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Objective: Reduced muscle mass is a characteristic finding in sarcopenia, the central element of physical frailty syndrome, and a major cause of physical function decay, morbidity and mortality in the elderly. Studies so far demonstrated reduced muscle mass in depressed patients with an average age over 60years. An open question is whether muscle mass reduction is already observed earlier. Therefore, muscle mass was assessed in middle-aged male and female depressive patients, and the findings were related to indicators of hypothalamus-pituitary adrenal axis activation, lifestyle factors, endocrine and immune measures., Methods: Sixty-seven depressed patients (mean age 38.6y; 58.2% female) and 26 healthy volunteers (mean age 40.5y; 61.5% female) were included. Muscle mass, adrenal gland volume, and intra-abdominal adipose tissue were assessed by magnetic resonance tomography. Laboratory parameters included fasting cortisol, pro-inflammatory cytokines, factors constituting the metabolic syndrome, and relative insulin resistance according to the homeostasis model assessment (HOMA-IR)., Results: We found significant effects of depression (F=4.2; P=0.043) and gender (F=182; P<0.001) on muscle mass. Muscle mass was reduced in depressed men compared to healthy men (F=3.4; P=0.044), particularly in those with chronic depression. In contrast, no such association was observed in depressed females. Adrenal gland volume and intra-abdominal fat was increased in depressed men and women, although not significantly. Correlations were observed for muscle mass with the amount of self-reported exercise and depression severity, and for depression severity with self-reported exercise. Further findings comprised lower self-reported activity and higher cortisol concentrations in depressed male and female compared to healthy probands., Conclusions: Muscle mass is reduced in middle-aged depressed men, particularly those with chronic disease course. This association is not observed in depressed females, possibly pointing to the role of female sex steroids in maintaining muscle mass. The increase of adrenal gland volume in depressed patients may point to the role of a dysregulated hypothalamus-pituitary-adrenal system. The inverse association of exercise with muscle mass demonstrates the importance of physical activity. Looking at the long term consequences of reduced muscle mass, interventions to preserve and rebuild muscle mass in depression - such as structured exercise interventions - should be recommended., Significant Outcomes: Muscle mass is decreased in male patients with major depressive disorder, particular those with chronic disease course. This difference was not observed in female depressed patients. The extent of muscle mass reduction is correlated to depression severity and inversely to physical activity, pointing to the role of depression associated inactivity. Low muscle mass is a risk factor for physical frailty, therefore interventions aiming at improving physical fitness may be recommended., Limitations: Sex steroids were not assessed in the study groups., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Major depressive disorder (MDD) is associated with an estimated fourfold risk for premature death, largely attributed to cardiovascular disorders. Pericardial adipose tissue (PAT), a fat compartment surrounding the heart, has been implicated in the development of coronary artery disease. An unanswered question is whether people with chronic MDD are more likely to have elevated PAT volumes versus acute MDD and controls (CTRL)., Methods: The study group consists of sixteen patients with chronic MDD, thirty-four patients with acute MDD, and twenty-five CTRL. PAT and adrenal gland volume were measured by magnetic resonance tomography. Additional measures comprised factors of the metabolic syndrome, cortisol, relative insulin resistance, and pro-inflammatory cytokines (interleukin-6; IL-6 and tumor necrosis factor-α, TNF-α)., Results: PAT volumes were significantly increased in patients with chronic MDD>patients with acute MDD>CTRL. Adrenal gland volume was slightly enlarged in patients with chronic MDD>acute MDD>CTRL, although this difference failed to reach significance. The PAT volume was correlated with adrenal gland volume, and cortisol concentrations were correlated with depression severity, measured by BDI-2 and MADRS. Group differences were found concerning the rate of the metabolic syndrome, being most frequent in chronic MDD>acute MDD>CTRL. Further findings comprised increased fasting cortisol, increased TNF-α concentration, and decreased physical activity level in MDD compared to CTRL., Conclusion: Our results extend the existing literature in demonstrating that patients with chronic MDD have the highest risk for developing cardiovascular disorders, indicated by the highest PAT volume and prevalence of metabolic syndrome. The correlation of PAT with adrenal gland volume underscores the role of the hypothalamus-pituitary-adrenal system as mediator for body-composition changes. Metabolic monitoring, health advices and motivation for the improvement of physical fitness may be recommended in depressed patients, in particular in chronic depression., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Alterations in brain glucose metabolism and in peripheral glucose metabolism have frequently been observed in major depressive disorder (MDD). The insulin independent glucose transporter 1 (GLUT1) plays a key role in brain metabolism while the insulin-dependent GLUT4 is the major glucose transporter for skeletal and cardiac muscle. We therefore examined methylation of GLUT1 and GLUT4 in fifty-two depressed inpatients and compared data to eighteen healthy comparison subjects. DNA methylation of the core promoter regions of GLUT1 and GLUT4 was assessed by bisulfite sequencing. Further factors determined were fasting glucose, cortisol, insulin, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). We found significantly increased methylation of the GLUT1 in depressed inpatients compared to healthy comparison subjects (CG). Further findings comprise increased concentrations of fasting cortisol, glucose, insulin, and increased IL-6 and TNF-α. After six weeks of inpatient treatment, significantly lower GLUT1 methylation was observed in remitted patients compared to non-remitters. GLUT4 methylation was not different between depressed patients and CG, and did not differ between remitted and non-remitted patients. Although preliminary we conclude from our results that the acute phase of major depressive disorder is associated with increased GLUT1 methylation and mild insulin resistance. The successful treatment of depression is associated with normalization of GLUT1 methylation in remitters, indicating that this condition may be reversible. Failure of normalization of GLUT1 methylation in non-remitters may point to a possible role of impeded brain glucose metabolism in the maintenance of MDD., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Emerging evidence indicates that treatment context profoundly affects psychopharmacological interventions. We review the evidence for the interaction between drug application and the context in which the drug is given both in human and animal research. We found evidence for this interaction in the placebo response in clinical trials, in our evolving knowledge of pharmacological and environmental effects on neural plasticity, and in animal studies analyzing environmental influences on psychotropic drug effects. Experimental placebo research has revealed neurobiological trajectories of mechanisms such as patients' treatment expectations and prior treatment experiences. Animal research confirmed that "enriched environments" support positive drug effects, while unfavorable environments (low sensory stimulation, low rates of social contacts) can even reverse the intended treatment outcome. Finally we provide recommendations for context conditions under which psychotropic drugs should be applied. Drug action should be steered by positive expectations, physical activity, and helpful social and physical environmental stimulation. Future drug trials should focus on fully controlling and optimizing such drug×environment interactions to improve trial sensitivity and treatment outcome., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Major depressive disorder (MDD) is associated with an increased risk for the development of cardio-metabolic diseases. Increased intra-abdominal (IAT) and pericardial adipose tissue (PAT) have been found in depression, and are discussed as potential mediating factors. IAT and PAT are thought to be the result of a dysregulation of the hypothalamus-pituitary-adrenal axis (HPAA) with subsequent hypercortisolism. Therefore we examined adrenal gland volume as proxy marker for HPAA activation, and IAT and PAT in depressed patients. Twenty-seven depressed patients and 19 comparison subjects were included in this case-control study. Adrenal gland volume, pericardial, intraabdominal and subcutaneous adipose tissue were measured by magnetic resonance imaging. Further parameters included factors of the metabolic syndrome, fasting cortisol, fasting insulin, and proinflammatory cytokines. Adrenal gland and pericardial adipose tissue volumes, serum concentrations of cortisol and insulin, and serum concentrations tumor-necrosis factor-α were increased in depressed patients. Adrenal gland volume was positively correlated with intra-abdominal and pericardial adipose tissue, but not with subcutaneous adipose tissue. Our findings point to the role of HPAA dysregulation and hypercortisolism as potential mediators of IAT and PAT enlargement. Further studies are warranted to examine whether certain subtypes of depression are more prone to cardio-metabolic diseases., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Diurnal (24-h) cortisol profiles were compared to DST and Dex/CRH test outcomes with regard to their discriminative power in depressive disorder. With regard to several statistical measures (effect sizes, area under the curve) we found 24-h cortisol profiles to better discriminate between healthy controls and inpatients with the melancholic subtype of depression compared to the DST and Dex/CRH test. In search of a shortened time interval we found the 2-h time window 1000-1200 h of the cortisol profile to be the one with the highest sensitivity (83.3%) and specificity (87.9%). The specificity of the DST was 93.3% and somewhat higher than that of the cortisol profiles and the Dex/CRH test (87.9% and 78.8.