[Prevalence of sleep-related breathing disorders of inpatients with psychiatric disorders]. / Prävalenz schlafbezogener Atmungsstörungen bei stationären Patienten mit psychischen Erkrankungen.

BACKGROUND: Sleep-related breathing disorders seriously impair well-being and increase the risk for relevant somatic and psychiatric disorders. Moreover, risk factors for sleep-related breathing disorders are highly prevalent in psychiatric patients. The aim of this study was for the first time in Germany to study the prevalence of obstructive sleep apnea syndrome (OSAS) as the most common form of sleep-related breathing disorder in patients with psychiatric disorders. METHODS: In 10 psychiatric hospitals in Germany and 1 hospital in Switzerland, a total of 249 inpatients underwent an 8­channel sleep polygraphy to investigate the prevalence of sleep apnea in this group of patients. RESULTS: With a conspicuous screening result of 23.7% of the subjects, a high prevalence of sleep-related breathing disorders was found to occur among this group of patients. Male gender, higher age and high body mass index (BMI) were identified as positive risk factors for the detection of OSAS. DISCUSSION: The high prevalence indicates that sleep apnea is a common sleep disorder among psychiatric patients. Although OSAS can lead to substantial disorders of the mental state and when untreated is accompanied by serious somatic health problems, screening procedures are not part of the routine work-up in psychiatric hospitals; therefore, sleep apnea is presumably underdiagnosed in psychiatric patients. In view of the results of this and previous studies, this topic complex should be the subject of further research studies.

QLiS-SF: Development of a short form of the quality of life in schizophrenia questionnaire.

BACKGROUND: There is a need for useful standardized Quality of Life (QoL) measures for people diagnosed with schizophrenia. Therefore, a short form of the self-administered Quality of Life in Schizophrenia (QLiS) scale was developed and validated. METHODS: Four steps were taken to develop the abridged version using samples from the Clinical Analysis of the Treatment of Schizophrenia (CATS) study. Firstly, a model with second order scales was developed using exploratory factor analysis (EFA). Secondly, it was tested in an independent sample using confirmatory factor analysis (CFA). Thirdly, this model served as the basis for selecting items for the short form. Distributional properties, content reviews, and factor loadings were taken into account in this step. Fourthly, the resulting short form was validated through confirmatory factor analysis (CFA). Composite reliability scores were calculated for the new subscales. RESULTS: Three second order scales were constructed: illness-related quality of life (QoL), social life and finances, and global subjective well-being. CFA of the new theoretical model resulted in a CFI of 0.67 and absolute fit indices of CMIN/df = 2.55, RMSEA = 0.08, SRMR = 0.09. The selected 13 items showed good statistical properties and good fit of content to subscale. Fit of the underlying theoretical model with the reduced number of items was tested in an independent sample. Absolute and fit indices of the short form model were satisfactory (CFI = 0.95, CMIN/df = 2.23, RMSEA = 0.06, SRMR = 0.04). Composite reliability scores for three subscales were above 0.70. CONCLUSIONS: The short form of the QLIS (QLiS-SF) showed good model fit and reliability. It should only be considered for use if the application of the long version is not suitable.

[Rank of outcome parameters in the treatment of depression : Results of a Delphi panel survey]. / Präferenz von Zielparametern bei der Behandlung der Depression : Ergebnisse einer Delphi-Panel-Erhebung.

BACKGROUND: In the context of new drug benefit assessments a list of outcome parameter are evaluated. Currently it is unclear, how different outcome parameters are weighed in the overall assessment. OBJECTIVES: The objective of the survey is to rank relevant outcome parameters in the treatment of depression, which may be considered in benefit the assessment of new antidepressants. MATERIALS AND METHODS: In 2015 a Delphi panel survey with 30 general practitioners and specialists in Germany was performed regarding the benefit assessment of antidepressants. On the basis of two fictive casuistics (patients with depressive disorders) the physicians weighed a range of relevant outcome parameters regarding efficacy, quality of life, safety and tolerability according to their relevance to clinical practice. RESULTS: Regarding efficacy, response, remission and recovery were rated as the most important outcomes. Regarding quality of life, handling of the daily household activities and mental performance were rated as most important. Suicidality was rated as the most important outcome regarding safety and tolerability. CONCLUSIONS: Individual outcome parameters were rated differently by the physicians regarding their relevance to clinical practice. The results indicate that outcome parameters should be weighed differently when assessing the overall benefit of new antidepressants.

