Immune signature of multiple sclerosis-associated depression.

Multiple neurobiological pathways have been implicated in the pathobiology of major depressive disorder (MDD). The identification of reliable biological substrates across the entire MDD spectrum, however, is hampered by a vast heterogeneity in the clinical presentation, presumably as a consequence of heterogeneous pathobiology. One way to overcome this limitation could be to explore disease subtypes based on biological similarity such as "inflammatory depression". As such a subtype may be particularly enriched in depressed patients with an underlying inflammatory condition, multiple sclerosis (MS) could provide an informative disease context for this approach. Few studies have explored immune markers of MS-associated depression and replications are missing. To address this, we analyzed data from two independent case-control studies on immune signatures of MS-associated depression, conducted at two different academic MS centers (overall sample size of n = 132). Using a stepwise data-driven approach, we identified CD4+CCR7lowTCM cell frequencies as a robust correlate of depression in MS. This signature was associated with core symptoms of depression and depression severity (but not MS severity per se) and linked to neuroinflammation as determined by magnetic resonance imaging (MRI). Furthermore, exploratory analyses of T cell polarization revealed this was largely driven by cells with a TH1-like phenotype. Our findings suggest (neuro)immune pathways linked to affective symptoms of autoimmune disorders such as MS, with potential relevance for the understanding of "inflammatory" subtypes of depression.

Metacognitive Training for Obsessive-Compulsive Disorder: a study protocol for a randomized controlled trial.

BACKGROUND: A high number of patients with obsessive-compulsive disorder (OCD) do not receive cognitive-behavioral therapy with exposure and response prevention, which is the most effective treatment for OCD. Therefore, Metacognitive Training for OCD (MCT-OCD) was developed, which is a structured group therapy aiming at the modification of dysfunctional (meta-)cognitive biases, beliefs and coping styles. It can be administered by less trained personnel, thus may reach a higher number of patients. An uncontrolled pilot study (MCT-OCD pilot version) provided first evidence that the training is highly accepted by patients; OC symptoms decreased with a high effect size (η2partial = 0.50). The aim of the present study is to address the shortcomings of the pilot study (e.g., no control group) and to assess the efficacy of the revised version of the MCT-OCD in the framework of a randomized controlled trial. METHODS: Eighty patients with OCD will be recruited. After a blinded assessment at baseline (-t1), patients will be randomly assigned either to the intervention group (MCT-OCD; n = 40) or to a care as usual control group (n = 40). The MCT-OCD aims to enhance patients' metacognitive competence in eight modules by addressing dysfunctional (meta-)cognitive biases and beliefs associated with OCD (e.g., intolerance of uncertainty). After 8 weeks, patients will be invited to a post assessment (t1), and then they will receive a follow-up online questionnaire 3 months following t1 (t2). The primary outcome is the Y-BOCS total score, and the secondary outcomes include the HDRS, OCI-R, OBQ-44, MCQ-30, WHOQOL-BREF, BDI-II, and subjective appraisal ratings of the MCT-OCD. We expect that OC symptoms will decrease more in the intervention group compared with the care as usual control group from -t1 to t1 and that treatment gains will be maintained until t2. DISCUSSION: The planned study is the first to investigate the MCT-OCD, a promising new treatment, in a randomized controlled trial. The MCT-OCD may help to overcome existing treatment barriers for patients with OCD. TRIAL REGISTRATION: German Registry for Clinical Studies ( DRKS00013539 ), 22.02.2018.

Session-specific effects of the Metacognitive Training for Obsessive-Compulsive Disorder (MCT-OCD).

Objective: Most studies focus on overall treatment effects by assessing symptom severity before and after treatment, but few investigate session-specific effects of an intervention. The aim of the present study was to elucidate session-specific effects of a group therapy for obsessive-compulsive disorder (OCD) that targets cognitive biases known as the Metacognitive Training for OCD (MCT-OCD).Method: In an uncontrolled pilot trial, 44 inpatients with OCD participated in the MCT-OCD once a week over four weeks. Before and after each session, patients answered questionnaires on thought monitoring, control of thoughts, obsessions, compulsions, and mood.Results: Primary analyses using linear mixed-effect models showed that the module on control of thoughts (within-session effect) significantly reduced patients' control of thoughts. Exploratory analyses displayed an improvement in thought monitoring, control of thoughts, obsessions, and compulsions over the treatment period. Control of thoughts decreaed after the module on biased attention/biased cognitive networks and compulsions reduced one week after the module on overestimation of threat/responsibility (between-session effect). More compulsions were reported one week after the module on thought-action fusion/control of thoughts.Conclusions: Certain MCT-OCD modules seemed to improve specific cognitive biases that might in turn act as mechanisms of change. The results are being used to revise the MCT-OCD.