%, respectively). However, the sensitivity of the DST was very low (30.8%), in fact similar to that of the Dex/CRH test (30.8%), but much lower than that of the 1000-1200 h interval (83.3%). The assessment of cortisol in plasma is an easy to perform, cost-saving method for the evaluation of the HPA system activity, which may have a series of clinical and scientific implications for the depressive disorder., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Objectives: The DEX/CRH test has been proposed to be suitable as a biomarker for the prediction of treatment response in depression., Methods: We performed the DEX/CRH test in 10 severely depressed male patients with melancholic features before initiation of antidepressant treatment with 20 mg fluoxetine., Results: We found a low cortisol response (as measured by cortisol AUC) to a single DEX/CRH test to be associated with clinical response to treatment., Conclusions: A strength of this study lies in the inclusion of patients after a drug wash-out phase. Despite a certain inconsistency described in the literature, several studies support the notion that it might be of importance to measure baseline HPA system activity before choice of treatment. Further systematic studies are warranted., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Objective: Body weight development is closely regulated by central nervous mechanisms. As has been demonstrated recently, the capability of the brain to actively demand energy from the body (brain-pull) is indispensable for the maintenance of systemic homeostasis. A deficit in this brain-pull may result in compensatory ingestive behavior followed by weight gain in the medium or long term. The aim of this study was to establish a biomarker of such an incompetent brain-pull. Since lactate is an alternative cerebral energy substrate to glucose, we investigated whether low fasting plasma lactate concentrations are associated with weight gain and increased feelings of hunger in patients with type 2 diabetes over a 3-year period., Methods: In a population based cohort study 134 type 2 diabetes patients were examined at baseline and 3-year follow-up. Plasma lactate concentrations and additional hormones associated with food intake such as e.g. insulin, or leptin, as well as psychological variables like hunger feelings before and after a standardized breakfast were measured. The relation between fasting plasma lactate concentrations and postprandial hunger as well as follow-up weight was analyzed., Results: Low fasting plasma lactate concentrations predicted a higher 3-year follow-up weight (B=-1.268, SE=0.625, p=0.04). Moreover, low fasting plasma lactate concentrations were associated with more pronounced feelings of postprandial hunger (B=-0.406, SE=0.137, p<0.01)., Conclusions: We conclude that low plasma lactate concentrations may represent a biomarker of an incompetent brain-pull, which is associated with weight gain and increased postprandial hunger in patients with type 2 diabetes mellitus. These results are in line with the view that plasma lactate can be used by the brain as an alternative energy substrate and thereby to some extent prevent overeating and obesity., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Obesity, increased visceral fat and disturbed glucose metabolism have been found in borderline personality disorder (BPD) patients. These conditions are often associated with disturbed androgen metabolism. Elevated androgens in women are related to polycystic ovaries (PCO) and might have an impact on psychopathology. Thus, higher prevalence of PCO and elevated androgen levels are suspected in BPD. In the study, we examined 31 BPD patients and 30 healthy controls ultrasonographically for PCO and measured their serum levels of androgens and interacting hormones. Furthermore, influence on psychopathology of free testosterone (FT) serum level was assessed. PCO was significantly more prevalent in BPD patients (30.4%) compared to healthy controls (6.9%). Testosterone, FT, androstenedione (A), and 17alpha-hydroxyprogesterone (17-OHP) were significantly elevated in the BPD group independently of BMI. FT serum level significantly correlated with depressive symptoms. In summary, our data suggest a disturbed androgen metabolism in BPD patients.

Background: Major depression has been associated with endocrine and immune alterations, in particular a dysregulation of the hypothalamus-pituitary-adrenal system with subsequent hypercortisolism and an imbalance of pro- and anti-inflammatory cytokines. Recent studies suggest that vascular endothelial growth factor (VEGF), a cytokine involved in angiogenesis and neurogenesis, may also be dysregulated during stress and depression. These observations prompted us to examine VEGF and other angiogenic factors in patients with major depressive disorder., Methods: Twelve medication-free female patients with a major depressive episode in the context of borderline personality disorder (MDD/BPD) and twelve healthy women were included. Concentrations of VEGF, VEGF receptors 1 and 2, basic fibroblast growth factor-2 (FGF-2), hepatocyte growth factor (HGF), angiopoetin-2, interleukin-8 (IL-8) and transforming growth factor-beta1 (TGF-beta1) were determined from serum profiles., Results: Increased concentrations of VEGF and FGF-2 were found in MDD/BPD patients compared to the healthy comparator group. No group differences were found concerning the other angiogenic factors examined., Conclusion: Depressive episodes in the context of borderline personality disorder may be accompanied by increased serum concentrations of VEGF and FGF-2. Similar findings have been observed in patients with major depression without a borderline personality disorder. A dysregulation of angiogenic factors may be another facet of the endocrine and immunologic disturbances frequently seen in patients with depressive episodes.

