Search

AbtractStudies conducted in psychotic disorders have shown that DNA-methylation (DNAm) is sensitive to the impact of Childhood Adversity (CA). However, whether it mediates the association between CA and psychosis is yet to be explored. Epigenome wide association studies (EWAS) using the Illumina Infinium-Methylation EPIC array in peripheral blood tissue from 366 First-episode of psychosis and 517 healthy controls was performed. Adversity scores were created for abuse, neglect and composite adversity with the Childhood Trauma Questionnaire (CTQ). Regressions examining (I) CTQ scores with psychosis; (II) with DNAm EWAS level and (III) between DNAm and caseness, adjusted for a variety of confounders were conducted. Divide-Aggregate Composite-null Test for the composite null-hypothesis of no mediation effect was conducted. Enrichment analyses were conducted with missMethyl package and the KEGG database. Our results show that CA was associated with psychosis (Composite: OR = 1.68; p = p < 0.001; neglect: OR = 2.27; p =

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, This work was supported by the Medical Research Council (G0901310) and the Wellcome Trust (grants 085475/B/08/Z, 085475/Z/08/Z). This study was supported by the NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust and University College London and by the NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust at King’s College London. Further support to EB: Mental Health Research UK’s John Grace QC award, BMA Margaret Temple grants 2016 and 2006, MRC—Korean Health Industry Development Institute Partnering Award (MC_PC_16014), MRC New Investigator Award and a MRC Centenary Award (G0901310), National Institute of Health Research UK post-doctoral fellowship, the Psychiatry Research Trust, the Schizophrenia Research Fund, the Brain and Behaviour Research foundation’s NARSAD Young Investigator Awards 2005, 2008, Wellcome Trust Research Training Fellowship, the NIHR Biomedical Research Centre at UCLH, and the NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and Institute of Psychiatry King’s College London. Further support to co-authors: The Brain and Behaviour Research foundation’s (NARSAD’s) Young Investigator Award (Grant 22604, awarded to CI). The BMA Margaret Temple grant 2016 to JT. A 2014 European Research Council Marie Curie award to A Díez-Revuelta. HI has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 747429. A Medical Research Council doctoral studentship to JH-S, IA-Z and AB. A Mental Health Research UK studentship to RM. VB is supported by a Wellcome Trust Seed Award in Science (200589/Z/16/Z). FWO Senior Clinical Fellowship to RvW. The infrastructure for the GROUP consortium is funded through the Geestkracht programme of the Dutch Health Research Council (ZON-MW, grant number 10-000-1001), and matching funds from participating pharmaceutical companies (Lundbeck, AstraZeneca, Eli Lilly, Janssen Cilag) and universities and mental health care organisations (Amsterdam: Academic Psychiatric Centre of the Academic Medical Centre and the mental health institutions: GGZ Ingeest, Arkin, Dijk en Duin, GGZ Rivierduinen, Erasmus Medical Centre, GGZ Noord Holland Noord. Groningen: University Medical Centre Groningen and the mental health institutions: Lentis, GGZ Friesland, GGZ Drenthe, Dimence, Mediant, GGNet Warnsveld, Yulius Dordrecht and Parnassia psycho-medical centre The Hague. Maastricht: Maastricht University Medical Centre and the mental health institutions: GGZ Eindhoven en De Kempen, GGZ Breburg, GGZ Oost-Brabant, Vincent van Gogh voor Geestelijke Gezondheid, Mondriaan, Virenze riagg, Zuyderland GGZ, MET ggz, Universitair Centrum Sint-Jozef Kortenberg, CAPRI University of Antwerp, PC Ziekeren Sint-Truiden, PZ Sancta Maria Sint-Truiden, GGZ Overpelt, OPZ Rekem. Utrecht: University Medical Centre Utrecht and the mental health institutions Altrecht, GGZ Centraal and Delta). The Santander cohort was supported by Instituto de Salud Carlos III (PI020499, PI050427, PI060507), SENY Fundació (CI 2005-0308007), Fundacion Ramón Areces and Fundacion Marqués de Valdecilla (API07/011, API10/13). We thank Valdecilla Biobank for providing the biological PAFIP samples and associated data included in this study and for its help in the technical execution of this work; we also thank IDIVAL Neuroimaging Unit for its help in the acquisition and processing of imaging PAFIP data.

This study was funded by the Medical Research Council, the European Community’s Seventh Framework Program grant [agreement HEALTH-F2-2009-241909 (Project EU-GEI)], São Paulo Research Foundation (grant 2012/0417-0), the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust and King’s College London, the NIHR BRC at University College London and the Wellcome Trust (grant 101272/Z/12/Z)., Tripoli, G., Quattrone, D., Ferraro, L., Gayer-Anderson, C., Rodriguez, V., La Cascia, C., La Barbera, D., Sartorio, C., Seminerio, F., Tarricone, I., Berardi, D., Szöke, A., Arango, C., Tortelli, A., Llorca, P.-M., De Haan, L., Velthorst, E., Bobes, J., Bernardo, M., Sanjuán, J., Santos, J.L., Arrojo, M., Del-Ben, C.M., Menezes, P.R., Selten, J.-P., Jones, P.B., Jongsma, H.E., Kirkbride, J.B., Lasalvia, A., Tosato, S., Richards, A., O'donovan, M., Rutten, B.P.F., Os, J.V., Morgan, C., Sham, P.C., Murray, R.M., Murray, G.K., Di Forti, M.