Blunted autonomic reactivity to pharmacological panic challenge under long-term escitalopram treatment in healthy men.

BACKGROUND: Central serotonergic pathways influence brain areas involved in vagal cardiovascular regulation and, thereby, influence sympathetic efferent activity. Selective serotonin reuptake inhibitors (SSRIs) affect multiple serotonergic pathways, including central autonomic pathways. However, only a few studies have assessed SSRI-mediated effects on autonomic reactivity in healthy individuals using heart rate variability (HRV). METHODS: The present study assessed the influence of long-term treatment with escitalopram (ESC) on autonomic reactivity to an intravenous application of 50 µg cholecystokinin tetrapeptide (CCK-4) in 30 healthy young men using a double-blind, placebo (PLA)-controlled, randomized, within-subject cross-over design. Main outcome measures were time- and frequency-domain HRV parameters, assessed at both baseline and immediately after CCK-4 application. RESULTS: Results showed substantial effects for the treatment × CCK-4 challenge interaction with respect to heart rate (p < 0.001; pη(2) = 0.499), SDNN (p < 0.001; pη(2) = 576), RMSSD (p = 0.015; pη(2) = 194), NN50% (p = 0.008; pη(2) = 0.224), and LF% (p = 0.014; pη(2) = 0.196), and moderate effects with respect HF% (p = 0.099; pη(2) = 0.094), with PLA subjects showing a higher increase in HR and SDNN and a higher decrease in RMSSD, NN50, LF and HF than subjects in the ESC condition. Thus, ESC treatment significantly blunted the autonomic reactivity to CCK-4. Secondary analysis indicated no effect of the 5-HTTLPR polymorphism on CCK-4-induced autonomic response. CONCLUSIONS: Our results support findings suggesting an effect of SSRI treatment on autonomic regulation and provide evidence that ESC treatment is associated with blunted autonomic reactivity in healthy men.

Sleep EEG effects of anti-gluco- and anti-mineralocorticoids in old-aged men: pilot study.

AIM: Age-related sleep changes have been associated with altered hypothalamic-pituitary-adrenal axis reactivity and impaired feedback inhibition at the glucocorticoid (GR) and mineralocorticoid (MR) receptor level. To further investigate the specific role of this binary receptor system in the elderly, sleep electroencephalogram (EEG) effects of the MR antagonist spironolactone and GR antagonist mifepristone in old-aged men were compared in this pilot study. METHODS: Old-aged healthy men (n = 6, 65-91 years) were treated on three occasions in a single-blinded design in random order with mifepristone, spironolactone and placebo, respectively, and nocturnal sleep EEG was recorded. RESULTS: Mifepristone led to increased wake time, decreased stage 2 and rapid eye movement (REM) sleep and prolonged REM sleep latency in the first half of the night, whereas spironolactone had no considerable effects on sleep EEG. CONCLUSION: GR antagonism can potentiate age-related sleep pattern alterations and further support the role of impaired GR signaling in age-related changes in sleep architecture.

Morning salivary dehydroepiandrosterone (DHEA) qualifies as the only neuroendocrine biomarker separating depressed patients with and without prior history of depression: An HPA axis challenge study.

