Publications by authors named "Bart P F Rutten"

137 Publications

Adiponectin-mimetic novel nonapeptide rescues aberrant neuronal metabolic-associated memory deficits in Alzheimer's disease.

Mol Neurodegener 2021 Apr 13;16(1):23. Epub 2021 Apr 13.

Division of Applied Life Science (BK 21 Four), College of Natural Science, Gyeongsang National University, Jinju, 52828, Republic of Korea.

Background: Recently, we and other researchers reported that brain metabolic disorders are implicated in Alzheimer's disease (AD), a progressive, devastating and incurable neurodegenerative disease. Hence, novel therapeutic approaches are urgently needed to explore potential and novel therapeutic targets/agents for the treatment of AD. The neuronal adiponectin receptor 1 (AdipoR1) is an emerging potential target for intervention in metabolic-associated AD. We aimed to validate this hypothesis and explore in-depth the therapeutic effects of an osmotin-derived adiponectin-mimetic novel nonapeptide (Os-pep) on metabolic-associated AD.

Methods: We used an Os-pep dosage regimen (5 μg/g, i.p., on alternating days for 45 days) for APP/PS1 in amyloid β oligomer-injected, transgenic adiponectin knockout (Adipo-/-) and AdipoR1 knockdown mice. After behavioral studies, brain tissues were subjected to biochemical and immunohistochemical analyses. In separate cohorts of mice, electrophysiolocal and Golgi staining experiments were performed. To validate the in vivo studies, we used human APP Swedish (swe)/Indiana (ind)-overexpressing neuroblastoma SH-SY5Y cells, which were subjected to knockdown of AdipoR1 and APMK with siRNAs, treated with Os-pep and other conditions as per the mechanistic approach, and we proceeded to perform further biochemical analyses.

Results: Our in vitro and in vivo results show that Os-pep has good safety and neuroprotection profiles and crosses the blood-brain barrier. We found reduced levels of neuronal AdipoR1 in human AD brain tissue. Os-pep stimulates AdipoR1 and its downstream target, AMP-activated protein kinase (AMPK) signaling, in AD and Adipo-/- mice. Mechanistically, in all of the in vivo and in vitro studies, Os-pep rescued aberrant neuronal metabolism by reducing neuronal insulin resistance and activated downstream insulin signaling through regulation of AdipoR1/AMPK signaling to consequently improve the memory functions of the AD and Adipo-/- mice, which was associated with improved synaptic function and long-term potentiation via an AdipoR1-dependent mechanism.

Conclusion: Our findings show that Os-pep activates AdipoR1/AMPK signaling and regulates neuronal insulin resistance and insulin signaling, which subsequently rescues memory deficits in AD and adiponectin-deficient models. Taken together, the results indicate that Os-pep, as an adiponectin-mimetic novel nonapeptide, is a valuable and promising potential therapeutic candidate to treat aberrant brain metabolism associated with AD and other neurodegenerative diseases.
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http://dx.doi.org/10.1186/s13024-021-00445-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042910PMC
April 2021

Examining the association between exposome score for schizophrenia and functioning in schizophrenia, siblings, and healthy controls: Results from the EUGEI study.

Eur Psychiatry 2021 Mar 19;64(1):e25. Epub 2021 Mar 19.

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands.

Background: A cumulative environmental exposure score for schizophrenia (exposome score for schizophrenia [ES-SCZ]) may provide potential utility for risk stratification and outcome prediction. Here, we investigated whether ES-SCZ was associated with functioning in patients with schizophrenia spectrum disorder, unaffected siblings, and healthy controls.

Methods: This cross-sectional sample consisted of 1,261 patients, 1,282 unaffected siblings, and 1,525 healthy controls. The Global Assessment of Functioning (GAF) scale was used to assess functioning. ES-SCZ was calculated based on our previously validated method. The association between ES-SCZ and the GAF dimensions (symptom and disability) was analyzed by applying regression models in each group (patients, siblings, and controls). Additional models included polygenic risk score for schizophrenia (PRS-SCZ) as a covariate.

Results: ES-SCZ was associated with the GAF dimensions in patients (symptom: B = -1.53, p-value = 0.001; disability: B = -1.44, p-value = 0.001), siblings (symptom: B = -3.07, p-value < 0.001; disability: B = -2.52, p-value < 0.001), and healthy controls (symptom: B = -1.50, p-value < 0.001; disability: B = -1.31, p-value < 0.001). The results remained the same after adjusting for PRS-SCZ. The degree of associations of ES-SCZ with both symptom and disability dimensions were higher in unaffected siblings than in patients and controls. By analyzing an independent dataset (the Genetic Risk and Outcome of Psychosis study), we replicated the results observed in the patient group.

Conclusions: Our findings suggest that ES-SCZ shows promise for enhancing risk prediction and stratification in research practice. From a clinical perspective, ES-SCZ may aid in efforts of clinical characterization, operationalizing transdiagnostic clinical staging models, and personalizing clinical management.
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http://dx.doi.org/10.1192/j.eurpsy.2021.19DOI Listing
March 2021

Schizophrenia and the Environment: Within-Person Analyses May be Required to Yield Evidence of Unconfounded and Causal Association-The Example of Cannabis and Psychosis.

Schizophr Bull 2021 Mar 8. Epub 2021 Mar 8.

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Centre, Maastricht, the Netherlands.

Hypotheses about the link between cannabis use and psychosis apply to the within-person level but have been tested mostly at the between-person level. We used a within-person design, in which a person serves as his own control, thus removing the need to consider confounding by any fixed (genetic and nongenetic) characteristic to study the prospective association between cannabis use and the incidence of attenuated psychotic experiences, and vice versa, adjusted for time-varying confounders. We combined 2 general population cohorts (at baseline: Early Developmental Stages of Psychopathology Study, n = 1395; Netherlands Mental Health Survey and Incidence Study-2, n = 6603), which applied a similar methodology to study cannabis use and attenuated psychotic experiences with repeated interviews (T0, T1, T2, and T3) over a period of approximately 10 years. The Hausman test was significant for the adjusted models, indicating the validity of the fixed-effects model. In the adjusted fixed-effects model, prior cannabis use was associated with psychotic experiences (aOR = 7.03, 95% CI: 2.39, 20.69), whereas prior psychotic experiences were not associated with cannabis use (aOR = 0.59, 95% CI: 0.21, 1.71). Longitudinal studies applying random-effects models to study associations between risk factors and mental health outcomes, as well as reverse causality, may not yield precise estimates. Cannabis likely impacts causally on psychosis but not the other way round.
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http://dx.doi.org/10.1093/schbul/sbab019DOI Listing
March 2021

Network dynamics of momentary affect states and future course of psychopathology in adolescents.

PLoS One 2021 4;16(3):e0247458. Epub 2021 Mar 4.

University Medical Center Groningen, University Center Psychiatry (UCP) Interdisciplinary Center Psychopathology and Emotion Regulation (ICPE), University of Groningen, Groningen, The Netherlands.

Background: Recent theories argue that an interplay between (i.e., network of) experiences, thoughts and affect in daily life may underlie the development of psychopathology.

Objective: To prospectively examine whether network dynamics of everyday affect states are associated with a future course of psychopathology in adolescents at an increased risk of mental disorders.