ENIGMA-CNV Working Group: van der Meer, Dennis; Sonderby, Ida E; Kaufmann, Tobias; Walters, G Bragi; Abdellaoui, Abdel; Ames, David; Amunts, Katrin; Andersson, Micael; Armstrong, Nicola J; Bernard, Manon; Blackburn, Nicholas B; Blangero, John; Boomsma, Dorret I; Brodaty, Henry; Brouwer, Rachel M; Bulow, Robin; Cahn, Wiepke; Calhoun, Vince D; Caspers, Svenja; Cavalleri, Gianpiero L; Ching, Christopher R K; Cichon, Sven; Ciufolini, Simone; Corvin, Aiden; Crespo-Facorro, Benedicto; Curran, Joanne E; Dalvie, Shareefa; Dazzan, Paola; de Geus, Eco J C; de Zubicaray, Greig I; de Zwarte, Sonja M C; Delanty, Norman; den Braber, Anouk; Desrivieres, Sylvane; Di Forti, Marta; Doherty, Joanne L; Donohoe, Gary; Ehrlich, Stefan; Eising, Else; Espeseth, Thomas; Fisher, Simon E; Fladby, Tormod; Frei, Oleksandr; Frouin, Vincent; Fukunaga, Masaki; Gareau, Thomas; Glahn, David C; Grabe, Hans J; Groenewold, Nynke A; Gustafsson, Omar; Haavik, Jan; Haberg, Asta K; Hashimoto, Ryota; Hehir-Kwa, Jayne Y; Hibar, Derrek P; Hillegers, Manon H J; Hoffmann, Per; Holleran, Laurena; Hottenga, Jouke-Jan; Hulshoff Pol, Hilleke E; Ikeda, Masashi; Jacquemont, Sebastien; Jahanshad, Neda; Jockwitz, Christiane; Johansson, Stefan; Jonsson, Erik G; Kikuchi, Masataka; Knowles, Emma E M; Kwok, John B; Le Hellard, Stephanie; Linden, David E J; Liu, Jingyu; Lundervold, Arvid; Lundervold, Astri J; Martin, Nicholas G; Mather, Karen A; Mathias, Samuel R; McMahon, Katie L; McRae, Allan F; Medland, Sarah E; Moberget, Torgeir; Moreau, Clara; Morris, Derek W; Muhleisen, Thomas W; Murray, Robin M; Nordvik, Jan E; Nyberg, Lars; Olde Loohuis, Loes M; Ophoff, Roel A; Owen, Michael J; Paus, Tomas; Pausova, Zdenka; Peralta, Juan M; Pike, Bruce; Prieto, Carlos; Quinlan, Erin Burke; Reinbold, Celine S; Reis Marques, Tiago; Rucker, James J H; Sachdev, Perminder S; Sando, Sigrid B; Schofield, Peter R; Schork, Andrew J; Schumann, Gunter; Shin, Jean; Shumskaya, Elena; Silva, Ana I; Sisodiya, Sanjay M; Steen, Vidar M; Stein, Dan J; Strike, Lachlan T; Tamnes, Christian K; Teumer, Alexander; Thalamuthu, Anbupalam; Tordesillas-Gutierrez, Diana; Uhlmann, Anne; Ulfarsson, Magnus O; van 't Ent, Dennis; van den Bree, Marianne B M; Vassos, Evangelos; Wen, Wei; Wittfeld, Katharina; Wright, Margaret J; Zayats, Tetyana; Dale, Anders M; Djurovic, Srdjan; Agartz, Ingrid; Westlye, Lars T; Stefansson, Hreinn; Stefansson, Kari; Thompson, Paul M; Andreassen, Ole A., [Importance] Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities., [Objective] To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance., [Design, Setting, and Participants] In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019., [Main Outcomes and Measures] The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age2, sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort., [Results] Of 45 756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23 754 (51.9%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = −0.41; SE, 0.08; P = 4.9 × 10−8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10−7), and a smaller nucleus accumbens (Cohen d = −0.27; SE, 0.07; P = 7.3 × 10−5). There was also a significant negative dose response on cortical thickness (β = −0.24; SE, 0.05; P = 6.8 × 10−7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cognitive ability was lower for deletion carriers compared with noncarriers on 5 of 7 tasks., [Conclusions and Relevance] These findings, from the largest CNV neuroimaging study to date, provide evidence that 15q11.2 BP1-BP2 structural variation is associated with brain morphology and cognition, with deletion carriers being particularly affected. The pattern of results fits with known molecular functions of genes in the 15q11.2 BP1-BP2 region and suggests involvement of these genes in neuronal plasticity. These neurobiological effects likely contribute to the association of this CNV with neurodevelopmental disorders., This study is supported in part by grants U54 EB20403, R01MH116147, and R56AG058854 from the National Institutes of Health, grant 609020 from the European Union Seventh Framework Programme, and grants 223273 and 276082 from the Research Council Norway. Part of this work was performed using the Service for Sensitive Data (TSD), which is developed and operated by the TSD Service Groupand owned by the University of Oslo.