BACKGROUND: Hypothalamic-pituitary-adrenal (HPA) axis abnormalities in major depression (MDD) have been consistently reported in psychiatry and extend to several neurosteroids. However, recurrence and chronicity may heavily influence HPA axis dynamics in MDD along its course and also explain conflicting results in literature. Thus, the mechanistic understanding of HPA axis (re)activity changes over time could be of major importance for unravelling the dynamic pathophysiology of MDD. METHODS: This study simultaneously assessed several baseline and dynamic HPA-axis-related endocrine biomarkers in both saliva (dehydroepiandrosterone, DHEA; sulfated DHEA, DHEA-s; cortisol, CORT) and plasma (CORT; adrenocorticotropic hormone, ACTH; copeptin, CoP) over three consecutive days using overnight HPA axis stimulation (metyrapone) and suppression (dexamethasone) challenges in order to investigate differences between antidepressant-free MDD patients (n = 14) with and without history of prior depressive episodes (i.e., first vs. recurrent episode). RESULTS: Our results suggest group differences only with respect to saliva DHEA levels, with recurrent-episode MDD patients showing overall lower saliva DHEA levels across the three days, and statistically significant differences mainly at day 1 (baseline) across all three timepoints (awakening, +30 min, +60 min), even after adjustment for confounders. CONCLUSIONS: Our study supports that salivary DHEA levels could represent a significant biomarker of MDD progression and individual stress resilience. DHEA deserves additional attention in the research of pathophysiology, staging and individualized treatment of MDD. Prospective longitudinal studies are needed to evaluate HPA axis reactivity along MDD course and progression to better understand temporal effects on stress-system-related alterations, related phenotypes and appropriate treatment.

Copeptin response to panic provocation with CO2 in healthy adults.

Repeated panic attacks are the core symptom of panic disorder and severely stressful for patients. Additional to the psychological response, the physiological symptoms are an important aspect of the experienced panic. However, data on the extent of hypothalamic-pituitary-adrenal (HPA)-axis activation during panic attacks is inconsistent. Therefore, in the present study, we aimed at investigating the stress-axis activity in more detail by including Copeptin (CoP) as a stable surrogate parameter for the vasopressinergic hypothalamic activity during experimentally induced panic attacks in healthy adults (N = 21). During a placebo-controlled panic challenge with 35% CO2 compared to normal air inhalation, we measured CoP and the peripheral effector hormones Adrenocorticotropic Releasing Hormone (ACTH) and cortisol in plasma along with the psychological response to panic anxiety. We analyzed hormonal secretion patterns, their correlations and individual panic ratings over time and explored differences between female and male participants. We found a significant CO2-induced increase of CoP plasma levels and psychological panic symptoms after CO2-administration, while no positive correlations of CoP levels with the peripheral HPA-axis hormones and with panic symptoms were present. No differences between female and male participants concerning their psychological response nor their baseline CoP levels, the release of CoP or its increase during the experiment were found. CoP could be a sensitive indicator for an organism's physiologic acute hypothalamic response during stress and panic attacks.

Decreased recognition of negative affect after selective serotonin reuptake inhibition is dependent on genotype.

Selective serotonin reuptake inhibitors (SSRIs) are known to influence the information processing of emotional material in depressed patients and healthy controls. The functional polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) has been shown to interact with the effectiveness of serotonin reuptake inhibitors. It is not known whether 5-HTTLPR has an influence on emotional processing in healthy controls. We report first data with long-term SSRI administration after genetic characterization of 5-HTTLPR in a randomized, double-blind, placebo-controlled, crossover design. In 30 healthy controls, 15 homozygous for the long and 15 for the short allele of 5-HTTLPR, emotionally valent images were used to elicit positive or negative emotions. We found a diminished perception of sad and fearful information under SSRI which was significant in the long allele group. These findings emphasize the importance of genetic variance in emotion processing research.

Session-specific effects of the Metacognitive Group Training for Obsessive-Compulsive Disorder: significant results for thought control.

The investigation of the session-specific effects is central for the understanding of psychological interventions. For the present study, we investigated the session-specific effects of the Metacognitive Group Training for Obsessive-Compulsive Disorder (MCT-OCD), which was revised based on data of a pilot study. Thirty-four outpatients with OCD participated in the MCT-OCD once a week over 8 weeks. Different metacognitive beliefs (e.g., thought control) and cognitive beliefs (e.g., intolerance of uncertainty), OC symptoms, as well as associated comorbid symptoms were assessed before and after each session. Linear mixed effects models showed that patients' obsessions and compulsions, thought control, the belief of being well informed about the disorder, and action fusion improved over the course of the training. The only session-specific effect emerged for thought control, which improved immediately after the respective module. We were able to replicate the findings of the pilot study and thus corroborate the session-specific effect of the module targeting thought control. Moreover, we generated information on the mode of action of the individual modules of the MCT-OCD that allows a more in-depth evaluation of the intervention. Notably, we were able to eliminate the adverse effects of the pilot version of the MCT-OCD.Trial Registration: German Clinical Trials Register (Deutsches Register Klinischer Studien [DRKS]; DRKS-ID: DRKS00013539; registration date: 22/02/2018).