The brain takes a primary position in the organism. We present the novel view that the brain gives priority to controlling its own adenosine triphosphate (ATP) concentration. It fulfils this tenet by orchestrating metabolism in the organism. The brain activates an energy-on-request system that directly couples cerebral supply with cerebral need. The request system is hierarchically organized among the cerebral hemispheres, the hypothalamus, and peripheral somatomotor, autonomic-visceromotor, and the neuroendocrine-secretomotor neurons. The system initiates allocative behavior (i.e. allocation of energy from body to brain), ingestive behavior (intake of energy from the immediate environment), or exploratory behavior (foraging in the distant environment). Cerebral projections coordinate all three behavioral strategies in such a way that the brain's energy supply is guaranteed continuously. In an ongoing learning process, the brain's request system adapts to various environmental conditions and stressful challenges. Disruption of a cerebral energy-request pathway is critical to the development of obesity: if the brain fails to receive sufficient energy from the peripheral body, it compensates for the undersupply by increasing energy intake from the immediate environment, leaving the body with a surplus. Obesity develops in the long term.

Borderline personality disorder (BPD) is characterized by a pervasive pattern of instability in affect regulation, impulse control, interpersonal relationships, and self-image. In previous studies, we have used portable mini-computers to assess the severity of recurrent states of aversive emotional distress and dissociation during ambulatory conditions. Here, we used this approach for the assessment of the hypothalamic-pituitary-adrenal (HPA) axis in patients with BPD. We studied 23 unmedicated female patients with BPD and 24 matched healthy controls. Salivary cortisol was collected from all participants during ambulatory conditions in response to reminders provided by portable mini-computers on 3 consecutive days every 2 h for 14 h after awakening. In addition, cortisol in response to awakening was determined in four 15 min intervals on days 1 and 2. After the last collection of cortisol on the second day, 0.5 mg dexamethasone was administered in order to achieve cortisol suppression on day 3 (low-dose dexamethasone suppression test, DST). Patients with BPD displayed significantly higher salivary cortisol levels than healthy controls as demonstrated by higher total cortisol in response to awakening and higher total daily cortisol levels. There were significantly more non-suppressors of cortisol in the low-dose DST in the patient group when compared to the control group. The ambulatory assessment of saliva cortisol is a suitable approach to study basic parameters of the HPA-axis in patients with BPD. Increased adrenal activity and lowered feedback sensitivity of the HPA-axis may characterise BPD. Further studies have to reveal reasons of heightened adrenal activity in these patients.

The brain occupies a special hierarchical position in the organism. It is separated from the general circulation by the blood-brain barrier, has high energy consumption and a low energy storage capacity, uses only specific substrates, and it can record information from the peripheral organs and control them. Here we present a new paradigm for the regulation of energy supply within the organism. The brain gives priority to regulating its own adenosine triphosphate (ATP) concentration. In that postulate, the peripheral energy supply is only of secondary importance. The brain has two possibilities to ensure its energy supply: allocation or intake of nutrients. The term 'allocation' refers to the allocation of energy resources between the brain and the periphery. Neocortex and the limbic-hypothalamus-pituitary-adrenal (LHPA) system control the allocation and intake. In order to keep the energy concentrations constant, the following mechanisms are available to the brain: (1) high and low-affinity ATP-sensitive potassium channels measure the ATP concentration in neurons of the neocortex and generate a 'glutamate command' signal. This signal affects the brain ATP concentration by locally (via astrocytes) stimulating glucose uptake across the blood-brain barrier and by systemically (via the LHPA system) inhibiting glucose uptake into the muscular and adipose tissue. (2) High-affinity mineralocorticoid and low-affinity glucocorticoid receptors determine the state of balance, i.e. the setpoint, of the LHPA system. This setpoint can permanently and pathologically be displaced by extreme stress situations (chronic metabolic and psychological stress, traumatization, etc.), by starvation, exercise, infectious diseases, hormones, drugs, substances of abuse, or chemicals disrupting the endocrine system. Disorders in the 'energy on demand' process or the LHPA-system can influence the allocation of energy and in so doing alter the body mass of the organism. In summary, the presented model includes a newly discovered 'principle of balance' of how pairs of high and low-affinity receptors can originate setpoints in biological systems. In this 'Selfish Brain Theory', the neocortex and limbic system play a central role in the pathogenesis of diseases such as anorexia nervosa and obesity., (Copyright 2004 Elsevier Ltd.)

