Katharina Schultebraucks

Cognitive function in patients with primary adrenal insufficiency (Addison's disease).

BACKGROUND Patients with primary adrenal insufficiency (AI) need to replace glucocorticoids and mineralocorticoids that act on glucocorticoid (GR) and mineralocorticoid receptors (MR). Both receptors are highly expressed in the hippocampus and are closely associated with cognitive function, which might be impaired by insufficient or increased GR and MR stimulation. However, little is known about cognitive function in patients with AI. METHODS It was examined whether patients with AI exhibit worse cognitive function compared to sex-, age-, and education-matched controls. Cognitive function (executive function, concentration, verbal memory, visual memory, working memory, and autobiographical memory) was assessed in 30 patients with AI (mean age 52.4 yrs. ±14.4, n=21 women, mean duration of illness 18.2 yrs. ±11.1) and 30 matched controls. We also measured depressive symptoms, body mass index (BMI), and blood pressure. RESULTS Patients with AI showed more depressive symptoms, had a greater BMI and lower systolic blood pressure compared to controls. Adjusted analyses controlling for these variables revealed that patients with AI performed significantly worse in verbal learning (F=7.8, p=.007). Executive function, concentration, working memory, verbal memory, visuospatial memory, and autobiographical memory did not differ between groups. CONCLUSIONS No clinically relevant cognitive impairment was found in patients with AI compared to matched controls. Even long-term glucocorticoid and mineralocorticoid substitution over almost two decades appears to have only subtle effects on cognition in patients with AI.

Stress reactivity and its effects on subsequent food intake in depressed and healthy women with and without adverse childhood experiences

BACKGROUND Adverse childhood experiences (ACE) increase the risk to develop major depressive disorder (MDD) and obesity or metabolic syndrome in adulthood. In addition, ACE may be associated with an exaggerated endocrine response to stress, which, in turn, may lead to enhanced food intake resulting in obesity and metabolic problems. METHODS We systematically examined the stress response and consecutive food intake in 32 women with MDD and ACE as determined by a clinical interview (Early Trauma Inventory), 52 women with MDD without ACE, 22 women with ACE but no current or lifetime MDD and 37 healthy women without either MDD or ACE. All participants underwent a psychosocial stress test (Trier Social Stress Test, TSST) and a control condition (Placebo-TSST) before they were offered a buffet of snacks. Participants were not aware that the primary outcome variable was the amount of consumed kilocalories (kcal). RESULTS The four groups did not differ in demographic variables. Stress resulted in higher cortisol release and higher blood pressure compared to the control condition. Patients with MDD without ACE had a significantly lower cortisol response to stress compared to controls. Across groups, we found higher kcal intake after stress compared to the control condition. Comparing high and low cortisol responders to stress, higher kcal intake after stress was only seen in those with low cortisol release. CONCLUSIONS This study provides evidence that blunted rather than enhanced cortisol release to stress might lead to increased food intake, independent from MDD and ACE.

The Role of Fludrocortisone in Cognition and Mood in Patients with Primary Adrenal Insufficiency (Addison's Disease).

Background: Primary adrenal insufficiency (AI) requires hormone replacement therapy with fludrocortisone and hydrocortisone stimulating glucocorticoid (GR) and mineralocorticoid receptors (MR). Evidence from animal and human studies shows that MR function is crucial for cognitive function and mood. Regarding patients with AI, very little is known about the role of MR in cognitive function and mood. Methods: A repeated-measures within-subject design was used to determine whether cognitive function and mood are related to MR occupation in patients with AI. Intraindividually, patients were examined twice, with 1 week between testing days: once with fludrocortisone (high MR occupation) and once without fludrocortisone (low MR occupation). All patients kept their stable regimen of hydrocortisone. The assessment of cognitive function included executive function, attention, and verbal, visuospatial and working memory. Additionally, mood and blood pressure were measured. Results: Verbal memory improved significantly during high MR occupation (after fludrocortisone intake) compared to low MR occupation [without fludrocortisone, t(29) = -2.1, p = 0.046]. There were trend level differences in the Number-Combination test [t(29) = -1.9, p = 0.074] and in the Stroop interference task [t(29) = -1.9, p = 0.068]. No significant differences in visuospatial and working memory were found. Furthermore, the current mood state was better during high MR occupation compared to low MR occupation [t(29) = -2.4, p = 0.023] as was diastolic blood pressure [F(2, 29) = 3.6, p = 0.07]. Conclusions: Cognitive function and mood in patients with AI depend in part on MR occupation. Because the medium effect size indicates a potential clinical significance, further studies should systematically examine which dosages of fludrocortisone are associated with optimal cognitive function and mood in AI patients.

