Association of clinical parameters and polygenic risk scores for body mass index, schizophrenia, and diabetes with antipsychotic-induced weight gain.

Antipsychotic-induced weight gain (AIWG) is a common adverse event in schizophrenia. Genome-wide association studies (GWAS) and polygenic risk scores (PRS) for other diseases or traits are recent approaches to disentangling the genetic architecture of AIWG. 200 patients with schizophrenia treated monotherapeutically with antipsychotics were included in this study. A multiple linear regression analysis with ten-fold crossvalidation was performed to predict the percentage weight change after five weeks of treatment. Independent variables were sex, age, body mass index (BMI) at baseline, medication-associated risk, and PRSs (BMI, schizophrenia, diabetes, and metabolic syndrome). An explorative GWAS analysis was performed on the same subjects and traits. PRSs for BMI (ß = 3.78; p = 0.0041), schizophrenia (ß = 5.38; p = 0.021) and diabetes type 2 (ß = 13.4; p = 0.046) were significantly associated with AIWG. Other significant factors were sex, baseline BMI and medication. Compared to the model without genetic factors, the addition of PRSs for BMI, schizophrenia, and diabetes type 2 increased the goodness of fit by 6.5 %. The GWAS identified the association of three variants (rs10668573, rs10249381 and rs1988834) with AIWG at a genome-wide level of p < 1 · 10-6. Using PRS for schizophrenia, BMI, and diabetes type 2 increased the explained variation of predicted weight gain, compared to a model without PRSs. For more precise results, PRSs derived from other traits (ideally AIWG) should be investigated. Potential risk variants identified in our GWAS need to be further investigated and replicated in independent samples.

The Interplay of Oxytocin and Attachment in Schizophrenic Patients: An fMRI Study.

BACKGROUND: Attachment theory offers an important framework for understanding interpersonal interaction experiences. In the present study, we examined the neural correlates of attachment patterns and oxytocin in schizophrenic patients (SZP) compared to healthy controls (HC) using fMRI. We assumed that male SZP shows a higher proportion of insecure attachment and an altered level of oxytocin compared to HC. On a neural level, we hypothesized that SZP shows increased neural activation in memory and self-related brain regions during the activation of the attachment system compared to HC. METHODS: We used an event-related design for the fMRI study based on stimuli that were derived from the Adult Attachment Projective Picture System to examine attachment representations and their neural and hormonal correlates in 20 male schizophrenic patients compared to 20 male healthy controls. RESULTS: A higher proportion of insecure attachment in schizophrenic patients compared to HC could be confirmed. In line with our hypothesis, Oxytocin (OXT) levels in SZP were significantly lower than in HC. We found increasing brain activations in SZP when confronted with personal relevant sentences before attachment relevant pictures in the precuneus, TPJ, insula, and frontal areas compared to HC. Moreover, we found positive correlations between OXT and bilateral dlPFC, precuneus, and left ACC in SZP only. CONCLUSION: Despite the small sample sizes, the patients' response might be considered as a mode of dysregulation when confronted with this kind of personalized attachment-related material. In the patient group, we found positive correlations between OXT and three brain areas (bilateral dlPFC, precuneus, left ACC) and may conclude that OXT might modulate within this neural network in SZP.

The multimodal Munich Clinical Deep Phenotyping study to bridge the translational gap in severe mental illness treatment research.