There is some evidence that the somatotrophic system in depression, as assessed by basal growth hormone (GH) concentrations and by GH releasing hormone (GHRH) challenge, might be dysfunctional. However, the rather limited data have been inconclusive so far and plasma concentrations of both insulin-like growth factor-1 (IGF-I) and binding proteins (IGFBP 1 to IGFBP-6) have not been measured simultaneously in depressed patients. We studied 24 severely depressed patients and 33 healthy controls and estimated 24-hour mean plasma cortisol, six-hour evening mean plasma growth hormone (GH), morning plasma IGF-I, IGFBP 2 and 3 and GH-binding protein (GH-BP). Twenty-four-hour mean cortisol (306 +/- 69 vs. 196 +/- 30 nmol/l, p < .001) and IGF-I (157 +/- 40 vs. 120 +/- 33 micrograms/l, p < .01) plasma concentrations were found to be significantly increased in depressed patients, while there was no difference in GH or binding proteins between both groups. MANOVA analysis revealed age and diagnosis to have main effects upon plasma IGF-I. Especially young age and a diagnosis of major depression are associated with higher plasma IGF-I. After treatment only patients in remission had attenuated IGF-I plasma concentrations. We conclude that plasma IGF-I is increased in acutely depressed patients similar to other states of hypercortisolemia.

We studied corticosteroid-binding globulin (CBG) in 25 drug-free depressed patients and 33 healthy controls over a wide age-range. CBG was measured at 0800, 1400, 2000 and 2400 h in all subjects. Analysis of variance (ANOVA) with repeated measurement design revealed a significant effect of gender and time, but not of diagnosis (depressed patients vs healthy controls) or age group (< 50/> 50 years). In females, regardless of diagnosis, CBG plasma concentrations were significantly increased, when compared with their male counterparts. Although as a group depressed patients had significantly higher plasma cortisol concentrations (108.0 +/- 23.1 vs 70.7 +/- 10.9 micrograms/l), CBG levels did not differ between the two groups. Thus we did not find hypercortisolemia in depression to be paralleled by a decrease in CBG. However, the exaggerated activity of the hypothalamus-pituitary-adrenocortical system in healthy and depressed females is associated with an increase in plasma CBG.

Semistarved rats develop high running wheel activity. This running activity induces increased norepinephrine, dopamine, and serotonin turnover in the hypothalamus. Corticosterone in plasma becomes increased while luteinizing hormone and testosterone are suppressed. In female rats cyclic gonadal function is suppressed. Running activity in the semistarved rats can be suppressed specifically by serotonin 1-c-agonists and by alpha 2-adrenoceptor agonists. This animal model is helpful in the understanding of the combined effects of starvation and hyperactivity, which are observed in many patients with anorexia nervosa. The observation of the serotonergic system might help to develop a pharmacological treatment of hyperactivity in anorectic patients.

Significant emotional and physical symptoms have been linked to hormonal changes during the menstrual cycle. A critical evaluation of the available studies questions the commonly held belief in menstrual-cycle-related complaints in the majority of normal women. The present study investigated changes in mood, somatic complaints and vegetative variables during the menstrual cycle in 30 healthy young women. Normal cycle function was evaluated and cycle phases were defined according to endocrine data. For all subjects, blood samples were taken at least three times a week to measure estradiol and progesterone. Daily ratings of psychological variables revealed no significant changes in global mood or depression over the cycle. Somatic complaints such as abdominal pain and breast tenderness were significantly related to the luteal, premenstrual, and menstrual phases. Appetite increased in the periovulatory and premenstrual phases. There was a tendency for sexual interest to be highest in the post-menstrual period. Affect and vegetative variables showed no association with hormone levels but were significantly correlated with subjective stress ratings. We conclude that in most healthy young women, cycle-related hormone fluctuations are not accompanied by marked affective changes. Specific physical complaints, however, do occur, particularly in the luteal, premenstrual, and menstrual phases.