A significant proportion of the global burden of disease can be attributed to mental illness. Despite important advances in identifying risk factors for mental health conditions, the biological processing underlying causal pathways to disease onset remain poorly understood. This represents a limitation to implement effective prevention and the development of novel pharmacological treatments. Epigenetic mechanisms have emerged as mediators of environmental and genetic risk factors which might play a role in disease onset, including childhood adversity (CA) and cannabis use (CU). Particularly, human research exploring DNA methylation has provided new and promising insights into the role of biological pathways implicated in the aetio-pathogenesis of psychiatric conditions, including: monoaminergic (Serotonin and Dopamine), GABAergic, glutamatergic, neurogenesis, inflammatory and immune response and oxidative stress. While these epigenetic changes have been often studied as disease-specific, similarly to the investigation of environmental risk factors, they are often transdiagnostic. Therefore, we aim to review the existing literature on DNA methylation from human studies of psychiatric diseases (i) to identify epigenetic modifications mapping onto biological pathways either transdiagnostically or specifically related to psychiatric diseases such as Eating Disorders, Post-traumatic Stress Disorder, Bipolar and Psychotic Disorder, Depression, Autism Spectrum Disorder and Anxiety Disorder, and (ii) to investigate a convergence between some of these epigenetic modifications and the exposure to known risk factors for psychiatric disorders such as CA and CU, as well as to other epigenetic confounders in psychiatry research., We thank our funding bodies. Dr Luis Alameda was supported at the beginning of the preparation of the current work by the Swiss national Foundation (P2LAP3 171804). Dr Chloe Wong is supported by a joint grant from the Economic and Social Research Council (ESRC) and Biotechnology and Biological Sciences Research Council [ES/N000277/1]. Dr Marta Di Forti work is supported by the Medical Research Council SRF MR/T007818/1.

This work was supported by funding from the European Community’s Seventh Framework Programme under grant agreement No. HEALTH-F2-2010-241909 (Project EU-GEI). (...) CA was supported by the Spanish Ministry of Science and Innovation; Instituto de Salud Carlos III (SAM16PE07CP1, PI16/02012, PI19/024), co-financed by ERDF Funds from the European Commission, ‘A way of making Europe’, CIBERSAM. Madrid Regional Government (B2017/BMD-3740 AGES-CM-2), Fundación Familia Alonso and Fundación Alicia Koplowitz. MB was supported by the Ministry of Economy and Competitivity (PI08/0208; PI11/00325; PI14/00612), Instituto de Salud Carlos III – ERDF Funds from the European Commission, ‘A way of making Europe’, CIBERSAM, by the CERCA Programme/Generalitat de Catalunya and Secretaria d’Universitats i Recerca del Departament d’Economia I Coneixement (2017SGR1355). Departament de Salut de la Generalitat de Catalunya, en la convocatoria corresponent a l’any 2017 de concessió de subvencions del PERIS 2016-2020, modalitat Projectes de recerca orientats a l’atenció primària, amb el codi d’expedient SLT006/17/00345; and grateful for the support of the Institut de Neurociències, Universitat de Barcelona., Rodriguez V., Alameda L., Quattrone D., Tripoli G., Gayer-Anderson C., Spinazzola E., Trotta G., Jongsma H.E., Stilo S., La Cascia C., Ferraro L., La Barbera D., Lasalvia A., Tosato S., Tarricone I., Bonora E., Jamain S., Selten J.-P., Velthorst E., De Haan L., Llorca P.-M., Arrojo M., Bobes J., Bernardo M., Arango C., Kirkbride J., Jones P.B., Rutten B.P., Richards A., Sham P.C., O'Donovan M., Van Os J., Morgan C., Di Forti M., Murray R.M., Vassos E.

The influence of psychosocial stressors on psychosis risk has usually been studied in isolation and after the onset of the disorder, potentially ignoring important confounding relationships or the fact that some stressors that may be the consequence of the disorder rather than preexisting. The study of subclinical psychosis could help to address some of these issues. In this study, we investigated whether there was (i) an association between dimensions of subclinical psychosis and several psychosocial stressors including: childhood trauma, self-reported discrimination experiences, low social capital, and stressful life experiences, and (ii) any evidence of environment-environment (ExE) interactions between these factors. Data were drawn from the EUGEI study, in which healthy controls (N = 1497) and siblings of subjects with a psychotic disorder (N = 265) were included in six countries. The association between psychosocial stressors and subclinical psychosis dimensions (positive, negative and depressive dimension as measured by the Community Assessment of Psychic Experiences (CAPE) scale) and possible ExE interactions were assessed using linear regression models. After adjusting for sex, age, ethnicity, country, and control/sibling status, childhood trauma (beta for positive dimension: 0.13, negative: 0.49, depressive: 0.26) and stressful life events (positive: 0.08, negative: 0.16, depressive: 0.17) were associated with the three dimensions. Lower social capital was associated with the negative and depression dimensions (negative: 0.26, depressive: 0.13), and self-reported discrimination experiences with the positive dimension (0.06). Our findings are in favor of independent, cumulative and non-specific influences of social adversities in subclinical psychosis in non-clinical populations, without arguments for E * E interactions. © The Author(s) 2021. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Premorbid functioning and cognitive measures may reflect gradients of developmental impairment across diagnostic categories in psychosis. In this study, we sought to examine the associations of current cognition and premorbid adjustment with symptom dimensions in a large first episode psychosis (FEP) sample. We used data from the international EU-GEI study. Bifactor modelling of the Operational Criteria in Studies of Psychotic Illness (OPCRIT) ratings provided general and specific symptom dimension scores. Premorbid Adjustment Scale estimated premorbid social (PSF) and academic adjustment (PAF), and WAIS-brief version measured IQ. A MANCOVA model examined the relationship between symptom dimensions and PSF, PAF, and IQ, having age, sex, country, self-ascribed ethnicity and frequency of cannabis use as confounders. In 785 patients, better PSF was associated with fewer negative (B=-0.12, 95% C.I. -0.18, -0.06, p

