City living and urban upbringing affect neural social stress processing in humans.

More than half of the world's population now lives in cities, making the creation of a healthy urban environment a major policy priority. Cities have both health risks and benefits, but mental health is negatively affected: mood and anxiety disorders are more prevalent in city dwellers and the incidence of schizophrenia is strongly increased in people born and raised in cities. Although these findings have been widely attributed to the urban social environment, the neural processes that could mediate such associations are unknown. Here we show, using functional magnetic resonance imaging in three independent experiments, that urban upbringing and city living have dissociable impacts on social evaluative stress processing in humans. Current city living was associated with increased amygdala activity, whereas urban upbringing affected the perigenual anterior cingulate cortex, a key region for regulation of amygdala activity, negative affect and stress. These findings were regionally and behaviourally specific, as no other brain structures were affected and no urbanicity effect was seen during control experiments invoking cognitive processing without stress. Our results identify distinct neural mechanisms for an established environmental risk factor, link the urban environment for the first time to social stress processing, suggest that brain regions differ in vulnerability to this risk factor across the lifespan, and indicate that experimental interrogation of epidemiological associations is a promising strategy in social neuroscience.

Cortisol, platelet serotonin content, and platelet activity in patients with major depression and type 2 diabetes: an exploratory investigation.

OBJECTIVE: Hypothalamic-pituitary-adrenal system dysfunction, serotonergic system alterations, and enhanced platelet activity may contribute to the increased cardiac risk in depression. This exploratory study examined associations between cortisol parameters, platelet serotonin (5-HT) content, and platelet activity markers in patients with newly diagnosed major depression (MD) and/or Type 2 diabetes (T2DM) compared with healthy controls. METHODS: We compared cortisol awakening response (CAR), diurnal decrease in salivary cortisol concentrations (slope), platelet 5-HT, and platelet markers (CD40, CD40 ligand [CD40L], soluble CD40L, CD62P, ß-thromboglobulin, and platelet factor-4) in 22 T2DM patients, 20 MD patients, 18 T2DM patients with MD, and 24 healthy controls. RESULTS: Platelet markers were elevated in MD (F(6,60) = 11.14, p < .001) and T2DM (F(6,60) = 13.07, p < .001). Subgroups did not differ in 5-HT or cortisol slope, whereas T2DM patients without depression had significantly lower CAR than did healthy controls (F(1,61) = 7.46, p = .008). In healthy controls, cortisol slope correlated with platelet activity for CD40 (r = -0.43, p = .048) and 5-HT was correlated with CD40L (r = 0.53, p = .007). In patients with both T2DM and MD, 5-HT and CD62P were correlated (r = 0.52, p = .033). CONCLUSIONS: Increased platelet activity in T2DM and MD may play a role in the association between diabetes, depression, and coronary artery disease. The present data suggest that group differences in cortisol or 5-HT as well as group-specific associations of cortisol or 5-HT with platelet markers might be of limited importance in the shared pathways of T2DM and depression in the pathophysiology of coronary artery disease.

A functional variant in the neuropeptide S receptor 1 gene moderates the influence of urban upbringing on stress processing in the amygdala.

We have previously shown that urban upbringing and city living were associated with stress-induced activity in the amygdala and the perigenual anterior cingulate cortex (pACC). This finding might link the epidemiological risk factor "urbanicity" to neurobiological mechanisms of psychiatric disorders. However, given the heritability of stress-related phenotypes, it appears likely that genetic factors can modulate the effect of urbanicity on social stress processing. In the present exploratory study, we investigated if a functional sequence variation in the neuropeptide S receptor gene (NPSR1 rs324981) is associated with brain activation patterns under acute psychosocial stress and if it modulates the link between urbanicity and central stress processing. In animals, neuropeptide S has strong anxiolytic effects and it induces hypothalamus-pituitary-adrenal (HPA) axis activation. In humans, rs324981 was found to be associated with anxiety and stress-related phenotypes. Forty-two subjects were exposed to a psychosocial stress task for scanner environments (ScanSTRESS). While no main effect of rs324981 on amygdala and pACC activity was detected, we found a distinct interaction between rs324981 and urban upbringing modulating right amygdala responses. Moreover, right amygdala responses were significantly higher in subjects who also showed a salivary cortisol response to the stress exposure. The present finding of a gene × environment interaction further supports the view that the brain NPS system is involved in central stress regulation. This study provides first evidence for the assumption that a NPSR1 variant modulates brain activation under stress, interacting with the environmental risk factor urban upbringing.

