Christoph Muhtz

Introducing a novel method to assess cumulative steroid concentrations: Increased hair cortisol concentrations over 6 months in medicated patients with depression

Depression has been linked to increased cortisol concentrations using point measures taken from urine, blood, or saliva samples. However, with regard to hypercortisolism-induced consequences, long-term cumulative cortisol burden is of relevance. Our objective was to use hair analysis as a new method to assess cortisol exposure over 6 months in depressed patients and healthy controls. We examined 23 depressed patients (8 men and 15 women, mean age: 41.6 years ( ± standard deviation (SD), 13.1 years); mean duration of current depressive episode 9 months ( ± SD, 13 months)) and 64 healthy controls, matched for age and gender. Cortisol concentrations in two 3-cm hair segments from near to the scalp were analyzed, representing cortisol secretion during the 6 months prior to sampling. Compared with healthy individuals, depressed patients had higher hair cortisol concentrations in the first (mean ± SD: 26.7 ± 20.8 vs. 18.7 ± 11.5 pg/mg, p < 0.05) and second hair segment (mean ± SD: 21.9 ± 23.7 vs. 13.4 ± 9.6 pg/mg, p < 0.05). In conclusion, hair cortisol analysis confirmed enhanced cortisol secretion in depressed patients over a prolonged time period. Because of the retrospective and cumulative nature of cortisol in hair, the assessment of hair cortisol concentration may help in addressing unanswered questions regarding hypothalamic–pituitary–adrenal axis overactivity and associated health consequences in psychiatric disorders.

Depressive symptoms and metabolic risk: Effects of cortisol and gender

We examined gender effects and the role of cortisol in the association between depressive symptoms and metabolic risk in the Stress, Atherosclerosis, and ECG Study (STRATEGY). In 215 healthy adults from the general population (n=107 men, n=108 women, distributed equally across four age groups, 30-70 years), we assessed depressive symptoms by the Patient Health Questionnaire (PHQ score >10) and measured variables of the metabolic syndrome: high-density lipoprotein (HDL), triglycerides, systolic and diastolic blood pressure, fasting blood glucose and waist circumference. Salivary cortisol was assessed at 08:00, 12:00, 16:00 and 22:00 h. Depressive symptoms were not associated with the metabolic syndrome as entity in the total sample or in men and women separately. However, women with depressive symptoms had larger waist circumferences, higher fasting blood glucose, lower HDL-cholesterol, higher diastolic blood pressure, and higher 16:00 and 22:00 h salivary cortisol compared to women without depressive symptoms. These results persisted after adjusting for age, education, smoking, and physical activity. In adjusted regression analyses, inclusion of cortisol attenuated the association between depressive symptoms and waist, fasting glucose, HDL and diastolic blood pressure in women. In men, we did not find an association between depressive symptoms and variables of the metabolic syndrome. In women, depressive symptoms are associated with several variables of the metabolic syndrome. Elevated afternoon and evening cortisol appear to partially mediate this association.

Effects of acute cortisol administration on autobiographical memory in patients with major depression and healthy controls

OBJECTIVE Overgeneral autobiographical memory has become a well established phenomenon within major depressive disorder (MDD). Neuroendocrinologically, MDD is often characterized by a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, i.e. hypercortisolemia and reduced feedback sensitivity. In healthy participants cortisol administration has been found to impair autobiographical memory retrieval. The purpose of this study was to compare the effects of acute cortisol administration on autobiographical memory in MDD patients with the effects observed in healthy controls. We hypothesized that in contrast to healthy control subjects acute cortisol administration would not affect autobiographical memory performance in MDD due to reduced central glucocorticoid sensitivity. METHODS In a placebo-controlled, double-blind crossover study, 16 patients with MDD and 16 healthy control subjects received a placebo or 10mg of hydrocortisone orally before autobiographical memory testing (AMT). RESULTS In the placebo condition depressed patients performed poorer than controls. After hydrocortisone intake, healthy subjects reported significantly fewer specific memories on the AMT compared to placebo treatment. In contrast, memory specificity of MDD patients was not affected by hydrocortisone treatment. CONCLUSIONS The present findings replicate previous findings of impaired autobiographical memory retrieval after hydrocortisone treatment in healthy subjects and of impaired AMT performance in depressed patients. We speculate that the missing acute impairing effect of hydrocortisone on autobiographical memory in depressed patients might reflect reduced central glucocorticoid sensitivity. However alternative explanations cannot be ruled out.