Methods: 159 adolescents from the East-Flanders Prospective Twin Study cohort participated in the study. At baseline, their momentary affect states were assessed using the Experience Sampling Method (ESM). The course of psychopathology was operationalized as the change in the Symptom Checklist-90 sum score after 1 year. Two groups were defined: one with a stable level (n = 81) and one with an increasing level (n = 78) of SCL-symptom severity. Group-level network dynamics of momentary positive and negative affect states were compared between groups.

Results: The group with increasing symptoms showed a stronger connections between negative affect states and their higher influence on positive states, as well as higher proneness to form 'vicious cycles', compared to the stable group. Based on permutation tests, these differences were not statistically significant.

Conclusion: Although not statistically significant, some qualitative differences were observed between the networks of the two groups. More studies are needed to determine the value of momentary affect networks for predicting the course of psychopathology.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247458PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932519PMC
March 2021

The Effects of Serum Removal on Gene Expression and Morphological Plasticity Markers in Differentiated SH-SY5Y Cells.

Cell Mol Neurobiol 2021 Mar 3. Epub 2021 Mar 3.

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Brain+Nerve Centre, Maastricht University Medical Centre+ (MUMC+), Maastricht, The Netherlands.

Despite the widespread use of the SH-SY5Y human neuroblastoma cell line in modeling human neurons in vitro, protocols for growth, differentiation and experimentation differ considerably across the literature. Many studies fully differentiate SH-SY5Y cells before experimentation, to investigate plasticity measures in a mature, human neuronal-like cell model. Prior to experimentation, serum is often removed from cell culture media, to arrest the cell growth cycle and synchronize cells. However, the exact effect of this serum removal before experimentation on mature, differentiated SH-SY5Y cells has not yet been described. In studies using differentiated SH-SY5Y cells, any effect of serum removal on plasticity markers may influence results. The aim of the current study was to systematically characterize, in differentiated, neuronal-like SH-SY5Y cells, the potentially confounding effects of complete serum removal in terms of morphological and gene expression markers of plasticity. We measured changes in commonly used morphological markers and in genes related to neuroplasticity and synaptogenesis, particularly in the BDNF-TrkB signaling pathway. We found that complete serum removal from already differentiated SH-SY5Y cells increases neurite length, neurite branching, and the proportion of cells with a primary neurite, as well as proportion of βIII-Tubulin and MAP2 expressing cells. Gene expression results also indicate increased expression of PSD95 and NTRK2 expression 24 h after serum removal. We conclude that serum deprivation in differentiated SH-SY5Y cells affects morphology and gene expression and can potentially confound plasticity-related outcome measures, having significant implications for experimental design in studies using differentiated SH-SY5Y cells as a model of human neurons.
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http://dx.doi.org/10.1007/s10571-021-01062-xDOI Listing
March 2021

Perceived major experiences of discrimination, ethnic group, and risk of psychosis in a six-country case-control study.

Psychol Med 2021 Mar 2:1-9. Epub 2021 Mar 2.

Department of Health Service and Population Research, Institute of Psychiatry, King's College London, LondonSE5 8AF, UK.

Background: Perceived discrimination is associated with worse mental health. Few studies have assessed whether perceived discrimination (i) is associated with the risk of psychotic disorders and (ii) contributes to an increased risk among minority ethnic groups relative to the ethnic majority.

Methods: We used data from the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions Work Package 2, a population-based case-control study of incident psychotic disorders in 17 catchment sites across six countries. We calculated odds ratios (OR) and 95% confidence intervals (95% CI) for the associations between perceived discrimination and psychosis using mixed-effects logistic regression models. We used stratified and mediation analyses to explore differences for minority ethnic groups.

Results: Reporting any perceived experience of major discrimination (e.g. unfair treatment by police, not getting hired) was higher in cases than controls (41.8% v. 34.2%). Pervasive experiences of discrimination (≥3 types) were also higher in cases than controls (11.3% v. 5.5%). In fully adjusted models, the odds of psychosis were 1.20 (95% CI 0.91-1.59) for any discrimination and 1.79 (95% CI 1.19-1.59) for pervasive discrimination compared with no discrimination. In stratified analyses, the magnitude of association for pervasive experiences of discrimination appeared stronger for minority ethnic groups (OR = 1.73, 95% CI 1.12-2.68) than the ethnic majority (OR = 1.42, 95% CI 0.65-3.10). In exploratory mediation analysis, pervasive discrimination minimally explained excess risk among minority ethnic groups (5.1%).

Conclusions: Pervasive experiences of discrimination are associated with slightly increased odds of psychotic disorders and may minimally help explain excess risk for minority ethnic groups.
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http://dx.doi.org/10.1017/S0033291721000453DOI Listing
March 2021

Association of the kynurenine pathway metabolites with clinical, cognitive features and IL-1β levels in patients with schizophrenia spectrum disorder and their siblings.

Schizophr Res 2021 Feb 17;229:27-37. Epub 2021 Feb 17.

Department of Psychiatry, Faculty of Medicine, Istanbul University, Istanbul, Turkey. Electronic address:

Objective: There is evidence suggesting that tryptophan (TRP)-kynurenine (KYN) pathway dysregulation is involved in the pathophysiology of schizophrenia and is regulated by inflammatory cytokines. The study investigate for the first time whether this dysregulation occurs in advanced stages of the disease as a byproduct or emerges as one of the early and inherited manifestations of schizophrenia.

Method: Sera of 148 patients with schizophrenia spectrum disorders (SCZ), 139 unaffected siblings (SIB) and 210 controls were investigated. Serum interleukin (IL)-1β levels were measured by ELISA, and TRP, KYN and kynurenic acid (KYNA) levels were measured by a high-performance liquid chromatography system. Also, we collected clinical data by applying Comprehensive Assessment of Symptoms and History in SCZ, and SIS-R in SIB and control groups.

Results: Compared to controls, SCZ and SIB groups had lower TRP and higher KYNA levels. TRP levels showed significant differences only between SCZ and controls (p < 0.01). KYNA levels of both SCZ (p ≤ 0.001) and SIB (p < 0.05) were higher than controls. No statistical significance was found for KYN levels across groups. SCZ and SIB groups had higher serum IL-1β levels than controls (p ≤ 0.001).

Conclusions: Patients with SCZ and their siblings exhibited similar clinical features and TRP metabolite levels suggesting that TRP-KYN dysregulation may be an inherited component of the disease putatively conferring increased risk to schizophrenia. Elevation of IL-1β is one of the factors promoting overconsumption of the TRP-KYN pathway leading to increased production of neuroregulatory KYNA and presumably to neurodegeneration.
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http://dx.doi.org/10.1016/j.schres.2021.01.014DOI Listing
February 2021

Obsessive-Compulsive Symptoms and Other Symptoms of the At-risk Mental State for Psychosis: A Network Perspective.

Schizophr Bull 2021 Feb 17. Epub 2021 Feb 17.

Department of Psychology, Psychological Methods, University of Amsterdam, Amsterdam, the Netherlands.

Background: The high prevalence of obsessive-compulsive symptoms (OCS) among subjects at Ultra-High Risk (UHR) for psychosis is well documented. However, the network structure spanning the relations between OCS and symptoms of the at risk mental state for psychosis as assessed with the Comprehensive Assessment of At Risk Mental States (CAARMS) has not yet been investigated. This article aimed to use a network approach to investigate the associations between OCS and CAARMS symptoms in a large sample of individuals with different levels of risk for psychosis.

