposed to a video-based cocaine-cue paradigm and the Trier Social Stress Test (TSST) or vice versa to investigate possible mutually augmenting effects of both stressors on physiological stress responses. Over the course of the experimental procedure, plasma cortisol, ACTH, noradrenaline, subjective stress, and craving were assessed repeatedly. To estimate the responses during the cocaine-cue paradigm and TSST, growth models and discontinuous growth models were used. Overall, though both groups did not differ in their endocrinological responses to the TSST, CU displayed lower ACTH levels at baseline. The TSST did not elevate craving in CU, but when the cocaine-cue video was shown first, CU displayed an enhanced cortisol response to the subsequent TSST. In CU, cocaine-cues robustly evoked craving but no physiological stress response, while cue-induced craving was intensified after the TSST. Taken together, though CU did not show an altered acute stress response during the TSST, stress and craving together seemed to have mutually augmenting effects on their stress response.

Empathy Modulates the Effects of Acute Stress on Anxious Appearance and Social Behavior in Social Anxiety Disorder

Abstract: Patients suffering from social anxiety disorder (SAD) fear social interaction and evaluation, which severely undermines their everyday life. There is evidence of increased prosocial behavior after acute social stress exposure in healthy individuals, which may be interpreted as stress-regulating “tend-and-befriend” behavior. In a randomized controlled trial, we measured empathic abilities in a first diagnostic session. In the following experimental session, we investigated how patients with SAD (n = 60) and healthy control participants (HC) (n = 52) respond to an acute social stressor (Trier Social Stress Test for groups) or a non-stressful control condition, and whether empathic abilities and acute social stress interact to modulate anxious appearance and social behavior in a social conversation test. Salivary cortisol, heart rate, and subjective stress response were repeatedly measured. The anxious appearance and social behavior of participants were rated by the conversation partner. SAD patients demonstrated stronger subjective stress responses while the biological responses did not differ from HC. Moreover, patients performed worse overall in the conversation task, which stress additionally undermined. Finally, we found that both emotional and cognitive empathy buffered the negative effects of acute stress on social behavior in SAD, but not in HC. Our data highlight the importance of empathic abilities for SAD during stressful situations and call for multimodal clinical diagnostics. This may help to differentiate clinical subtypes and offer better-tailored treatment for patients. General Scientific Summary: This study shows that high levels of cognitive and emotional empathy can buffer the negative effects of acute stress on social behavior in social anxiety disorder (SAD). Empathic abilities may be included as an additional diagnostic resource marker for SAD.

Hair cortisol levels in schizophrenia and metabolic syndrome

Abstract: Individuals with schizophrenia demonstrate higher rates of metabolic syndrome (MetS) than the general population. Hair cortisol concentrations (HCC) reflect longer‐term cortisol secretion and can provide additional insights into the role of the hypothalamic pituitary adrenal (HPA) axis in schizophrenia and co‐occurring MetS.

Determining the direction of prediction of the association between parasympathetic dysregulation and exhaustion symptoms

Abstract: Stress-related exhaustion symptoms have a high prevalence which is only likely to increase further in the near future. Understanding the physiological underpinnings of exhaustion has important implications for accurate diagnosis and the development of effective prevention and intervention programs. Given its integrative role in stress-regulation, the parasympathetic branch of the autonomic nervous systems has been a valid starting point in the exploration of the physiological mechanisms behind exhaustion. The aim of the present study was to examine the directionality and specificity of the association between exhaustion symptoms and vagally-mediated heart rate variability (vmHRV), a relatively pure measure of parasympathetic tone. Exhaustion symptoms and vmHRV were measured at four annually assessment waves (2015-2018) of the Dresden Burnout Study. A total sample of N = 378 participants who attended at least two of the four annual biomarker measurements were included in the present analyses. Cross-lagged multi-level panel modelling adjusting for various covariates (e.g., age, sex, BMI) revealed that vmHRV was meaningfully predictive of exhaustion symptoms and not vice versa. In addition, these effects were specific for exhaustion symptoms as no effect was shown for the other burnout sub-dimensions, or for depressive symptoms. Our findings indicate a clear link between exhaustion symptoms and vmHRV which may hold great potential for both enhancing the diagnosis and treatment of exhaustion symptoms.