Vasopressin Surrogate Marker Copeptin as a Potential Novel Endocrine Biomarker for Antidepressant Treatment Response in Major Depression: A Pilot Study.

BACKGROUND: Major depressive disorder (MDD) constitutes the leading cause of disability worldwide. Although efficacious antidepressant pharmacotherapies exist for MDD, only about 40-60% of the patients respond to initial treatment. However, there is still a lack of robustly established and applicable biomarkers for antidepressant response in everyday clinical practice. OBJECTIVE: This study targets the assessment of the vasopressin (AVP) surrogate marker Copeptin (CoP), as a potential peripheral hypothalamic-level biomarker of antidepressant treatment response in MDD. METHODS: We measured baseline and dynamic levels of plasma CoP along with plasma ACTH and cortisol (CORT) in drug-naive outpatients with MDD before and after overnight manipulation of the hypothalamic-pituitary-adrenal (HPA) axis [i.e., stimulation (metyrapone) and suppression (dexamethasone)] on three consecutive days and their association with treatment response to 4 weeks of escitalopram treatment. RESULTS: Our findings suggest significantly higher baseline and post-metyrapone plasma CoP levels in future non-responders, a statistically significant invert association between baseline CoP levels and probability of treatment response and a potential baseline plasma CoP cut-off level of above 2.9 pmol/L for future non-response screening. Baseline and dynamic plasma ACTH and CORT levels showed no association with treatment response. CONCLUSIONS: This pilot study provide first evidence in humans that CoP may represent a novel, clinically easily applicable, endocrine biomarker of antidepressant response, based on a single-measurement, cut-off level. These findings, underline the role of the vasopressinergic system in the pathophysiology of MDD and may represent a significant new tool in the clinical and biological phenotyping of MDD enhancing individual-tailored therapies.

Bottom-up or top-down?: The role of child and parent chronic pain and anxiety in the context of parental catastrophizing and solicitousness.

PURPOSE: Children of parents with chronic pain are a high-risk group to develop own chronic pain. There is evidence that parental responses such as catastrophizing and solicitousness play an important role in the familial transmission of chronic pain. However, little is known about factors that modulate these responses. Based on the literature, we assumed that top-down processes, such as parent chronic pain and anxiety, would be associated with increased catastrophizing and solicitousness. Bottom-up processes, such as child chronic pain and anxiety, were assumed to moderate this association. METHODS: N = 118 parents (mean age: 43 years, 80.5% females) with chronic pain and/or anxiety symptoms with N = 190 children (mean age: 11 years, 49% females) were recruited in specialized hospitals and via online panels. Parents reported chronic pain, anxiety, catastrophizing and solicitousness by use of validated questionnaires. Child pain and anxiety were assessed via parent report. RESULTS: Multilevel model results showed that top-down processes, rather than bottom-up processes, predicted parental responses to child's pain. Specifically, parents with more severe chronic pain reported less catastrophizing. Parent anxiety was positively associated with parental catastrophizing and solicitousness. While child chronic pain and anxiety did not exert an impact on parental responses, the parents' and child's age emerged as additional modulating factors for parental solicitousness. CONCLUSION: Findings support the assumption that top-down processes, particularly parent anxiety, rather than bottom-up processes, exert an impact on parental responses. Specific interventions to decrease parent anxiety in the context of chronic pain and effects of adult treatment on parental responses to child's pain warrant further investigation. SIGNIFICANCE: This study increases our knowledge on modulating factors on maladaptive parental reactions such as parental pain-related catastrophizing towards their children in pain. According to our findings, it is not the child variables, that is (parental perception of) child chronic pain or anxiety that modulate parental reactions but parent factors, particularly parent anxiety. Thus, parent anxiety should be regularly assessed and addressed during pain treatment of adult populations, and in interventional studies in children with chronic pain and their parents with chronic pain and anxiety symptoms.