Pineal gland volume in primary insomnia and healthy controls: a magnetic resonance imaging study.

Little is known about the relation between pineal volume and insomnia. Melatonin promotes sleep processes and, administered as a drug, it is suitable to improve primary and secondary sleep disorders in humans. Recent magnetic resonance imaging studies suggest that human plasma and saliva melatonin levels are partially determined by the pineal gland volume. This study compares the pineal volume in a group of patients with primary insomnia to a group of healthy people without sleep disturbance. Pineal gland volume (PGV) was measured on the basis of high-resolution 3 Tesla MRI (T1-magnetization prepared rapid gradient echo) in 23 patients and 27 controls, matched for age, gender and educational status. Volume measurements were performed conventionally by manual delineation of the pineal borders in multi-planar reconstructed images. Pineal gland volume was significantly smaller (P < 0.001) in patients (48.9 ± 26.6 mm(3) ) than in controls (79 ± 30.2 mm(3) ). In patients PGV correlated negatively with age (r = -0.532; P = 0.026). Adjusting for the effect of age, PGV and rapid eye movement (REM) latency showed a significant positive correlation (rS  = 0.711, P < 0.001) in patients. Pineal volume appears to be reduced in patients with primary insomnia compared to healthy controls. Further studies are needed to clarify whether low pineal volume is the basis or the consequence of functional sleep changes to elucidate the molecular pathology for the pineal volume loss in primary insomnia.

Leptin plasma concentrations increase during antidepressant treatment with amitriptyline and mirtazapine, but not paroxetine and venlafaxine: leptin resistance mediated by antihistaminergic activity?

Treatment with several psychopharmacological agents has been associated with increased leptin plasma concentrations. We measured leptin plasma concentrations in 76 adult depressed patients after a 6-day washout phase and again after 35 days of treatment with amitriptyline or paroxetine, as well as in 73 depressed patients after 28 days of treatment with either mirtazapine or venlafaxine. Leptin plasma concentrations increased during treatment with amitriptyline and mirtazapine, even after controlling for increased body mass index and irrespective of response to treatment [14.5 (13.8) vs 20.3 (18.7) ng/mL, and 12.2 (15.8) vs 14.4 (16.5) ng/mL in the 2 cohorts, respectively]. In contrast, paroxetine and venlafaxine treatment was not associated with changes in leptin plasma concentrations [14.8 (12.0) vs 13.6 (10.6); 15.9 (17.3) vs 13.5 (14.6) ng/mL] nor with weight gain. We conclude that treatment with amitriptyline or mirtazapine is associated with an increase in leptin secretion beyond change in weight. Thus, high leptin levels apparently are ineffective in the control of weight gain, indicating leptin resistance. Leptin resistance may be mediated by an antihistaminergic effect on hypothalamic nuclei integrating signals relevant for energy balance.

Rethinking restimulation: a case report.

The individual time-course of the seizure threshold (ST) in electroconvulsive therapy is mostly unknown. It is assumed that a typical seizure is followed by a short refractory period and that ST increases in the long run. We hypothesize ST to be lowered immediately after the refractory period, particularly after inadequate or abortive seizures where risk for prolonged seizures is generally higher. Ketamine anesthesia does not possess pronounced anticonvulsive properties like propofol, etomidate, thiopental, or methohexital. It is therefore ideal to test such a hypothesis. We report the case of a geriatric patient with a major depressive episode, who received 5 consecutive electroconvulsive therapies with S-ketamine, all with identical right unilateral high-energy stimulation and restimulation. Whereas all primary stimulations were inadequate, all restimulations showed significantly improved seizure parameters such as midictal amplitude, maximal postictal heart rate, and average seizure energy index. In this patient, the refractory period turned out to be longer than 1 minute, and ST was lower in all 5 instances of restimulation. This ST decrease could be clinically useful in one-session restimulations.