Introduction: Treatment of severe mental illness (SMI) symptoms, especially negative symptoms and cognitive dysfunction in schizophrenia, remains a major unmet need. There is good evidence that SMIs have a strong genetic background and are characterized by multiple biological alterations, including disturbed brain circuits and connectivity, dysregulated neuronal excitation-inhibition, disturbed dopaminergic and glutamatergic pathways, and partially dysregulated inflammatory processes. The ways in which the dysregulated signaling pathways are interconnected remains largely unknown, in part because well-characterized clinical studies on comprehensive biomaterial are lacking. Furthermore, the development of drugs to treat SMIs such as schizophrenia is limited by the use of operationalized symptom-based clusters for diagnosis. Methods: In line with the Research Domain Criteria initiative, the Clinical Deep Phenotyping (CDP) study is using a multimodal approach to reveal the neurobiological underpinnings of clinically relevant schizophrenia subgroups by performing broad transdiagnostic clinical characterization with standardized neurocognitive assessments, multimodal neuroimaging, electrophysiological assessments, retinal investigations, and omics-based analyzes of blood and cerebrospinal fluid. Moreover, to bridge the translational gap in biological psychiatry the study includes in vitro investigations on human-induced pluripotent stem cells, which are available from a subset of participants. Results: Here, we report on the feasibility of this multimodal approach, which has been successfully initiated in the first participants in the CDP cohort; to date, the cohort comprises over 194 individuals with SMI and 187 age and gender matched healthy controls. In addition, we describe the applied research modalities and study objectives. Discussion: The identification of cross-diagnostic and diagnosis-specific biotype-informed subgroups of patients and the translational dissection of those subgroups may help to pave the way toward precision medicine with artificial intelligence-supported tailored interventions and treatment. This aim is particularly important in psychiatry, a field where innovation is urgently needed because specific symptom domains, such as negative symptoms and cognitive dysfunction, and treatment-resistant symptoms in general are still difficult to treat.

Examining the synergistic effects of a cognitive control video game and a home-based, self-administered non-invasive brain stimulation on alleviating depression: the DiSCoVeR trial protocol.

Enhanced behavioral interventions are gaining increasing interest as innovative treatment strategies for major depressive disorder (MDD). In this study protocol, we propose to examine the synergistic effects of a self-administered home-treatment, encompassing transcranial direct current stimulation (tDCS) along with a video game based training of attentional control. The study is designed as a two-arm, double-blind, randomized and placebo-controlled multi-center trial (ClinicalTrials.gov: NCT04953208). At three study sites (Israel, Latvia, and Germany), 114 patients with a primary diagnosis of MDD undergo 6 weeks of intervention (30 × 30 min sessions). Patients assigned to the intervention group receive active tDCS (anode F3 and cathode F4; 2 mA intensity) and an action-like video game, while those assigned to the control group receive sham tDCS along with a control video game. An electrode-positioning algorithm is used to standardize tDCS electrode positioning. Participants perform their designated treatment at the clinical center (sessions 1-5) and continue treatment at home under remote supervision (sessions 6-30). The endpoints are feasibility (primary) and safety, treatment efficacy (secondary, i.e., change of Montgomery-Åsberg Depression Rating Scale (MADRS) scores at week six from baseline, clinical response and remission, measures of social, occupational, and psychological functioning, quality of life, and cognitive control (tertiary). Demonstrating the feasibility, safety, and efficacy of this novel combined intervention could expand the range of available treatments for MDD to neuromodulation enhanced interventions providing cost-effective, easily accessible, and low-risk treatment options.ClinicalTrials.gov: NCT04953208.

Prospective DNA Methylation Analysis of the CpG GABRA2 Receptor Subunit in Alcohol Dependence during Detoxification.

Background and Objectives: Variants of GABRA2 have been repeatedly associated with alcohol dependence risk. However, no study investigated potential epigenetic alterations in the GABRA2 gene in alcohol-dependent (AD) subjects during alcohol withdrawal. We investigated DNA methylation pattern in the regulatory region of GABRA2 gene in peripheral leukocytes of AD patients and controls. Further, GABRA2 methylation patterns were analysed in neuroblastoma cells under ethanol exposure and withdrawal. Materials and Methods: In the present study, blood samples were obtained from 41 AD subjects on the day of inpatient admission, after the first and second week of inpatient treatment. The comparison group included 47 healthy controls. GABRA2 methylation of 4 CpG sites in the CpG island was compared to neuroblastoma cells which were exposed to 100 mM of ethanol for 2, 5 and 9 days, followed by a withdrawal interval of 4 days. Results: no significant differences in GABRA2 methylation patterns were found in AD subjects over time and vs. controls, after controlling for age. Further, no influence of withdrawal severity, alcohol consumption before admission and other alcohol dependence characteristics were found. Conclusions: The results indicate that GABRA2 methylation in AD individuals and in a cell model is unaffected by alcohol exposition and withdrawal. Influences of GABRA2 on characteristics of alcohol dependence may be exerted by mechanisms other than epigenetic alterations related to alcohol intoxication or withdrawal.