Inverse autonomic stress reactivity in depressed patients with and without prior history of depression.

BACKGROUND: There is a considerable association between major depressive disorder (MDD) and cardiovascular disease, most possibly relying on abnormalities in the autonomic nervous system (ANS)-related cardiac reactivity, although the exact underlying pathophysiological pathway is unclear. This study tends to shed some additional light on this background by investigating ANS reactivity in MDD with respect to previous depression history through an objective stress challenge paradigm. METHODS: The study assessed the effects of an overnight hypothalamus-pituitary-adrenal (HPA) axis stimulation with metyrapone (MET) on baseline ANS activity through linear and non-linear heart rate variability (HRV) measures in the morning of two continuous days in a group of 14 physically healthy, antidepressant-free patients with clinical, non-psychotic MDD, to investigate differences in autonomic reactivity with respect to prior MDD history. RESULTS: The main findings of this study include statistically significant time × group interactions with respect to several HRV measures, suggesting substantial differences on autonomic reactivity between patients with and without depression history. Hereby, recurrent-episode MDD patients showed lower vagal activity, while first-episode MDD patients increased PNS activity after HPA axis stimulation. CONCLUSIONS: These findings indicate that HPA axis stimulation in MDD patients leads to inverse vagal response according to MDD history. We suggest that chronic stress system overactivation, as found in MDD, might lead to a progressive inversion of the original stress response through HPA axis and ANS divergence over the course of a recurrent illness. HRV could, thus, represent a significant biomarker in MDD with temporal sensitivity.

The selective serotonin re-uptake inhibitor escitalopram modulates the panic response to cholecystokinin tetrapeptide in healthy men depending on 5-HTTLPR genotype.

Selective serotonin re-uptake inhibitors, such as escitalopram, are currently the treatment of choice for patients with panic disorder. The panic response to intravenous cholecystokinin tetrapeptide, a potentially useful paradigm for volunteer translational studies, has so far not been investigated in healthy man after respective pre-treatment. In a double-blind, placebo-controlled, randomized, within subject cross-over design 30 healthy young men, 15 each with the long/long or short/short genotype for the serotonin transporter linked polymorphic region, were pre-treated with 10mg/d of escitalopram orally for six weeks and then challenged with 50 microg of cholecystokinin tetrapeptide. The primary outcome measure was the increase of Acute Panic Inventory ratings by cholecystokinin tetrapeptide. The increase of anxiety, tension and stress hormone secretion were secondary outcome measures. A significant treatment by genotype effect on the increases of Acute Panic Inventory ratings emerged. Panic induced by cholecystokinin tetrapeptide was significantly more pronounced in the short/short genotype subjects under escitalopram vs. placebo pre-treatment. With the exception of significantly elevated serum prolactin after escitalopram, no effects in the secondary outcome measures were detected. Contrary to our expectation, no inhibitory effect of escitalopram upon panic symptoms elicited by choleystokinin tetrapeptide could be demonstrated in healthy men. These findings do not support the potential usefulness of this panic model for proof-of-concept studies. The biological underpinnings of the increased panic symptoms after escitalopram in our volunteers with short/short genotype need further research.

Vagal effects of endocrine HPA axis challenges on resting autonomic activity assessed by heart rate variability measures in healthy humans.

BACKGROUND: The hypothalamic-pituitary-adrenal axis (HPA axis) and the autonomic nervous system (ANS) are considered to play the most crucial role in the pathophysiology of stress responsiveness and are increasingly studied together. However, only few studies have simultaneously assessed HPA axis and ANS activity to investigate their direct interaction in pathophysiology, while no study so far has assessed the dynamic interplay between the two systems in healthy subjects through endocrine challenges. METHODS: The present study assessed the direct effects of overnight pharmacoendocrine HPA axis challenges with dexamethasone (suppression) and metyrapone (stimulation) on ANS activity at rest as determined by linear and nonlinear measures of heart rate variability (HRV) in 39 young healthy individuals. RESULTS: Findings indicated significant effects of metyrapone, but not dexamethasone on autonomic activity at rest based on HRV measures. HRV after metyrapone was overall significantly reduced in comparison to baseline or post-dexamethasone conditions, while the combined metyrapone-related reduction of HRV measures RMSSD, NN50(%) and HF(%) with concomitant increase of the unifractal scaling coefficient αfast value jointly indicated a specifically diminished vagal activity. CONCLUSIONS: We provide first data that HPA axis stimulation (metyrapone) is associated with reduced vagal tone, while HPA axis suppression (dexamethasone) has no effect on autonomic modulation of heart function. Our results support a vital role of the parasympathetic nervous system in the interplay between ANS and HPA axis and, thus, in the modulation of stress-related cardiovascular responsiveness and the susceptibility to stress-related disorders.

