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Large population-based cohort studies offer the chance to assess a broad number of diseases and intermediate phenotypes and to estimate their frequencies in the general population. Because of their large sample size new symptom clusters and interactions of genetic, environmental and clinical factors in the onset and course of disease can be described. The German National Cohort (GNC) is one of the mega cohorts with a study-specific concept for the assessment of different psychiatric diseases and a focus on affective disorders and on emotional and cognitive functions. Aim of this manuscript is to describe different design approaches for a priorisation in the assessment of phenotypes for psychiatric and/or neurological disorders in large cohorts and to introduce the concept of studying emotional and cognitive functions and related disorders in GNC. [ABSTRACT FROM AUTHOR]

Background Age-of-onset (AO) is increasingly used in molecular genetics of bipolar I disorder (BP-I) as a phenotypic specifier with the goal of reducing genetic heterogeneity. However, questions regarding the cut-off age for defining early onset (EO), as well as the number of onset groups characterizing BP-I have emerged over the last decade with no definite conclusion. The aims of this paper are: 1) to see whether a mixture of three distributions better describes the AO of BP-I than a mixture of two distributions in different independent samples; 2) to compare the morbid risk (MR) for BP-I and for major affective disorders and schizophrenia in first degree relatives of BP-I probands by proband onset group derived from commingling analysis, since the MR to relatives is a trait with strong genetic background. Methods We applied commingling (admixture) analysis to the AO of three BP-I samples from Romania (n=621), Germany (n=882), and Poland (n=354). Subsequently, the morbid risk (MR) for BP-I and for major psychoses (BP-I, BP-II, Mdd-UP, schizoaffective disorders, schizophrenia) was estimated in first degree relatives by proband AO-group derived from admixture analysis in the Romanian sample. Results In the three independent samples and in the combined sample two- and three-AO-group distributions fitted the empirical data equally well. The upper EO limit varied between 21 and 25 years from sample to sample. The MR for both BP-I and for all major psychoses was similar in first degree relatives of EO probands (AO?21) and in relatives of intermediate-onset probands (AO=22-34). Significant MR differences appeared only when comparing the EO group to the late-onset (LO) group (AO>34). Similar to Mdd-UP and schizophrenia, a significant MR decrease in proband first degree relatives was visible after proband AO of 34 years. Under the three-AO-group classification the MR for both BP-I and all major psychoses in first degree relatives did not differ by relative sex in any proband AO-group. Under the two-AO-group classification female relatives of LO probands (AO>24) had a significantly higher MR for all major psychoses than male relatives, while there was no sex difference for the relatives of EO probands. Limitations MR was not computed in the German and Polish samples because family data were not available and 34% of the relatives of the Romanian probands were not available for direct interview. Conclusion Similar to other clinical traits, the MR for major psychoses to relatives failed to support a three-AO-group classification in BP-I suggesting that this is not more useful for the molecular analysis than a two-AO-group classification. [ABSTRACT FROM AUTHOR]

Alcohol consumption dates back to the Neolithic period, and alcohol dependence contributes substantially to the current global burden of disease. Despite this, optimal therapies and preventive strategies are lacking. Formal genetic studies of alcohol dependence have shown that genetic factors play as large a role in disease etiology as environmental factors. Molecular genetic studies may identify causal factors and facilitate the development of novel preventive and therapeutic approaches. Whereas earlier studies involved the use of linkage- and candidate-gene approaches, recent years have witnessed the introduction of genome-wide association studies (GWAS). The present review provides a brief overview of the findings of formal genetic studies, summarizes the results of earlier molecular-genetic investigations, and presents a detailed overview of all published GWAS in the field of alcohol dependence research. To date, few genome-wide significant findings have been reported. However, through the polygenic approach, GWAS have both confirmed the existence of a multitude of novel risk genes and indicated interesting new candidates. [ABSTRACT FROM AUTHOR]

Background: Genome-wide association studies are a powerful tool for unravelling the genetic background of complex disorders such as major depression. Methods: We conducted a genome-wide association study of 604 patients with major depression and 1364 population based control subjects. The top hundred findings were followed up in a replication sample of 409 patients and 541 control subjects. Results: Two SNPs showed nominally significant association in both the genome-wide association study and the replication samples: 1) rs9943849 (p combined = 3.24E-6) located upstream of the carboxypeptidase M (CPM) gene and 2) rs7713917 (p combined = 1.48E-6), located in a putative regulatory region of HOMER1. Further evidence for HOMER1 was obtained through gene-wide analysis while conditioning on the genotypes of rs7713917 (p combined = 4.12E-3). Homer1 knockout mice display behavioral traits that are paradigmatic of depression, and transcriptional variants of Homer1 result in the dysregulation of cortical-limbic circuitry. This is consistent with the findings of our subsequent human imaging genetics study, which revealed that variation in single nucleotide polymorphism rs7713917 had a significant influence on prefrontal activity during executive cognition and anticipation of reward. Conclusion: Our findings, combined with evidence from preclinical and animal studies, suggest that HOMER1 plays a role in the etiology of major depression and that the genetic variation affects depression via the dysregulation of cognitive and motivational processes. [ABSTRACT FROM AUTHOR]

Abstract: Background: Premorbid adjustment (PMA) in schizophrenia (SZ) has been widely studied and shown to be worse in individuals who develop SZ as compared to controls. It has been proposed as a predictor of clinical presentation and outcome, and may delineate a specific SZ phenotype for genetic and other biological studies. Research into PMA in BD has been scarce and inconclusive. Aims: The authors compared PMA in individuals suffering from BD with that of healthy controls and investigated whether levels of PMA in BD patients correlate with specific phenotypic features. Methods: The authors investigated 344 BD patients and 137 population-based controls. Retrospective PMA assessment was performed using the Premorbid Adjustment Scale (PAS). An overall score as well as sub-scores for age ranges and functional domains were obtained. Results: Patients had a better overall PAS score than controls and outperformed controls during early and late adolescence. They scored significantly better than controls in the functional domains “sociability and withdrawal” and “adaptation to school”. No differences were observed for the other subscales and there were no differences between groups during childhood. No association was observed between PMA and any of the phenotype characteristics investigated. Conclusions: In the largest study to date on PMA in BD, PMA was shown to be better in bipolar patients than in healthy controls. PMA in BD is not a simple proxy for commonly studied phenotypic markers of severity. PMA emerges as a phenotype in its own right, and highlights an aspect of disparity rather than overlap between SZ and BD. [Copyright &y& Elsevier]

Objective: G72 is among the most frequently replicated vulnerability genes for schizophrenia and bipolar disorder. The authors previously found identical haplotypes of markers M23 and M24 to be associated with schizophrenia, bipolar disorder, and panic disorder. Given both the well-recognized familial clustering across these disorders and recent linkage findings implicating the region harboring G72 in the etiology of major depression and panic disorder, we can hypothesize that G72 should also be involved in the etiology of major depression. Neuroticism, measuring trait anxiety, may be the endophenotypic link underlying genetic associations with G72 across diagnostic boundaries. The authors tested whether the previously observed risk haplotypes are also associated with major depression and neuroticism. Method: The authors performed a standard haplotype analysis in a group of 500 major depression patients and 1,030 population-based comparison subjects. The authors also performed an exploratory analysis on 10 additional G72 markers using a novel haplotype-sharing approach. They performed a quantitative trait haplotype analysis in an independent group of 907 individuals phenotyped for neuroticism. Results: The previously identified M23-M24 risk haplotype was significantly associated with major depression and high levels of neuroticism. The haplotype-sharing analysis also implicated the same region, whereas more proximal markers showed no association with major depression. Conclusions: This is the first study to the authors' knowledge to implicate the G72 locus in the etiology of major depression and neuroticism. The results strengthen the notion of a genetic overlap between diagnoses, commonly conceptualized as distinct entities. Neuroticism may constitute the common underlying endophenotypic link. [ABSTRACT FROM AUTHOR]

Highlights from the article: B Overall Abstract: b In many branches of medicine the earliest clinical impact of genomic research has been in the field of pharmacogenetics. Genome-wide significant variants implicate enzymatic genes that trace the metabolic pathways of clozapine and nor-clozapine. Dr Sophie Legge will present the first genome-wide analysis of clozapine-associated neutropenia in those of African ancestry, a group underserved by clinical services and under-represented in research.