The President of the International Association for the Study of Pain (IASP) established a Taskforce on Cannabis and Cannabinoid Analgesia, to systematically examine the evidence on (i) analgesic pharmacology of cannabinoids and preclinical evidence on their efficacy in animal models of injury-related or pathological persistent pain, (ii) the clinical efficacy of cannabis, cannabinoids and cannabis-based medicines (CBM) for pain, (iii) harms related to long-term use of cannabinoids, as well as (iv) societal issues and policy implications related to the use of these compounds for pain management. Here, we summarize key knowledge gaps identified in the Taskforce outputs and propose a research agenda for generating high-quality evidence on the topic. The systematic assessment of preclinical and clinical literature identified gaps in rigor of study design and reporting across the translational spectrum. We provide recommendations to improve the quality, rigor, transparency, and reproducibility of preclinical and clinical research on cannabis and cannabinoids for pain, as well as for the conduct of systematic reviews on the topic. Gaps related to comprehensive understanding of the endocannabinoid system and cannabinoid pharmacology, including pharmacokinetics and drug formulation aspects, are discussed. We outline key areas where high quality clinical trials with cannabinoids are needed. Important remaining questions about long-term and short-term safety of cannabis and cannabinoids are emphasized. Finally, regulatory, societal and policy challenges associated with medicinal and non-medicinal use of cannabis are highlighted, with recommendations for improving patient safety and reducing societal harms in the context of pain management.

BackgroundNeuroanatomical abnormalities in first-episode psychosis (FEP) tend to be subtle and widespread. The vast majority of previous studies have used small samples, and therefore may have been underpowered. In addition, most studies have examined participants at a single research site, and therefore the results may be specific to the local sample investigated. Consequently, the findings reported in the existing literature are highly heterogeneous. This study aimed to overcome these issues by testing for neuroanatomical abnormalities in individuals with FEP that are expressed consistently across several independent samples.MethodsStructural Magnetic Resonance Imaging data were acquired from a total of 572 FEP and 502 age and gender comparable healthy controls at five sites. Voxel-based morphometry was used to investigate differences in grey matter volume (GMV) between the two groups. Statistical inferences were made at p < 0.05 after family-wise error correction for multiple comparisons.ResultsFEP showed a widespread pattern of decreased GMV in fronto-temporal, insular and occipital regions bilaterally; these decreases were not dependent on anti-psychotic medication. The region with the most pronounced decrease – gyrus rectus – was negatively correlated with the severity of positive and negative symptoms.ConclusionsThis study identified a consistent pattern of fronto-temporal, insular and occipital abnormalities in five independent FEP samples; furthermore, the extent of these alterations is dependent on the severity of symptoms and duration of illness. This provides evidence for reliable neuroanatomical alternations in FEP, expressed above and beyond site-related differences in anti-psychotic medication, scanning parameters and recruitment criteria.

We performed a systematic analysis of blood DNA methylation profiles from 4483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia, and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. We implemented a stringent pipeline to meta-analyze epigenome-wide association study (EWAS) results across datasets, identifying 95 DMPs associated with psychosis and 1048 DMPs associated with schizophrenia, with evidence of colocalization to regions nominated by genetic association studies of disease. Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia.

BackgroundFirst episode psychosis (FEP) patients who use cannabis experience more frequent psychotic and euphoric intoxication experiences compared to controls. It is not clear whether this is consequent to patients being more vulnerable to the effects of cannabis use or to their heavier pattern of use. We aimed to determine whether extent of use predicted psychotic-like and euphoric intoxication experiences in patients and controls and whether this differs between groups.MethodsWe analysed data on patients who had ever used cannabis (n = 655) and controls who had ever used cannabis (n = 654) across 15 sites from six countries in the EU-GEI study (2010–2015). We used multiple regression to model predictors of cannabis-induced experiences and to determine if there was an interaction between caseness and extent of use.ResultsCaseness, frequency of cannabis use and money spent on cannabis predicted psychotic-like and euphoric experiences (p ⩽ 0.001). For psychotic-like experiences (PEs) there was a significant interaction for caseness × frequency of use (p < 0.001) and caseness × money spent on cannabis (p = 0.001) such that FEP patients had increased experiences at increased levels of use compared to controls. There was no significant interaction for euphoric experiences (p > 0.5).ConclusionsFEP patients are particularly sensitive to increased psychotic-like, but not euphoric experiences, at higher levels of cannabis use compared to controls. This suggests a specific psychotomimetic response in FEP patients related to heavy cannabis use. Clinicians should enquire regarding cannabis related PEs and advise that lower levels of cannabis use are associated with less frequent PEs.

The European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) Project was funded by grant agreement Health-F2-2010-241909 (Project EU-GEI) from the European Community’s Seventh Framework programme. The Brazilian study was funded by grant 2012-0417-0 from the São Paulo Research Foundation. Dr Jongsma is funded by the Economic and Social Research Council (grant ES/S011714/1). Dr Kirkbride is funded by the Wellcome Trust and Royal Society (Grant 101272/Z/13/Z). Dr Jongsma and Professor Jones are funded by the National Institute of Health Research Collaboration of Leadership in Applied Health Research and Care East of England. Professor Rutten is funded by the Netherlands Scientific Organisation (VIDI award number 91718336). Dr Jongsma and Dr Kirkbride are supported by the National Institute for Health Research, University College London Hospital, Biomedical Research Centre., Jongsma, H.E., Gayer-Anderson, C., Tarricone, I., Velthorst, E., Van Der Ven, E., Quattrone, D., Di Forti, M., Menezes, P.R., Del-Ben, C.M., Arango, C., Lasalvia, A., Berardi, D., La Cascia, C., Bobes, J., Bernardo, M., Sanjuán, J., Santos, J.L., Arrojo, M., De Haan, L., Tortelli, A., Szöke, A., Murray, R.M., Rutten, B.P., Van Os, J., Morgan, C., Jones, P.B., Kirkbride, J.B.