Dysregulated diurnal cortisol patterns are associated with cardiovascular mortality: Findings from the KORA-F3 study.

Psychosocial stress has been associated with an increased risk for cardiovascular disease and death. Dysregulated diurnal cortisol slopes, which have also been associated with stress, might mediate this association. However, existing evidence on the cardiovascular health consequences of dysregulated cortisol slopes remains limited and inconclusive. To elucidate whether dysregulated diurnal cortisol slopes are related to cardiovascular mortality, we assessed salivary cortisol and cardiovascular morbidity and mortality in 1090 participants from the KORA-F3 study, a prospective, observational cohort study of a random representative sample from the general population. Eighty-seven deaths were registered during the mean follow-up period of approximately 11 years, 31 of which were classified as cardiovascular deaths. A more pronounced cortisol awakening response was associated with a lower risk of cardiovascular mortality in the adjusted Cox proportional hazards analysis (HR 0.59 [95-%-CI 0.36-0.96], p = 0.03). A greater diurnal cortisol peak-to-bedtime ratio at baseline also predicted a decreased risk of cardiovascular mortality (HR 0.50 [95-%-CI 0.34-0.73], p 0.01) and a decreased risk of stroke (HR 0.71 [95-%-CI 0.55-0.92], p 0.01). Increased levels of late night salivary cortisol predicted a higher risk of cardiovascular mortality (HR 1.49 [95-%-CI 1.13-1.97], p 0.01) and an increased risk of stroke (HR 1.24 [95-%-CI 1.01-1.52], p = 0.04). There was no association between measures of cortisol and non-cardiovascular related mortality. In conclusion, dysregulated diurnal cortisol patterns are associated with cardiovascular mortality, while greater diurnal cortisol variation seems to have a protective effect. This adds evidence to suggest a pathophysiological role of diurnal cortisol secretion patterns in cardiovascular health.

Differential expression of neuronal dopamine and serotonin transporters DAT and SERT in megakaryocytes and platelets generated from human MEG-01 megakaryoblasts.

In the central nervous system, serotonergic and dopaminergic signaling is terminated by the activity of specialized transporter proteins for serotonin (SERT) and dopamine (DAT). These transporter proteins are found both on the cell surface and in intracellular transport vesicles. Trafficking between these subcellular domains regulates the efficiency of removal of extracellular neurotransmitters and hence the efficacy of neuronal signaling. Therefore, it is of high interest to gain more insight into the regulatory mechanisms of the human DAT and SERT cell surface expression in their natural surroundings, i.e., in human cells. Because it is not possible to cultivate human neuronal cells expressing these transporter proteins, there is a need to find other human cells expressing these neuronal proteins. Here, we have investigated the expression of human SERT and DAT on developing megakaryocytes and platelet-like particles derived from the megakaryocyte progenitor cell line MEG-01 upon differentiation by valproic acid (VPA) and all-trans retinoic acid (ATRA). Our results show that MEG-01 cells express SERT and DAT and that VPA and ATRA induce a significant increase of transporter expression on developing megakaryocytes and platelets. As compared to ATRA, VPA more efficiently induced SERT expression but not DAT expression. Comparable to naïve platelets and neurons, SERT was localized to both the cell surface and intracellular compartments. Hence, VPA and ATRA-treated MEG-01 cells provide a model well-suited to studying neuronal monoamine transporter expression, not only during transcription and translation but also with respect to protein trafficking to and from the cell surface.

The effect of a 4-week treatment with reboxetine on metabolic parameters of depressed inpatients.

In the present study, we examined several metabolic parameters in a group of 19 acutely depressed inpatients with major depression (DSM-IV) at baseline and investigated their development after 4 weeks of antidepressant treatment with reboxetine (8-12 mg per day). We performed oral glucose tolerance tests and additionally assessed free saliva cortisol and post-dexamethasone cortisol levels, as well as whole cholesterol, HDL- and LDL-cholesterol, triglycerides, free fatty acids, waist and hip circumference, heart rate, systolic and diastolic blood pressure. Furthermore, we evaluated the incidence of a metabolic syndrome and investigated the metabolic changes in depressed patients with and without a metabolic syndrome. We found 42.1% of patients to fulfil the criteria for a metabolic syndrome. Overall, reboxetine was well tolerated with essentially no side effects during the observation period. A 4-week treatment with reboxetine showed a beneficial effect on several metabolic parameters that was independent from treatment outcome and could therefore theoretically be attributed to the pharmacological profile of the drug. Due to the preliminary character of the present investigation, no conclusions about the clinical efficacy of reboxetine can be drawn.