Current nosography classifies major psychoses as separate disorders, but their symptomatological presentation during illness episodes largely overlaps and diagnoses may change during a lifetime. Few analyses of major psychoses symptomatology have been performed so far because of the large number of subjects needed to obtain stable factors. The purpose of this study was, therefore, to identify the symptomatologic structure common to major psychoses based on lifetime symptoms. Two thousand and forty-one inpatients affected by schizophrenic (n=1008), bipolar (n=563), major depressive (n=352), delusional (n=108) and psychotic not otherwise specified disorder (n=210) were rated for lifetime symptoms using the Operational Criteria Checklist for Psychotic Illness (OPCRIT) and included in a factorial analysis. Four factors were obtained, the first consisted of excitement symptoms, the second comprised psychotic features (delusions and hallucinations), the third comprised depression and the fourth disorganization. When scored by the OPCRIT checklist, major psychoses symptomatology is composed of excitement, depressive, delusion and disorganization symptoms. [ABSTRACT FROM AUTHOR]

Focuses on a study that investigated a number of patients with schizophrenia or schizoaffective disorder receiving long-term neuroleptic medication for tardive dyskinesia. Discussion on neuroleptic-induced tardive dyskinesia; Subjects and methods; Results.

S/S carriers of 5-HTTLPR have been found to be more risk seeking for losses compared to L/L carriers. This finding may be the result of reduced top-down control from the frontal cortex due to altered signal pathways involving the amygdala and ventral striatum. The serotonergic system is known to be involved in neurodevelopment and neuroplasticity. Therefore, the aim of this study was to investigate whether structural differences in white matter can explain the differences in risk-seeking behaviour. Lower structural connectivity in S/S compared to L/L carriers and a negative relationship between risk seeking for losses and connectivity were assumed. Diffusion-weighted imaging was used to compute diffusion parameters for the frontostriatal and uncinate tract in 175 genotyped individuals. The results showed no significant relationship between diffusion parameters and risk seeking for losses. Furthermore, we did not find significant differences in diffusion parameters of the S/S vs. L/L group. There were only group differences in the frontostriatal tract showing stronger structural connectivity in the S/L group, which is also reflected in the whole brain approach. Therefore, the data do not support the hypothesis that the association between 5-HTTLPR and risk seeking for losses is related to differences in white matter pathways implicated in decision-making. [ABSTRACT FROM AUTHOR]

Highlights from the article: B Overall Abstract: b Alcohol dependence (AD) is 50% heritable and there is also strong evidence for environmental influences on risk. AD genome wide association studies (GWAS) have detected genome-wide significant associations (p < 5x10-8) with alcohol metabolizing genes and also variably with several other genes. AD is frequently found to be comorbid with a range of psychiatric illnesses and the relative contribution of risk factors for these comorbidities is likely to have an influence on the.

The evidence for repetitive transcranial magnetic stimulation (rTMS) to treat negative symptoms in schizophrenia (SCZ) is increasing, although variable response rates remain a challenge. Subject´s sex critically influences rTMS´ treatment outcomes. Females with major depressive disorder are more likely to respond to rTMS, while SCZ data is scarce. Using data from the 'rTMS for the Treatment of Negative Symptoms in Schizophrenia' (RESIS) trial we assessed the impact of sex on rTMS´ clinical response rate from screening up to 105 days after intervention among SCZ patients. The impact of resting motor threshold (RMT) on response rates was also assessed. 157 patients received either active or sham rTMS treatment. No significant group differences were observed. Linear mixed model showed no effects on response rates (all p > 0.519). Apart from a significant sex*time interaction for the positive subscale of the positive and negative syndrome scale (PANSS) scores (p = 0.032), no other significant effects of sex on continuous PANSS scores were observed. RMT had no effect on response rate. In the largest rTMS trial on the treatment of SCZ negative symptoms we did not observe any significant effect of sex on treatment outcomes. Better assessments of sex-related differences could improve treatment individualisation. [ABSTRACT FROM AUTHOR]

Objectives: Bipolar disorder (BD) and major depressive disorder (MDD) are characterized by specific alterations of mood. In both disorders, alterations in cognitive domains such as impulsivity, decision‐making, and risk‐taking have been reported. Identification of similarities and differences of these domains in BD and MDD could give further insight into their etiology. The present study assessed impulsivity, decision‐making, and risk‐taking behavior in BD and MDD patients from bipolar multiplex families. Methods: Eighty‐two participants (BD type I, n = 25; MDD, n = 26; healthy relatives (HR), n = 17; and healthy controls (HC), n = 14) underwent diagnostic interviews and selected tests of a cognitive battery assessing neurocognitive performance across multiple subdomains including impulsivity (response inhibition and delay aversion), decision‐making, and risk behavior. Generalized estimating equations (GEEs) were used to analyze whether the groups differed in the respective cognitive domains. Results: Participants with BD and MDD showed higher impulsivity levels compared to HC; this difference was more pronounced in BD participants. BD participants also showed lower inhibitory control than MDD participants. Overall, suboptimal decision‐making was associated with both mood disorders (BD and MDD). In risk‐taking behavior, no significant impairment was found in any group. Limitations: As sample size was limited, it is possible that differences between BD and MDD may have escaped detection due to lack of statistical power. Conclusions: Our findings show that alterations of cognitive domains—while present in both disorders—are differently associated with BD and MDD. This underscores the importance of assessing such domains in addition to mere diagnosis of mood disorders. [ABSTRACT FROM AUTHOR]

Genetic factors contribute significantly to interindividual differences in the susceptibility to stress‐related disorders. As stress can also be conceptualized as environmental exposure, controlled gene–environment interaction (GxE) studies with an in‐depth phenotyping may help to unravel mechanisms underlying the interplay between genetic factors and stress. In a prospective‐longitudinal quasi‐experimental study, we investigated whether polygenic scores (PGS) for depression (DEP‐PGS) and neuroticism (NEU‐PGS), respectively, were associated with responses to chronic stress in daily life. We examined law students (n = 432) over 13 months. Participants in the stress group experienced a long‐lasting stress phase, namely the preparation for the first state examination for law students. The control group consisted of law students without particular stress exposure. In the present manuscript, we analyzed perceived stress levels assessed at high frequency and in an ecologically valid manner by ambulatory assessments as well as depression symptoms and two parameters of the cortisol awakening response. The latter was only assessed in a subsample (n = 196). No associations between the DEP‐PGS and stress‐related variables were found. However, for the NEU‐PGS we found a significant GxE effect. Only in individuals experiencing academic stress a higher PGS for neuroticism predicted stronger increases of perceived stress levels until the exam. At baseline, a higher NEU‐PGS was associated with higher perceived stress levels in both groups. Despite the small sample size, we provide preliminary evidence that the genetic disposition for neuroticism is associated with stress level increases in daily life during a long‐lasting stress period. [ABSTRACT FROM AUTHOR]

