Faculty Bibliography

Acute stress affects interoception, but it remains unclear if this is due to activation of the sympatho-adreno-medullary (SAM) or hypothalamic-pituitary-adrenocortical axis. This study aimed to investigate the effect of SAM axis activation on interoceptive accuracy (IAcc). Central alpha2-adrenergic receptors represent a negative feedback mechanism of the SAM axis. Major depressive disorder and adverse childhood experiences (ACE) are associated with alterations in the biological stress systems, including central alpha2-adrenergic receptors. Here, healthy individuals with and without ACE as well as depressive patients with and without ACE (n = 114; all without antidepressant medication) were tested after yohimbine (alpha2-adrenergic antagonist) and placebo. We assessed IAcc and sensibility in a heartbeat counting task. Increases in systolic and diastolic blood pressure after yohimbine confirmed successful SAM axis activation. IAcc decreased after yohimbine only in the healthy group with ACE, but remained unchanged in all other groups (Group × Drug interaction). This effect may be due to selective upregulation of alpha2-adrenergic receptors after childhood trauma, which reduces capacity for attention focus on heartbeats. The sympathetic neural pathway including alpha2-adrenergic circuitries may be essential for mediating interoceptive signal transmission. Suppressed processing of physical sensations in stressful situations may represent an adaptive response in healthy individuals who experienced ACE.

In this pilot study, we explored the immune phenotype of patients with severe obesity and comorbid depressive symptoms compared to non-depressed patients with obesity and normal-weight controls. Immune cell subsets were analysed by flow cytometry and depressive symptoms assessed using the Patient Health Questionnaire (PHQ-9). Cell frequencies were correlated with depressive symptom scores and waist-to-hip ratio (WHR). Patients with obesity and comorbid depression showed significantly lower numbers of circulating cytotoxic natural killer cells, dendritic cells and CD8⁺ effector memory T cells, compared to normal-weight controls. Regulatory T cells and CD4⁺ central memory T cells were increased compared to non-depressed patients with obesity and compared to normal-weight controls, respectively. Frequencies of cytotoxic natural killer cells and CD4⁺ central memory T cells significantly correlated with PHQ-9 scores, but not with WHR. Reduced numbers of dendritic cells were observed in both patient groups with obesity and correlated with PHQ-9 scores and WHR. These findings provide evidence for an altered immune composition in comorbid obesity and depression, supporting a pathobiological overlap between the two disorders.

Posttraumatic stress disorder (PTSD) is characterized by alterations in the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS). There is evidence for a blunted HPA axis reactivity to psychosocial stress. Less is known about how the SNS reacts to psychosocial stress. Here, we compared the HPA axis and SNS responses to psychosocial stress and a non-stressful condition in patients with PTSD and in healthy individuals. Twenty-one women with PTSD and 32 healthy women participated in the Trier social stress test (TSST) and placebo TSST (P-TSST). We measured salivary cortisol, alpha amylase activity and blood pressure before and after the tests. Subjective perceived stress response was also assessed. We found a blunted cortisol response to the TSST in patients with PTSD compared with healthy participants 10 min (t (51) = -2.58, p = .01) and 25 min (t (51) = -2.16, p = .04) after TSST. We found no evidence for an increased SNS reactivity after psychosocial stress in patients with PTSD (all p > .05). Patients with PTSD, but not healthy participants, reported more dissociative symptoms (t (20) = -2.31, p = .03) and being more tired (t (20) = 2.90, p = .01) directly after TSST compared with the placebo condition. Our results suggest a blunted HPA stress reactivity and an increased subjective perceived stress response in female patients with PTSD. Longitudinal studies could test if these altered stress responses constitute a predisposition to or a cause of PTSD. Future studies should investigate whether these results are transferable to men.

Background: Adverse childhood experiences (ACE) are associated with an increased risk of major depressive disorder (MDD) and hypothalamic-pituitary-adrenal (HPA) axis dysregulation. Within the HPA axis, corticotropin-releasing hormone and vasopressin (AVP) synergistically stimulate the release of adrenocorticotropic hormone, which promotes cortisol release. The cleavage product copeptin is produced during AVP synthesis and is a surrogate marker of AVP release. Children with ACE and young adults with depressive symptoms have higher levels of copeptin than healthy controls. Objective: To uncover the effects of MDD and ACE on copeptin levels in adult females. Methods: We recruited 94 women (mean age: 34.0 ± 3.6 years): 23 with MDD and ACE, 24 with MDD without ACE, 22 with ACE without MDD, and 25 healthy controls. ACE was defined as repeated sexual or physical abuse at least once a month over at least one year before the age of 18 years. MDD was defined by the DSM-IV criteria. Copeptin plasma levels were measured with an immunoluminometric assay. Results: The four groups did not differ in demographic variables. We found a significant negative correlation between body mass index (BMI) and copeptin plasma levels (r = -.21; p = .045). Copeptin plasma levels did not differ between the four groups after controlling for BMI. Conclusion: Neither MDD nor ACE was associated with altered plasma copeptin levels. Thus, copeptin does not seem to play a major role in MDD and ACE in adult females.