Impact of early parental child-rearing behavior on young adults' cardiometabolic risk profile: a prospective study.

OBJECTIVE: To examine prospectively whether early parental child-rearing behavior is a predictor of cardiometabolic outcome in young adulthood when other potential risk factors are controlled. Metabolic factors associated with increased risk for cardiovascular disease have been found to vary, depending on lifestyle as well as genetic predisposition. Moreover, there is evidence suggesting that environmental conditions, such as stress in pre- and postnatal life, may have a sustained impact on an individual's metabolic risk profile. METHODS: Participants were drawn from a prospective, epidemiological, cohort study followed up from birth into young adulthood. Parent interviews and behavioral observations at the age of 3 months were conducted to assess child-rearing practices and mother-infant interaction in the home setting and in the laboratory. In 279 participants, anthropometric characteristics, low-density lipoprotein and high-density lipoprotein cholesterol, apolipoproteins, and triglycerides were recorded at age 19 years. In addition, structured interviews were administered to the young adults to assess indicators of current lifestyle and education. RESULTS: Adverse early-life interaction experiences were significantly associated with lower levels of high-density lipoprotein cholesterol and apolipoprotein A1 in young adulthood. Current lifestyle variables and level of education did not account for this effect, although habitual smoking and alcohol consumption also contributed significantly to cardiometabolic outcomes. CONCLUSIONS: These findings suggest that early parental child-rearing behavior may predict health outcome in later life through its impact on metabolic parameters in adulthood.

Antidepressant treatment with mirtazapine, but not venlafaxine, lowers cortisol concentrations in saliva: a randomised open trial.

Lowering the concentrations of free cortisol in depressed patients may be an important prerequisite to prevent glucocorticoid-related sequelae of depression. We tested the hypothesis that the hypothalamus-pituitary-adrenal (HPA) system-dampening effects of venlafaxine and mirtazapine differ. We compared the course of morning (08.00h) and afternoon saliva cortisol (16.00h) in 42 mirtazapine- and 45 venlafaxine-treated depressed patients during a 1-week wash-out and a 4-week treatment period in a randomised open trial. Mirtazapine lowered afternoon cortisol from week 1 to 4. In contrast, during the course of the entire treatment period, venlafaxine did not attenuate saliva cortisol concentrations. Treatment effects of mirtazapine on cortisol concentrations did not differ in remitters and non-remitters to treatment. High baseline cortisol concentrations, on the other hand, were related to an unfavourable course during venlafaxine treatment and patients remitting during venlafaxine treatment had significantly lower afternoon cortisol concentrations in saliva, when compared to non-remitting patients. Thus, mirtazapine and venlafaxine show different effects on HPA system activity as measured by saliva cortisol. This may be of relevance with regard to physical sequelae of depression.

Cortisol metabolism in depressed patients and healthy controls.

BACKGROUND: Chronic stress as well as major depressive disorders are associated with hypercortisolemia and impaired hypothalamic-pituitary-adrenocortical axis functioning. The aim of this study was to determine whether in major depression changes in the activity patterns of local modulators of glucocorticoid action might contribute to an increase in cortisol bioavailability and if they change during antidepressant treatment and clinical response. METHODS: Concentrations of urinary total cortisol (UFF), urinary total cortisone (UFE), tetrahydrocortisone (THE), tetrahydrocortisol (THF) and allo-THF (5alpha-THF) were measured in 10-hour nocturnal urine samples of 19 depressed patients and 15 healthy controls. The activity of 11beta-hydroxysteroid dehydrogenases (11beta-HSD) as well as 5alpha- and 5beta-reductases was assessed by calculating the ratios of glucocorticoid metabolites. Patients were treated for 28 days with either mirtazapine or venlafaxine. Enzyme activity was observed during the course of treatment and compared to healthy controls. Responders to treatment were selected for this analysis. RESULTS: Depressed patients showed reduced 5alpha-reductase activity manifested as a significantly lower amount of 5alpha-THF (102.8 +/- 167.2 vs. 194.6 +/- 165.8 microg, p = 0.019). The increase in the UFF/UFE ratio (0.73 +/- 0.32 vs. 0.29 +/- 0.13, p < 0.0001) indicates reduced activity of renal 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2). During pharmacological treatment, 5alpha-reductase activity in patients returned to the level of the control group, while the decrease in 11beta-HSD2 activity persisted until day 28. CONCLUSIONS: Our results show changes in activity of intracellular modulators of steroid action in major depressive disorders, particularly a reduced activity of the intracellular cortisol-deactivating enzymes 5alpha-reductase and 11beta-HSD2. These changes suggest an increase in cortisol bioavailability within tissues.