Objectives: To describe the cognitive test battery of the German National Cohort (NAKO), a population-based mega cohort of 205,000 randomly selected participants, and to examine associations with demographic variables and selected psychiatric and neurological conditions. Methods: Initial data from 96,401 participants providing data on the cognitive performance measured by a brief cognitive test battery (12-word list recall task, semantic fluency, Stroop test, digit span backwards) was examined. Test results were summarised in cognitive domain scores using exploratory and confirmatory factor analyses. Associations with sociodemographic and psychiatric factors were analysed using linear regression and generalised additive models. Results: Cognitive test results were best represented by two domain scores reflecting memory and executive functions. Lower cognitive functions were associated with increasing age and male sex. Higher education and absence of childhood trauma were associated with better cognitive function. Moderate to severe levels of anxiety and depression, and a history of stroke, were related to lower cognitive function with a stronger effect on executive function as compared to memory. Some associations with cognition differed by German language proficiency. Conclusions: The NAKO cognitive test battery and the derived cognitive domain scores for memory and executive function are sensitive measures of cognition. [ABSTRACT FROM AUTHOR]

Objectives: The present study introduces the assessment of depression and depressive symptoms in the German National Cohort (NAKO), a population-based mega cohort. Distribution of core measures, and associations with sociodemographic factors are examined. Methods: The current analysis includes data from the first 101,667 participants (NAKO data freeze 100,000). Depression and depressive symptoms were assessed using a modified version of the depression section of the Mini-International Neuropsychiatric Interview (MINI), selfreported physician's diagnosis of depression, and the depression scale of the Patient Health Questionnaire (PHQ-9). Results: A lifetime physician's diagnosis of depression was reported by 15.0% of participants. Of those, 47.6% reported having received treatment for depression within the last 12months. Of the subset of 26,342 participants undergoing the full depression section of the modified MINI, 15.9% were classified by the MINI with a lifetime depressive episode. Based on the PHQ-9, 5.8% of the participants were classified as currently having a major or other depression by the diagnostic algorithm, and 7.8% according to the dimensional assessment (score ≥ 10). Increased frequency of depression measures and higher depression scores were observed in women and participants with lower education level or a family history of depression. Conclusions: The observed distributions of all depression measures and their associations with sociodemographic variables are consistent with the literature on depression. The NAKO represents a valuable epidemiologic resource to investigate depression, and the range of measures for lifetime and current depression allows users to select the most suitable instrument for their specific research question. [ABSTRACT FROM AUTHOR]

Objectives. Evaluate the block-adaptive number series task of reasoning, as a time-efficient proxy of general cognitive ability in the Level-2 sample of the German National Cohort (NAKO), a population-based mega cohort. Methods. The number series task consisted of two blocks of three items each, administered as part of the touchscreen-based assessment. Based on performance on the first three items, a second block of appropriate difficulty was automatically administered. Scoring of performance was based on the Rasch model. Relations of performance scores to age, sex, education, study centre, language proficiency, and scores on other cognitive tasks were examined. Results. Except for one very difficult item, the data of the remaining 14 items showed sufficient fit to the Rasch model (Infit: 0.89-1.04; Outfit: 0.80-1.08). The resulting performance scores (N = 21,056) had a distribution that was truncated at very high levels of ability. The reliability of the performance estimates was satisfactory. Relations to age, sex, education, and the executive function factor of the other cognitive tasks in the NAKO supported the validity. Conclusions. The number series task provides a valid proxy of general cognitive ability for the Level-2 sample of the NAKO, based on a highly time-efficient assessment procedure. [ABSTRACT FROM AUTHOR]

Objectives: Childhood maltreatment affects 20-30% of the German population and is an important risk factor for physical and mental diseases in adult life. This study reports first results of the distribution of childhood maltreatment in the population-based mega cohort German National Cohort (NAKO) and estimates associations with affective symptoms in adulthood. Methods: The Childhood Trauma Screener (CTS), a short version of the Childhood Trauma Questionnaire, was used in 83,995 adults (age: 20-72 years; 47.3% men) of NAKO. The five-item CTS assesses the severity of three types of childhood abuse and two types of childhood neglect. Results: Overall, 21,131 participants (27.5%) reported at least one type of childhood maltreatment; 14,017 participants (18.3%) reported exactly one type and 250 participants (0.3%) reported all five types of childhood maltreatment. Small differences regarding age (mean absolute deviation around the mean (MAD) = 0.47), sex (MAD = 0.07) and education (MAD = 0.82) were observed. The severity of childhood maltreatment was associated with more severe symptoms of depression (β = 0.23), anxiety (β = 0.21) and perceived stress (β = 0.23) in adulthood, validated particularly for emotional abuse and emotional neglect. Conclusions: The distribution of childhood maltreatment in NAKO is similar to previous reports. Additionally, our results suggest differential associations with psychopathological symptoms for the five types of childhood maltreatment. [ABSTRACT FROM AUTHOR]

Objectives: Anxiety disorders (AD) are common in the general population, leading to high emotional distress and disability. The German National Cohort (NAKO) is a population-based megacohort study, examining participants in 16 German regions. The present study includes data of the first 101,667 participants and investigates the frequency and severity of generalised anxiety symptoms and panic attacks (PA). Methods: The Generalised Anxiety Disorder Symptoms Scale (GAD-7) and the first part of the Patient Health Questionnaire Panic Disorder (PHQ-PD) were filled out by NAKO participants (93,002). We examined the correlation of GAD-7 and PHQ-PD with demographic variables, stress (PHQ-Stress), depression (PHQ-9) and childhood trauma (CTS). Results: The total proportion of prior lifetime diagnoses of AD in the NAKO cohort reached 7.8%. Panic attacks were reported by 6.0% and possible/probable current GAD symptoms in 5.2% of the examined participants. Higher anxiety severity was associated with female sex, lower education level, German as a foreign language and younger age as well as high perceived stress and depression. Conclusions: Clinically relevant GAD symptoms as well as panic attacks are frequent in the NAKO and are associated with sociodemographic factors, and high anxiety symptoms are accompanied by pronounced stress and depression levels. [ABSTRACT FROM AUTHOR]

Abstract Background Inflammation may play an important role in depression and its treatment. A previous study found that increased C-reactive protein (CRP), a marker of systemic inflammation, is associated with worse response to the serotonergic antidepressant escitalopram and better response to the noradrenergic antidepressant nortriptyline. It is unclear whether this reflects genetic disposition to inflammation. Methods We analyzed genotype data and weekly Montgomery-Åsberg Depression Rating Scale scores (MADRS) from 755 unrelated individuals obtained over a 12-week period in the Genome-Based Therapeutic Drugs for Depression (GENDEP) study. We calculated a polygenic risk score for CRP level based on genome-wide meta-analysis results from the CHARGE Consortium. Results A higher polygenic risk score for CRP was associated with slightly better response to escitalopram and slightly worse response to nortriptyline, reflected in a statistically significant interaction between polygenic risk score and drug (beta = 1.07, 95% CI = 0.26–1.87, p = 0.0093). Discussion A differential association between CRP-PRS and antidepressant drug that is in a direction opposite to that found with serum CRP measurement suggests that previously observed effect of inflammation on antidepressant efficacy may be driven by state factors distinct from genetic influences on systemic inflammation. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to a previously published article about molecular genetic research which would lead to psychiatric nosology by Kenneth S. Kendler.