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.

[Cardiac and metabolic risk factors in severe mental disorders. Task of a prevention manager]. / Kardiale und metabolische Risikofaktoren bei schweren psychischen Erkrankungen. Aufgaben eines Präventionsmanagers.

People with severe mental disorders have a reduction in life expectancy of 13-30 % compared with the general population. This severe disadvantage is primarily due to an increased prevalence of cardiac and metabolic disorders, especially coronary heart disease (CHD) and type 2 diabetes mellitus and are the result of untoward health behavior characterized by smoking, low levels of physical activity and unhealthy dietary habits. Obesity, arterial hypertension and lipid disorders are also associated with this behavior and further increase the risk of CHD and type 2 diabetes. Thus, people with mental disorders constitute a population with a high risk of cardiovascular events. Appropriate measures for prevention and therapy are urgently indicated but rarely applied. This article presents new organizational structures to overcome this deficit with a prevention manager playing a central role in organizing and applying preventive and therapeutic care. Results from cardiology and diabetic medicine have shown the effectiveness of pooling this responsibility. The measure has the potential to reduce the increased mortality of people with severe mental disorders.

Changes of serum concentrations of brain-derived neurotrophic factor (BDNF) during treatment with venlafaxine and mirtazapine: role of medication and response to treatment.

INTRODUCTION: Depression, stress and antidepressant treatment have been found to modulate the expression of brain-derived neurotrophic factor (BDNF). Recent research suggests that serum BDNF concentration is reduced in depression and that antidepressant treatment leads to an increase in serum BDNF concentration. METHODS: We studied depressed patients receiving a randomized antidepressant treatment with either mirtazapine (n=29) or venlafaxine (n=27) for 28 days in a prospective design. Changes in the concentrations of serum neurotrophins in response to antidepressant treatment were assessed. RESULTS: There was a significant "treatment" by "medication" interaction effect on BDNF serum concentrations that indicated a decline of BDNF in venlafaxine-treated patients (7.82±3.75-7.18±5.64 ng/mL), while there was an increase in mirtazapine-treated patients (7.64±6.23-8.50±5.37 ng/mL). There was a trend for a "treatment" by "remission" interaction with a favourable clinical course being related to increasing serum BDNF. DISCUSSION: Changes in BDNF serum concentrations as a result of antidepressant therapy depend on the antidepressant and potentially on the clinical course.

Assessment of cardiovascular disease risk in patients with schizophrenia spectrum disorders in German psychiatric hospitals: results of the pharmacoepidemiologic CATS study.

PURPOSE: Patients with severe mental illness are at high risk for metabolic and cardiac disorders. Thus, monitoring of cardiovascular risks is imperative and schedules for screening for lipids, glucose, body mass index (BMI), waist-hip ratio and blood pressure have been developed. We intended to analyze screening for metabolic disorders in German patients with schizophrenia spectrum disorders in routine psychiatric care. METHODS: We included 674 patients with any F2 diagnosis in out- and inpatient settings and analyzed metabolic screening procedures as practiced under conditions of usual care. RESULTS: Except BMI (54 %), all other values were documented only in a minority of patients: waist circumference (23 %), cholesterol (28 %), fasting glucose (19 %), triglycerides (25 %) and blood pressure (37 %). We found evidence for less than perfect quality of blood pressure measures. The group of patients who met the individual metabolic syndrome ATP III criteria was comparable to the US CATIE trial. CONCLUSIONS: We conclude that frequency and quality of metabolic monitoring in German in- and outpatients settings are not in accordance with the respective recommendations. Similar to previous reports we found evidence for a high prevalence of metabolic disturbances in German patients with schizophrenia spectrum disorders.

The differential effect of risperidone and olanzapine on insulin sensitivity after 3 weeks of treatment: a HOMA pilot study.

BACKGROUND AND METHODS: Patients with an acute psychotic episode underwent HOMA testing for insulin sensitivity (IS) prior to and after 3 weeks of treatment with olanzapine (n = 7) or risperidone (n = 7). RESULTS AND DISCUSSION: The HOMA-IS index was reduced in the olanzapine group, but significantly increased in patients treated with risperidone. There was a significant "time × medication" interaction (p = 0.03). The BMI significantly increased as a result of both treatments. IS can be acutely ameliorated by antipsychotic treatment with risperidone despite weight increase. CONCLUSIONS: Compared to risperidone, the IS is impaired after a 3-week treatment with olanzapine. Already short-term antipsychotic treatment may have eff ects on insulin sensitivity.