Method: Three hundred and forty-one UHR and 66 healthy participants were included, who participated in the EU-GEI study. Data analysis consisted of constructing a network of CAARMS symptoms, investigating central items in the network, and identifying the shortest pathways between OCS and positive symptoms.

Results: Strong associations between OCS and anxiety, social isolation and blunted affect were identified. Depression was the most central symptom in terms of the number of connections, and anxiety was a key item in bridging OCS to other symptoms. Shortest paths between OCS and positive symptoms revealed that unusual thought content and perceptual abnormalities were connected mainly via anxiety, while disorganized speech was connected via blunted affect and cognitive change.

Conclusions: Findings provide valuable insight into the central role of depression and the potential connective component of anxiety between OCS and other symptoms of the network. Interventions specifically aimed to reduce affective symptoms might be crucial for the development and prospective course of symptom co-occurrence.
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http://dx.doi.org/10.1093/schbul/sbaa187DOI Listing
February 2021

Cognitive functioning throughout adulthood and illness stages in individuals with psychotic disorders and their unaffected siblings.

Authors:
Eva Velthorst Josephine Mollon Robin M Murray Lieuwe de Haan Inez Myin Germeys David C Glahn Celso Arango Els van der Ven Marta Di Forti Miguel Bernardo Sinan Guloksuz Philippe Delespaul Gisela Mezquida Silvia Amoretti Julio Bobes Pilar A Saiz María Paz García-Portilla José Luis Santos Estela Jiménez-López Julio Sanjuan Eduardo J Aguilar Manuel Arrojo Angel Carracedo Gonzalo López Javier González-Peñas Mara Parellada Cem Atbaşoğlu Meram Can Saka Alp Üçok Köksal Alptekin Berna Akdede Tolga Binbay Vesile Altınyazar Halis Ulaş Berna Yalınçetin Güvem Gümüş-Akay Burçin Cihan Beyaz Haldun Soygür Eylem Şahin Cankurtaran Semra Ulusoy Kaymak Nadja P Maric Marina M Mihaljevic Sanja Andric Petrovic Tijana Mirjanic Cristina Marta Del-Ben Laura Ferraro Charlotte Gayer-Anderson Peter B Jones Hannah E Jongsma James B Kirkbride Caterina La Cascia Antonio Lasalvia Sarah Tosato Pierre-Michel Llorca Paulo Rossi Menezes Craig Morgan Diego Quattrone Marco Menchetti Jean-Paul Selten Andrei Szöke Ilaria Tarricone Andrea Tortelli Philip McGuire Lucia Valmaggia Matthew J Kempton Mark van der Gaag Anita Riecher-Rössler Rodrigo A Bressan Neus Barrantes-Vidal Barnaby Nelson Patrick McGorry Chris Pantelis Marie-Odile Krebs Stephan Ruhrmann Gabriele Sachs Bart P F Rutten Jim van Os Behrooz Z Alizadeh Therese van Amelsvoort Agna A Bartels-Velthuis Richard Bruggeman Nico J van Beveren Jurjen J Luykx Wiepke Cahn Claudia J P Simons Rene S Kahn Frederike Schirmbeck Ruud van Winkel Abraham Reichenberg

Mol Psychiatry 2021 Jan 7. Epub 2021 Jan 7.

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Important questions remain about the profile of cognitive impairment in psychotic disorders across adulthood and illness stages. The age-associated profile of familial impairments also remains unclear, as well as the effect of factors, such as symptoms, functioning, and medication. Using cross-sectional data from the EU-GEI and GROUP studies, comprising 8455 participants aged 18 to 65, we examined cognitive functioning across adulthood in patients with psychotic disorders (n = 2883), and their unaffected siblings (n = 2271), compared to controls (n = 3301). An abbreviated WAIS-III measured verbal knowledge, working memory, visuospatial processing, processing speed, and IQ. Patients showed medium to large deficits across all functions (ES range = -0.45 to -0.73, p < 0.001), while siblings showed small deficits on IQ, verbal knowledge, and working memory (ES = -0.14 to -0.33, p < 0.001). Magnitude of impairment was not associated with participant age, such that the size of impairment in older and younger patients did not significantly differ. However, first-episode patients performed worse than prodromal patients (ES range = -0.88 to -0.60, p < 0.001). Adjusting for cannabis use, symptom severity, and global functioning attenuated impairments in siblings, while deficits in patients remained statistically significant, albeit reduced by half (ES range = -0.13 to -0.38, p < 0.01). Antipsychotic medication also accounted for around half of the impairment in patients (ES range = -0.21 to -0.43, p < 0.01). Deficits in verbal knowledge, and working memory may specifically index familial, i.e., shared genetic and/or shared environmental, liability for psychotic disorders. Nevertheless, potentially modifiable illness-related factors account for a significant portion of the cognitive impairment in psychotic disorders.
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http://dx.doi.org/10.1038/s41380-020-00969-zDOI Listing
January 2021

Symptom-network dynamics in irritable bowel syndrome with comorbid panic disorder using electronic momentary assessment: A randomized controlled trial of escitalopram vs. placebo.

J Psychosom Res 2021 02 24;141:110351. Epub 2020 Dec 24.

Department of Psychiatry and Psychology, School of Mental Health and Neuroscience (MHeNS), Maastricht University Medical Centre, Maastricht, the Netherlands. Electronic address:

Introduction: Momentary ecological assessment indicated alleviated abdominal pain in escitalopram treatment of irritable bowel syndrome (IBS) with comorbid panic disorder. Hitherto, little is known about symptom formation, i.e., how psychological impact physical symptoms, and vice versa, and about the effect of SSRI-treatment on symptom formation.

Objective: To investigate how psychological and somatic symptoms co-vary over time in IBS patients with comorbid panic disorder and how they are affected by escitalopram treatment.

Methods: Experience sampling data from 14 IBS patients with panic disorder were obtained from a single-centre, double-blind, parallel-group, randomized controlled trial on escitalopram versus placebo. At baseline, after three and six months, multilevel time-lagged linear regression analysis was used to construct symptom networks. Network connections represented coefficients between various affect and gastrointestinal items.

Results: Connectivity increased up to 3 months in both groups. Between 3 and 6 months, connectivity decreased for placebo and further increased in the escitalopram group. Additionally, a steep increase in node strength for negative affect nodes was observed in the escitalopram network and the opposite for positive affect nodes. Over time, group symptom networks became increasingly different from each other. Anxious-anxious and enthusiastic-relaxed became significantly different between groups at 6 months. The connection that changed significantly in all analyses was anxious-anxious.

Conclusions: Escitalopram treatment was associated with changes in the symptom networks in IBS patients with panic disorder. While mood and physical symptoms improve over time, mainly connectivity between mood nodes changed, possibly pointing towards a healthier emotion regulation resulting in alleviation of physical symptoms.
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http://dx.doi.org/10.1016/j.jpsychores.2020.110351DOI Listing
February 2021

Do Current Measures of Polygenic Risk for Mental Disorders Contribute to Population Variance in Mental Health?

Schizophr Bull 2020 12;46(6):1353-1362

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Centre, Maastricht, The Netherlands.