Background: Migrants present high rates of psychosis. A better understanding of this phenomenon is needed. Methods: We conducted a multicentre First-Episode Psychosis (FEP) prospective study over two years (January 2012–December 2013) to evaluate first-generation migrants presenting with FEP at the participating Community Mental Health Centers (CMHCs). Results: 109 FEP migrants were identified. Almost half of them were highly educated, employed and in a stable affective relationship. The average age was 32.8 (± 9.8) years, and the average length of stay in Italy was 8.6 (± 8.8) years. About 2/3 of patients were referred to CMHCs following Emergency Department access or psychiatric admission. Conclusions: Our finding of a “high functioning portrait” of FEP migrants allow us to hypothesize that a high burden of negative psychosocial factors is likely to be needed for the FEP onset. Furtherly, mental health services should implement more appropriate resources and organizational methods to respond to migrants’ health needs.

The European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) Project is funded by grant agreement HEALTH-F2-2010-241909 (Project EU-GEI) from the European Community’s Seventh Framework Programme., Aas, M; Alameda, L; Di Forti, M; Quattrone, D; Dazzan, P; Trotta, A; Ferraro, L; Rodriguez, V; Vassos, E; Sham, P; Tripoli, G; La Cascia, C; La Barbera, D; Tarricone, I; Muratori, R; Berardi, D; Lasalvia, A; Tosato, S; Szoke, A; Llorca, PM; Arango, C; Tortelli, A; de Haan, L; Velthorst, E; Bobes, J; Bernardo, M; Sanjuan, J; Santos, JL; Arrojo, M; Del-Ben, CM; Menezes, PR; Selten, JP; Jones, PB; Jongsma, HE; Kirkbride, JB; Rutten, BPF; van Os, J; Gayer-Anderson, C; Murray, RM; Morgan, C

The EU-GEI Project is funded by the European Community’s Seventh Framework Programme under grant agreement No. HEALTH-F2-2010–241909 (Project EU-GEI)., Ajnakina, O., Rodriguez, V., Quattrone, D., Di Forti, M., Vassos, E., Arango, C., Berardi, D., Bernardo, M., Bobes, J., De Haan, L., Del-Ben, C.M., Gayer-Anderson, C., Jongsma, H.E., Lasalvia, A., Tosato, S., Llorca, P.-M., Menezes, P.R., Rutten, B.P., Santos, J.L., Sanjuán, J., Selten, J.-P., Szöke, A., Tarricone, I., D'andrea, G., Richards, A., Tortelli, A., Velthorst, E., Jones, P.B., Arrojo Romero, M., La Cascia, C., Kirkbride, J.B., Van Os, J., O'donovan, M., Murray, R.M.

Background\ud \ud Recent evidence has highlighted the potential role of complement component 4 (C4) in the development of schizophrenia. However, it remains unclear whether C4 is also relevant for clinical outcome and if it could be considered a possible therapeutic target. The aim of this naturalistic longitudinal study was to investigate whether baseline levels of C4 predict worse clinical outcome at 1-year follow-up in patients with first episode psychosis.\ud Methods\ud \ud Twenty-five patients with first episode psychosis were assessed at baseline and followed-up prospectively for their clinical outcome at 1 year from baseline assessment. Concentrations of complement component 4 (C4) were measured using ELISA methods from baseline serum samples. Twelve patients were classified as non-responders and 13 as responders. ANCOVA analyses were conducted to investigate differences in baseline C4 levels between responders and non-responders at 1-year covarying for baseline severity of symptoms and for levels of C reactive protein.\ud Results\ud \ud Non-responders show significantly higher baseline C4 levels compared with responders when controlling for baseline psychopathology and baseline levels of C reactive protein (552.5 ± 31.3 vs 437.6 ± 25.5 mcg/ml; p = 0.008). When investigating the ability of C4 levels to distinguish responders from non-responders, we found that the area under the ROC curve was 0.795 and the threshold point for C4 to distinguish between responders and non-responders appear to be around 490 mcg/ml.\ud Conclusions\ud \ud Our preliminary findings show that baseline C4 levels predict clinical outcome at 1-year follow-up in patients with first episode psychosis.

The typical reliance on self-report questionnaires in retrospective case-control studies of childhood abuse and psychotic disorders has been criticised, due to the potential for recall bias associated with, amongst other factors, cognitive impairments and detachment from reality, among individuals with psychosis. One way to establish if any substantial bias may exist is to examine whether the concordance of reports of childhood abuse established from retrospective self-report methods versus more comprehensive interviewer-rated assessments differ between individuals with psychosis and controls. Data from the Childhood Adversity and Psychosis (CAPsy) study were used to examine the accuracy, strength of agreement, and convergent validity of two distinct retrospective measures of childhood abuse: a self-report questionnaire (the Childhood Trauma Questionnaire; CTQ) and a comprehensive interview (the Childhood Experiences of Care and Abuse schedule; CECA). In a sample of 234 cases with first-episode psychosis and 293 controls, we found no strong evidence that the validity of the two measures differed between cases and controls. For reports of sexual and emotional abuse, we found fair levels of agreement between CECA and CTQ ratings in both groups (kappa coefficients 0.43–0.53), moderate to high sensitivity and specificity, and reasonably high convergent validity (tetrachoric correlations of 0.78–0.80). For physical abuse, convergent validity was slightly lower in cases compared with controls. Both measures can be used in future studies to retrospectively assess associations between childhood abuse and psychotic phenomena, but time-permitting, the CECA is preferable as it provides additional important contextual details of abuse exposure.