Persisting neuropsychiatric symptoms, Alzheimer’s disease, and cerebrospinal fluid cortisol and dehydroepiandrosterone sulfate

Abstract: Neuropsychiatric symptoms are important treatment targets in the management of dementia and can be present at very early clinical stages of neurodegenerative diseases. Increased cortisol has been reported in Alzheimer's disease (AD) and has been associated with faster cognitive decline. Elevated cortisol output has been observed in relation to perceived stress, depression, and anxiety. Dehydroepiandrosterone sulfate (DHEAS) has known anti-glucocorticoid effects and may counter the effects of cortisol.We aimed to examine whether CSF cortisol and DHEAS levels were associated with (1) neuropsychiatric symptoms at baseline, (2) changes in neuropsychiatric symptoms over 3 years, and (3) whether these associations were related to or independent of AD pathology.One hundred and eighteen participants on a prospective study in a memory clinic setting, including patients with cognitive impairment (n = 78), i.e., mild cognitive impairment or mild dementia, and volunteers with normal cognition (n = 40), were included. Neuropsychiatric symptoms were assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q). CSF cortisol and DHEAS, as well as CSF AD biomarkers, were obtained at baseline. Neuropsychiatric symptoms were re-assessed at follow-up visits 18 and 36 months from baseline. We constructed linear regression models to examine the links between baseline neuropsychiatric symptoms, the presence of AD pathology as indicated by CSF biomarkers, and CSF cortisol and DHEAS. We used repeated-measures mixed ANCOVA models to examine the associations between the neuropsychiatric symptoms' changes over time, baseline CSF cortisol and DHEAS, and AD pathology.Higher CSF cortisol was associated with higher NPI-Q severity scores at baseline after controlling for covariates including AD pathology status (B = 0.085 [0.027; 0.144], p = 0.027; r = 0.277). In particular, higher CSF cortisol was associated with higher baseline scores of depression/dysphoria, anxiety, and apathy/indifference. Elevated CSF cortisol was also associated with more marked increase in NPI-Q scores over time regardless of AD status (p = 0.036, η2 = 0.207), but this association was no longer significant after controlling for BMI and the use of psychotropic medications. CSF DHEAS was associated neither with NPI-Q scores at baseline nor with their change over time. Cortisol did not mediate the association between baseline NPI-Q and changes in clinical dementia rating sum of boxes over 36 months.Higher CSF cortisol may reflect or contribute to more severe neuropsychiatric symptoms at baseline, as well as more pronounced worsening over 3 years, independently of the presence of AD pathology. Our findings also suggest that interventions targeting the HPA axis may be helpful to treat neuropsychiatric symptoms in patients with dementia.

No long-term effects of antenatal synthetic glucocorticoid exposure on epigenetic regulation of stress-related genes

Abstract: Antenatal synthetic glucocorticoid (sGC) treatment is a potent modifier of the hypothalamic-pituitary-adrenal (HPA) axis. In this context, epigenetic modifications are discussed as potential regulators explaining how prenatal exposure to GCs might translate into persistent changes of HPA axis "functioning". The purpose of this study was to investigate whether DNA methylation and gene expression profiles of stress-associated genes (NR3C1; FKBP5; SLC6A4) may mediate the persistent effects of sGC on cortisol stress reactivity that have been previously observed. In addition, hair cortisol concentrations (hairC) were investigated as a valid biomarker of long-term HPA axis activity. This cross-sectional study comprised 108 term-born children and adolescents, including individuals with antenatal GC treatment and controls. From whole blood, DNA methylation was analyzed by targeted deep bisulfite sequencing. Relative mRNA expression was determined by RT-qPCR experiments and qBase analysis. Acute stress reactivity was assessed by the Trier Social Stress Test (TSST) measuring salivary cortisol by ELISA and hairC concentrations were determined from hair samples by liquid chromatography coupled with tandem mass spectrometry. First, no differences in DNA methylation and mRNA expression levels of the stress-associated genes between individuals treated with antenatal sGC compared to controls were found. Second, DNA methylation and mRNA expression levels were neither associated with cortisol stress reactivity nor with hairC. These findings do not corroborate the belief that DNA methylation and mRNA expression profiles of stress-associated genes (NR3C1; FKBP5; SLC6A4) play a key mediating role of the persistent effects of sGC on HPA axis functioning.