Effects of mineralocorticoid-receptor stimulation on risk taking behavior in young healthy men and women

Risk taking is influenced by stress, with riskier decisions after exposure to an acute stressor and consecutively elevated cortisol levels. In the brain, cortisol acts on two receptors with different functional profiles: the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). In the current study we investigated the effect of MR stimulation on risk taking behavior in 80 young healthy participants (40 women, mean age=23.9). We administered 0.4mg fludrocortisone, a MR agonist, in a between-subjects, placebo controlled design. Subsequently, participants conducted an established risk taking paradigm, the Balloon-Analogue-Risk-Task (BART). We also used two questionnaires to assess risk taking and decision behavior as trait measures. We found a treatment effect with riskier decisions in the fludrocortisone group. Furthermore, we found a sex effect with more risk taking in men. There was no statistically significant interaction between both factors. Our results indicate that acute MR stimulation leads to riskier decisions in women and men. Our findings argue for an important role of the MR in decision making processes.

Mineralocorticoid receptor stimulation effects on spatial memory in healthy young adults: A study using the virtual Morris Water Maze task

OBJECTIVES Stress hormones such as cortisol are known to influence a wide range of cognitive functions, including hippocampal based spatial memory. In the brain, cortisol acts via two different receptors: the glucocorticoid (GR) and the mineralocorticoid receptor (MR). As the MR has a high density in the hippocampus, we examined the effects of pharmacological MR stimulation on spatial memory. METHODS Eighty healthy participants (40 women, 40 men, mean age=23.9years±SD=3.3) completed the virtual Morris Water Maze (vMWM) task to test spatial encoding and spatial memory retrieval after receiving 0.4mg fludrocortisone, a MR agonist, or placebo. RESULTS There was no effect of MR stimulation on spatial encoding during the vMWM task. However, participants who received fludrocortisone exhibited improved spatial memory retrieval performance. There was neither a main effect of sex nor a sex-by-treatment interaction. CONCLUSION In young healthy participants, MR stimulation improved hippocampal based spatial memory retrieval in a virtual Morris Water Maze task. Our study not only confirms the importance of MR function in spatial memory, but suggests beneficial effects of acute MR stimulation on spatial memory retrieval in humans.

The dexamethasone corticotropin releasing hormone test in healthy and depressed women with and without childhood adversity

BACKGROUND Alterations of the hypothalamic-pituitary-adrenal (HPA) axis are a prominent finding in patients with major depressive disorder (MDD). Inconsistencies regarding a hyper- or hypoactive HPA axis may be explained by the moderating effect of childhood adverse experiences (ACE) which are associated with both HPA axis dysfunction and MDD in adulthood. We aimed to systematically disentangle the effects of ACE and MDD on HPA axis by comparing healthy women with and without childhood adversity and women with MDD with and without ACE. METHODS The dexamethasone/corticotropin-releasing hormone (DEX/CRH) test was administered in 35 women with MDD and ACE as determined by a clinical interview (SCID, Early Trauma Inventory), 51 women with MDD without ACE, 21 women with ACE but no current or lifetime MDD and 37 healthy women without either MDD or ACE. RESULTS There were no group differences in age, smoking, body mass index, and intake of oral contraceptives. Free salivary cortisol responses were not significantly different between the four groups. CONCLUSIONS This study shows no evidence for a dysregulation of the HPA axis as measured by the DEX/CRH test in depressed women with and without childhood adversity as compared to mentally healthy women with or without early life stress. Our results do not support the assumption of distinct neuroendocrine endophenotypes in MDD with regard to ACE.