The polygenic risk score (PRS) allows for quantification of the relative contributions of genes and environment in population-based studies of mental health. We analyzed the impact of transdiagnostic schizophrenia PRS and measures of familial and environmental risk on the level of and change in general mental health (Short-Form-36 mental health) in the Netherlands Mental Health Survey and Incidence Study-2 general population sample, interviewed 4 times over a period of 9 years, yielding 8901 observations in 2380 individuals. Schizophrenia PRS, family history, somatic pain, and a range of environmental risks and social circumstances were included in the regression model of level of and change in mental health. We calculated the relative contribution of each (group of) risk factor(s) to the variance in (change in) mental health. In the combined model, familial and environmental factors explained around 17% of the variance in mental health, of which around 5% was explained by age and sex, 30% by social circumstances, 16% by pain, 22% by environmental risk factors, 24% by family history, and 3% by PRS for schizophrenia (PRS-SZ). Results were similar, but attenuated, for the model of mental health change over time. Childhood trauma and gap between actual and desired social status explained most of the variance. PRS for bipolar disorder, cross-disorder, and depression explained less variance in mental health than PRS-SZ. Polygenic risk for mental suffering, derived from significance-testing in massive samples, lacks impact in analyses focusing on prediction in a general population epidemiological setting. Social-environmental circumstances, particularly childhood trauma and perceived status gap, drive most of the attributable variation in population mental health.
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http://dx.doi.org/10.1093/schbul/sbaa086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707067PMC
December 2020

Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies methylation changes in AHRR.

Nat Commun 2020 11 24;11(1):5965. Epub 2020 Nov 24.

University of California San Diego, Department of Psychiatry, La Jolla, CA, USA.

Epigenetic differences may help to distinguish between PTSD cases and trauma-exposed controls. Here, we describe the results of the largest DNA methylation meta-analysis of PTSD to date. Ten cohorts, military and civilian, contribute blood-derived DNA methylation data from 1,896 PTSD cases and trauma-exposed controls. Four CpG sites within the aryl-hydrocarbon receptor repressor (AHRR) associate with PTSD after adjustment for multiple comparisons, with lower DNA methylation in PTSD cases relative to controls. Although AHRR methylation is known to associate with smoking, the AHRR association with PTSD is most pronounced in non-smokers, suggesting the result was independent of smoking status. Evaluation of metabolomics data reveals that AHRR methylation associated with kynurenine levels, which are lower among subjects with PTSD. This study supports epigenetic differences in those with PTSD and suggests a role for decreased kynurenine as a contributor to immune dysregulation in PTSD.
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http://dx.doi.org/10.1038/s41467-020-19615-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686485PMC
November 2020

Predictive Performance of Exposome Score for Schizophrenia in the General Population.

Schizophr Bull 2021 Mar;47(2):277-283

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands.

Previously, we established an estimated exposome score for schizophrenia (ES-SCZ) as a cumulative measure of environmental liability for schizophrenia to use in gene-environment interaction studies and for risk stratification in population cohorts. Hereby, we examined the discriminative function of ES-SCZ for identifying individuals diagnosed with schizophrenia spectrum disorder in the general population by measuring the area under the receiver operating characteristic curve (AUC). Furthermore, we compared this ES-SCZ method to an environmental sum score (Esum-SCZ) and an aggregate environmental score weighted by the meta-analytical estimates (Emet-SCZ). We also estimated ORs and Nagelkerke's R2 for ES-SCZ in association with psychiatric diagnoses and other medical outcomes. ES-SCZ showed a good discriminative function (AUC = 0.84) and statistically significantly performed better than both Esum-SCZ (AUC = 0.80) and Emet-SCZ (AUC = 0.80). At optimal cut point, ES-SCZ showed similar performance in ruling out (LR- = 0.20) and ruling in (LR+ = 3.86) schizophrenia. ES-SCZ at optimal cut point showed also a progressively greater magnitude of association with increasing psychosis risk strata. Among all clinical outcomes, ES-SCZ was associated with schizophrenia diagnosis with the highest OR (2.76, P < .001) and greatest explained variance (R2 = 14.03%), followed by bipolar disorder (OR = 2.61, P < .001, R2 = 13.01%) and suicide plan (OR = 2.44, P < .001, R2 = 12.44%). Our findings from an epidemiologically representative general population cohort demonstrate that an aggregate environmental exposure score for schizophrenia constructed using a predictive modeling approach-ES-SCZ-has the potential to improve risk prediction and stratification for research purposes and may help gain insight into the multicausal etiology of psychopathology.
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http://dx.doi.org/10.1093/schbul/sbaa170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7965069PMC
March 2021

Transcranial Magnetic Stimulation-Induced Plasticity Mechanisms: TMS-Related Gene Expression and Morphology Changes in a Human Neuron-Like Cell Model.

Front Mol Neurosci 2020 19;13:528396. Epub 2020 Oct 19.

Department of Cognitive Neuroscience, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, Netherlands.

Transcranial Magnetic Stimulation (TMS) is a form of non-invasive brain stimulation, used to alter cortical excitability both in research and clinical applications. The and Theta Burst Stimulation (iTBS and cTBS) protocols have been shown to induce opposite after-effects on human cortex excitability. Animal studies have implicated synaptic plasticity mechanisms long-term potentiation (LTP, for iTBS) and depression (LTD, for cTBS). However, the neural basis of TMS effects has not yet been studied in human neuronal cells, in particular at the level of gene expression and synaptogenesis. To investigate responses to TBS in living neurons, we differentiated human SH-SY5Y cells toward a mature neural phenotype, and stimulated them with iTBS, cTBS, or sham (placebo) TBS. Changes in (a) mRNA expression of a set of target genes (previously associated with synaptic plasticity), and (b) morphological parameters of neurite outgrowth following TBS were quantified. We found no general effects of stimulation condition or time on gene expression, though we did observe a significantly enhanced expression of plasticity genes and 24 h after iTBS as compared to sham TBS. This specific effect provides unique support for the widely assumed plasticity mechanisms underlying iTBS effects on human cortex excitability. In addition to this protocol-specific increase in plasticity gene expression 24 h after iTBS stimulation, we establish the feasibility of stimulating living human neuron with TBS, and the importance of moving to more complex human models to understand the underlying plasticity mechanisms of TBS stimulation.
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http://dx.doi.org/10.3389/fnmol.2020.528396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604533PMC
October 2020

Clinical, cognitive and neuroanatomical associations of serum NMDAR autoantibodies in people at clinical high risk for psychosis.

Mol Psychiatry 2020 Oct 19. Epub 2020 Oct 19.

Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's Health Partners, King's College London, London, UK.

