Barbara Scharnholz

MORC1 exhibits cross-species differential methylation in association with early life stress as well as genome-wide association with MDD.

Early life stress (ELS) is associated with increased vulnerability for diseases in later life, including psychiatric disorders. Animal models and human studies suggest that this effect is mediated by epigenetic mechanisms. In humans, epigenetic studies to investigate the influence of ELS on psychiatric phenotypes are limited by the inaccessibility of living brain tissue. Due to the tissue-specific nature of epigenetic signatures, it is impossible to determine whether ELS induced epigenetic changes in accessible peripheral cells, for example, blood lymphocytes, reflect epigenetic changes in the brain. To overcome these limitations, we applied a cross-species approach involving: (i) the analysis of CD34+ cells from human cord blood; (ii) the examination of blood-derived CD3+ T cells of newborn and adolescent nonhuman primates (Macaca mulatta); and (iii) the investigation of the prefrontal cortex of adult rats. Several regions in MORC1 (MORC family CW-type zinc finger 1; previously known as: microrchidia (mouse) homolog) were differentially methylated in response to ELS in CD34+ cells and CD3+ T cells derived from the blood of human and monkey neonates, as well as in CD3+ T cells derived from the blood of adolescent monkeys and in the prefrontal cortex of adult rats. MORC1 is thus the first identified epigenetic marker of ELS to be present in blood cell progenitors at birth and in the brain in adulthood. Interestingly, a gene-set-based analysis of data from a genome-wide association study of major depressive disorder (MDD) revealed an association of MORC1 with MDD.

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.

Do depressed patients without activation of the hypothalamus—pituitary—adrenal (HPA) system have metabolic disturbances?

This study compared features of the metabolic syndrome between healthy controls and depressed patients without activation of the hypothalamus-pituitary-adrenal (HPA) system. After exclusion of non-suppressors to 1mg dexamethasone, we included 20 depressed inpatients and 34 healthy controls in the analyses. We assessed HPA system activity (diurnal saliva cortisol profile, cortisol excretion), normetanephrine excretion as well as fasting glucose, lipid profile and blood pressure. With regard to body composition, we measured waist circumference as well as visceral fat and adrenal volume by magnetic resonance (MR) imaging. Five depressed patients (25%) and five healthy controls (15%) fulfilled the criteria of the metabolic syndrome according NCEP-ATP-III. Depression was significantly related with fasting glucose and negatively associated with mean blood pressure (BP) and, by trend, with low HDL-cholesterol. We conclude that depressed patients may have modest metabolic disturbances even in the complete absence of activation of stress-responsive systems. Hence some metabolic disturbances in depressed patients may not be explicable by HPA activation. Additional factors are required to mediate the link between affective and metabolic disorders.

Does night-time cortisol excretion normalize in the long-term course of depression?

INTRODUCTION While there is extensive literature on HPA system activity in acutely depressed patients, there is only limited information about the presence of hypercortisolemia during the interepisode interval of affective disorders. We hypothesized an increase in HPA system activity in depressed patients compared to controls, and proposed that night-time cortisol excretion during follow-up will depend on clinical outcome. METHODS We measured night-time cortisol excretion in 27 patients during an acute episode of major depression as well as a 20-week follow-up. 40 healthy subjects served as control group. RESULTS During the acute episode depressed patients showed increased levels of night-time cortisol excretion compared to healthy controls. Both, patients with full and sustained remission (n=8) as well as patients with incomplete remission or relapse (n=19) showed declining cortisol excretion in night-time urine during follow-up. At the end of follow-up cortisol excretion did not differ between patients with affective disorder and healthy controls. DISCUSSION Irrespective of residual depressive symptoms, HPA system activity declines after the generally investigated acute depressive episode.