Insulin secretion and sensitivity after single-dose amisulpride, olanzapine or placebo in young male subjects: double blind, cross-over glucose clamp study.

INTRODUCTION: Increased risks of weight gain and diabetes mellitus have been reported for schizophrenic patients under long-term treatment with several atypical antipsychotic drugs including olanzapine. Among other antipsychotic drugs, treatment with the selective dopamine D2 and D3 receptor antagonist amisulpride has been implicated with a lower risk for metabolic complications. PATIENTS AND METHODS: In this study we compared the acute, non-adiposity related effects of a single dose of olanzapine, amisulpride and placebo on insulin sensitivity and secretion in 10 healthy subjects in a randomised, double blind cross-over design. Subjects underwent euglycemic-hyperinsulinemic and hyperglycemic clamp tests using an automated clamp device. C-peptide and pro-insulin levels were determined using highly specific immuno-assays. RESULTS: Insulin sensitivity was not significantly different between both verum medications and placebo. However, C-peptide secretion during hyperglycemic clamp was significantly higher after administration of amisulpride than after olanzapine or placebo. This was true both for the early phase and for the second phase of insulin secretion (C-peptide at 0, 5,10 and 30 min: amisulpride 1.49±0.49; 4.22±1.45; 3.19±1.22; 5.33±1.85; olanzapine 1.35±0.47; 3.84±1.37; 2.72±0.91; 4.28±1.96; placebo 1.72±0.82; 3.59±1.19; 2.71±1.02; 4.54±1.42 ng/mL, mean±SD; ANOVA p=0.043). Pro-insulin levels did not differ significantly between groups. DISCUSSION: A low dose of the D2/D3 antagonist amisulpride, but not olanzapine appears to acutely increase pancreatic insulin secretion in healthy controls. Stimulation of ß-cells could be a protective factor against the development of diabetes mellitus.

[Depression and diabetes mellitus type 2]. / Depression und Diabetes mellitus Typ 2.

Depression and diabetes mellitus type 2 are frequently comorbid conditions. Both disorders may increase the incidence of the other disorder and impair the prognosis. Thus, it is important for psychiatrists to consider depressed patients as high-risk diabetes subjects to screen for metabolic risks and to consider metabolic risks of antidepressant treatment.

[Epigenetic mechanisms in major depression]. / Epigenetische Mechanismen der Depression.

The term epigenetics describes mechanisms that can change the function of genes in the absence of an alteration of the actual DNA sequence. Among others, histone protein modifications (methylation, acetylation and phosphorylation) and DNA methylation constitute epigenetic mechanisms. Histone methylation and histone deacetylation in promoter regions of neurotrophic factors that have been associated with depression lead to their reduced expression. The methylation of DNA in promoter regions of genes coding for receptors and neurotrophic factors also results in their reduced expression, as was revealed for depressive disorders. Preclinical studies have shown that maternal care has a crucial influence on the reactivity of the hypothalamic-pituitary-adrenocortical axis of the offspring due to epigenetic mechanisms. These are acquired modifications that can be partially reversed by drug treatment (antidepressants).

[The role of the glutamatergic system in pathophysiology and pharmacotherapy for depression: preclinical and clinical data]. / Die Bedeutung des glutamatergen Systems für Pathophysiologie und Pharmakotherapie der Depression: präklinische und klinische Daten.

An increasing significance has been attributed to the glutamatergic system in the pathophysiology of affective disorders. Glutamate is the most important excitatory neurotransmitter in the central nervous system. Glia cells are crucial regulators of the glutamatergic metabolism. Several studies have reported a dysfunction or reduced number of glia cells in patients suffering from depression. This could result in hyperfunctioning of the glutamatergic system leading to a toxic accumulation of glutamate. Commonly used antidepressants influence the glutamate metabolism and antiglutamatergic substances [e. g., riluzol] and NMDA-receptor antagonists [e. g., ketamine] have shown antidepressant properties in mostly preclinical and some clinical trials. Further substances are currently being investigated. This review provides an insight into the newest developments in this field.

Valproic acid and all trans retinoic acid differentially induce megakaryopoiesis and platelet-like particle formation from the megakaryoblastic cell line MEG-01.