Background: Personality traits may predict antidepressant discontinuation and response. However, previous studies were rather small, only explored a few personality traits and did not include adverse drug effects nor the interdependency between antidepressant discontinuation patterns and response. Methods: GENDEP included 589 patients with unipolar moderate-severe depression treated with escitalopram or nortriptyline for 12 weeks. Seven personality dimensions were measured using the self-reported 240-item Temperament and Character Inventory-Revised (TCI-R). We applied Cox proportional models to study discontinuation patterns, logistic and linear regression to investigate response and remission after 8 and 12 weeks, and mixed-effects linear models regarding time-varying treatment response and adverse drug reactions. Results: Low harm avoidance, low cooperativeness, high self-transcendence and high novelty seeking were associated with higher risks for antidepressant discontinuation, independent of depressed mood, adverse drug reactions, drug, sex and age. Regression analyses showed that higher novelty seeking and cooperativeness scores were associated with a greater likelihood of response and remission after 8 and 12 weeks, respectively, but we found no correlations with response in the mixed-effects models. Only high harm avoidance was associated with more self-reported adverse effects. Conclusions: This study, representing the largest investigation between several personality traits and response to two different antidepressants, suggests that correlations between personality traits and antidepressant treatment response may be confounded by differential rates of discontinuation. Future trials on personality in the treatment of depression need to consider this interdependency and study whether interventions aiming at improving compliance for some personality types may improve response to antidepressants. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic severely affected the lives of families and the well-being of both parents and their children. Various factors, including prenatal stress, dysregulated stress response systems, and genetics may have influenced how the stress caused by the pandemic impacted the well-being of different family members. The present work investigated if emotional well-being during the COVID-19 pandemic could be predicted by developmental stress-related and genetic factors. Emotional well-being of 7–10 year-old children (n = 263) and mothers (n = 241) (participants in a longitudinal German birth cohort (POSEIDON)) was assessed during the COVID-19 pandemic using the CRISIS questionnaire at two time periods (July 2020–October 2020; November 2020–February 2021). Associations of the children's and mothers' well-being with maternal perceived stress, of the children's well-being with their salivary and morning urine cortisol at 45 months, and polygenic risk scores (PRSs) for depression, schizophrenia, loneliness were investigated. Lower emotional well-being was observed in both children and mothers during compared to before the pandemic, with the children's but not the mothers' emotional well-being improving over the course of the pandemic. A positive association between the child and maternal emotional well-being was found. Prenatally assessed maternal perceived stress was associated with a lower well-being in children, but not in mothers. Cortisol measures and PRSs were not significantly associated with the children's emotional well-being. The present study confirms that emotional well-being of children and mothers are linked, and were negatively affected by the COVID-19 pandemic, with differences in development over time. [ABSTRACT FROM AUTHOR]

The ability to delay gratification is related to success in school and other aspects of life. Genetic as well as environmental factors such as parenting style partly explain the development of delay of gratification (DoG). However, it is unclear whether parental personality impacts children's DoG, and how maternal and paternal personalities contribute to this relationship. The present study investigates the relationship between parental personality and 45-month-old children's DoG (N = 329). Personality was measured using the NEO-Five-Factor-Inventory-30, DoG was operationalized through waiting time in the marshmallow test. In model 1, using only maternal data to predict DoG, maternal openness to experience was associated with shorter waiting time of the child in the marshmallow test, whereas maternal agreeableness was associated with longer waiting time. In model 2, using only paternal data to predict DoG, paternal agreeableness was related to longer waiting time. In model 3, combining maternal and paternal data to predict DoG, maternal openness to experience as well as paternal agreeableness remained significant predictors of DoG. The present study underlines the influence of both parents' personalities on the development of children's DoG and indicates differential maternal and paternal effects. Future studies should investigate the relationship between parental personality and children's DoG in detail and take further factors into account, such as genetic factors, other environmental factors and the personality of the child. Highlights: Investigation of parental personality jointly and separately to predict child's DoG. Separate models: Agreeableness of both parents predicts DoG (positively). Separate models: Maternal openness predicts DoG (negatively). Joint model: Maternal openness & paternal agreeableness stay significant predictors. The results indicate differential maternal and paternal effects on children's DoG. [ABSTRACT FROM AUTHOR]

Precision psychiatry is an emerging field with transformative opportunities for mental health. However, the use of clinical prediction models carries unprecedented ethical challenges, which must be addressed before accessing the potential benefits of precision psychiatry. This critical review covers multidisciplinary areas, including psychiatry, ethics, statistics and machine-learning, healthcare and academia, as well as input from people with lived experience of mental disorders, their family, and carers. We aimed to identify core ethical considerations for precision psychiatry and mitigate concerns by designing a roadmap for research and clinical practice. We identified priorities: learning from somatic medicine; identifying precision psychiatry use cases; enhancing transparency and generalizability; fostering implementation; promoting mental health literacy; communicating risk estimates; data protection and privacy; and fostering the equitable distribution of mental health care. We hope this blueprint will advance research and practice and enable people with mental health problems to benefit from precision psychiatry. [ABSTRACT FROM AUTHOR]

Cognitive impairment is a common feature in schizophrenia and the strongest prognostic factor for long-term outcome. Identifying a trait associated with the genetic background for cognitive outcome in schizophrenia may aid in a deeper understanding of clinical disease subtypes. Fast sleep spindles may represent such a biomarker as they are strongly genetically determined, associated with cognitive functioning and impaired in schizophrenia and unaffected relatives. We measured fast sleep spindle density in 150 healthy adults and investigated its association with a genome-wide polygenic score for schizophrenia (SCZ-PGS). The association between SCZ-PGS and fast spindle density was further characterized by stratifying it to the genetic background of intelligence. SCZ-PGS was positively associated with fast spindle density. This association mainly depended on pro-cognitive genetic variants. Our results strengthen the evidence for a genetic background of spindle abnormalities in schizophrenia. Spindle density might represent an easily accessible marker for a favourable cognitive outcome which should be further investigated in clinical samples. [ABSTRACT FROM AUTHOR]

Major Depression and Bipolar Disorder Type I (BIP-I) and Type II (BIP-II), are characterized by depressed, manic, and hypomanic episodes in which specific changes of physical activity, circadian rhythm, and sleep are observed. It is known that genetic factors contribute to variation in mood disorders and biological rhythms, but unclear to what extent there is an overlap between their underlying genetics. In the present study, data from genome-wide association studies were used to examine the genetic relationship between mood disorders and biological rhythms. We tested the genetic correlation of depression, BIP-I, and BIP-II with physical activity (overall physical activity, moderate activity, sedentary behaviour), circadian rhythm (relative amplitude), and sleep features (sleep duration, daytime sleepiness). Genetic correlations of depression, BIP-I, and BIP-II with biological rhythms were compared to discover commonalities and differences. A gene-based analysis tested for associations of single genes and common circadian genes with mood disorders. Depression was negatively correlated with overall physical activity and positively with sedentary behaviour, while BIP-I showed associations in the opposite direction. Depression and BIP-II had negative correlations with relative amplitude. All mood disorders were positively correlated with daytime sleepiness. Overall, we observed both genetic commonalities and differences across mood disorders in their relationships with biological rhythms: depression and BIP-I differed the most, while BIP-II was in an intermediate position. Gene-based analysis suggested potential targets for further investigation. The present results suggest shared genetic underpinnings for the clinically observed associations between mood disorders and biological rhythms. Research considering possible joint mechanisms may offer avenues for improving disease detection and treatment. [ABSTRACT FROM AUTHOR]