Serum neuronal autoantibodies, such as those to the NMDA receptor (NMDAR), are detectable in a subgroup of patients with psychotic disorders. It is not known if they are present before the onset of psychosis or whether they are associated with particular clinical features or outcomes. In a case-control study, sera from 254 subjects at clinical high risk (CHR) for psychosis and 116 healthy volunteers were tested for antibodies against multiple neuronal antigens implicated in CNS autoimmune disorders, using fixed and live cell-based assays (CBAs). Within the CHR group, the relationship between NMDAR antibodies and symptoms, cognitive function and clinical outcomes over 24 month follow-up was examined. CHR subjects were not more frequently seropositive for neuronal autoantibodies than controls (8.3% vs. 5.2%; OR = 1.50; 95% CI: 0.58-3.90). The NMDAR was the most common target antigen and NMDAR IgGs were more sensitively detected with live versus fixed CBAs (p < 0.001). Preliminary phenotypic analyses revealed that within the CHR sample, the NMDAR antibody seropositive subjects had higher levels of current depression, performed worse on the Rey Auditory Verbal Learning Task (p < 0.05), and had a markedly lower IQ (p < 0.01). NMDAR IgGs were not more frequent in subjects who later became psychotic than those who did not. NMDAR antibody serostatus and titre was associated with poorer levels of functioning at follow-up (p < 0.05) and the presence of a neuronal autoantibody was associated with larger amygdala volumes (p < 0.05). Altogether, these findings demonstrate that NMDAR autoantibodies are detectable in a subgroup of CHR subjects at equal rates to controls. In the CHR group, they are associated with affective psychopathology, impairments in verbal memory, and overall cognitive function: these findings are qualitatively and individually similar to core features of autoimmune encephalitis and/or animal models of NMDAR antibody-mediated CNS disease. Overall the current work supports further evaluation of NMDAR autoantibodies as a possible prognostic biomarker and aetiological factor in a subset of people already meeting CHR criteria.
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http://dx.doi.org/10.1038/s41380-020-00899-wDOI Listing
October 2020

Evidence, and replication thereof, that molecular-genetic and environmental risks for psychosis impact through an affective pathway.

Psychol Med 2020 Oct 19:1-13. Epub 2020 Oct 19.

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Centre, Maastricht, The Netherlands.

Background: There is evidence that environmental and genetic risk factors for schizophrenia spectrum disorders are transdiagnostic and mediated in part through a generic pathway of affective dysregulation.

Methods: We analysed to what degree the impact of schizophrenia polygenic risk (PRS-SZ) and childhood adversity (CA) on psychosis outcomes was contingent on co-presence of affective dysregulation, defined as significant depressive symptoms, in (i) NEMESIS-2 (n = 6646), a representative general population sample, interviewed four times over nine years and (ii) EUGEI (n = 4068) a sample of patients with schizophrenia spectrum disorder, the siblings of these patients and controls.

Results: The impact of PRS-SZ on psychosis showed significant dependence on co-presence of affective dysregulation in NEMESIS-2 [relative excess risk due to interaction (RERI): 1.01, p = 0.037] and in EUGEI (RERI = 3.39, p = 0.048). This was particularly evident for delusional ideation (NEMESIS-2: RERI = 1.74, p = 0.003; EUGEI: RERI = 4.16, p = 0.019) and not for hallucinatory experiences (NEMESIS-2: RERI = 0.65, p = 0.284; EUGEI: -0.37, p = 0.547). A similar and stronger pattern of results was evident for CA (RERI delusions and hallucinations: NEMESIS-2: 3.02, p < 0.001; EUGEI: 6.44, p < 0.001; RERI delusional ideation: NEMESIS-2: 3.79, p < 0.001; EUGEI: 5.43, p = 0.001; RERI hallucinatory experiences: NEMESIS-2: 2.46, p < 0.001; EUGEI: 0.54, p = 0.465).

Conclusions: The results, and internal replication, suggest that the effects of known genetic and non-genetic risk factors for psychosis are mediated in part through an affective pathway, from which early states of delusional meaning may arise.
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http://dx.doi.org/10.1017/S0033291720003748DOI Listing
October 2020

Early warning signals in psychopathology: what do they tell?

BMC Med 2020 10 14;18(1):269. Epub 2020 Oct 14.

Department of Psychiatry, Interdisciplinary Center Psychopathology and Emotion regulation (ICPE), University of Groningen, University Medical Center Groningen, Internal Postal Code: CC72, Triade Building Entrance 24, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.

Background: Despite the increasing understanding of factors that might underlie psychiatric disorders, prospectively detecting shifts from a healthy towards a symptomatic state has remained unattainable. A complex systems perspective on psychopathology implies that such symptom shifts may be foreseen by generic indicators of instability, or early warning signals (EWS). EWS include, for instance, increasing variability, covariance, and autocorrelation in momentary affective states-of which the latter was studied. The present study investigated if EWS predict (i) future worsening of symptoms as well as (ii) the type of symptoms that will develop, meaning that the association between EWS and future symptom shifts would be most pronounced for congruent affective states and psychopathological domains (e.g., feeling down and depression).

Methods: A registered general population cohort of adolescents (mean age 18 years, 36% male) provided ten daily ratings of their affective states for 6 consecutive days. The resulting time series were used to compute EWS in feeling down, listless, anxious, not relaxed, insecure, suspicious, and unwell. At baseline and 1-year follow-up, symptom severity was assessed by the Symptom Checklist-90 (SCL-90). We selected four subsamples of participants who reported an increase in one of the following SCL-90 domains: depression (N = 180), anxiety (N = 192), interpersonal sensitivity (N = 184), or somatic complaints (N = 166).

Results: Multilevel models showed that EWS in feeling suspicious anticipated increases in interpersonal sensitivity, as hypothesized. EWS were absent for other domains. While the association between EWS and symptom increases was restricted to the interpersonal sensitivity domain, post hoc analyses showed that symptom severity at baseline was related to heightened autocorrelations in congruent affective states for interpersonal sensitivity, depression, and anxiety. This pattern replicated in a second, independent dataset.

Conclusions: The presence of EWS prior to symptom shifts may depend on the dynamics of the psychopathological domain under consideration: for depression, EWS may manifest only several weeks prior to a shift, while for interpersonal sensitivity, EWS may already occur 1 year in advance. Intensive longitudinal designs where EWS and symptoms are assessed in real-time are required in order to determine at what timescale and for what type of domain EWS are most informative of future psychopathology.
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http://dx.doi.org/10.1186/s12916-020-01742-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557008PMC
October 2020

A replication study of JTC bias, genetic liability for psychosis and delusional ideation.

Psychol Med 2020 Oct 13:1-7. Epub 2020 Oct 13.

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Centre, Maastricht, the Netherlands.

Background: This study attempted to replicate whether a bias in probabilistic reasoning, or 'jumping to conclusions'(JTC) bias is associated with being a sibling of a patient with schizophrenia spectrum disorder; and if so, whether this association is contingent on subthreshold delusional ideation.

Methods: Data were derived from the EUGEI project, a 25-centre, 15-country effort to study psychosis spectrum disorder. The current analyses included 1261 patients with schizophrenia spectrum disorder, 1282 siblings of patients and 1525 healthy comparison subjects, recruited in Spain (five centres), Turkey (three centres) and Serbia (one centre). The beads task was used to assess JTC bias. Lifetime experience of delusional ideation and hallucinatory experiences was assessed using the Community Assessment of Psychic Experiences. General cognitive abilities were taken into account in the analyses.

Results: JTC bias was positively associated not only with patient status but also with sibling status [adjusted relative risk (aRR) ratio : 4.23 CI 95% 3.46-5.17 for siblings and aRR: 5.07 CI 95% 4.13-6.23 for patients]. The association between JTC bias and sibling status was stronger in those with higher levels of delusional ideation (aRR interaction in siblings: 3.77 CI 95% 1.67-8.51, and in patients: 2.15 CI 95% 0.94-4.92). The association between JTC bias and sibling status was not stronger in those with higher levels of hallucinatory experiences.