Biobanking in everyday clinical practice in psychiatry-The Munich Mental Health Biobank.

Translational research on complex, multifactorial mental health disorders, such as bipolar disorder, major depressive disorder, schizophrenia, and substance use disorders requires databases with large-scale, harmonized, and integrated real-world and research data. The Munich Mental Health Biobank (MMHB) is a mental health-specific biobank that was established in 2019 to collect, store, connect, and supply such high-quality phenotypic data and biosamples from patients and study participants, including healthy controls, recruited at the Department of Psychiatry and Psychotherapy (DPP) and the Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital of the Ludwig-Maximilians-University (LMU), Munich, Germany. Participants are asked to complete a questionnaire that assesses sociodemographic and cross-diagnostic clinical information, provide blood samples, and grant access to their existing medical records. The generated data and biosamples are available to both academic and industry researchers. In this manuscript, we outline the workflow and infrastructure of the MMHB, describe the clinical characteristics and representativeness of the sample collected so far, and reveal future plans for expansion and application. As of 31 October 2021, the MMHB contains a continuously growing set of data from 578 patients and 104 healthy controls (46.37% women; median age, 38.31 years). The five most common mental health diagnoses in the MMHB are recurrent depressive disorder (38.78%; ICD-10: F33), alcohol-related disorders (19.88%; ICD-10: F10), schizophrenia (19.69%; ICD-10: F20), depressive episode (15.94%; ICD-10: F32), and personality disorders (13.78%; ICD-10: F60). Compared with the average patient treated at the recruiting hospitals, MMHB participants have significantly more mental health-related contacts, less severe symptoms, and a higher level of functioning. The distribution of diagnoses is also markedly different in MMHB participants compared with individuals who did not participate in the biobank. After establishing the necessary infrastructure and initiating recruitment, the major tasks for the next phase of the MMHB project are to improve the pace of participant enrollment, diversify the sociodemographic and diagnostic characteristics of the sample, and improve the utilization of real-world data generated in routine clinical practice.

Efficacy of Sertraline Plus Placebo or Add-On Celecoxib in Major Depressive Disorder: Macrophage Migration Inhibitory Factor as a Promising Biomarker for Remission After Sertraline-Results From a Randomized Controlled Clinical Trial.

Introduction: Previous research delivers strong indications that inflammatory activation leads to treatment resistance in a subgroup of patients with Major Depressive Disorder (MDD). Thus, tailored interventions are needed. The present study aimed to find potential biomarkers that may enable patients to be stratified according to immune activation. Methods: A phase IIa randomized placebo-controlled trial was performed to assess levels of inflammatory compounds in responders/remitters and non-responders/non-remitters to sertraline plus celecoxib (n = 20) and sertraline plus placebo (n = 23). Levels of macrophage migration inhibitory factor, neopterin, and tumor necrosis factor alpha were determined by enzyme-linked immunosorbent assay; response and remission were measured by reduction of the Montgomery Åsberg Depression Rating Scale score. Results: Both treatment groups showed a significant decline in depression symptoms, but no difference was found between groups. A clear pattern emerged only for macrophage migration inhibitory factor: placebo remitters showed significantly lower baseline levels than non-remitters (a similar trend was seen in responders and non-responders) while celecoxib responders showed a trend for higher baseline levels than non-responders. Conclusion: Small subsample sizes are a notable limitation, wherefore results are preliminary. However, the present study provides novel insights by suggesting macrophage migration inhibitory factor as a promising biomarker for treatment choice. The trial was registered in EU Clinical Trials Register (EU-CTR): https://www.clinicaltrialsregister.eu/ctr-search/trial/2009-011990-34/DE, EudraCT-No.: 2009-011990-34.