Long-term cortisol stress response in depression and comorbid anxiety is linked with reduced N-acetylaspartate in the anterior cingulate cortex

Abstract: Abstract Objectives Major Depression (MDD) and anxiety disorders are stress-related disorders that share pathophysiological mechanisms. There is evidence for alterations of glutamate-glutamine, N-acetylaspartate (NAA) and GABA in the anterior cingulate cortex (ACC), a stress-sensitive region affected by hypothalamic-pituitary-adrenal axis (HPA). The aim was to investigate metabolic alterations in the ACC and whether hair cortisol, current stress or early life adversity predict them. Methods We investigated 22 patients with MDD and comorbid anxiety disorder and 23 healthy controls. Proton magnetic resonance spectroscopy was performed with voxels placed in pregenual (pg) and dorsal (d) ACC in 3 T. Analysis of hair cortisol was performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results The N-acetylaspartate/Creatin ratio (NAA/Cr) was reduced in patients in both pgACC (p = .040) and dACC (p = .016). A significant interactive effect of diagnosis and cortisol on both pg-NAA/Cr (F = 5.00, p = .033) and d-NAA/Cr (F = 7.86, p = .009) was detected, whereby in controls cortisol was positively correlated with d-NAA/Cr (r = 0.61, p = .004). Conclusions Our results suggest a relationship between NAA metabolism in ACC and HPA axis activity as represented by long-term cortisol output.

Pro- and anti-inflammatory cytokines Interleukin-6 and Interleukin-10 predict therapy outcome of female patients with posttraumatic stress disorder

Abstract: Abstract PTSD patients show alterations of the immune system, mainly a ‘low-grade inflammation’. Psychotherapeutic treatments are meant to reduce symptom burden of PTSD patients but 30–50% of PTSD patients do not benefit from psychotherapy. Therefore, in this study, the predictive effect of cytokine levels on therapy outcome are investigated. Pro- (IL-6) and anti-inflammatory (IL-10) cytokines in female PTSD patients (N = 17) were assessed under acute stress during a Trier social stress test (TSST) before therapeutic treatment. The predictive effects of IL-6 and IL-10 on therapy outcome (SCL_GSI, BDI) after an inpatient psychotherapeutic treatment at the University Medical Center Carl Gustav Carus, Technische Universität Dresden was investigated. Areas under the curve with respect to ground (AUC G ) and increase (AUC I ) for IL-6 and IL-10 levels during the TSST were calculated and used as predictors in regression analyses with pre-treatment scores. Models including all three predictors show good model fits (R 2 = 0.255 to 0.744). Models including AUC G and AUC I scores show superior fits compared with models including pre-treatment scores alone (ΔR 2 = 0.196 to 0.444). IL-6 AUC G and AUC I scores are significant predictors for post-treatment SCL-GSI and BDI (β = −0.554 to 0.853), whereas IL-10 AUC G significantly predicts SCL-GSI and BDI (β = −0.449 to −0.509). Therefore, pro- and anti-inflammatory IL-6 and IL-10 levels under acute stress before therapy predict therapy outcome of female PTSD patients regarding general symptom burden and depressive symptoms. Future studies should further address the link between inflammation and therapy outcome, especially underlying mechanisms and influencing factors.

Perceived stress and hair cortisol concentration in a study of Mexican and Icelandic women

Abstract: Hair cortisol concentration (HCC) represent a potential biomarker of chronic psychological stress. Previous studies exploring the association between perceived stress and HCC have been limited to relatively small and selected populations. We collected hair samples from 881 women from the Mexican Teachers’ Cohort (MTC) and 398 women from the Icelandic SAGA pilot-cohort following identical protocols. HCC was quantified using liquid chromatography coupled with tandem mass spectrometry. The self-reported Perceived Stress Scale (PSS, 10 and 4 item, range 0–40 and 0–16) was used to assess psychological stress. We conducted multivariable linear regression analyses to assess the association between perceived stress and log-transformed HCC in the combined sample and in each cohort separately. MTC participants had slightly higher HCC and PSS scores than SAGA participants (median HCC 6.0pg/mg vs. 4.7pg/mg and mean PSS-10 score 12.4 vs. 11.7, respectively). After adjusting for sociodemographic factors and health behaviors, we observed a 1.4% (95% CI 0.6, 2.1) increase in HCC for each unit increase in the PSS-10 score in the combined sample. Furthermore, PSS-10 quintiles were associated with a 24.3% (95% CI 8.4, 42.6, mean logHCC 1.8 vs 1.6) increase in HCC when comparing the highest to the lowest quintile, after multivariable adjustment. Similar results were obtained when we analyzed each cohort separately and when using the PSS-4. Despite relatively small absolute differences, an association between perceived stress and HCC was found in a sample of women from two diverse geographical and cultural backgrounds supporting the hypothesis that HCC is a viable biomarker in studies of chronic psychological stress.