Increased DHEA and DHEA-S plasma levels in patients with post-traumatic stress disorder and a history of childhood abuse

Current findings about dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulphate (DHEA-S) in patients with post-traumatic stress disorder (PTSD) have been inconsistent. We investigated whether a history of severe childhood traumatisation affects these steroids in PTSD patients. Patients of 33 with chronic PTSD (15 with and 18 without sexual and/or severe physical abuse before age 12) were studied in a combined low dose dexamethasone/corticotropin-releasing hormone (CRH) test. Mean pre-CRH levels of both plasma DHEA and DHEA-S were significantly increased in the subgroup with childhood abuse, the respective ratios with plasma cortisol were significantly lower. In the entire population of PTSD patients significant amounts of the variation of these parameters could be explained by childhood trauma history. Further studies are needed to clarify the potential role of DHEA and DHEA-S as biomarkers for severe early adverse events in patients suffering from PTSD and in other stress-related disorders.

Changes in cortisol secretion during antidepressive treatment and cognitive improvement in patients with major depression: A longitudinal study

OBJECTIVES We have previously reported that cognitive deficits are cross-sectionally associated with elevated cortisol in depressed patients. Here, we longitudinally examined if changes in cortisol secretion during treatment are associated with improvement of cognition. METHODS Cognitive function and salivary cortisol levels were longitudinally examined in 52 patients with major depression before and after 3 weeks of standardized selective serotonin reuptake inhibitor (SSRI) and an add-on treatment modulating the mineralocorticoid receptor and compared to a healthy control group (n=50) matched for age, gender and years of education. RESULTS Across add-on treatment groups, SSRI treatment reduced salivary cortisol in patients to levels of healthy controls (time×group interaction p=.05). In patients, reduction of cortisol significantly correlated with improvement in depressive symptoms (r=.52, p<.01), speed of information processing (r=.50, p<.01), and cognitive set-shifting (r=.34, p=.03). Improved depressive symptoms were only associated with improved attention and working memory. CONCLUSIONS Improvement of some cognitive domains during SSRI treatment was associated with decreasing cortisol secretion and was only to a lesser extent associated with improved depressive symptoms.

Hair cortisol and cortisol awakening response are associated with criteria of the metabolic syndrome in opposite directions.

Findings on the association between hypothalamic-pituitary-adrenal (HPA) axis activity and metabolic risk are equivocal. Different methods of measuring HPA activity might indicate adverse vs. beneficial effects of HPA activity on metabolic risk thus contributing to heterogenous findings. In this study, we aimed to determine whether (1) the salivary cortisol awakening response (CAR) as a marker of awakening-induced activation of the HPA axis and (2) hair cortisol as a marker of long-term cortisol secretion are associated with criteria of the metabolic syndrome. Therefore, we recruited 41 healthy individuals (26 women, mean age: 41.2 years) and 44 patients with major depression (28 women, 41.4 years) and assessed CAR and hair cortisol values as well as all criteria of the metabolic syndrome (abdominal obesity, blood pressure, plasma glucose, triglycerides and high-density cholesterol levels) according to the International Diabetes Federation. CAR and hair cortisol values were divided into tertiles. Across groups, participants with hair cortisol or hair cortisone in the highest tertile showed significantly more criteria of the metabolic syndrome compared to participants in the medium or low tertile (F2,64=3.37, p=.04). These results were corroborated by significant positive correlations between mean hair cortisol values with waist circumference (r=.29, p=.03), triglycerides (r=.34, p=.01) and systolic blood pressure (r=.29, p=.04) and between mean hair cortisone and triglycerides (r=.46, p<.01). In contrast, mean CAR values correlated negatively with diastolic (r=-.29, p=.03) and systolic blood pressure (r=-.32, p=.02). Our results indicate that higher hair cortisol and hair cortisone levels but lower CAR values are associated with an unfavorable metabolic and cardiovascular risk profile.

Cortisol Response to Experimental Pain in Patients with Chronic Low Back Pain and Patients with Major Depression

OBJECTIVE Chronic pain and major depression have been associated with alterations of the hypothalamus-pituitary-adrenal axis (HPA) activity. Previous studies suggested that HPA activity is diminished in chronic pain but increased in depression. However, little is known about the effects of experimentally induced acute pain on cortisol secretion in patients with chronic pain and depression. METHODS On three different occasions (day 1, day 8, day 90), we repeatedly examined 20 patients with chronic low back pain without depression, 22 patients with major depression without pain, and 33 healthy subjects using heat stimuli. Pain intensity was rated by participants using a visual analog scale. Salivary cortisol was assessed prior to 10 blocks of repeated painful heat stimuli, and 45 and 60 minutes afterwards. RESULTS In repeated measures analyses of covariance adjusting for age, sex, and time of examination, we found a significant effect of group (P < 0.01) and post-hoc tests confirmed that patients with chronic pain had lower cortisol area-under-the-curve values compared with healthy controls and depressed patients at all time points (all P values <0.01). However, cortisol secretion in depressed patients did not differ from controls. CONCLUSIONS Across groups, experimental heat pain stimuli did not elicit a significant cortisol response. Chronic pain appears to be associated with low cortisol secretion. The mechanisms linking chronic pain with low cortisol deserve further study.