Assessing the links between childhood trauma, C-reactive protein and response to antidepressant treatment in patients with affective disorders.

Adverse Childhood Experiences (ACE) are a well-known risk-factor for depression. Additionally, (high-sensitive) C-reactive Protein (hsCRP) is elevated in subgroups of depressed patients and high following ACE. In this context the literature considers hsCRP and ACE to be associated with treatment resistant depression. With the data being heterogenous, this study aimed to explore the associations of ACE, hsCRP levels and response to antidepressant treatment in uni- and bipolar depression. N = 76 patients diagnosed with uni- or bipolar depression and N = 53 healthy controls were included. Treatment was over 6 weeks in an inpatient psychiatric setting within an observatory study design. Depressive symptoms were assessed by the Montgomery-Asberg Depression Rating Scale (MADRS), ACE were assessed by the Childhood Trauma Questionnaire (CTQ); the body-mass-index (BMI) and hsCRP were measured. HsCRP levels did not differ between the study population and the healthy controls. While the depressive symptoms decreased, the hsCRP levels increased. Sexual abuse was associated with significant higher and emotional abuse with lower levels of hsCRP after 6 weeks. The baseline hsCRP levels and the ACE subgroups did not show significant associations with the treatment response in unipolar depressed patients. The long-lasting effects of specific forms of ACE may have relevant impact on inflammation, supporting hsCRP to be a suitable biomarker. With ACE and hsCRP not showing any significant associations with treatment response in the unipolar depressed subgroup, a more differentiate research concerning biomarkers and treatment regimens is needed when talking about treatment response.

Role of psychiatric hospitals during a pandemic: introducing the Munich Psychiatric COVID-19 Pandemic Contingency Plan.

BACKGROUND: Psychiatry is facing major challenges during the current coronavirus disease 2019 (COVID)-19 pandemic. These challenges involve its actual and perceived role within the medical system, in particular how psychiatric hospitals can maintain their core mission of attending to people with mental illness while at the same time providing relief to overstretched general medicine services. Although psychiatric disorders comprise the leading cause of the global burden of disease, mental healthcare has been deemphasised in the wake of the onslaught of the pandemic: to make room for emergency care, psychiatric wards have been downsized, clinics closed, psychiatric support systems discontinued and so on. To deal with this pressing issue, we developed a pandemic contingency plan with the aim to contain, decelerate and, preferably, avoid transmission of COVID-19 and to enable and maintain medical healthcare for patients with mental disorders. AIMS: To describe our plan as an example of how a psychiatric hospital can share in providing acute care in a healthcare system facing an acute and highly infectious pandemic like COVID-19 and at the same time provide support for people with mental illness, with or without a COVID-19 infection. METHOD: This was a descriptive study. RESULTS: The plan was based on the German national pandemic strategy and several legal recommendations and was implemented step by step on the basis of the local COVID-19 situation. In addition, mid- and long-term plans were developed for coping with the aftermath of the pandemic. CONCLUSIONS: The plan enabled the University Hospital to maintain medical healthcare for patients with mental disorders. It has offered the necessary flexibility to adapt its implementation to the first and second waves of the COVID-19 pandemic in Germany. The plan is designed to serve as an easily adaptable blueprint for psychiatric hospitals around the world.

Acute alcohol withdrawal and recovery in men lead to profound changes in DNA methylation profiles: a longitudinal clinical study.