Pituitary-adrenal and sympathetic nervous system responses to stress in women remitted from recurrent major depression.

OBJECTIVE: To better understand the changes in hypothalamus-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS) function after remission of depression. We characterized these systems at baseline and in response to a psychosocial stressor in a cohort of women remitted from recurrent major depression as well as in never-depressed healthy female controls. METHODS: Baseline HPA function was measured via saliva cortisol sampling at 8 AM and 4 PM over 7 days as well as quantification of urinary overnight cortisol secretion. The HPA system response to a psychosocial stressor was assessed by measuring serum cortisol and adrenocorticotropic hormone (ACTH) levels and SNS reactivity by determining serum epinephrine (E) and norepinephrine (NE) concentrations as well as autonomic nervous system changes by analysis of heart rate variability (HRV). The stressor included a speech task, mental arithmetic, and a cognitive challenge. RESULTS: In all, we studied 22 women remitted from recurrent major depression (age = 51.0 +/- 1.7 years) and 20 healthy controls (age = 54.2 +/- 1.6 years). Morning saliva cortisol concentrations were lower in remitted patients, paralleled by lower serum cortisol concentrations before stress testing. This group also displayed a blunted cortisol and ACTH response to the stressor, as compared with healthy controls. No between-group differences in HRV parameters were observed. CONCLUSION: In this group of women remitted from recurrent major depressive disorder, we found evidence of HPA system hypoactivity, both in the basal state and in response to a psychosocial stressor.

How depression may increase cardiac risk: effect of hypercortisolism on platelet activation markers: preliminary data.

INTRODUCTION: Hypercortisolism, as seen in the majority of patients with major depression, may be associated with the generation of platelets that show signs of increased activation. METHODS: Within a study using a placebo-controlled double-blind cross-over design, 9 healthy subjects ingested hydrocortisone (daily dose = 40 mg) or placebo on 7 consecutive days. At the end of each study segment, we analyzed platelets for the surface activation markers P-selectin, glycoprotein 53, and PAC-1 and measured platelet-leucocyte aggregates in serum. RESULTS: Hydrocortisone ingestion was not associated with changes in the platelet activation markers P-selectin and PAC-1 or the number of circulating platelet-leucocyte aggregates but with a trend (p = 0.056) toward higher expression of glycoprotein 53 on the platelet surface. CONCLUSIONS: Induction of hypercortisolism in healthy volunteers was not associated with a major increase in platelet activation markers.

No association between cardiometabolic risk and neural reactivity to acute psychosocial stress.

BACKGROUND: Exaggerated reactivity to acute psychosocial stress is associated with an increased risk of cardiovascular and metabolic disease. A dysfunction of the cortico-limbic network coordinating the peripheral adaptation to acute stress exposure may constitute a brain mechanism underlying this association. We opted to characterize the changes of this network associated with acute psychosocial stress exposure in individuals with low and high cardiometabolic risk (CMR). METHODS: In 57 subjects without overt cardiac or cerebral disease, the Framingham risk score and presence/absence of type 2 diabetes or metabolic syndrome defined CMR. Psychosocial stress was induced during functional magnetic resonance imaging (fMRI) of brain activity by an established social threat paradigm. Measurements of heart rate, blood pressure and saliva cortisol quantified the peripheral stress reaction. Regression analyses for the anterior cingulate cortex, hippocampus, amygdala, insula and regulatory prefrontal regions evaluated the association of stress-associated brain activation and CMR. RESULTS: Psychosocial stress exposure was associated with an increased activity of a brain network including anterior and posterior cingulate cortex, putamen, insula, parahippocampus and right hippocampus. Psychosocial stress-associated brain activation did neither covary with Framingham risk score nor differ between groups with low or high CMR. CONCLUSION: Exposure to acute psychosocial stress induces the activation of a well-defined cortico-limbic network. However, we did not find an association between CMR and this network's stress reactivity.