Adverse environments during pregnancy impact neurodevelopment including cognitive abilities of the developing children. The mediating biological alterations are not fully understood. Maternal stress may impact the neurotrophic regulation of the offspring as early as in utero and at birth. Brain-derived neurotrophic factor (BDNF) is essential for neurodevelopment. Short-term higher levels of BDNF in mice upon stressors associate with lower BDNF later in life, which itself associates with depression in animals and humans. Stress including glucocorticoids may impact BDNF, but there is a lack of data at birth. This study investigated if stress near term associates with fetal BDNF at birth in humans. Pregnant women near term who underwent primary cesarean sections (at 38.80±0.64 weeks), were included in this study (n=41). Stress at the end of pregnancy was assessed before the cesarean section by determining maternal depressive symptoms (EDPS), maternal state and trait anxiety (STAI-S and STAI-T), maternal prenatal distress (PDQ), stress over the past month (PSS), prenatal attachment to the offspring (PAI), maternal social support (F-Sozu), maternal early life stress (CTQ), socioeconomic status, and the glucocorticoids cortisol and cortisone (n=40) in amniotic fluid at birth. The association with fetal BDNF was analyzed. Cord blood serum of n=34 newborns at birth was analyzed for BDNF and newborn anthropometrics (weight, length and head circumference per gestational age at birth) were assessed. The association of fetal BDNF with anthropometrics at birth was analyzed. After a BDNF-outlier (>3 SD) was removed, higher fetal BDNF associated significantly with maternal depressive symptoms (r=0.398, p=0.022), with lower socioeconomic status as assessed by the average number of people per room in the household (r=0.526, p=0.002) and with borderline significance with net income per person in the household (r=-0.313, p=0.087) in the bivariate analyses. In multivariable analysis, BDNF stayed positively associated with maternal depressive symptoms (β=0.404, 95% CI [7.057, 306.041], p=0.041) and lower net income per person in the household (β=-0.562, 95% CI [-914.511, −60.523], p=0.027) when controlling for maternal age, maternal pre-pregnancy BMI, fetal sex and gestational age. Fetal BDNF did not associate with newborn anthropometrics with the outlier removed in bivariate analyses or in multivariable analyses when controlling for maternal BMI and fetal sex. Maternal depressive symptoms and lower socioeconomic status associated with higher fetal BDNF when controlling for confounders. Fetal BDNF did not associate with newborn anthropometrics with the outlier removed. Further studies should investigate how early altered BDNF associate with the development and possibly psychopathology of the offspring. • Maternal depression associates with high fetal BDNF in cord blood at birth. • Low socioeconomic status links to high fetal BDNF at birth. • Cortisol and cortisone in amniotic fluid are not associated with fetal BDNF. • Fetal BDNF does not associate with newborn anthropometrics. [ABSTRACT FROM AUTHOR]

Abstract Schizophrenia is a genetically influenced disease with a broad and heterogeneous phenotype transmitted in families. Of particular interest is the familial-genetic relationship between schizophrenia and affective disorders. Taking advantage of refined epidemiological methods, the dichotomy between both groups of disorders is not less consistently found than expected. Recently, linkage studies identified multiple candidate regions for susceptibility genes for each of both disorders. [ABSTRACT FROM AUTHOR]

Background: To investigate the prevalence of depression, suicidal ideations, alcohol and nicotine consumption in adults in an agrarian society mostly unchanged by the effects of urbanization. Methods: The Central India Eye and Medical Study is a population-based study in rural Central India close to the tribal belt and included 4711 subjects (aged 30+ years). Depression was assessed by the Center for Epidemiologic Studies Depression Scale (CESD), suicidal ideation by six standardized questions, nicotine use by the Fagerstroem Nicotine Tolerance Questionnaire (FTNQ), and alcohol consumption by the Alcohol Use Disorders Identification Test (AUDIT). Results: Mild to moderate depression (CESD sum score: 15–21) was detected in 1862 (39.6%) individuals (33.5% of men, 44.8 of women), and major depression (CESD sum score >21) in 613 (13.0%) individuals (8.1 of men, 17.3% of women). Suicide attempt was reported by 199 (4.2%) participants and suicidal thoughts during the last 6 months by 238 (5.1%) individuals. There were 887 (18.9%) smokers and smokeless tobacco was consumed by 1968 (41.8%) subjects. Alcohol consumption was reported by 1081 (23.0%) participants; 283 (6.0%) subjects had an AUDIT score ≥8 (hazardous drinking), and 108 (4.63%) subjects a score ≥13 (women) or ≥15 (men) (alcohol dependence). Conclusions: In rural Central India, prevalence of major depression was comparable to figures reported from other developing countries. Prevalence of smoking and hazardous alcohol consumption was higher than as reported from urban regions. Measures should be taken to address the relatively high prevalence of suicide attempts and thoughts on suicide in rural Central India. [ABSTRACT FROM AUTHOR]

(1) Background: Epigenome-wide association studies (EWAS) in peripheral blood have repeatedly found associations between tobacco smoking and aberrant DNA methylation (DNAm), but little is known about DNAm signatures of smoking in the human brain, which may contribute to the pathophysiology of addictive behavior observed in chronic smokers. (2) Methods: We investigated the similarity of DNAm signatures in matched blood and postmortem brain samples (n = 10). In addition, we performed EWASs in five brain regions belonging to the neurocircuitry of addiction: anterior cingulate cortex (ACC), Brodmann Area 9, caudate nucleus, putamen, and ventral striatum (n = 38–72). (3) Results: cg15925993 within the LOC339975 gene was epigenome-wide significant in the ACC. Of 16 identified differentially methylated regions, two (PRSS50 and LINC00612/A2M-AS1) overlapped between multiple brain regions. Functional enrichment was detected for biological processes related to neuronal development, inflammatory signaling and immune cell migration. Additionally, our results indicate the association of the well-known AHRR CpG site cg05575921 with smoking in the brain. (4) Conclusion: The present study provides further evidence of the strong relationship between aberrant DNAm and smoking. [ABSTRACT FROM AUTHOR]