BACKGROUND AND AIMS: Withdrawal is a serious and sometimes life-threatening event in alcohol-dependent individuals. It has been suggested that epigenetic processes may play a role in this context. This study aimed to identify genes and pathways involved in such processes which hint to relevant mechanisms underlying withdrawal. DESIGN: Cross-sectional case-control study and longitudinal within-cases study during alcohol withdrawal and after 2 weeks of recovery SETTING: Addiction medicine departments in two university hospitals in southern Germany. PARTICIPANTS/CASES: Ninety-nine alcohol-dependent male patients receiving in-patient treatment and suffering from severe withdrawal symptoms during detoxification and 95 age-matched male controls. MEASUREMENTS: Epigenome-wide methylation patterns were analyzed in patients during acute alcohol withdrawal and after 2 weeks of recovery, as well as in age-matched controls using Illumina EPIC bead chips. Methylation levels of patients and controls were tested for association with withdrawal status. Tests were adjusted for technical and batch effects, age, smoking and cell type distribution. Single-site analysis, as well as an analysis of differentially methylated regions and gene ontology analysis, were performed. FINDINGS: We found pronounced epigenome-wide significant [false discovery rate (FDR) < 0.05] differences between patients during withdrawal and after 2 weeks [2876 cytosine-phosphate-guanine (CpG) sites], as well as between patients and controls (9845 and 6094 CpG sites comparing patients at time-point 1 and patients at time-point 2 versus controls, respectively). Analysis of differentially methylated regions and involved pathways revealed an over-representation of gene ontology terms related to the immune system response. Differences between patients and controls diminished after recovery (> 800 CpG sites less), suggesting a partial reversibility of alcohol- and withdrawal-related methylation. CONCLUSIONS: Acute alcohol withdrawal in severely dependent male patients appears to be associated with extensive changes in epigenome-wide methylation patterns. In particular, genes involved in immune system response seem to be affected by this condition.

The novel seizure quality index for the antidepressant outcome prediction in electroconvulsive therapy: association with biomarkers in the cerebrospinal fluid.

For patients with depression treated with electroconvulsive therapy (ECT), the novel seizure quality index (SQI) can predict the risk of non-response (and non-remission)-as early as after the second ECT session-based the extent of several ictal parameters of the seizure. We aim to test several CSF markers on their ability to predict the degree of seizure quality, measured by the SQI to identify possible factors, that could explain some variability of the seizure quality. Baseline CSF levels of metabolites from the kynurenine pathway, markers of neurodegeneration (tau proteins, ß-amyloids and neurogranin), elements of the innate immune system, endocannabinoids, sphingolipids, neurotrophic factors (VEGF) and Klotho were measured before ECT in patients with depression (n = 12) to identify possible correlations with the SQI by Pearson's partial correlation. Negative, linear relationships with the SQI for response were observed for CSF levels of T-tau (rpartial = - 0.69, p = 0.019), phosphatidylcholines (rpartial = - 0.52, p = 0.038) and IL-8 (rpartial = - 0.67, p = 0.047). Regarding the SQI for remission, a negative, linear relationship was noted with CSF levels of the endocannabinoid AEA (rpartial = - 0.70, p = 0.024) and CD163 (rpartial = - 0.68, p = 0.029). In sum, CSF Markers for the innate immune system, for neurodegeneration and from lipids were found to be associated with the SQI for response and remission after adjusting for age. Consistently, higher CSF levels of the markers were always associated with lower seizure quality. Based on these results, further research regarding the mechanism of seizure quality in ECT is suggested.

Childhood Adversity and Current Stress are related to Pro- and Anti-inflammatory Cytokines in Major Depression.