Conclusions: These findings replicate earlier findings that JTC bias is associated with familial liability for psychosis and that this is contingent on the degree of delusional ideation but not hallucinations.
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http://dx.doi.org/10.1017/S0033291720003578DOI Listing
October 2020

Network approach of mood and functional gastrointestinal symptom dynamics in relation to childhood trauma in patients with irritable bowel syndrome and comorbid panic disorder.

J Psychosom Res 2020 12 2;139:110261. Epub 2020 Oct 2.

Department of Psychiatry and Neuropsychology, School of Mental Health and NeuroScience (MHeNS), Maastricht University Medical Centre, Maastricht, the Netherlands. Electronic address:

Objective: Irritable bowel syndrome (IBS) has a high comorbidity with mental disorders. The present paper aims to visualise the interplay between IBS and affect (anxiety and mood) in daily life. Furthermore, this interplay may be different depending on risk factors such as childhood trauma.

Methods: Using momentary assessment (Experience Sampling Method), data of 24 individuals diagnosed with both IBS and panic disorder were analysed (15 non-trauma and 9 low-trauma-score patients). Networks were constructed, based on multilevel time-lagged linear regression analysis. Regression coefficients present network connections including three negative affect items (down, irritated, rushed), three positive affect items (happy, enthusiastic, cheerful), three abdominal complaints (abdominal pain, bloating, nausea) and one social item (feeling lonely). Those networks were stratified by levels of childhood trauma based on the Childhood Trauma Questionnaire.

Results: Connections within the group of mood items and within the group of abdominal complaints were more frequent than between abdominal complaints and mood items. When data were stratified by childhood trauma, networks were different. In addition, node strengths were stronger in low-trauma than in non-trauma, although only one was significantly different (enthusiastic). Overall, there were mainly non-significant connections and a clear pattern was not visible.

Conclusions: A time-lagged network provides additional insight in connections between abdominal complaints and affective complaints, in patients with IBS and panic disorder, with different levels of childhood trauma. More research is needed to gain a better understanding of symptom formation and the impact of variation in context on individual symptom experiences in IBS with affective comorbidity. Baseline data of a clinical trial: NCT01551225 (http://www.clinicaltrials.gov).
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http://dx.doi.org/10.1016/j.jpsychores.2020.110261DOI Listing
December 2020

Relationship between jumping to conclusions and clinical outcomes in people at clinical high-risk for psychosis.

Psychol Med 2020 Oct 6:1-9. Epub 2020 Oct 6.

Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.

Background: Psychosis is associated with a reasoning bias, which manifests as a tendency to 'jump to conclusions'. We examined this bias in people at clinical high-risk for psychosis (CHR) and investigated its relationship with their clinical outcomes.

Methods: In total, 303 CHR subjects and 57 healthy controls (HC) were included. Both groups were assessed at baseline, and after 1 and 2 years. A 'beads' task was used to assess reasoning bias. Symptoms and level of functioning were assessed using the Comprehensive Assessment of At-Risk Mental States scale (CAARMS) and the Global Assessment of Functioning (GAF), respectively. During follow up, 58 (16.1%) of the CHR group developed psychosis (CHR-T), and 245 did not (CHR-NT). Logistic regressions, multilevel mixed models, and Cox regression were used to analyse the relationship between reasoning bias and transition to psychosis and level of functioning, at each time point.

Results: There was no association between reasoning bias at baseline and the subsequent onset of psychosis. However, when assessed after the transition to psychosis, CHR-T participants showed a greater tendency to jump to conclusions than CHR-NT and HC participants (55, 17, 17%; χ2 = 8.13, p = 0.012). There was a significant association between jumping to conclusions (JTC) at baseline and a reduced level of functioning at 2-year follow-up in the CHR group after adjusting for transition, gender, ethnicity, age, and IQ.

Conclusions: In CHR participants, JTC at baseline was associated with adverse functioning at the follow-up. Interventions designed to improve JTC could be beneficial in the CHR population.
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http://dx.doi.org/10.1017/S0033291720003396DOI Listing
October 2020

Dual-specificity phosphatases in mental and neurological disorders.

Prog Neurobiol 2021 Mar 6;198:101906. Epub 2020 Sep 6.

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands; European Graduate School of Neuroscience, Maastricht University, Maastricht, the Netherlands. Electronic address:

The dual-specificity phosphatase (DUSP) family includes a heterogeneous group of protein phosphatases that dephosphorylate both phospho-tyrosine and phospho-serine/phospho-threonine residues within a single substrate. These protein phosphatases have many substrates and modulate diverse neural functions, such as neurogenesis, differentiation, and apoptosis. DUSP genes have furthermore been associated with mental disorders such as depression and neurological disorders such as Alzheimer's disease. Herein, we review the current literature on the DUSP family of genes concerning mental and neurological disorders. This review i) outlines the structure and general functions of DUSP genes, and ii) overviews the literature on DUSP genes concerning mental and neurological disorders, including model systems, while furthermore providing perspectives for future research.
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http://dx.doi.org/10.1016/j.pneurobio.2020.101906DOI Listing
March 2021

Development of Proteomic Prediction Models for Transition to Psychotic Disorder in the Clinical High-Risk State and Psychotic Experiences in Adolescence.

JAMA Psychiatry 2021 Jan;78(1):77-90

Institute of Psychiatry, Psychology & Neuroscience, Department of Psychosis Studies, King's College London, London, United Kingdom.

Importance: Biomarkers that are predictive of outcomes in individuals at risk of psychosis would facilitate individualized prognosis and stratification strategies.

Objective: To investigate whether proteomic biomarkers may aid prediction of transition to psychotic disorder in the clinical high-risk (CHR) state and adolescent psychotic experiences (PEs) in the general population.

Design, Setting, And Participants: This diagnostic study comprised 2 case-control studies nested within the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) and the Avon Longitudinal Study of Parents and Children (ALSPAC). EU-GEI is an international multisite prospective study of participants at CHR referred from local mental health services. ALSPAC is a United Kingdom-based general population birth cohort. Included were EU-GEI participants who met CHR criteria at baseline and ALSPAC participants who did not report PEs at age 12 years. Data were analyzed from September 2018 to April 2020.

Main Outcomes And Measures: In EU-GEI, transition status was assessed by the Comprehensive Assessment of At-Risk Mental States or contact with clinical services. In ALSPAC, PEs at age 18 years were assessed using the Psychosis-Like Symptoms Interview. Proteomic data were obtained from mass spectrometry of baseline plasma samples in EU-GEI and plasma samples at age 12 years in ALSPAC. Support vector machine learning algorithms were used to develop predictive models.

Results: The EU-GEI subsample (133 participants at CHR (mean [SD] age, 22.6 [4.5] years; 68 [51.1%] male) comprised 49 (36.8%) who developed psychosis and 84 (63.2%) who did not. A model based on baseline clinical and proteomic data demonstrated excellent performance for prediction of transition outcome (area under the receiver operating characteristic curve [AUC], 0.95; positive predictive value [PPV], 75.0%; and negative predictive value [NPV], 98.6%). Functional analysis of differentially expressed proteins implicated the complement and coagulation cascade. A model based on the 10 most predictive proteins accurately predicted transition status in training (AUC, 0.99; PPV, 76.9%; and NPV, 100%) and test (AUC, 0.92; PPV, 81.8%; and NPV, 96.8%) data. The ALSPAC subsample (121 participants from the general population with plasma samples available at age 12 years (61 [50.4%] male) comprised 55 participants (45.5%) with PEs at age 18 years and 61 (50.4%) without PEs at age 18 years. A model using proteomic data at age 12 years predicted PEs at age 18 years, with an AUC of 0.74 (PPV, 67.8%; and NPV, 75.8%).