Abstract: Recent studies have emphasized an important role for neurotrophins, such as brain-derived neurotrophic factor (BDNF), in regulating the plasticity of neural circuits involved in the pathophysiology of stress-related diseases. The aim of the present study was to examine the interplay of the BDNF Val66Met and the serotonin transporter promoter (5-HTTLPR) polymorphisms in moderating the impact of early-life adversity on BDNF plasma concentration and depressive symptoms. Participants were taken from an epidemiological cohort study following the long-term outcome of early risk factors from birth into young adulthood. In 259 individuals (119 males, 140 females), genotyped for the BDNF Val66Met and the 5-HTTLPR polymorphisms, plasma BDNF was assessed at the age of 19 years. In addition, participants completed the Beck Depression Inventory (BDI). Early adversity was determined according to a family adversity index assessed at 3 months of age. Results indicated that individuals homozygous for both the BDNF Val and the 5-HTTLPR L allele showed significantly reduced BDNF levels following exposure to high adversity. In contrast, BDNF levels appeared to be unaffected by early psychosocial adversity in carriers of the BDNF Met or the 5-HTTLPR S allele. While the former group appeared to be most susceptible to depressive symptoms, the impact of early adversity was less pronounced in the latter group. This is the first preliminary evidence indicating that early-life adverse experiences may have lasting sequelae for plasma BDNF levels in humans, highlighting that the susceptibility to this effect is moderated by BDNF Val66Met and 5-HTTLPR genotype. [Copyright &y& Elsevier]

Altered ventral striatal (vST) activation to reward expectancy is a well-established intermediate phenotype for psychiatric disorders, specifically schizophrenia (SZ). Preclinical research suggests that striatal alterations are related to a reduced inhibition by the hippocampal formation, but its role in human transdiagnostic reward-network dysfunctions is not well understood. We performed functional magnetic resonance imaging during reward processing in 728 individuals including healthy control subjects (n = 396), patients (SZ: n = 46; bipolar disorder: n = 45; major depressive disorder: n = 60), and unaffected first-degree relatives (SZ: n = 46; bipolar disorder: n = 50; major depressive disorder: n = 85). We assessed disorder-specific differences in functional vST-hippocampus coupling and transdiagnostic associations with dimensional measures of positive, negative, and cognitive symptoms. We also probed the genetic underpinning using polygenic risk scores for SZ in a subset of healthy participants (n = 295). Functional vST-hippocampus coupling was 1) reduced in patients with SZ and bipolar disorder (p FWE <.05, small-volume corrected [SVC]); 2) associated transdiagnostically to dimensional measures of positive (p FWE =.01, SVC) and cognitive (p FWE =.02, SVC), but not negative, (p FWE >.05, SVC) symptoms; and 3) reduced in first-degree relatives of patients with SZ (p FWE =.017, SVC) and linked to the genetic risk for SZ in healthy participants (p =.035). We provide evidence that reduced vST-hippocampus coupling during reward processing is an endophenotype for SZ linked to positive and cognitive symptoms, supporting current preclinical models of the emergence of psychosis. Moreover, our data indicate that vST-hippocampus coupling is familial and linked to polygenic scores for SZ, supporting the use of this measure as an intermediate phenotype for psychotic disorders. [ABSTRACT FROM AUTHOR]

Bipolar disorder (BD) might be associated with higher infection rates of coronavirus disease (COVID-19) which in turn could result in worsening the clinical course and outcome. This may be due to a high prevalence of somatic comorbidities and an increased risk of delays in and poorer treatment of somatic disease in patients with severe mental illness in general. Vaccination is the most important public health intervention to tackle the ongoing pandemic. We undertook a systematic review regarding the data on vaccinations in individuals with BD. Proportion of prevalence rates, efficacy and specific side effects of vaccinations and in individuals with BD were searched. Results show that only five studies have investigated vaccinations in individuals with BD, which substantially limits the interpretation of overall findings. Studies on antibody production after vaccinations in BD are very limited and results are inconsistent. Also, the evidence-based science on side effects of vaccinations in individuals with BD so far is poor. [ABSTRACT FROM AUTHOR]

• Prenatal, perinatal, and postnatal factors shape neurobiological functioning. • The gut microbiome is established early in life, and interacts with the brain. • Cognitive functioning was assessed in 380 preschoolers. • Microbiome profile and one taxa (family Enterobacteriaceae) showed associations. • Interventions to improve cognitive functioning could be directed at the microbiome. Prenatal, perinatal, and postnatal factors have been shown to shape neurobiological functioning and alter the risk for mental disorders later in life. The gut microbiome is established early in life, and interacts with the brain via the brain-immune-gut axis. However, little is known about how the microbiome relates to early-life cognitive functioning in children. The present study, where the fecal microbiome of 380 children was characterized using 16S rDNA and metagenomic sequencing aimed to investigate the association between the microbiota and cognitive functioning of children at the age of 45 months measured with the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III). Overall the microbiome profile showed a significant association with cognitive functioning. A strong correlation was found between cognitive functioning and the relative abundance of an unidentified genus of the family Enterobacteriaceae. Follow-up mediation analyses revealed significant mediation effects of the level of this genus on the association of maternal smoking during pregnancy and current cigarette smoking with cognitive function. Metagenomic sequencing of a subset of these samples indicated that the identified genus was most closely related to Enterobacter asburiae. Analysis of metabolic potential showed a nominally significant association of cognitive functioning with the microbial norspermidine biosynthesis pathway. Our results indicate that alteration of the gut microflora is associated with cognitive functioning in childhood. Furthermore, they suggest that the altered microflora might interact with other environmental factors such as maternal cigarette smoking. Interventions directed at altering the microbiome should be explored in terms of improving cognitive functioning in young children. [ABSTRACT FROM AUTHOR]

Background: Despite high heritability, the genetic variants influencing bipolar disorder (BD) susceptibility remain largely unknown. Low statistical power to detect the small effect-size alleles believed to underlie much of the genetic risk and possible heterogeneity between cohorts are an increasing concern. Integrative biology approaches might offer advantages over genetic analysis alone by combining different genomic datasets at the higher level of biological processes rather than the level of specific genetic variants or genes. We employed this strategy to identify biological processes involved in BD etiopathology. Method: Three genome-wide association studies and a brain gene-expression study were combined with the Human Protein Reference Database protein–protein interaction network data. We used bioinformatic analysis to search for biological networks with evidence of association on the basis of enrichment among both genetic and differential-expression associations with BD. Results: We identified association with gene networks involved in transmission of nerve impulse, Wnt, and Notch signaling. Three features stand out among these genes: 1) they localized to the human postsynaptic density, which is crucial for neuronal function; 2) their mouse knockouts present altered behavioral phenotypes; and 3) some are known targets of the pharmacological treatments for BD. Conclusions: Genetic and gene-expression associations of BD cluster in discrete regions of the protein–protein interaction network. We found replicated evidence for association for networks involving several interlinked signaling pathways. These genes are promising candidates to generate animal models and pharmacological interventions. Our results demonstrate the potential advantage of integrative biology analyses of BD datasets. [ABSTRACT FROM AUTHOR]

Recent studies suggest that variation in complex disorders (e.g., schizophrenia) is explained by a large number of genetic variants with small effect size (Odds Ratio∼1.05-1.1). The statistical power to detect these genetic variants in Genome Wide Association (GWA) studies with large numbers of cases and controls (∼15,000) is still low. As it will be difficult to further increase sample size, we decided to explore an lternative method for analyzing GWA data in a study of schizophrenia, dramatically reducing the number of statistical tests. The underlying hypothesis was that at least some of the genetic variants related to a common outcome are collocated in segments of chromosomes at a wider scale than single genes. Our approach was therefore to study the association between relatively large segments of DNA and disease status. An association test was performed for each SNP and the number of nominally significant tests in a segment was counted. We then performed a permutation-based binomial test to determine whether this region contained significantly more nominally significant SNPs than expected under the null hypothesis of no association, taking linkage into account. Genome Wide Association data of three independent schizophrenia case/control cohorts with European ancestry (Dutch, German, and US) using segments of DNA with variable length (2 to 32 Mbp) was analyzed. Using this approach we identified a region at chromosome 5q23.3-q31.3 (128-160 Mbp) that was significantly enriched with nominally associated SNPs in three independent case-control samples. We conclude that considering relatively wide segments of chromosomes may reveal reliable relationships between the genome and schizophrenia, suggesting novel methodological possibilities as well as raising theoretical questions. [ABSTRACT FROM AUTHOR]