BACKGROUND: Stress during early childhood, for example as a result of maltreatment, can predict inflammation in adulthood. The association of depression with inflammation and current and long-term stress resulting from childhood maltreatment and threatening experiences in the past year has not yet been studied. Therefore, we assessed these variables in a group of patients with major depressive disorder (MDD) and measured levels of the pro-inflammatory cytokine IL-6 and the anti-inflammatory cytokine IL-10. High levels of IL-6 are associated with depression and of IL-10 with stress. METHODS: We included 44 patients who fulfilled DSM-IV diagnostic criteria for MDD and 44 age- and gender-matched healthy controls. We used Cohen's Perceived Stress Scale (PSS), the list of life-threatening experiences questionnaire (LTE-Q) and the childhood trauma questionnaire (CTQ) to assess the level of stress and analyzed IL-6 and IL-10 cytokines in venous blood plasma. RESULTS: The patient group showed significantly higher scores on the maltreatment scale LTE-Q (2.7 vs. 1.1; P = 0.001, and the stress scales CTQ (emotional abuse; P = 0.048 and physical neglect; P = 0.002) and PSS (35.2 vs 15.5; P < 0.001) as well as significantly higher levels of IL-6 (1.5pg/ml vs. 0.9pg/ml; P = 0.012). They also had significantly higher levels of IL-10 (1.1pg/ml vs. 0.7pg/ml; P < 0.001). Higher actual stress levels were associated with childhood maltreatment and higher IL-6 (tau = 0.004) and IL-10 (tau = 0.027) levels. LIMITATIONS: The results need to be replicated in a larger sample, and the study did not evaluate causal relationships. Although the assessment of childhood trauma was retrospective, the CTQ is a well-established assessment instrument. CONCLUSIONS: The patients with MDD in this study showed an immune activation in response to stress. This study highlights the association of childhood trauma and current and long-term stress with an increased immune activation in MDD.

Short-term changes in global methylation and hydroxymethylation during alcohol detoxification.

Alcohol dependence is a common public health problem and epigenetics may offer new aspects in understanding the biological and genetic underpinnings and improve treatment of this complex disease. Supposedly, methylation and hydroxymethylation are altered in brain tissues and in synapse-related genes due to chronic alcohol intake and during withdrawal. To assess potential epigenetic changes after cessation of chronic alcohol intake, we compared 23 alcohol-dependent individuals during inpatient alcohol detoxification with 13 carefully matched controls. Blood samples were taken on the day of admission, after one and after two weeks at the end of inpatient treatment. Genome-wide global methylation and global DNA hydroxymethylation were compared across groups. There were significant differences in global methylation across time from admission to one and two weeks of inpatient withdrawal (p < 0.001). These findings were paralleled to changes in global DNA hydroxymethylation across time when age was employed as a cofactor (p < 0.001). Several potentially influencing variables like severity of withdrawal, dose of withdrawal medication and alcohol intake before admission did not yield significant influence on epigenetic changes. The results confirm previous findings of significant alterations of epigenetic patterns during alcohol intoxication and present for the first time hydroxymethylation changes in these individuals.

Biomarkers for Antidepressant Efficacy of Electroconvulsive Therapy: An Exploratory Cerebrospinal Fluid Study.

BACKGROUND: No candidate biomarkers based on cerebrospinal fluid (CSF) have been identified as prognostic factors in patients with major depression treated with electroconvulsive therapy (ECT), yet. METHOD: Following different underlying hypotheses, we analysed baseline CSF levels of markers of neurodegeneration (tau proteins, ß-amyloids and neurogranin), elements of the innate immune system (interleukin [IL]-6, neopterin, soluble CD14, soluble CD163, migration inhibitory factor and monocyte chemotactic protein 1), endocannabinoids, sphingolipids and Klotho before ECT in patients with depression (n = 12) to identify possible correlations with the clinical antidepressant response to ECT. RESULTS: Correlation with the reduction of the depressive symptoms could be observed especially for markers of neurodegeneration and elements of the innate immune system. Differences for CSF levels of several markers were found between the groups of responders and non-responders at the trend level. LIMITATIONS: The sample size is small and the -distribution of responders and non-responders is uneven. CONCLUSIONS: It is this first study on CSF biomarkers for antidepressant efficacy of ECT warrants further research regarding the mechanism of ECT and personalized antidepressant therapy.