INTRODUCTION:Many studies have investigated the influence of stress on decision-making. However, results are equivocal and the exact role of increased noradrenaline and cortisol after stress remains unclear. Using pharmacological manipulation, we investigated the influence of noradrenergic and glucocorticoid activity on risky decision-making in a gambling task that included mixed-gamble trials (gains and losses are possible) and gain-only trials. METHODS AND MATERIALS:One hundred-and-four healthy young men participated in our randomized, double-blind, placebo-controlled, between-group study. Participants were randomly assigned to one of four groups: (A) yohimbine, (B) hydrocortisone, (C) yohimbine and hydrocortisone, or (D) placebo. Frequency of risky choices, i.e., monetary risk taking, was the dependent variable. We also investigated the influence of hydrocortisone and yohimbine on loss aversion, which is the tendency to overweigh losses compared with gains. RESULTS:Participants chose the risky option less often after receiving hydrocortisone compared with no hydrocortisone. This effect was strongest in the gain-only trials. Yohimbine had no effect. Loss aversion was not affected by hydrocortisone or yohimbine. DISCUSSION:Decreased reward processing may explain the reduction of risk taking by hydrocortisone in gain-only trials. The effects of stress hormones on different decision-related constructs and processes hence require further investigation.

BACKGROUND:Across psychopathologies, trauma-exposed individuals suffer from difficulties in inhibiting emotions and regulating attention. In trauma-exposed individuals without psychopathology, only subtle alterations of neural activity involved in regulating emotions have been reported. It remains unclear how these neural systems react to demanding environments, when acute (non-traumatic but ordinary) stress serves to perturbate the system. Moreover, associations with subthreshold clinical symptoms are poorly understood. METHODS:The present fMRI study investigated response inhibition of emotional faces before and after psychosocial stress situations. Specifically, it compared 25 women (mean age 31.5 ± 9.7 years) who had suffered severe early life trauma but who did not have a history of or current psychiatric disorder, with 25 age- and education-matched trauma-naïve women. RESULTS:Under stress, response inhibition related to fearful faces was reduced in both groups. Compared to controls, trauma-exposed women showed decreased left inferior frontal gyrus (IFG) activation under stress when inhibiting responses to fearful faces, while activation of the right anterior insula was slightly increased. Also, groups differed in brain-behaviour correlations. Whereas stress-induced false alarm rates on fearful stimuli negatively correlated with stress-induced IFG signal in controls, in trauma-exposed participants, they positively correlated with stress-induced insula activation. CONCLUSION:Neural facilitation of emotion inhibition during stress appears to be altered in trauma-exposed women, even without a history of or current psychopathology. Decreased activation of the IFG in concert with heightened bottom-up salience of fear related cues may increase vulnerability to stress-related diseases.

Major depressive disorder (MDD) has been associated with changes in the biological stress systems, including the locus coeruleus-noradrenergic system. Accumulated evidence suggests an upregulation of central alpha2-receptors, leading to decreased noradrenergic activity on a central level in MDD patients. Adverse childhood experiences (ACE) such as physical or sexual abuse might contribute to those changes. Furthermore, noradrenaline can affect cognitive processes, e.g. learning and memory. Cognitive dysfunctions constitute an important symptom of MDD. We aimed to investigate the relationship of alpha2-receptor dysregulation with learning processes in MDD by conducting a differential fear conditioning paradigm after double-blind administration of the alpha2-receptor antagonist yohimbine versus placebo. To investigate the role of ACE systematically, we included four groups of healthy participants and MDD patients with and without ACE (MDD-/ACE-: N = 44, MDD-/ACE+: N = 26, MDD+/ACE-: N = 24, MDD+/ACE+: N = 24; without antidepressant medication). We found increased noradrenergic activity after yohimbine administration across groups as measured by alpha-amylase and blood pressure. Overall, fear responses were higher after yohimbine as indicated by skin conductance responses and fear-potentiated startle responses. While we found no significant MDD effect, ACE had significant impact on the ability to discriminate between both conditioned stimuli (CS+ predicting an aversive stimulus, CS- predicting none), depending on drug condition. After yohimbine, CS discrimination decreased in individuals without ACE, but not in individuals with ACE. Differences in the response to yohimbine might be explained by aberrant alpha2-receptor regulation in individuals with ACE. Impaired discrimination of threat and safety signals might contribute to enhanced vulnerability following ACE.