Both, the activity of transcription factors as well as epigenetic alterations in defined DNA regions regulate cellular differentiation processes. Hence, neuronal differentiation from neural progenitor cells is promoted by the transcription factor all trans retinoic acid (ATRA) and the histone deacetylase inhibitor valproic acid (VPA). VPA has also been shown to be involved in differentiation of tumor cells and to greatly improve the reprogramming of human somatic cells to induced pluripotent stem cells. Here we have investigated the impact of ATRA and VPA on the differentiation of megakaryoctes and platelets from the megakaryocyte progenitor cell line MEG-01. Our results show that treatment with ATRA (10⁻¹¹ M) and VPA (2 × 10⁻³ M) induces megakaryopoiesis of MEG-01 cells as estimated by polyploidy, formation of characteristic proplatelets and elevated expression of the megakaryocytic markers CD41 and CD61. The resulting megakaryocytes stayed viable for more than 3 weeks and shed platelet-like particles positive for CD41, CD61 and CD42b into the supernatant. Platelet-like particles responded to thrombin receptor activating peptide (TRAP-6) with increased externalization of P-selectin. Thus, ATRA and VPA proved to be efficient agents for the gentle induction of megakaryopoiesis and thrombopoiesis of MEG-01 cells providing the possibility to study molecular events underlying megakaryopoiesis and human platelet production over longer time periods.

Finasteride treatment inhibits adult hippocampal neurogenesis in male mice.

INTRODUCTION: The 5-alpha-reductase inhibitor finasteride is used for the treatment of androgenic alopecia, benign prostate hyperplasia and prostate cancer. Besides inhibiting the conversion of testosterone to the biologically more active 5alpha-dihydrotestosterone, it also inhibits the production of neurosteroids. Decreased neurosteroid levels are postulated to be involved in the pathophysiology of psychiatric disorders such as depression. As neurosteroids metabolized by 5-alpha-reductase influence neural plasticity, we investigated whether finasteride treatment alters adult hippocampal neurogenesis, implicated in the pathophysiology of depression. METHODS: Male C57BL/6N mice were treated subchronically (7 days) with finasteride or vehicle. Adult neurogenesis was assessed at two different time points after treatment (day 1; day 35) using immunohistochemistry. RESULTS: Finasteride treatment led to a significant decrease in brain 5alpha-dihydrotestosterone levels and induced a reversible reduction in the number of newborn cells and young neurons in the hippocampus. 35 days after the last finasteride injection, neurogenesis had returned to normal. DISCUSSION: These data indicate that inhibition of 5-alpha-reductase activity by finasteride treatment influences neuronal plasticity on a structural level. These changes might contribute to the pathophysiology of depressive episodes observed after finasteride treatment.

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.

[Insomnia in the elderly. An under-diagnosed and over-treated syndrome]. / Schlafstörungen bei älteren Menschen. Ein unterdiagnostiziertes und überbehandeltes Syndrom.

In elderly patients, insomnia is a common symptom. Insomnia exerts immediate negative effects on quality of life, but also shows a strong bidirectional relationship with serious medical problems. The complex etiology of insomnia in elderly persons warrants meticulous diagnostic assessment. In patients with secondary insomnia, therapy of the causative factors is initiated. Non-pharmacological therapies and behavioral advice constitute the mainstay of symptomatic treatment of insomnia. However, in elderly persons, the efficacy of these measures has not been well established. In general, the therapeutic benefit of hypnotic drugs is small. On the other hand, most substances may have considerable negative side effects. For short-term symptomatic treatment of acute insomnia, hypnotic drugs may be employed. For this indication, Benzodiazepine receptor agonists and prolonged-release Melatonin are drugs of first choice. Generally, prolonged treatment of chronic insomnia in elderly patients is not indicated due to the unclear long-term efficacy and negative side effects of the hypnotic drugs currently available.

Epigenetics-by-sex interaction for somatization conferred by methylation at the promoter region of SLC6A4 gene.

