Faculty Bibliography

OBJECTIVE:To investigate the association between childhood trauma and multiple sclerosis (MS) by comparing histories of child abuse and neglect between patients with MS and adults from the general population in a cross-sectional case-control study. Previous research has demonstrated a connection between MS and a variety of emotional stressors, but childhood trauma, which is known to have long-lasting negative consequences for physical health decades into adulthood, has not been studied. METHODS:The self-reported Childhood Trauma Questionnaire for the assessment of emotional, physical, and sexual abuse and emotional and physical neglect was administered to 234 patients with definite MS and 885 adults from the general population. RESULTS:After adjusting for sociodemographic factors and current depression, patients with MS scored significantly higher in all Childhood Trauma Questionnaire subscales apart from physical abuse and neglect than adults from the general population. Adjusted odds ratios for these types of childhood trauma were higher in the MS group than in controls, ranging from 2.0 for emotional neglect (95% confidence interval = 1.3-3.2) to 3.4 for emotional abuse (95% confidence interval = 2.0-5.7). Although childhood trauma was not associated with the degree of current MS-related disability, patients with MS with histories of physical and/or sexual abuse had significantly higher relapse rates than patients without early-life stress. CONCLUSIONS:Our findings suggest an association between childhood trauma and MS in this cross-sectional study. Larger prospective longitudinal studies are needed to clarify the relationship between early-life stress and the risk for MS in genetically susceptible individuals.

BACKGROUND:Statins are among the most commonly prescribed medications worldwide. Although their benefits for cardiovascular disease are well established, the effects of statins on depressive symptoms are unknown. METHOD/METHODS:We examined the association between baseline statin use (2000-2002) and subsequent depressive symptoms in a prospective cohort study of 965 outpatients with coronary disease from 12 outpatient clinics in the San Francisco Bay Area. Depressive symptoms were assessed annually for 6 years using the Patient Health Questionnaire (PHQ) (primary outcome measure). We evaluated the cross-sectional association between statin use and risk of depressive symptoms at baseline and the longitudinal association between baseline statin use and risk of depressive symptoms during follow-up. RESULTS:Of the 965 participants, 629 (65%) used statins. At baseline, statin users had lower mean ± SE PHQ depression scores than nonusers (4.8 ± 0.2 vs 5.9 ± 0.3, P < .01). Statin users were less likely than nonusers to have depression (PHQ score ≥ 10) at baseline (17% vs 24%; P = .02) and during follow-up (28% vs 40%; P < .01). Among the 776 patients without depressive symptoms at baseline (PHQ < 10), statin use was associated with a 48% decreased odds of developing depression during follow-up (odds ratio [OR], 0.52; 95% CI, 0.38-0.73; P < .01). After we adjusted for potentially confounding variables, statin use remained associated with a 38% decreased odds of subsequent depression (adjusted OR, 0.62; 95% CI, 0.41-0.95; P = .02). CONCLUSIONS:We found that statin use was associated with a decreased risk of subsequent depressive symptoms in patients with coronary heart disease. Whether use of statins prevents depressive symptoms deserves further study.

BACKGROUND:In the present study, we aimed to compare the effect of exogenous cortisol on memory retrieval in posttraumatic stress disorder (PTSD) with the effects in healthy controls. In healthy participants, administration of cortisol impairs declarative memory retrieval. Only a few studies have investigated these effects in PTSD yielding mixed results. METHODS:In a placebo-controlled crossover study, 44 patients with PTSD and 65 healthy controls received either placebo or 10mg of hydrocortisone orally before memory testing. In addition to declarative memory retrieval (word list learning), we also tested autobiographical memory retrieval specificity. RESULTS:In both tasks opposing effects of cortisol on memory were observed when comparing patients with controls. In controls, cortisol had impairing effects on memory retrieval, while in PTSD patients cortisol had enhancing effects on memory retrieval in both memory domains. CONCLUSIONS:The present results suggest beneficial effects of acute cortisol elevations on hippocampal mediated memory processes in PTSD. Possible neurobiological mechanisms underlying these findings are discussed.

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the CNS with a high prevalence of depression. Both MS and depression have been linked to elevated cortisol levels and inflammation, indicating disturbed endocrine-immune regulation. An imbalance in mineralocorticoid versus glucocorticoid signaling in the CNS has been proposed as a pathogenetic mechanism of depression. Intriguingly, both receptors are also expressed in lymphocytes, but their role for 'escape' of the immune system from endocrine control is unknown. Using steroid sensitivity of T cell function as a read-out system, we here investigate a potential role of mineralocorticoid receptor (MR) versus glucocorticoid receptor (GR) regulation in the immune system as a biological mechanism underlying MS-associated major depression. Twelve female MS patients meeting diagnostic criteria for current major depressive disorder (MDD) were compared to twelve carefully matched MS patients without depression. We performed lymphocyte phenotyping by flow cytometry. In addition, steroid sensitivity of T cell proliferation was tested using hydrocortisone as well as MR (aldosterone) and GR (dexamethasone) agonists. Sensitivity to hydrocortisone was decreased in T cells from depressed MS patients. Experiments with agonists suggested disturbed MR regulation, but intact GR function. Importantly, there were no differences in lymphocyte composition and frequency of T cell subsets, indicating that the differences in steroid sensitivity are unlikely to be secondary to shifts in the immune compartment. To our knowledge, this study provides first evidence for altered steroid sensitivity of T cells from MS patients with comorbid MDD possibly due to MR dysregulation.