Classical Risk Factors and Inflammatory Biomarkers: One of the Missing Biological Links between Cardiovascular Disease and Major Depressive Disorder.

BACKGROUND: Cardiovascular disorders (CVD) and major depressive disorder (MDD) are the most frequent diseases worldwide responsible for premature death and disability. Behavioral and immunological variables influence the pathophysiology of both disorders. We therefore determined frequency and severity of MDD in CVD and studied whether MDD without CVD or other somatic diseases influences classical and inflammatory biomarkers of cardiovascular risk. In addition, we investigated the influence of proinflammatory cytokines on antidepressant treatment outcome. METHODS: In a case-control design, 310 adults (MDD patients without CVD, CVD patients, and cardiologically and psychiatrically healthy matched controls) were investigated. MDD patients were recruited after admission in a psychiatric university hospital. Primary outcome criteria were clinical depression ratings (HAM-D scale), vital signs, classical cardiovascular risk factors and inflammatory biomarkers which were compared between MDD patients and healthy controls. RESULTS: We detected an enhanced cardiovascular risk in MDD. Untreated prehypertension and signs directing to a metabolic syndrome were detected in MDD. Significantly higher inflammatory biomarkers such as the high sensitivity C-reaktive protein (hsCRP) and proinflammatory acute phase cytokines interleukine-1ß (IL-1ß) and interleukine-6 (IL-6) underlined the higher cardiovascular risk in physically healthy MDD patients. Surprisingly, high inflammation markers before treatment were associated with better clinical outcome and faster remission. The rate of MDD in CVD patients was high. CONCLUSIONS: Patients suffering from MDD are at specific risk for CVD. Precise detection of cardiovascular risks in MDD beyond classical risk factors is warranted to allow effective prophylaxis and treatment of both conditions. Future studies of prophylactic interventions may help to provide a basis for prophylactic treatment of both MDD and CVD. In addition, the high risk for MDD in CVD patients was confirmed and underlines the requirement for clinical attention.

Shared genetic etiology between alcohol dependence and major depressive disorder.

The clinical comorbidity of alcohol dependence (AD) and major depressive disorder (MDD) is well established, whereas genetic factors influencing co-occurrence remain unclear. A recent study using polygenic risk scores (PRS) calculated based on the first-wave Psychiatric Genomics Consortium MDD meta-analysis (PGC-MDD1) suggests a modest shared genetic contribution to MDD and AD. Using a (~10 fold) larger discovery sample, we calculated PRS based on the second wave (PGC-MDD2) of results, in a severe AD case­control target sample. We found significant associations between AD disease status and MDD-PRS derived from both PGC-MDD2 (most informative P-threshold=1.0, P=0.00063, R2=0.533%) and PGC-MDD1 (P-threshold=0.2, P=0.00014, R2=0.663%) meta-analyses; the larger discovery sample did not yield additional predictive power. In contrast, calculating PRS in a MDD target sample yielded increased power when using PGC-MDD2 (P-threshold=1.0, P=0.000038, R2=1.34%) versus PGC-MDD1 (P-threshold=1.0, P=0.0013, R2=0.81%). Furthermore, when calculating PGC-MDD2 PRS in a subsample of patients with AD recruited explicitly excluding comorbid MDD, significant associations were still found (n=331; P-threshold=1.0, P=0.042, R2=0.398%). Meanwhile, in the subset of patients in which MDD was not the explicit exclusion criteria, PRS predicted more variance (n=999; P-threshold=1.0, P=0.0003, R2=0.693%). Our findings replicate the reported genetic overlap between AD and MDD and also suggest the need for improved, rigorous phenotyping to identify true shared cross-disorder genetic factors. Larger target samples are needed to reduce noise and take advantage of increasing discovery sample size.

The effect of oxytocin on group formation and strategic thinking in men.