Many patients with depression do not respond sufficiently to antidepressant treatment, necessitating other treatment approaches. HMG-CoA reductase inhibitors (i.e. statins), which are frequently used for their cardioprotective properties, have also been studied regarding potential antidepressant effects. Possible mechanisms underlying an antidepressant effect of statins may include the anti-inflammatory, antioxidant and lipid lowering properties of this class of drugs. This review provides an overview of this field by reviewing the following aspects: 1) Candidate mechanisms that could mediate putative antidepressant effects of statins; 2) The evidence for and against antidepressant effects of statins in patients with major depressive disorder and among individuals with a medical disease and depressive symptoms; and 3) The safety of statin treatment. Three small placebo-controlled trials conducted in Iran (total N=172) have found that statins as add-on to selective serotonin reuptake inhibitors (SSRIs) have antidepressant effects in patients with major depressive disorder (MDD). Statin treatment in individuals without MDD do not seem to affect mood or protect against development of depression. Treatment with statins - including the combination with SSRIs - is generally considered to be safe. While the initial evidence for the antidepressant effect of the combination of an SSRI and a statin is promising, larger clinical trials, appropriately powered, and with depression as a pre-defined primary endpoint are needed.

Objective: Multiple sclerosis (MS) is characterized by impairments in basic cognitive functions such as information processing speed as well as in more complex, higher-order domains such as social cognition. However, as these deficits often co-occur, it has remained challenging to determine whether they have a specific pathological basis or are driven by shared biology. Methods: To identify neural signatures of social cognition deficits in MS, data were analyzed from n = 29 patients with relapsing-remitting MS and n = 29 healthy controls matched for age, sex, and education. We used neuropsychological assessments of information processing speed, attention, learning, working memory, and relevant aspects of social cognition (theory of mind, emotion recognition (ER), empathy) and employed neuroimaging of CNS networks using resting-state functional connectivity. Results: MS patients showed significant deficits in verbal learning and memory, as well as implicit ER. Performance in these domains was uncorrelated. Functional connectivity analysis identified a distinct network characterized by significant associations between poorer ER and lower connectivity of the fusiform gyrus (FFG) with the right lateral occipital cortex, which also showed lower connectivity in patients compared to controls. Moreover, while ER was correlated with MS symptoms such as fatigue and motor/sensory functioning on a behavioral level, FFG connectivity signatures of social cognition deficits showed no overlap with these symptoms. Conclusions: Our analyses identify distinct functional connectivity signatures of social cognition deficits in MS, indicating that these alterations may occur independently from those in other neuropsychological functions.

BACKGROUND:While electroconvulsive therapy (ECT) is considered the gold standard for acute treatment of patients with otherwise treatment-resistant depression, ketamine has recently emerged as a fast-acting treatment alternative for these patients. Efficacy and onset of action are currently among the main factors that influence clinical decision making, however, the effect of these treatments on cognitive functions should also be a crucial point, given that cognitive impairment in depression is strongly related to disease burden and functional recovery. ECT is known to induce transient cognitive impairment, while little is known about ketamine's impact on cognition. This study therefore aims to compare ECT and serial ketamine administration not only with regard to their antidepressant efficacy but also to acute neurocognitive effects. METHODS:Fifty patients suffering from depression were treated with either serial ketamine infusions or ECT. Depression severity and cognitive functions were assessed before, during, and after treatment. RESULTS:ECT and ketamine administration were equally effective, however, the antidepressant effects of ketamine occurred faster. Ketamine improved neurocognitive functioning, especially attention and executive functions, whereas ECT was related to a small overall decrease in cognitive performance. CONCLUSIONS:Due to its pro-cognitive effects and faster antidepressant effect, serial ketamine administration might be a more favorable short-term treatment option than ECT. LIMITATIONS:As this research employed a naturalistic study design, patients were not systematically randomized, there was no control group and patients received concurrent and partially changing medications during treatment. CLINICAL TRIALS REGISTRATION:Functional and Metabolic Changes in the Course of Antidepressive Treatment, https://clinicaltrials.gov/ct2/show/NCT02099630, NCT02099630.