No effect of six weeks of treatment with escitalopram on mood in healthy volunteers--irrespective of genotype for the promoter of the serotonin transporter.

Data on emotional effects of chronic antidepressants in normal subjects are scarce and contradictory. Thirty healthy men were given 10 mg/day of escitalopram for 6 weeks in a double-blind, placebo-controlled, within-subject cross-over study. No significant effect on negative affect, positive affect, or state anxiety was detected, irrespective of serotonin transporter gene-linked polymorphism.

T Cell Phenotype and T Cell Receptor Repertoire in Patients with Major Depressive Disorder.

While a link between inflammation and the development of neuropsychiatric disorders, including major depressive disorder (MDD) is supported by a growing body of evidence, little is known about the contribution of aberrant adaptive immunity in this context. Here, we conducted in-depth characterization of T cell phenotype and T cell receptor (TCR) repertoire in MDD. For this cross-sectional case-control study, we recruited antidepressant-free patients with MDD without any somatic or psychiatric comorbidities (n = 20), who were individually matched for sex, age, body mass index, and smoking status to a non-depressed control subject (n = 20). T cell phenotype and repertoire were interrogated using a combination of flow cytometry, gene expression analysis, and next generation sequencing. T cells from MDD patients showed significantly lower surface expression of the chemokine receptors CXCR3 and CCR6, which are known to be central to T cell differentiation and trafficking. In addition, we observed a shift within the CD4+ T cell compartment characterized by a higher frequency of CD4+CD25highCD127low/- cells and higher FOXP3 mRNA expression in purified CD4+ T cells obtained from patients with MDD. Finally, flow cytometry-based TCR Vß repertoire analysis indicated a less diverse CD4+ T cell repertoire in MDD, which was corroborated by next generation sequencing of the TCR ß chain CDR3 region. Overall, these results suggest that T cell phenotype and TCR utilization are skewed on several levels in patients with MDD. Our study identifies putative cellular and molecular signatures of dysregulated adaptive immunity and reinforces the notion that T cells are a pathophysiologically relevant cell population in this disorder.

Copeptin - A potential endocrine surrogate marker of CCK-4-induced panic symptoms?

Intravenous cholecystokinin-tetrapeptide (CCK-4) administration reliably and dose-dependently provokes panic anxiety in man, accompanied by adrenocorticotropic hormone (ACTH) and cortisol release. Preclinical findings suggest that behavioral and endocrine effects of CCK-4 are mediated via corticotropin-releasing hormone (CRH) release. Anxiogenic stimulation of the central CCK-receptors in man was shown to increase as well vasopressin (AVP), which acts synergistically with CRH as pituitary-adrenocortical axis stimulator during stress. Copeptin (CoP), the C-terminal part of pre-pro-AVP, is released in an equimolar ratio to AVP. It is more stable in the circulation and easier to determine than AVP and it was found to closely mirror the production of AVP. So far, CoP secretion has not been characterized during panic provocation. In 30 healthy male human subjects, we repeatedly measured CoP in plasma during a panic challenge and studied its correlation to Acute Panic Inventory (API) ratings and plasma ACTH and cortisol. CoP levels correlated positively with the increase in API ratings (r=0.41, p=0.03), while ACTH or cortisol did not (r=0.08, p=0.68 and r=0.12, p=0.53, respectively). CoP levels correlated also positively with ACTH (r=0.48, p=0.009) and cortisol (r=0.48, p=0.01) concentrations throughout the CCK-4 challenge. As expected, we found a positive correlation between plasma ACTH and cortisol levels (r=0.57, p=0.001). A vasopressinergic activation during CCK-4 induced panic was demonstrated, which was correlated positively to panic symptoms and pituitary-adrenocortical release. Our findings suggest a role of CoP as a potential surrogate marker of CCK-4 panic symptoms. Further studies are needed to replicate our results and to further clarify the role of CoP as a stress-sensitive hormone in different panic paradigms as well as in panic patients.