Decision-making in groups is a remarkable and decisive element of human societies. Humans are able to organize themselves in groups, engage in collaborative decision-making processes and arrive at a binding agreement, even in the absence of unanimous consent. However, the transfer of decision-making autonomy requires a willingness to deliberately expose oneself to the decisions of others. A lack of trust in the abilities of others or of the underlying decision-making process, i.e. public trust, can lead to a breakdown of organizations in political or economic domains. Recent studies indicate that the biological basis of trust on an individual level is related to Oxytocin, an endogenous neuropeptide and hormone, which is also associated with pro-social behavior and positive conflict resolution. However, little is known about the effects of Oxytocin on the inclination of individuals to form or join groups and to deliberately engage in collaborative decision-making processes. Here, we show that intranasal administration of Oxytocin (n = 60) compared to placebo (n = 60) in males causes an adverse effect on the choice for forming groups in the presence of a competitive environment. In particular, Oxytocin negatively affects the willingness to work collaboratively in a p-Beauty contest game, whereas the effect is most pronounced for participants with relatively high strategic sophistication. Since our data provide initial evidence that Oxytocin has a positive effect on strategic thinking and performance in the p-Beauty contest game, we argue that the adverse effect on group formation might be rooted in an enhanced strategic sophistication of participants treated with Oxytocin.

QTc prolongation in short-term treatment of schizophrenia patients: effects of different antipsychotics and genetic factors.

Antipsychotics are effective in treating schizophrenia but may lead to a higher cardiovascular risk due to QTc prolongation. Besides drugs, genetic and clinical factors may contribute to QTc prolongation. The aim of this study is to examine the effect of candidate genes known for QTc prolongation and their interaction with common antipsychotics. Thus, 199 patients were genotyped for nine polymorphisms in KCNQ1, KCNH2, SCN5A, LOC10537879, LOC101927066, NOS1AP and NUBPL. QTc interval duration was measured before treatment and weekly for 5 weeks while being treated with risperidone, quetiapine, olanzapine, amisulpride, aripiprazole and haloperidol in monotherapy. Antipsychotics used in this study showed a different potential to affect the QTc interval. We found no association between KCNH2, KCNQ1, LOC10537879, LOC101927066, NOS1AP and NUBPL polymorphisms and QTc duration at baseline and during antipsychotic treatment. Mixed general models showed a significant overall influence of SCN5A (H558R) on QTc duration but no significant interaction with antipsychotic treatment. Our results do not provide evidence for an involvement of candidate genes for QTc duration in the pathophysiology of QTc prolongation by antipsychotics during short-term treatment. Further association studies are needed to confirm our findings. With a better understanding of these interactions the cardiovascular risk of patients may be decreased.

Antidepressant efficacy of electroconvulsive therapy is associated with a reduction of the innate cellular immune activity in the cerebrospinal fluid in patients with depression.

OBJECTIVES: A bidirectional link between the antidepressant effects of electroconvulsive therapy (ECT) and the modulation of the immune system has been proposed. To elucidate the interplay between antidepressant treatment and macrophage/microglia activation in humans, we performed a study on the effects of the antidepressant treatment by ECT on markers of macrophage/microglia activation in patients with depression. METHODS: We measured six different markers (IL-6, neopterin, sCD14, sCD163 MIF and MCP1) of macrophage/microglia activation in the cerebrospinal fluid (CSF) and blood of 12 patients with a severe, treatment-resistant depressive episode before and after a course of ECT. RESULTS: Some markers in the CSF of remitters were reduced after the ECT course and differed from non-remitters, but no differences were found before and after ECT independently from the antidepressant efficacy. CSF baseline levels of some markers could predict the reduction of depressive psychopathology during ECT. Higher CSF levels indicating increased macrophage/microglia activation at baseline predicted a better treatment response to ECT. CONCLUSIONS: Although the sample size was small, our data suggest that macrophages/microglia are involved in the pathophysiology of major depression and that antidepressant efficacy by ECT might be partly explained by the modulation of the innate immune system within the brain.