Background: Patients with schizophrenia often suffer from cognitive dysfunction, including impaired learning and memory. We recently demonstrated that long-term potentiation in rat hippocampus, a mechanistic model of learning and memory, is linked to gene expression changes in immunity-related processes involved in complement activity and antigen presentation. We therefore aimed to examine whether key regulators of these processes are genetic susceptibility factors in schizophrenia. Methods: Analysis of genetic association was based on data mining of genotypes from a German genome-wide association study and a multiplex GoldenGate tag single nucleotide polymorphism (SNP)-based assay of Norwegian and Danish case–control samples (Scandinavian Collaboration on Psychiatric Etiology), including 1133 patients with schizophrenia and 2444 healthy control subjects. Results: Allelic associations were found across all three samples for eight common SNPs in the complement control-related gene CSMD2 (CUB and Sushi Multiple Domains 2) on chromosome 1p35.1-34.3, of which rs911213 reached a statistical significance comparable to that of a genome wide threshold (p value = 4.0 × 10−8; odd ratio = .73, 95% confidence interval = .65–.82). The second most significant gene was CSMD1 on chromosome 8p23.2, a homologue to CSMD2. In addition, we observed replicated associations in the complement surface receptor CD46 as well as the major histocompatibility complex genes HLA-DMB and HLA-DOA. Conclusions: These data demonstrate a significant role of complement control-related genes in the etiology of schizophrenia and support disease mechanisms that involve the activity of immunity-related pathways in the brain. [Copyright &y& Elsevier]

Highlights from the article: To allow data from these consortia to flow together, three common cross-sectional platforms for biomaterials, clinical data and imaging data were established. B Results: b A data protection concept and a broad informed consent based on the national data protection guidelines was developed which was positively assessed by the Munich ethics commission (LMU) and serves as an example for further ethics commissions. Pseudonyms used in each research consortium within the research network are converted again into another pseudonym.

Objective. This evaluation focuses on polymorphisms of the cytochrome-P450 (CYP) isoenzymes 2C9, 2C19 and 2D6 and their association with plasma concentrations within a typical clinical setting. Side effects and treatment response were analysed in an exploratory approach in poor and ultra-rapid metabolisers. Patients and methods. We analysed 136 Caucasian depressed inpatients treated with amitriptyline, citalopram, clomipramine, doxepin, fluvoxamine, mirtazapine, paroxetine, sertraline and venlafaxine, who underwent weekly plasma concentration measurements, assessment of the severity of illness and side effects during their stay in the hospital. Patients were genotyped with respect to CYP2C9 alleles *1 and *2, the CYP2C19 alleles *1, *2 and *3 and the CYP2D6 alleles *1 to *9 and CYP2D6 gene duplication. Results. CYP2D6 poor metaboliser genotype and co-medication with inhibitors of CYP2D6 were associated with higher plasma concentrations than the drug-specific median plasma concentration when normalised to dose; plasma concentrations of CYP2C19 extensive metabolisers and smokers were significantly lower than the drug-specific median. Five of the six CYP2D6 poor metabolisers experienced side effects. Response was not associated with plasma concentrations above or below the lower limit of a presumed therapeutic range. Conclusion. These data indicate a significant influence of the CYP2D6 genotype, minor influence of the CYP2C19 genotype and no influence of the CYP2C9 genotype on plasma concentrations of patients taking mainly second-generation antidepressants. Because of the good tolerability of the latter and the flat dose–response relationship, genotyping should only be considered in cases of suspected side effects. [ABSTRACT FROM AUTHOR]

Anxiety and depression are common mental health disorders and have a higher prevalence in females. They are modestly heritable, share genetic liability with other psychiatric disorders, and are highly heterogeneous. There is evidence that genetic liability to neurodevelopmental disorders, such as attention deficit hyperactivity disorder (ADHD) is associated with anxiety and depression, particularly in females. We investigated sex differences in family history for neurodevelopmental and psychiatric disorders and neurodevelopmental genetic risk burden (indexed by ADHD polygenic risk scores (PRS) and rare copy number variants; CNVs) in individuals with anxiety and depression, also taking into account age at onset. We used two complementary datasets: 1) participants with a self-reported diagnosis of anxiety or depression (N = 4,178, 65.5% female; mean age = 41.5 years; N = 1,315 with genetic data) from the National Centre for Mental Health (NCMH) cohort and 2) a clinical sample of 13,273 (67.6% female; mean age = 45.2 years) patients with major depressive disorder (MDD) from the Psychiatric Genomics Consortium (PGC). We tested for sex differences in family history of psychiatric problems and presence of rare CNVs (neurodevelopmental and >500kb loci) in NCMH only and for sex differences in ADHD PRS in both datasets. In the NCMH cohort, females were more likely to report family history of neurodevelopmental and psychiatric disorders, but there were no robust sex differences in ADHD PRS or presence of rare CNVs. There was weak evidence of higher ADHD PRS in females compared to males in the PGC MDD sample, particularly in those with an early onset of MDD. These results do not provide strong evidence of sex differences in neurodevelopmental genetic risk burden in adults with anxiety and depression. This indicates that sex may not be a major index of neurodevelopmental genetic heterogeneity, that is captured by ADHD PRS and rare CNV burden, in adults with anxiety and depression. [ABSTRACT FROM AUTHOR]

Introduction: Oxytocin is a key mediator of emotional and social behavior that seems to be of relevance for the development and maintenance of addictive behaviors. We thus investigated the effect of oxytocin on neural response and behavior during a face-matching task in a sample of social drinkers. Methods: Thirteen social drinkers underwent a randomized double-blind placebo-controlled cross-over functional magnetic resonance imaging face-matching task with and without prior intranasal application of 24 international units oxytocin. Effects of oxytocin and task condition (faces, shapes) on brain activation and individual task performance were assessed. Results: Face-matching compared to shape-matching trials resulted in higher brain activation in the bilateral amygdala, hippocampus and parts of the occipital gyri. Oxytocin application vs. placebo reduced activation in bilateral amygdala, parts of the frontal gyri, and the parietal lobe. Region of interest analyses indicated that the oxytocin-induced attenuation of amygdala response was specific to face-stimuli and associated with lower subjective alcohol craving, and a lower percentage of heavy-drinking days (defined as ≥ 5 standard drinks/day). Conclusion: For the first time, we could show that a larger oxytocin-induced attenuation of amygdala response to fearful faces is associated with lower subjective craving for alcohol and percentage of heavy drinking days in social drinkers. Modulation of amygdala activation, induced by emotional stimuli, might represent a neurobiological substrate of oxytocin's protective effects on drug seeking behavior. [ABSTRACT FROM AUTHOR]