Metabotropic glutamate2/3 receptor agonism facilitates autonomic recovery after pharmacological panic challenge in healthy humans.

Group II metabotropic glutamate receptors (mGluR2/3) are suggested to modulate anxiety, arousal, and stress including autonomic control. However, no study has investigated mGluR2/3-related effects on baseline autonomic activity and reactivity to emotional challenge in humans as yet. Using a double-blind, randomized placebo-controlled, cross-over study design, we investigated the influence of a 1-week treatment with the mGluR2/3 agonist LY544344, prodrug of LY354740, on autonomic reactivity to a cholecystokinin tetrapeptide (CCK-4) panic challenge in eight healthy young men. The main outcome measures were time and frequency domain heart rate variability parameters during baseline, CCK-4 challenge, and recovery. There was no evidence for LY544344-mediated effects on baseline and CCK-4 challenge vagal activity, but a significantly lower recovery low frequency (%) and low frequency/high frequency ratio in the LY544344 group, suggesting enhanced autonomic recovery. This pilot study provides first human data indicating that mGluR2/3 agonism is involved in autonomic responsiveness, suggesting an important role of mGluR2/3 in central autonomic regulation.

Increasing leptin precedes craving and relapse during pharmacological abstinence maintenance treatment of alcoholism.

The appetite regulating peptide leptin has recently been associated with craving for alcohol and lifetime ethanol intake. However, effects of anti-craving drugs on leptin have not been studied until now. The objective of our study was to test the hypothesis whether leptin plasma concentration in abstinent alcohol addicts during treatment with naltrexone vs. acamprosate is associated with abstinence duration and craving for alcohol. Leptin plasma concentration was measured in 160 recently detoxified alcohol addicts during a double-blind, placebo-controlled relapse prevention trial with naltrexone vs. acamprosate vs. naltrexone plus acamprosate. During placebo treatment, increasing leptin plasma concentration was observed, whereas during combined treatment with naltrexone and acamprosate, leptin decreased significantly. The change from baseline of leptin plasma levels after weeks 4, 8 and 12 was inversely correlated with duration of abstinence and, after 4 weeks, positively correlated with self-rated craving. In summary, the study presents first evidence for an association of increasing leptin plasma concentrations with relapse to renewed alcohol intake in detoxified alcoholics. Moreover, there are hints for an interaction between pharmacological anti-craving treatment, plasma concentration of leptin, and abstinence duration.

Overnight suppression of HPA axis after mineraolocorticoid receptor stimulation: A sleep endocrine study.

Nocturnal hyperactivity of hypothalamic-pituitary-adrenal axis (HPA) indicates decreased feedback inhibition with stress-related conditions such as major depression and sleep disorders. To characterize the role of mineralocorticoid (MR) in regulation of HPA axis activity during nocturnal sleep and involvement in sleep architecture, we investigated sleep endocrine effects of the MR agonist fludrocortisone in healthy men after pretreatment with metyrapone to minimize the impact of endogenous cortisol. Subjects (n=8) were treated on three occasions in a single-blinded design in random order with a) metyrapone, b) fludrocortisone after metyrapone, and c) placebo. Polysomnography was recorded and blood samples were drawn for determination of adrenocorticotropic hormone (ACTH) and cortisol during the entire night. After metyrapone administration ACTH was significantly enhanced, while overall nocturnal cortisol secretion remained largely unchanged. Whereas administration of fludrocortisone induced a significant inhibitory effect on basal ACTH and cortisol secretion, no considerable effects on sleep pattern were detectable. While the involvement of MR in sleep regulation needs further study, endocrine findings underline the role of MR in tonic regulation of HPA axis during nocturnal sleep and demonstrate the ability of fludrocortisone to further suppress HPA axis activity overnight. Additional studies would be required to evaluate endocrine and clinical fludrocortisone effects in depressive patients showing HPA hyperactivity.