Maternal hypothalamus-pituitary-adrenal (HPA) system activity and stress during pregnancy: Effects on gestational age and infant’s anthropometric measures at birth

BACKGROUND Prenatal maternal stress might be a risk for the developing fetus and may have long-lasting effects on child and adult vulnerability to somatic and psychiatric disease. Over-exposure of the unborn to excess glucocorticoids and subsequent alteration of fetal development is hypothesized to be one of the key mechanisms linking prenatal stress with negative child outcome. METHODS In this prospective longitudinal study, mothers-to-be (n = 405) in late pregnancy (36.8 ± 1.9 weeks of gestational age) and their singleton neonates were studied. We investigated the impact of different prenatal stress indices derived from six stress variables (perceived stress, specific prenatal worries, negative life events, symptoms of depression, trait anxiety, neuroticism) and diurnal maternal saliva cortisol secretion on gestational age and anthropometric measures at birth. RESULTS Maternal prenatal distress during late gestation was associated with significant reduction in birth weight (-217 g; p = .005), birth length (-1.2 cm; p = .005) and head circumference (-0.8 cm; p = .001). Prenatal stress was modestly but significantly associated with altered diurnal cortisol pattern (flattened cortisol decline and higher evening cortisol), which in turn was significantly related to reduced length of gestation. No evidence for a profound interaction between maternal cortisol level in late pregnancy and infants anthropometric measures at birth (i.e., birth weight, length, head circumference) was found. CONCLUSION Prenatal stress is associated with flattened circadian saliva cortisol profiles and reduced infants anthropometric measures at birth. HPA system activity during pregnancy may be related to low gestational age. The effect of prenatal stress might be partly mediated by maternal-placental-fetal neuroendocrine mechanisms especially the dysregulation of diurnal cortisol profile.

Antidepressant Treatment with Venlafaxine and Mirtazapine: no Effect on Serum Concentration of Vascular Endothelial Growth Factor (VEGF)

INTRODUCTION Depression, stress and antidepressant treatment have been found to modulate the expression of growth factors. METHODS We studied depressed patients receiving randomized treatment with venlafaxine or mirtazapine for 28 days. RESULTS There was no significant difference between baseline VEGF concentrations in depressed patients compared to healthy controls. We found no significant effect of antidepressant treatment on serum VEGF. DISCUSSION In contrast to serum BDNF, VEGF may not be a suitable biomarker for effects of antidepressant treatment with venlafaxine or mirtazapine.

Treatment with mirtazapine and venlafaxine increases noradrenaline excretion in depressed patients.