Associations between burnout symptoms and social behaviour: exploring the role of acute stress and vagal function

Abstract: The study aimed to investigate the link between burnout symptoms and prosocial behaviour, as well as the role of acute stress and vagally-mediated heart rate variability (vmHRV) on this association.Seventy men were randomly assigned to either the stress or the control condition of the Trier Social Stress Test for Groups (TSST-G). Prosocial behaviour was assessed via a social decision-making paradigm during the respective TSST-G condition.Correlation analyses revealed negative correlations between prosocial behaviour and burnout symptoms. Acute stress was also associated with reduced prosocial behaviour, whereas no interaction effects with burnout symptoms could be revealed. Exploratory analyses showed that vmHRV was negatively correlated with burnout symptoms during the social decision-making paradigm but did not mediate the link between burnout and prosocial behaviour.In conclusion, we report first experimental evidence that burnout symptoms are negatively associated with prosocial behaviour. Further studies are needed to explore the causal relations.

Immune Cell Deformability in Depressive Disorders: Longitudinal Associations Between Depression, Glucocorticoids and Cell Deformability

Abstract: Background: Cell deformability of all major blood cell types is increased in depressive disorders (DD). Furthermore, impaired glucocorticoid secretion is causally related to DD. Nevertheless, there are no longitudinal studies examining changes in glucocorticoid output and depressive symptoms regarding cell deformability in DD. Aim: To investigate, whether changes in depressive symptoms or hair glucocorticoids predict cell deformability in DD. Methods: In 136 individuals, depressive symptoms (PHQ-9) and hair glucocorticoids (cortisol and cortisone) were measured at timepoint one (T1), while one year later (T2) depressive symptoms and hair glucocorticoids were remeasured and additionally cell deformability of peripheral blood cells was assessed and DD status was determined by clinical interview. Results: Depression severity at T1 predicted higher cell deformability in monocytes and lymphocytes over the entire sample. Subjects with continuously high depressive symptoms at T1 and T2 showed elevated monocyte deformability as compared to subjects with low depressive symptoms. Depression severity at T1 of subjects with a lifetime persistent depressive disorder (PDD) was associated with elevated monocyte, neutrophil, and granulo-monocyte deformability. Depression severity at T1 of subjects with a 12-month PDD was positively associated with monocyte deformability. Furthermore, increases in glucocorticoid concentrations from T1 to T2 tended to be associated with higher immune cell deformability, while strongest associations emerged for the increase in cortisone with elevated neutrophil and granulo-monocyte deformability in the 12-month PDD group. Conclusion: Continuously elevated depressive symptomatology as well as an increase in glucocorticoid levels over one year are associated with higher immune cell deformability, particularly in PDD. These findings suggest, that persistent depressive symptomatology associated with increased glucocorticoid secretion may lead to increased immune cell deformability thereby compromising immune cell function and likely contributing to the perpetuation of PDD.

Neuropsychiatric symptoms, Alzheimer’s Disease and Cerebrospinal Fluid Cortisol and Dehydroepiandrosterone Sulfate: a Prospective Study

Abstract: Neuropsychiatric symptoms (NPS) are important treatment targets in the management of dementia, can be present at very early stages of neurodegeneration, and are associated with more rapid clinical disease progression. Increased cortisol has been reported in Alzheimer’s disease (AD), and has been associated with cognitive decline. At the same time, cortisol is often referred to as the “stress hormone” and elevated cortisol output has been observed in association with depression and delirium. Dehydroepiandrosterone sulfate (DHEAS) has known anti‐glucocorticoid effects and may counter the effects of cortisol.