Resistin and adiponectin in major depression: the association with free cortisol and effects of antidepressant treatment.

Major depression is associated with an increased risk for myocardial infarction. Adipokines have been shown to link obesity with metabolic disturbances. Based on this finding the present study was designed to investigate the effect of antidepressive treatment with either amitriptyline or paroxetine on circulating concentrations of resistin and adiponectin in depressed patients, and to establish, whether these adipokines are associated with the activation of the hypothalamic-pituitary-adrenal (HPA)-system. Thirty-seven depressed in-patients were treated in a double-blind, randomized protocol with either amitriptyline or paroxetine over a period of five weeks. After six drug free days blood was drawn on day 1 and again 36 days after antidepressive treatment for the measurement of resistin and adiponectin, fasting glucose and insulin concentrations. For quantification of free cortisol levels saliva was obtained daily at 0800 hours during weeks 1 and 5. While resistin concentrations decreased in patients remitting under amitriptyline and paroxetine (p<0.03), no changes were observed in non-remitters. At baseline, though not during treatment, circulating resistin concentrations correlated positively with free cortisol levels and with BMI (p<0.01). Adiponectin levels, however, did not change during treatment and were not associated with free cortisol concentrations but were instead positively related to QUICKI (p<0.03). In conclusion, the present data revealed resistin but not adiponectin to be related to free cortisol concentrations and to decline in remitters to antidepressive treatment.

Metabolic changes in elderly patients with major depression: evidence for increased accumulation of visceral fat at follow-up.

The accumulation of visceral fat is promoted by a specific endocrine syndrome, which is similarly found in major depression. The aim of this study was to investigate whether visceral fat depots increase in depressed patients during a follow-up period explaining the increased risk for cardiovascular disorders. Intraabdominal fat was measured in 29 depressed patients and 17 controls by computer tomography at the level of lumbar vertebra 4. In patients fat measurements were done initially during a major depressive episode and again after a follow-up period of 14 months; in controls the mean time interval between measurements was 28 months. In both groups, saliva was taken at 800 h over a period of seven days prior to each CT for the estimation of free cortisol. In patients only, an oral glucose tolerance test was also carried out. Compared to controls hyper- and normocortisolemic depressed patients showed a larger accumulation of visceral fat mass over time (hypercort.:132.0 +/- 45 vs. 144.7 +/- 47 cm(2), p = 0.07; normocort.: 115.5 +/- 53 vs. 135.0 +/- 51 cm(2), p = 0.002; controls: 130.1 +/- 66 vs. 137.3 +/- 76 cm(2), p = 0.4), despite similar weight gain (hypercort.: 2.1 +/- 5 kg, normocort.: 1.7 +/- 5 kg and controls: 2.3 +/- 4 kg). Further, normocortisolemic patients showed a trend for an higher percentile increase in visceral fat accumulation than controls (23.9 +/- 27 vs. 5.8 +/- 28%, p = 0.07). At follow-up, free cortisol concentrations were still above normal in patients who had been hypercortisolemic at first assessment (35.0 +/- 8 vs. 28.8 +/- 18 nmol/l, p = 0.1). Fasting and 2 h glucose concentrations were higher in hypercortisolemic compared to normocortisolemic patients at the index examination (6.2 +/- 1.1 vs. 5.0 +/- 0.05 mmol/l, p = 0.02; 11.5 +/- 2.7 vs. 7.8 +/- 1.9 mmol/l, p = 0.01). The larger proportion of visceral fat accumulation in patients may constitute a link for explaining the increased cardiovascular mortality in patients suffering from major depression.