To the Editors: Depression is a risk factor for cardiovascular morbidity and mortality, but the precise pathophysiological mechanisms are not fully understood. An increased sympathetic tone in depressed patients may contribute to the increased risk for cardiac events in depressed patients. Prolonged sympathoadrenergic activation may lead to impaired health. High plasma and urine levels of noradrenaline (NA) have been found to be associated with reduced survival in otherwise healthy elderly as well as in patients with heart disease. Several mechanism have been discussed to explain the pathophysiological link between high NA levels and increased risk of mortality such as down-regulation of Q-receptors, hypertension, and metabolic disorders. Sympathetic activity may be assessed by measuring catecholamines and their metabolites in plasma or urine as well as indirectly, for example, by heart rate variability. With regard to NA excretion, several studies have shown increased sympathetic activity related to depression, to depressive symptoms in healthy subjects, and to depression in patients with coronary artery disease. Thus, disbalance of the autonomous nervous systemwith predominantly sympathoadrenergic tone may contribute to the cardiovascular risk of depressed patients. Interestingly, there is only limited information on the effect of antidepressants on NA excretion, and there are no studies on the effects of venlafaxine and mirtazapine on NA in plasma or urine. We conducted this study to test the hypothesis that mirtazapine and venlafaxine increase the sympathoadrenergic tone. We included 95 adult patients with unipolar major depressive episodes (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) and a score of at least 18 points on the Hamilton Depression Rating Scale (HDRS, 21 items). Upon inclusion, they had either been untreated or were then kept off their psychiatric medication.We did not include patients who had been taking fluoxetine or long-acting injectable antipsychotics. We examined 65 female (52.2 T 16.2 years) and 30 male patients (45.6 T 14.5 years) along with 16 age-matched healthy volunteers (7 women and 9 men; age, 48.3 T 18.9 years). Patients were being treated on an inpatient basis and participated in all routine ward activities; healthy controls were not hospitalized but remained in their regular environment. Exclusion criteria were lifetime diagnosis of schizophrenia or bipolar disorder, current substance dependence, and all physical disorders and medications (eg, A-blocker) that may interfere with sympathetic activity or excretion of catecholamines (eg, impaired renal function). Semistandardized diagnostic interviews in healthy controls revealed no axis I disorder. Before enrollment, all subjects had provided written informed consent. The study had been approved by the local ethics committee and was conducted in accordance with the Declaration of Helsinki. Patients were kept off psychiatric medication for a period of at least 6 days (week j1), after which they were treated with either venlafaxine or mirtazapine over a period of 4 weeks. Their assignment to either antidepressant treatment (arm) was at random. With the exception of lorazepam and zolpidem as needed, no additional psychotropic medication was allowed. Venlafaxine was dispensed at either 8:30 A.M. or at 2 time points (8:30 A.M. and 12:30 P.M.). Mirtazapine was dispensed at 12:30 P.M. Drugs were given in flexible doses with a minimum dose of 75 mg venlafaxine (final dosage, 150Y300 mg/d; mean, 202 T 57 mg/d) and 30 mg mirtazapine (final dosage, 30Y60 mg/d; mean, 46 T 9 mg/d). Psychopathologic assessment was conducted weekly (HDRS). Patients with less than 18 points on the HDRS at the end of the drug-free washout period or a drop of 10 or more points were excluded from the study (n = 8). Remission was defined as a final HDRS score of 7 or less. Patients and controls were instructed to void at 10 P.M. and to sample all urine after 10 P.M., including the morning urine at 8 A.M. Urine was sampled on 10-mL hydrochloride to allow NA estimation. We collected one urine sample from controls and 2 samples from patients (baseline; day 28). Urine volume was measured, and aliquots were frozen at j20-C until analysis. After completion of the study, the samples were shipped in dry ice to the laboratory for quantification of NA concentration by means of a commercially available radioimmunoassay (Labor Diagnostika Nord, Nordhorn, Germany). Shortly, NAwas extracted from urine samples using a cis-diolspecific affinity gel fixed to the bottom of the wells of a microtiter plate and further acylated to N-acylnoradrenaline. After release, N-acylnoradrenaline was enzymatically converted (S-adenosylmethionine + catechol-3-O-methyl-transferase) to its respective O-methyl-derivative N-acylnormetanephrine. Final quantification took place by means of a manually performed conventional double antibody competitive radioimmunoassay. Between-run coefficient of variations were 8.9% at a concentration range of 18.6 to 117 Kg/L. We used repeated-measurement analysis of variance (ANOVA) (ANOVA-rm) to first analyze the effect of medication (mirtazapine vs venlafaxine) and then the effect of response (remitters vs nonremitters) separately before combining both factors for further analysis of treatment outcome. All withinand between-group comparisons were analyzed by using paired and unpaired t tests. Noradrenaline concentration multiplied with nighttime urine volume was used as excretion variable. As NA excretion showed no normal distribution, we used logarithmus naturalis-normalized values in all analyses but still reported the original values. All P values are 2-tailed. The level of significance was set at P G 0.05. Eight patients had to be excluded after the washout period (G18 HDRS or drop of Q10 points), leaving in 87 patients for the active treatment phase of the study. Fortytwo patients were treated with mirtazapine, and 45 patients were treated with venlafaxine. After exclusion of patients failing to meet study requirements due to missing or, in all likelihood, incomplete urine samples, and patients using Q-blockers, we analyzed 24 mirtazapine-treated patients (16 women and 8 men; age, 50.0 T 17.2 years; HDRS, 22.9 T 4.2) and 27 venlafaxinetreated patients (17 women and 10 men; age, 55.1 T 13.0 years; HDRS, 23.4 T 5.1). In mirtazapine-treated subjects, there was a significant decline in severity of depression (HDRS, day 28: 8.0 T 5.4) and 11 of 24 subjects were in complete remission at the end of the study period. Similarly, we found a significant decline in severity of depression in the venlafaxine-treated group of patients (HDRS, day 28: 8.9 T 6.6), with 13 of 27 patients considered to be in full remission at the end of the study. There was no statistically significant difference in sex distribution, age, or severity of depression between treatment groups; nor was there a difference between treatment groups and healthy controls (7 women, 54.6 T 12.6 years; 9 men, 43.4 T 17.2 years) regarding sex, age, or urine volume. Sex had no effect on NA excretion in either healthy controls Letters to the Editors Journal of Clinical Psychopharmacology & Volume 32, Number 4, August 2012