Background Jumping to conclusions (JTC) is a well-established reasoning and data gathering bias found in patients with psychosis even at illness onset (First Episode Psychosis, FEP). Preliminary work in this field focused primarily on the association with delusions, although jumping to conclusions has also been found in non-deluded schizophrenia patients after remission, and in individual with at risk mental state. Moreover, psychotic patients tend to show impairments in social cognition, struggling in identifying, processing and interpreting social clues. Deficits in facial emotion recognition (FER) – a key component of the construct – represent a well-replicated finding in schizophrenia. Furthermore, deficits in global facial affect recognition have been found in FEP with the same severity as at further stages, especially for anger recognition. The present study aims to measure JTC and FER bias in a sample of FEP recruited across 5 European countries, compared with healthy controls. Methods Data on JTC (Beads task 60:40), FER (Degraded Facial Recognition task – DFAR) and socio-demographics have been analysed in a sample of 643 FEP and 1019 population controls recruited as part as the EU-GEI study across UK, Netherlands, France, Spain, and Italy. IQ scores were used to exclude cases and controls with current IQ

Background Current diagnostic models of psychosis have been questioned since Kraepelin’s original dichotomy of dementia praecox and manic depression. Indeed, increasing evidence has suggested that a dimensional approach might be a valid alternative platform for research. However, while an increasing number of studies have investigated how environmental risk factors for affective and non-affective psychosis map onto symptom dimensions, only a few have examined these dimensions in relation to genetic variants as summarised by Polygenic Risk Score (PRS). Furthermore, no studies have examined the putative effect of PRS for Schizophrenia (SZ), Bipolar Disorder (BP), and Major Depressive Disorder (MDD) on previously identified general and specific symptom dimensions. At the same time, only one study has investigated how symptoms vary according to epidemiological factors such as living in urban neighbourhoods. The objectives of this study were to: 1) test whether a bi-factor model statistically fits the conceptualization of psychosis as composed of general and specific dimensions; 2) examine the extent to which SZ, BP, and MDD PRSs explain the phenotypic variance due to general and specific dimensions; 3) test the hypothesis that the general psychosis dimension would be more severe in highly urban environments. Methods We used clinical and epidemiological data from the EUropean network of national schizophrenia networks studying Gene-Environment Interactions (EUGEI) study, including 2322 First Episode Psychosis (FEP) patients recruited in 17 sites across 6 countries. Genetic variants were collectively analyzed for 800 individuals. The following analysis steps were performed: 1) Psychopathology items were analysed using multidimensional item response modelling in MPlus to estimate unidimensional, multidimensional, and bi-factor models of psychosis. Model fit statistics included Log-Likelihood, and Akaike and Bayesian Information Criteria to compare these models. 2) SZ, BP, and MDD PRSs for general and specific dimensions were built using PRSice. Summary statistics from large case-control mega-analyses from the Psychiatric Genomics Consortium were used as base data sets and general and specific dimension scores were used as discovery data sets. Individuals’ number of risk alleles in the discovery sample was weighted by the log odds ratio from the base samples, accounting for population stratification, and summed into the three PRSs. 3) Multilevel regression analysis was used in STATA 14 to examine the variance in general dimension due to the population density levels across the sites. Results A bi-factor solution, composed of one general and five specific symptom dimensions, showed the best model fit statistics. Higher SZ PRS score was associated with higher scores on positive dimensions (β= 0.27, t=2.11, p

Background: Robust evidence has demonstrated that cannabis use increases the risk to develop psychotic disorders. However, a limited number of studies have investigated if and how cannabis use influences psychopathology profiles at first episode psychosis (FEP). Based on the evidence that dopamine dysfunction contributes to explain positive symptoms in psychosis, and that the main cannabis’ psychoactive component, Δ9-Tetrahydrocannabinol (THC), modulates the dopamine system, we hypothesise that: 1) positive symptoms at FEP are more common among psychotic patients who used cannabis compared with never users; 2) this association is a dose-response relationship. Methods: We analyzed a sample of 1130 FEP patients as part of the EUGEI study, recruited across six countries. The MRC Socio-demographic Schedule was used to collect sociodemographic information. Psychopathology was assessed with the OPerational CRITeria (OPCRIT), and symptom items were analyzed using Mplus to estimate a multidimensional model of psychosis. The Cannabis Experience Questionnaire modified version (CEQmv) was administered to collect information on cannabis, and different patterns of use were computed based on frequency of consumption and type of cannabis, as a proxy of exposure to THC. Results: The lifetime rate of cannabis use was 63%. Fifty-five percent of cannabis users consumed mostly high-potency cannabis, and 46% showed a daily frequency. Mixed-effects linear regression revealed that frequency of cannabis use was associated with the positive symptom dimension score. Daily users of high-potency cannabis presented with the strongest association (Β=0.19, 95%CI=0.02–0.38), even after gender, age, ethnicity, other drug use, and study site were controlled for. Discussion: Our results show that patients with a history of daily use of high potency cannabis express more positive symptoms at psychosis onset, even after taking into account other substance use and relevant sociodemographic factors.