Conclusions And Relevance: In individuals at risk of psychosis, proteomic biomarkers may contribute to individualized prognosis and stratification strategies. These findings implicate early dysregulation of the complement and coagulation cascade in the development of psychosis outcomes.
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http://dx.doi.org/10.1001/jamapsychiatry.2020.2459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450406PMC
January 2021

Association of Recent Stressful Life Events With Mental and Physical Health in the Context of Genomic and Exposomic Liability for Schizophrenia.

JAMA Psychiatry 2020 12;77(12):1296-1304

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, the Netherlands.

Importance: Both adulthood stressful life events (SLEs) and liability for schizophrenia have been associated with poor mental and physical health in the general population, but their interaction remains to be elucidated to improve population-based health outcomes.

Objective: To test whether recent SLEs interact with genetic and environmental liability for schizophrenia in models of mental and physical health.

Design, Setting, And Participants: The Netherlands Mental Health Survey and Incidence Study-2 is a population-based prospective cohort study designed to investigate the prevalence, incidence, course, and consequences of mental disorders in the Dutch general population. Participants were enrolled from November 5, 2007, to July 31, 2009, and followed up with 3 assessments during 9 years. Follow-up was completed on June 19, 2018, and data were analyzed from September 1 to November 1, 2019.

Exposures: Recent SLEs assessed at each wave and aggregate scores of genetic and environmental liability for schizophrenia: polygenic risk score for schizophrenia (PRS-SCZ) trained using the Psychiatric Genomics Consortium analysis results and exposome score for schizophrenia (ES-SCZ) trained using an independent data set.

Main Outcomes And Measures: Independent and interacting associations of SLEs with ES-SCZ and PRS-SCZ on mental and physical health assessed at each wave using regression coefficients.

Results: Of the 6646 participants included at baseline, the mean (SD) age was 44.26 (12.54) years, and 3672 (55.25%) were female. The SLEs were associated with poorer physical health (B = -3.22 [95% CI, -3.66 to -2.79]) and mental health (B = -3.68 [95% CI, -4.05 to -3.32]). Genetic and environmental liability for schizophrenia was associated with poorer mental health (ES-SCZ: B = -3.07 [95% CI, -3.35 to -2.79]; PRS-SCZ: B = -0.93 [95% CI, -1.31 to -0.54]). Environmental liability was also associated with poorer physical health (B = -3.19 [95% CI, -3.56 to -2.82]). The interaction model showed that ES-SCZ moderated the association of SLEs with mental (B = -1.08 [95% CI, -1.47 to -0.69]) and physical health (B = -0.64 [95% CI, -1.11 to -0.17]), whereas PRS-SCZ did not. Several sensitivity analyses confirmed these results.

Conclusions And Relevance: In this study, schizophrenia liability was associated with broad mental health outcomes at the population level. Consistent with the diathesis-stress model, exposure to SLEs, particularly in individuals with high environmental liability for schizophrenia, was associated with poorer health. These findings underline the importance of modifiable environmental factors during the life span for population-based mental health outcomes.
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http://dx.doi.org/10.1001/jamapsychiatry.2020.2304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711318PMC
December 2020

Genetic copy number variants, cognition and psychosis: a meta-analysis and a family study.

Mol Psychiatry 2020 Jul 27. Epub 2020 Jul 27.

Division of Psychiatry, University College London, London, UK.

The burden of large and rare copy number genetic variants (CNVs) as well as certain specific CNVs increase the risk of developing schizophrenia. Several cognitive measures are purported schizophrenia endophenotypes and may represent an intermediate point between genetics and the illness. This paper investigates the influence of CNVs on cognition. We conducted a systematic review and meta-analysis of the literature exploring the effect of CNV burden on general intelligence. We included ten primary studies with a total of 18,847 participants and found no evidence of association. In a new psychosis family study, we investigated the effects of CNVs on specific cognitive abilities. We examined the burden of large and rare CNVs (>200 kb, <1% MAF) as well as known schizophrenia-associated CNVs in patients with psychotic disorders, their unaffected relatives and controls (N = 3428) from the Psychosis Endophenotypes International Consortium (PEIC). The carriers of specific schizophrenia-associated CNVs showed poorer performance than non-carriers in immediate (P = 0.0036) and delayed (P = 0.0115) verbal recall. We found suggestive evidence that carriers of schizophrenia-associated CNVs had poorer block design performance (P = 0.0307). We do not find any association between CNV burden and cognition. Our findings show that the known high-risk CNVs are not only associated with schizophrenia and other neurodevelopmental disorders, but are also a contributing factor to impairment in cognitive domains such as memory and perceptual reasoning, and act as intermediate biomarkers of disease risk.
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http://dx.doi.org/10.1038/s41380-020-0820-7DOI Listing
July 2020

Lower emotional complexity as a prospective predictor of psychopathology in adolescents from the general population.

Emotion 2020 Jul 13. Epub 2020 Jul 13.

Department of Psychiatry, Interdisciplinary Center Psychopathology and Emotion Regulation, University Medical Center Groningen, University of Groningen.

Emotional complexity (EC) involves the ability to distinguish between distinct emotions (differentiation) and the experience of a large range of emotions (diversity). Lower EC has been related to psychopathology in cross-sectional studies. This study aimed to investigate (a) whether EC prospectively predicts psychopathology and (b) whether this effect is contingent on stressful life events. To further explore EC, we compared the effects of differentiation and diversity. Adolescents from the general population ( = 401) rated 8 negatively valenced emotions 10 times a day for 6 consecutive days. Further, they completed the Symptom Checklist-90 (baseline and 1-year follow-up) and a questionnaire on past year's life events at follow-up. Logistic regression analyses tested whether EC-reflected by emotion differentiation (intraclass correlation coefficient [ICC]) and diversity (diversity index [DI])-predicted prognosis (good: remitting or lacking symptoms vs. bad: worsening or persisting symptoms). EC predicted prognoses but only when based on the ICC ( = 1.42, = .02). An 1 above average increased the probability of good prognosis from .67 to .74. This effect was not related to stressful life events ( × Life events = 1.03, = .86) and disappeared when emotion intensity (mean level) was taken into account ( = 1.20, = .20). Predicting future prognosis does not necessitate complex measures of emotional experience (ICC, DI) but rather might be achieved through simpler indices (mean). The discrepant effects of the ICC and DI on prognosis suggest that impaired emotion representation (ICC) plays a more important role in vulnerability to mental ill health than does low diversity of emotions (DI). (PsycInfo Database Record (c) 2020 APA, all rights reserved).
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http://dx.doi.org/10.1037/emo0000778DOI Listing
July 2020

Analysis of GWAS-Derived Schizophrenia Genes for Links to Ischemia-Hypoxia Response of the Brain.

Front Psychiatry 2020 12;11:393. Epub 2020 May 12.

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Centre, Maastricht, Netherlands.