Major depression and atrial natriuretic peptide: the role of adverse childhood experiences

Atrial natriuretic peptide (ANP) exerts anxiolytic effects in animals and humans. Patients with anxiety, trauma-associated and depressive disorders exhibit lower ANP plasma levels compared to healthy individuals. However, the role of ANP in patients with major depressive disorder (MDD) with and without concomitant adverse childhood experiences (ACE) and in healthy individuals with and without ACE is not clear. We recruited a total of 93 women: 23 women with MDD and ACE, 24 women with MDD without ACE, 22 women with ACE but no current or lifetime MDD, and 24 healthy women without ACE. ANP plasma levels were measured with a radioimmunoassay. The four groups did not differ in demographic and clinical variables. We found a positive correlation between age and plasma levels of ANP (r = .39; p <  .001). After controlling for age, there was no significant main effect of MDD or ACE on ANP plasma levels, but a significant interaction between MDD and ACE such that ACE was associated with reduced basal ANP levels in the absence of MDD. We assume that low plasma ANP might be a consequence of ACE in the absence of current psychopathology. Therefore, future studies are needed to replicate our findings and to characterize the influencing factors of ACE on ANP more comprehensively, for example by including a comprehensive trauma and comorbidity anamnesis as well as cardiovascular state and risk factors.

Altered Cellular Immune Reactivity in Traumatized Women with and without Major Depressive Disorder

Alterations of the hypothalamic-pituitary-adrenal (HPA) axis such as altered glucocorticoid receptor sensitivity and increased immune reactivity might contribute to the pathogenesis of major depressive disorder (MDD). Exposure to adverse childhood experiences (ACE) precipitates vulnerability to MDD and might be associated with endocrine and immune alterations in the disorder. In order to disentangle the effects of ACE and MDD, we recruited 87 women: n = 23 with MDD and ACE as determined by clinical interview and questionnaires (Structured Clinical Interview for DSM-IV, Early Trauma Inventory, Childhood Trauma Questionnaire), n = 24 with MDD without ACE, n = 21 with ACE but no current or lifetime MDD, and n = 26 healthy women without either MDD or ACE. Glucocorticoid signaling and mitogen-stimulated proliferation were analyzed ex vivo in peripheral blood-derived mononuclear cells. Additionally, mRNA expression of the glucocorticoid and the mineralocorticoid receptor (GR / MR) was assessed. Peripheral GR sensitivity as well as GR and MR expression levels were not significantly different between groups. Women with ACE showed an increased immune response after mitogen stimulation independent of the presence of MDD. Our results provide evidence for a functionally altered ex-vivo immune response in cell cultures from women with a history of ACE. Thus, ACE might contribute to the pathogenesis of MDD through inflammatory pathways.

Are adverse childhood experiences and depression associated with impaired glucose tolerance in females? An experimental study

Adverse childhood experiences (ACE) enhance the risk for mental disorders, e.g. major depressive disorder (MDD). Increasing evidence suggests an association between ACE and impaired physical health, e.g. metabolic syndrome. The aim of this study was to assess several metabolic risk markers in healthy individuals with and without ACE and depressed patients with and without ACE. We examined glucose and insulin release in the oGTT in 33 women with MDD and ACE, 47 women with MDD without ACE, 21 women with ACE but no current or lifetime MDD and 36 healthy women without either MDD or ACE. Several metabolic markers such as triglycerides, cholesterol, LDL, HDL, HbA1c, BMI and waist to hip ratio were assessed. The four groups did neither differ in insulin release and glucose concentrations in the oGTT nor with respect to other metabolic variables. Depressed patients with and without psychotropic medication did not differ in any outcome variable, but there was a trend towards higher glucose concentrations in the oGTT in patients with current psychotropic medication. In this physically healthy sample neither ACE nor MDD were associated with metabolic risk factors. Thus, metabolic alterations might not directly be linked to ACE and depression.

Cognitive function in patients with primary adrenal insufficiency (Addison's disease) and the role of mineralocorticoid receptors.

a decrease of omissions. Analogously, after the TSST, participants showed a decreases of the correct trials and an increase of omissions. In addition tobehavioral results,we found that theoscillatory activity in alpha (8–12Hz) and gamma bands (30–70Hz) were different in both conditions. Behavioral and electrophysiological results, suggest that psychosocial stress directs the attention internally, limiting the attentional resources for attending the external demands and inducing cognitive failures.