Background: Patients presenting to psychiatric services with their first episode of psychosis (FEP) report higher rates of previous cannabis use than the general population (Donoghue et al., 2011; Myles, Myles and Large, 2016). Evidence suggested that patients suffering from psychosis with a history of cannabis use have an earlier age of onset of psychosis (AOP) than those who never used it (Di Forti et al., 2013). We aim to investigate if the reported association between use of cannabis and AOP is consistent across different countries, once having taken into account different patterns of cannabis use (i.e. frequency of use and age at first use). Methods: We analysed data on patterns of lifetime cannabis use and AOP from FEP=1,149 (61.7% males) from 5 European countries and Brazil part of the European network of national schizophrenia networks studying European Gene-Environment-Interaction (EUGEI) study. Patients met ICD-10 criteria for psychosis, ascertained by using OPCRIT (McGuffin et al., 1991). The CEQmv (Di Forti et al., 2009) further modified for the EUGEI study, was used to collect data on lifetime frequency of cannabis use (never used/ used at least once but less than daily/ everyday use) and age at first use in years (then dichotomized according to mean age at first use ≤15 years or ≥16 years). We used two ANOVAs: age of onset was used as the outcome variable and frequency of cannabis use and age of first use were respectively entered as independent predictors, along with country, gender and self-ascribed ethnicity. Results: 63.3% of our sample used cannabis at least once in lifetime. Among those who used cannabis in their lifetime, mean age at first use was 16.8 years (sd=4.6) and median age was 16 years, 42.3% tried first time cannabis at 15 years or before, 57.7% at 16 years or older. Patients who smoked cannabis on a recreational basis (mean age 29.0; contrast=5.8, CI 95% 4.3, 7.2, p

Background Cannabis use remains the most widely used recreational drug worldwide. Following from several USA states legalisation policies, European countries are reconsidering their cannabis laws. While a significant amount of Epidemiological evidence has reported that cannabis use increases the risk of psychosis it is still unclear: 1) what underpins individual differences in developing a psychotic disorder following cannabis use; 2) if variations in availability of cannabis have affected rate of Psychotic disorders across Europe. Methods Using detailed data on lifetime pattern of cannabis use from the EUGEI first episode case-control study (N=2300) and the available Incidence rates of Psychosis calculated for each European site of the same study, we aim 1) to estimate if differences in age at first use, especially of high potency cannabis among cannabis users resulted in differences in their probability to develop psychosis across the study sites; 2) to calculate the proportion of new cases of psychosis attributable to early adolescence-high Potency cannabis in the 5 countries; 3) to relate data on prevalence of cannabis use in each study site with the corresponding Incidence rates for psychotic disorders. Results Cannabis users starting using cannabis at age 15 and younger who live in those EU countries where high potency cannabis is available have the highest probability to develop psychosis, compared to never users (Adj ORs from 2.6–5.9; p

Background Vitamin D is a neuro-steroid hormone important in brain development, maturation and function as it modulates the production of numerous brain growth factors. Indeed insufficient levels seem to compromise brain development and confer an increased risk of developing schizophrenia later on in life. Finally patients with first-episode psychosis tend to have lower levels of vitamin D than healthy controls. We aimed to explore: 1) The association between vitamin levels and brain structure (i.e. cortical thickness and surface area) in FEP individuals; 2) Differences in brain structure (i.e. cortical thickness and surface area) between FEP individuals with optimal and sub-optimal levels of Vitamin D. Methods Sample: 49 patients with first episode of psychosis (mean age: 27.8 SD ± 9.1 years) part of the BRC Psychosis Theme study on Genetics and Psychosis (GAP). Vitamin D: Vitamin D (serum 25-hydroxyvitamin D) levels were determined by immunoassay. Patients were considered to have sub-optimal levels if vitamin D concentration was below 20 ng/ml, with higher concentrations deemed optimal. Twenty patients had sub-optimal levels of Vitamin D whereas 29 had optimal Vitamin D concentration. Brain Structure: 3T MRI scan were used to evaluate the cortical thickness and the surface area in 49 FEP patients. FreeSurfer 5.3.0 was used to correlate Vitamin D levels with both cortical thickness and surface area in a vertex-by-vertex analysis. afterwards differences in cortical thickness and surface area between FEP participants with both optimal and sub-optimal Vitamin D levels were examined using a vertex-by-vertex General Linear Model analysis in FreeSurfer 5.3.0. Results were corrected for multiples comparison with Montecarlo simulation. Results Vitamin D levels positively correlated with cortical thickness in the left superior-frontal gyrus and surface area in the right peri-calcarine and right inferior-parietal gyrus (all p FEP patients with sub-optimal levels of Vitamin D (below 20 ng/ml) had reduced cortical thickness in the right medial-orbitofrontal gyrus and lingual gyrus compared to those with optimal levels of Vitamin D (all p Discussion Vitamin D levels are associated with reduced cortical thickness and smaller surface area in frontal, temporal, parietal and occipital brain regions in individuals with FEP. Interestingly, these areas complete their maturation well into late adolescence, thus potentially being exposed to low Vitamin D levels over a long period of time may contribute to specific brain structure in adulthood. The identification of a specific brain conformation associated to low levels of Vitamin D would promote greater understanding of the interface between physical and mental illness fostering the development of precision psychiatry.

Various psychological and biological pathways have been proposed as mediators between childhood adverse events (CA) and psychosis. A systematic review of the evidence in this domain is needed. The aim of this work is to systematically review the evidence on psychological and biological mediators between CA and psychosis across the psychosis spectrum. This systematic review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (registration number: CRD42018100846). Articles published between 1979 and July 2019 were identified through a literature search in OVID (PsychINFO; Medline and Embase). The evidence by each analysis and each study results are presented by group of mediator categories found in the review. The percentage of total effect mediated was calculated. 47 studies were included, with a total of 79,668 from general population (GP) and 3,189 from clinical samples. The quality of studies was judged as “fair”. Our results showed (i) solid evidence of mediation between CA and psychosis by negative cognitive schemas about the self, the world, and others (NS); by dissociation and other PTSD symptoms; (ii) evidence of al mediation through an affective pathway (affective dysregulation, anxiety, and depression) in GP; (iii) lack of studies exploring biological mediators. To conclude, we found evidence suggesting that various overlapping and not competing pathways contribute partially to the link between adversity and psychosis. Experiences of adversity, along with relevant mediators such as PTSD and mood related symptoms and NS, should be routinely assessed in patients with psychosis. Targeting such mediators through cognitive behavioural aproaches using trauma-focused therapy and/or pharmacological means could be a useful addition to the traditional treatment of positive symptoms.