Effects of chronic posttraumatic stress disorder on metabolic risk, quality of life, and stress hormones in aging former refugee children.

It is still unclear whether the association between traumatic stress and physical disease is mediated by posttraumatic stress disorder (PTSD). Therefore, we examined the long-term consequences of PTSD on cardiovascular risk, stress hormones, and quality of life in a sample of former refugee children who were severely traumatized more than six decades ago. In 25 subjects with chronic PTSD and 25 trauma-controlled subjects, we measured the variables of metabolic syndrome supplemented by the ankle-brachial index and highly sensitive C-reactive protein. Quality of life was assessed using the 36-item Short-Form Health Survey. Cortisol, adrenocorticotropin-releasing hormone (ACTH), and dehydroepiandrosterone (DHEA) were measured using the low-dose-dexamethasone suppression test. In addition, salivary cortisol was assessed at 8:00 a.m., 12:00 p.m., 4:00 p.m., and 8:00 p.m. We found a significant group effect between participants with and without PTSD regarding quality of life but not in any metabolic parameter including the ankle-brachial index or cortisol, ACTH, and DHEA in plasma before and after dexamethasone or salivary cortisol. The postulated association between traumatic stress and physical illness does not appear to be mediated by PTSD in this population. Nevertheless, the search for subgroups of PTSD patients with childhood traumatization leading to different metabolic and endocrine long-term consequences in aging PTSD patients is needed.

Langzeitfolgen von in der Kindheit am Ende des II. Weltkrieges erlebter Flucht und Vertreibung

Little is known about long-term consequences of flight and expulsion during childhood. The aim of this study was to interview aging former refugee children about their recollection of traumatic experiences and to screen for full and partial posttraumatic stress disorder (PTSD) and their differential impact on todays quality of life and mental health. In 502 participants from the former German eastern territories who were displaced as children at the end of World War II (at the age of 5-12 years) we examined traumatic experiences, posttraumatic stress symptoms (PDS), comorbid symptoms (SCL-90-R), depressive symptoms (BDI) and quality of life (SF-36). 31.5% participants reported posttraumatic stress symptoms indicating current full PTSD, and 33.7% fulfilled the criteria of a current partial PTSD. Participants with full and partial PTSD reported a significantly reduced quality of life, often depressive and comorbid symptoms and were compromised in their well-being compared to participants without PTSD. The study demonstrates the long-term consequences of flight and expulsion during childhood in aging former refugee children more than 60 years later. Posttraumatic stress symptoms play a prominent role for quality of life and well-being in this population.

Effects of Acute Hydrocortisone Administration on Declarative Memory in Patients With Major Depressive Disorder: A Placebo-Controlled, Double-Blind Crossover Study

OBJECTIVE Major depressive disorder (MDD) has been associated with hypercortisolism, reduced glucocorticoid feedback sensitivity, and impaired memory function. In healthy subjects, administration of hydrocortisone impairs declarative memory. The aim of this study was to examine the effects of acute hydrocortisone administration on memory retrieval in MDD patients and healthy controls. We further tested whether the enhancing or impairing effects of hydrocortisone would prevail when it was given after encoding and when delayed retrieval was tested at a time point when glucocorticoid levels were still elevated. METHOD In a placebo-controlled, double-blind crossover study, 44 patients with DSM-IV MDD and 51 healthy control participants received either placebo or 10 mg of hydrocortisone orally before memory testing. A word list paradigm and the Logical Memory Test from the Wechsler Memory Scale were applied. The study was conducted from April 2008 until April 2010 at sites in Bielefeld and Hamburg, Germany. RESULTS In both memory tests, patients with MDD performed worse than controls. Healthy controls showed impaired memory performance after hydrocortisone administration compared to placebo. In contrast, hydrocortisone had no effects on memory in MDD patients. Furthermore, in healthy controls we found that administration of hydrocortisone immediately after learning did not lead to an enhanced free recall during increased cortisol levels. CONCLUSIONS It appears that the impairing effects of hydrocortisone on memory performance are missing in patients with MDD. This might be interpreted in the context of reduced central glucocorticoid receptor functioning.