BACKGROUND: Depression, anxiety and somatoform disorders are all more prevalent in women than in men. However, specific biological mechanisms contributing to such sex differences remain unknown. Serotonergic pathways are involved in mood and behavior regulation and thus have been suggested to be altered in several psychiatric disorders. The serotonin transporter (SERT), encoded by SLC6A4 gene, has received major attention due to its crucial role in serotonergic transmission. METHODS: 148 monozygotic twin subjects were assessed for (i) lifetime categorical diagnosis of anxious-depressive disorders, following SCID-I-based DSM-IV criteria, and (ii) current psychiatric symptomatology, from a dimensional approach, by means of the Brief Symptom Inventory (BSI). SLC6A4 gene methylation was analyzed by means of Infinium HumanMethylation450 in a subset of the sample. CpG-specific methylation at the promoter region of SLC6A4 gene was further analyzed by means of pyrosequencing technology in the total sample. RESULTS: SLC6A4 methylation was found to be significantly higher in women when compared to men independent of DSM-IV diagnosis. SLC6A4 methylation was further associated with the BSI-derived somatization dimension. CONCLUSIONS: Female hypermethylation of a discrete region located within SLC6A4 promoter region could underlie differential SERT expression in women when compared to men and could be one of the causative mechanisms by which women exhibit increased prevalence of somatic symptoms.

Stress reactivity in preschool-aged children: Evaluation of a social stress paradigm and investigation of the impact of prenatal maternal stress.

Prenatal maternal stress is an established risk factor for somatic and psychological health of the offspring. A dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in offspring has been suggested as an important mechanism. However, the impact of prenatal stress on stress reactivity in preschool-aged children is not yet well understood. This is partly due to the fact that for this age group there is no stress test as well established as for older children and adults. In the present work a previously published stress test (Kryski et al., 2011) was evaluated in a large sample of 45-month-old children (n = 339). Furthermore, the relation between measures of prenatal maternal stress and cortisol reactivity was investigated. Prenatal stress was defined as psychopathology (self-report available for n = 339; expert-rating available for a subsample of n = 246) and perceived stress (n = 244) during pregnancy. The stress paradigm elicited significant increases in salivary cortisol 30 and 40 min after the test, and 60.8% of the children were classified as responders. Lower cortisol levels after the stress test were observed in the group of children with prenatal stress defined as maternal psychopathology (both self-reported and expert-rated). Maternal perceived stress as a continuous measure was not significantly associated with cortisol levels. However, when comparing children in the highest quartile of maternal perceived stress to all other children, significantly lower cortisol values were observed in the prenatally stressed group. The present study confirms the paradigm by Kryski et al. as an effective stress test for preschool-aged children. Moreover, it provides further evidence that prenatal stress impacts HPA axis reactivity. Future studies should target the timing, nature, and intensity of prenatal stressors and their effect on the stress response in offspring at different developmental stages.

Prenatal maternal stress is associated with lower cortisol and cortisone levels in the first morning urine of 45-month-old children.

Prenatal stress (PS) has been related to altered hypothalamic-pituitary-adrenal (HPA) axis activity later in life. So far, studies in children assessing HPA axis functioning have focused on salivary cortisol, reflecting daytime activity. The present work is part of a prospective study and aims to extend knowledge about the association between PS and HPA axis regulation in children. To do so, we investigated cortisol, cortisone, and the ratio cortisone/(cortisone + cortisol) in the first morning urine of 45-month-old children in relation to several measures of maternal stress during pregnancy. Urinary cortisol and cortisone were measured by online turbulent flow chromatography coupled with high performance liquid chromatography-tandem mass spectrometry. PS was defined as: perceived stress for aim 1 (Perceived Stress Scale; n = 280); presence of self-reported (n = 371) and expert-rated psychopathology for aim 2 (Mini International Neuropsychiatric Interview; n = 281); continuous measures of anxiety and depression for exploratory aim 3 (State-Trait Anxiety Inventory and Edinburgh Postnatal Depression Scale; n = 280). Aim 1: Perceived maternal PS showed negative associations with cortisol and cortisone levels. Aim 2: The presence of expert-rated maternal psychopathology was associated with reduced morning cortisone. Aim 3: Continuous measures of anxiety and depression showed negative associations with cortisol and cortisone levels. After correcting for multiple testing, perceived maternal PS (aim 1) and prenatal level of anxiety (aim 3) were significant predictors of children's urinary cortisol and cortisone in the morning (and, in the case of cortisone, also prenatal level of depression). The ratio cortisone/(cortisone + cortisol) as a global marker for the balance between the enzymes metabolizing cortisol to cortisone and vice versa (11ß-hydroxysteroid dehydrogenases type 1 and 2; 11ß-HSD1 and 2) was not associated with any measure of maternal PS (aims 1-3). The present study provides insight into possible programming effects of PS on nocturnal HPA axis activity and a proxy of 11ß-HSD in a large sample. The results suggest that the nocturnal rate of cortisol production is lower in children exposed to PS, but do not support the hypothesis of divergent 11ß-HSD activity.