Repetitive transcranial magnetic stimulation (rTMS) is a safe non-invasive neuromodulation technique used for the treatment of various neuropsychiatric disorders. The effect of rTMS applied to the cortex on autonomic functions has not been studied in detail in patient cohorts, yet patients who receive rTMS may have disease-associated impairments in the autonomic system and may receive medication that may pronounce autonomic dysfunctions. Using data from the 'rTMS for the Treatment of Negative Symptoms in Schizophrenia' (RESIS) trial we evaluated the effect of rTMS applied to the left dorsolateral prefrontal cortex (DLPFC) on autonomic nervous system-related parameters such as blood pressure (BP) and heart rate (HR) in both reclining and standing postures from screening up to 105 days after intervention among patients with schizophrenia. 157 patients received either active (n = 76) or sham (n = 81) rTMS treatment. Apart from gender no significant group differences were observed. During intervention, Linear Mixed Model (LMM) analyses showed no significant time × group interactions nor time effects for any of the variables (all p > 0.055). During the whole trial beside a significant time × group interaction for diastolic BP (p = 0.017) in the standing posture, no significant time × group interactions for other variables (all p > 0.140) were found. These secondary analyses of the largest available rTMS trial on the treatment of negative symptoms in schizophrenia did not show a significant effect of active rTMS compared to sham rTMS on heart rate or blood pressure, neither during the intervention period nor during the follow-up period. [ABSTRACT FROM AUTHOR]

Sex-specific differences in schizophrenia (SCZ) are pervasive and have been reported for various aspects of the disease. Previous authors have therefore hypothesized that genetic risk factors on the X chromosome play a role in the complex interplay that leads to the development of this multifactorial and highly polygenic disorder. Nevertheless, few studies specifically targeted the investigation of these sex-specific genetic risk factors. In recent years, large-scale systematic genetic studies in SCZ have broadened the spectrum of genetic variation contributing to the disease and identified, among others, several X-chromosomal risk-associated loci. The world´s largest copy number variant (CNV) analysis for SCZ reported the first potential risk-associated CNV on the X chromosome. Duplications in Xq28,distal confer risk to SCZ in both sexes and span eight different protein-coding genes. Due to the shared genomic breakpoints of the duplications described to date, the issue of which gene/s at this locus is/are relevant in terms of SCZ pathogenesis remains unclear. In order to detect an enrichment of rare and potentially damaging variants in possible disease-relevant genes, the objective was to provide a detailed analysis of the genetic burden within the Xq28,distal locus using high-throughput, multiplex targeted sequencing. All coding regions of the implicated genes were sequenced in a large, European SCZ case-control cohort (n= 1935 patients with SCZ and n=1905 population-based controls) using the single molecule molecular inversion probe method on an Illumina HiSeq2500. To identify rare and potentially damaging variants, the analyses focused on non-synonymous single-nucleotide variants and Indels with a minor allele frequency ≤ 0.1% and a Combined Annotation Dependent Depletion score ≥ 20. The burden analysis was performed in a gene-wise manner and with sex as a covariate using the X-chromosomal model of the Optimal Unified Sequence Kernel Association Test adjusting for possible sex-specific effects. A total of n=73 independent variants passed the applied quality control criteria. After filtering for rare and potentially damaging variants, a total of n= 13 independent variants, as identified in four cases and eleven controls, were subjected to the consecutive burden analysis. For the genes within the Xq28,distal locus, no significant single-gene association was identified (smallest value in BRCC3 with p=0.103, p-adjusted=0.515), on the level of rare and potentially damaging variants. Overall, the present study confirms the recent gene-based results for the implicated genes of the Xq28, distal locus in the latest meta-analysis of exome sequencing data in SCZ conducted by the SCHEMA Consortium. The small number of identified variants is partly explained by the strict filter criteria and limited sample size. These findings might indicate a possible contribution of ultra-rare variants locus and a high degree of conservation within this region. Moreover, this may point towards alternative pathomechanisms not investigated in the present analyses; such as the involvement of sex-dependent risk factors, a genuine overexpression of a disease-relevant gene or the disruption of topologically associated domains in the context of duplications at Xq28,distal. Although inconclusive, the present findings highlight the need for more research into the role of X-chromosomal genetic risk factors in SCZ. [ABSTRACT FROM AUTHOR]

This narrative review summarizes and discusses the implications of the Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 and the upcoming International Classification of Diseases (ICD)-11 classification systems on the prevalence of bipolar disorder and on the validity of the DSM-5 diagnosis of bipolar disorder according to the Robin and Guze criteria of diagnostic validity. Here we review and discuss current data on the prevalence of bipolar disorder diagnosed according to DSM-5 versus DSM-IV, and data on characteristics of bipolar disorder in the two diagnostic systems in relation to extended Robin and Guze criteria: 1) clinical presentation, 2) associations with para-clinical data such as brain imaging and blood-based biomarkers, 3) delimitation from other disorders, 4) associations with family history / genetics, 5) prognosis and long-term follow-up, and 6) treatment effects. The review highlights that few studies have investigated consequences for the prevalence of the diagnosis of bipolar disorder and for the validity of the diagnosis. Findings from these studies suggest a substantial decrease in the point prevalence of a diagnosis of bipolar with DSM-5 compared with DSM-IV, ranging from 30–50%, but a smaller decrease in the prevalence during lifetime, corresponding to a 6% reduction. It is concluded that it is likely that the use of DSM-5 and ICD-11 will result in diagnostic delay and delayed early intervention in bipolar disorder. Finally, we recommend areas for future research. [ABSTRACT FROM AUTHOR]

While 17% of US adults use tobacco regularly, smoking rates among persons with schizophrenia are upwards of 60%. Research supports a shared etiological basis for smoking and schizophrenia, including findings from genome-wide association studies (GWAS). However, few studies have directly tested whether the same or distinct genetic variants also influence smoking behavior among schizophrenia cases. Using data from the Psychiatric Genomics Consortium (PGC) study of schizophrenia (35476 cases, 46839 controls), we estimated genetic correlations between these traits and tested whether polygenic risk scores (PRS) constructed from the results of smoking behaviors GWAS were associated with schizophrenia risk or smoking behaviors among schizophrenia cases. Results indicated significant genetic correlations of schizophrenia with smoking initiation (r g = 0.159; P = 5.05 × 10−10), cigarettes-smoked-per-day (r g = 0.094; P = 0.006), and age-of-onset of smoking (r g = 0.10; P = 0.009). Comparing smoking behaviors among schizophrenia cases to the general population, we observe positive genetic correlations for smoking initiation (r g = 0.624, P = 0.002) and cigarettes-smoked-per-day (r g = 0.689, P = 0.120). Similarly, TAG-based PRS for smoking initiation and cigarettes-smoked-per-day were significantly associated with smoking initiation (P = 3.49 × 10−5) and cigarettes-smoked-per-day (P = 0.007) among schizophrenia cases. We performed the first GWAS of smoking behavior among schizophrenia cases and identified a novel association with cigarettes-smoked-per-day upstream of the TMEM106B gene on chromosome 7p21.3 (rs148253479, P = 3.18 × 10−8, n = 3520). Results provide evidence of a partially shared genetic basis for schizophrenia and smoking behaviors. Additionally, genetic risk factors for smoking behaviors were largely shared across schizophrenia and non-schizophrenia populations. Future research should address mechanisms underlying these associations to aid both schizophrenia and smoking treatment and prevention efforts. [ABSTRACT FROM AUTHOR]