Obstetric complications (OCs) can induce major adverse conditions for early brain development and predispose to mental disorders, including schizophrenia (SCZ). We previously hypothesized that SCZ candidate genes respond to ischemia-hypoxia as part of OCs which impacts neurodevelopment. We here tested for an overlap between SCZ genes from genome-wide association study (GWAS) (n=458 genes from 145 loci of the most recent GWAS dataset in SCZ) and gene sets for ischemia-hypoxia response. Subsets of SCZ genes were related to (a) mutation-intolerant genes (LoF database), (b) role in monogenic disorders of the nervous system (OMIM, manual annotations), and (c) synaptic function (SynGO). Ischemia-hypoxia response genes of the brain (IHR genes, n=1,629), a gene set from RNAseq in focal brain ischemia (BH, n=2,449) and genes from HypoxiaDB (HDB, n=2,289) were overlapped with the subset of SCZ genes and tested for enrichment with Chi-square tests (p < 0.017). The SCZ GWAS dataset was enriched for LoF (n=112; p=0.0001), and the LoF subset was enriched for IHR genes (n=25; p=0.0002), BH genes (n=35; p=0.0001), and HDB genes (n=23; p=0.0005). N=96 genes of the SCZ GWAS dataset (21%) could be linked to a monogenic disorder of the nervous system whereby IHR genes (n=19, p=0.008) and BH genes (n=23; p=0.002) were found enriched. N=46 synaptic genes were found in the SCZ GWAS gene set (p=0.0095) whereby enrichments for IHR genes (n=20; p=0.0001) and BH genes (n=13; p=0.0064) were found. In parallel, detailed annotations of SCZ genes for a role of the hypoxia-inducible factors (HIFs) identified n=33 genes of high interest. Genes from SCZ GWAS were enriched for mutation-intolerant genes which in turn were strongly enriched for three sets of genes for the ischemia-hypoxia response that may be invoked by OCs. A subset of one fifth of SCZ genes has established roles in monogenic disorders of the nervous system which was enriched for two gene sets related to ischemia-hypoxia. SCZ genes related to synaptic functions were also related to ischemia-hypoxia. Variants of SCZ genes interacting with ischemia-hypoxia provide a specific starting point for functional and genomic studies related to OCs.
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http://dx.doi.org/10.3389/fpsyt.2020.00393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235330PMC
May 2020

Association of preceding psychosis risk states and non-psychotic mental disorders with incidence of clinical psychosis in the general population: a prospective study in the NEMESIS-2 cohort.

World Psychiatry 2020 Jun;19(2):199-205

Department of Psychiatry and Neuropsychology, School of Mental Health and Neuroscience, Maastricht University Medical Centre, Maastricht, The Netherlands.

The validity and clinical utility of the concept of "clinical high risk" (CHR) for psychosis have so far been investigated only in risk-enriched samples in clinical settings. In this population-based prospective study, we aimed - for the first time - to assess the incidence rate of clinical psychosis and es-timate the population attributable fraction (PAF) of that incidence for preceding psychosis risk states and DSM-IV diagnoses of non-psychotic mental disorders (mood disorders, anxiety disorders, alcohol use disorders, and drug use disorders). All analyses were adjusted for age, gender and education. The incidence rate of clinical psychosis was 63.0 per 100,000 person-years. The mutually-adjusted Cox proportional hazards model indicated that preceding diagnoses of mood disorders (hazard ratio, HR=10.67, 95% CI: 3.12-36.49), psychosis high-risk state (HR=7.86, 95% CI: 2.76-22.42) and drug use disorders (HR=5.33, 95% CI: 1.61-17.64) were associated with an increased risk for clinical psychosis incidence. Of the clinical psychosis incidence in the population, 85.5% (95% CI: 64.6-94.1) was attributable to prior psychopathology, with mood disorders (PAF=66.2, 95% CI: 33.4-82.9), psychosis high-risk state (PAF=36.9, 95% CI: 11.3-55.1), and drug use disorders (PAF=18.7, 95% CI: -0.9 to 34.6) as the most important factors. Although the psychosis high-risk state displayed a high relative risk for clinical psychosis outcome even after adjusting for other psychopathology, the PAF was comparatively low, given the low prevalence of psychosis high-risk states in the population. These findings provide empirical evidence for the "prevention paradox" of targeted CHR early intervention. A comprehensive prevention strategy with a focus on broader psychopathology may be more effective than the current psychosis-focused approach for achieving population-based improvements in prevention of psychotic disorders.
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http://dx.doi.org/10.1002/wps.20755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215054PMC
June 2020

Integrated DNA methylation analysis reveals a potential role for ANKRD30B in Williams syndrome.

Neuropsychopharmacology 2020 09 18;45(10):1627-1636. Epub 2020 Apr 18.

Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Williams syndrome (WS) is a rare genetic disorder, caused by a microdeletion at the 7q11.23 region. WS exhibits a wide spectrum of features including hypersociability, which contrasts with social deficits typically associated with autism spectrum disorders. The phenotypic variability in WS likely involves epigenetic modifications; however, the nature of these events remains unclear. To better understand the role of epigenetics in WS phenotypes, we integrated DNA methylation and gene expression profiles in blood from patients with WS and controls. From these studies, 380 differentially methylated positions (DMPs), located throughout the genome, were identified. Systems-level analysis revealed multiple co-methylation modules linked to intermediate phenotypes of WS, with the top-scoring module related to neurogenesis and development of the central nervous system. Notably, ANKRD30B, a promising hub gene, was significantly hypermethylated in blood and downregulated in brain tissue from individuals with WS. Most CpG sites of ANKRD30B in blood were significantly correlated with brain regions. Furthermore, analyses of gene regulatory networks (GRNs) yielded master regulator transcription factors associated with WS. Taken together, this systems-level approach highlights the role of epigenetics in WS, and provides a possible explanation for the complex phenotypes observed in patients with WS.
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http://dx.doi.org/10.1038/s41386-020-0675-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419304PMC
September 2020

Daily use of high-potency cannabis is associated with more positive symptoms in first-episode psychosis patients: the EU-GEI case-control study.

Psychol Med 2020 Mar 18:1-9. Epub 2020 Mar 18.

Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 8AF, UK.

Background: Daily use of high-potency cannabis has been reported to carry a high risk for developing a psychotic disorder. However, the evidence is mixed on whether any pattern of cannabis use is associated with a particular symptomatology in first-episode psychosis (FEP) patients.

Method: We analysed data from 901 FEP patients and 1235 controls recruited across six countries, as part of the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) study. We used item response modelling to estimate two bifactor models, which included general and specific dimensions of psychotic symptoms in patients and psychotic experiences in controls. The associations between these dimensions and cannabis use were evaluated using linear mixed-effects models analyses.

Results: In patients, there was a linear relationship between the positive symptom dimension and the extent of lifetime exposure to cannabis, with daily users of high-potency cannabis having the highest score (B = 0.35; 95% CI 0.14-0.56). Moreover, negative symptoms were more common among patients who never used cannabis compared with those with any pattern of use (B = -0.22; 95% CI -0.37 to -0.07). In controls, psychotic experiences were associated with current use of cannabis but not with the extent of lifetime use. Neither patients nor controls presented differences in depressive dimension related to cannabis use.

Conclusions: Our findings provide the first large-scale evidence that FEP patients with a history of daily use of high-potency cannabis present with more positive and less negative symptoms, compared with those who never used cannabis or used low-potency types.
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http://dx.doi.org/10.1017/S0033291720000082DOI Listing
March 2020