BACKGROUND:Alterations of the hypothalamus-pituitary-adrenal (HPA) axis are hallmarks in major depressive disorder (MDD) and there is some evidence about similar patterns in borderline personality disorder (BPD). This study examines HPA axis abnormalities with respect to clinical characteristics in both BPD (n=24) and MDD patients (n=33) as well as in healthy control participants (n=41). METHOD/METHODS:A 0.5mg dexamethasone suppression test was administered to evaluate basal cortisol release and HPA feedback sensitivity via salivary cortisol. Traumatic experiences in childhood as well as severity of borderline and depressive symptom severity and dissociation were obtained by self-report questionnaires. RESULTS:Compared to the healthy control group, BPD and MDD patients exhibited both enhanced cortisol concentrations before and after the administration of 0.5mg dexamethasone. Higher cortisol levels were positively correlated to a history of childhood trauma, current dissociative symptoms and severity of borderline and depressive symptoms. Regression analyses revealed that some aspects of early trauma were associated with cortisol release before and after dexamethasone, whereas psychopathology did not contribute to the regression model. CONCLUSIONS:HPA dysfunctions appear to be related rather to childhood trauma than to psychopathology in adulthood. Exposure to childhood trauma may contribute to long-lasting alterations in HPA activity and might enhance the risk for the development of later mental disorder.

Depression is associated with increased cortisol secretion and occurs more often in women than in men. Thus, it has been hypothesized that differences in cortisol secretion might, in part, be responsible for the greater risk of developing depression in women. However, only few studies have examined sex differences in baseline cortisol secretion in depressed patients and healthy controls. We examined sex effects on cortisol secretion in 52 medication-free patients with major depression (37 women, 15 men, mean +/- SD age 35 +/- 11 years, Hamilton Depression Scale mean score 27 +/- 5) and 50 healthy age- and sex-matched control subjects. Salivary cortisol concentrations were measured at 8:00, 12:00, 16:00, and 22:00 h. Repeated measures analysis of covariance revealed a group x sex interaction (p = 0.05). Post hoc tests revealed higher cortisol concentrations in depressed compared to healthy men [F(1;29) = 7.5, p = 0.01]. No differences were found between depressed and non-depressed women. Our results do not support the hypothesis that differences in cortisol secretion between depressed and non-depressed subjects are more pronounced in women than in men. Study characteristics and methods as well as sex-specific confounding variables such as menstrual cycle, menopause and the use of oral contraceptives may account for inconclusive results across studies

A plethora of studies have examined the efficacy and effectiveness of cognitive-behavioral therapy (CBT) for adult anxiety disorders. In recent years, several meta-analyses have been conducted to quantitatively review the evidence of CBT for anxiety disorders, each using different inclusion criteria for studies, such as use of control conditions or type of study environment. This review aims to summarize and to discuss the current state of the evidence regarding CBT treatment for panic disorder, generalized anxiety disorder, social anxiety disorder, obsessive-compulsive disorder, and post-traumatic stress disorder. Overall, CBT demonstrates both efficacy in randomized controlled trials and effectiveness in naturalistic settings in the treatment of adult anxiety disorders. However, due to methodological issues, the magnitude of effect is currently difficult to estimate. In conclusion, CBT appears to be both efficacious and effective in the treatment of anxiety disorders, but more high-quality studies are needed to better estimate the magnitude of the effect.

BACKGROUND: The hypothalamic-pituitary-adrenal axis is a major stress response system hypothesized to be involved in the pathogenesis of posttraumatic stress disorder (PTSD). However, few studies have prospectively examined the relationships among pre-exposure hypothalamic-pituitary-adrenal activity, acute stress reactions and PTSD. METHODS: Two hundred ninety-six police recruits were assessed during academy training before critical incident exposure and provided salivary cortisol at first awakening and after 30 minutes. A measure of cortisol awakening response (CAR) was computed as the change in cortisol level from the first to the second collection. At 12, 24, and 36 months following the start of active police service, officers were assessed for peritraumatic distress, peritraumatic dissociation, acute stress disorder (ASD) symptoms, and PTSD symptoms to their self-identified worst duty-related critical incident. Mixed models for repeated measures were used to analyze the effects of CAR on the outcome variables pooled across the three follow-up assessments. RESULTS: After controlling for time of awakening, first awakening cortisol levels, and cumulative critical incident stress exposure, CAR during academy training was associated with greater peritraumatic dissociation, beta = .14, z = 3.49, p < .0001, and greater ASD symptoms during police service assessed at 12, 24, and 36 months, beta = .09, Z = 2.03, p < .05, but not with peritraumatic distress, beta = .03, z = .81, p = .42, or PTSD symptoms, beta = -.004, z = -.09, p = .93. CONCLUSIONS: These findings suggest that greater cortisol response to awakening is a pre-exposure risk factor for peritraumatic dissociation and ASD symptoms during police service

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

OBJECTIVE: Depression and fatigue are among the most common symptoms of multiple sclerosis (MS). These symptoms frequently co-occur and partially overlap in MS but their underlying biological substrates are unclear. In this study, the relative role of cytokines and hypothalamic-pituitary-adrenal (HPA) axis activity in depression and fatigue were examined in patients with relapsing-remitting MS (RRMS). METHODS: HPA axis function and frequency of stimulated cytokine (interferon gamma (IFNgamma) and tumour necrosis factor alpha (TNFalpha)) producing T cells was measured cross sectionally in 44 female patients with RRMS. All subjects completed a neurological examination, the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) and self-report questionnaires. RESULTS: 10 patients met diagnostic criteria for major depressive disorder (MDD). MS patients with comorbid MDD showed normal morning but elevated evening salivary cortisol levels, resulting in a flattened slope. While a higher frequency of cytokine producing CD8+ T cells was also seen in MS patients with MDD, these markers were more closely associated with fatigue than depression. CONCLUSIONS: This study supports a role for HPA axis hyperactivity in major depression in MS. In addition, inflammatory and neuroendocrine factors may differentially mediate fatigue and depressive symptoms