Aim\ud People with psychotic disorders have increased premature mortality in comparison with the general population, with high rates of cigarette use a contributing factor. We aimed to describe the prevalence of cigarette use and nicotine dependence (ND) in first episode psychosis (FEP), and established psychosis; and to investigate associations between clinical symptoms and ND.\ud \ud Methodology\ud Smoking and clinical data were collected from two cohorts: 181 people with FEP recruited as part of the Physical Health and Substance Use Measures in First Onset Psychosis (PUMP) study and from 432 people with established psychosis recruited as part of the Improving\ud physical health and reducing substance use in psychosis randomised controlled trial (IMPaCT RCT).\ud \ud Results\ud The prevalence of cigarette smoking was 78% in FEP and 62% in established psychosis. Forty nine percent (n=60) of smokers in the FEP cohort and 69% (n=183) of smokers with established psychosis were highly nicotine dependent. Being a highly nicotine dependent\ud smoker was significantly associated with higher PANSS positive symptom scores (F= 5.480 p= 0.004), and with decreased scores on the Rosenberg self-esteem scale (F=3.261, p=0.039) in established psychosis. There was no diagnostic specificity identified in relation to smoking or ND in both groups.\ud \ud Conclusion\ud High rates of cigarette usage and nicotine dependence are problems from the early stages of psychosis. ND is higher in people with established psychosis. Smoking cessation\ud strategies as part of comprehensive management of psychotic disorders at every stage require further development and evaluation.

The notion that behaviour may be on a causal path from genetics to psychiatric disorders, such as schizophrenia, highlights a potential for practical interventions. Motivated by this, we test the association between schizophrenia (SCZ) polygenic risk scores (PRS) and 420 behavioural traits (personality, psychological, lifestyle, nutritional) in a psychiatrically healthy sub-cohort of the UK Biobank. Higher schizophrenia PRS was associated with a range of traits, including lower verbal-numerical reasoning (P= 6×10−61), higher nervous feelings (P= 2×10−51) and higher self-reported risk-taking (P= 2×10−41). We follow-up the risk-taking association, hypothesising that the association may be due to a genetic propensity for risk-taking leading to greater migration, urbanicity or drug-taking – reported environmental risk factors for schizophrenia, and all positively associated with risk-taking in these data. However, schizophrenia PRS was also associated with traits, such as tea drinking (P= 2×10−34), that are highly unlikely to be on a causal path to schizophrenia. We depict four causal relationships that may in theory underlie such PRS-trait associations and illustrate ways of testing for each. For example, we contrast PRS-trait trends in the healthy sub-cohort to the corresponding trait values of medicated and non-medicated individuals diagnosed with schizophrenia, allowing some differentiation of mediation-by-behaviour, disease-onset effects and treatment effects. However, dedicated follow-up studies and new methods are required to fully disentangle these relationships. Thus, while we urge caution in interpretation of simple PRS cross-trait associations, we propose that well-designed PRS analyses can contribute to identifying behaviours on the causal path from genetics to disease.

BACKGROUND: It is well established that Bipolar Disorder (BD) and Major Depression Disorder (MDD) run in families, and that this genetic susceptibility is due to many hundreds of common variants, each one conferring a fractional risk. Using the so-called polygenic risk score (PRS) method we can summarise the individual risks for an illness across those associated variants into a quantitative score. However, the variance explained by PRS for identifying case-control status is lower than expected, which can be partially explained by the heterogeneity within groups, but more importantly by the genetic overlap between disorders. Using data from the EUGEI case-control study of first-episode psychosis (FEP), we test whether PRS for schizophrenia (SZ), BP and MDD can distinguish between affective psychosis diagnosis beyond the genetic overlap. METHODS: DNA was obtained from most participants at baseline (73.6% of 1130 cases and 78.5% of 1499 controls) among 16 European cities as part of the EUGEI case-control study. The sample was split based on ancestry and analyses were done on the subsample representing white population (n=1659). PRS for SZ, BD and MDD were built using las available data from the Psychiatric Genomic Consortium (PGC). DSM-IV based diagnoses were extracted utilizing the Operational Criteria Checklist at baseline and were grouped into diagnostic groups (Bipolar Disorder, Psychotic Depression, Affective psychosis, Non-affective psychosis) for clinical status comparisons. We built different logistic regression models using separately the different PRSs as predictors for each clinical comparison, adjusted by population stratification using the first 10 principal components (PC). A further model was built including all diagnostic categories as outcome (using control as reference group) and the three PRS as independent variables in a multinomial logistic regression, adjusting by 10 PC. RESULTS: PRS SZ was the only able to distinguish between affective and non-affective psychosis, showing an association with non-affective psychosis (OR=0.36, 95% CI .19 - .67, p=0.001). When comparing bipolar disorder with psychotic depression PRS SZ was the only able to distinguish between categories, showing an association with bipolar disorder (OR=2.89 95% CI 1.01 – 8.24, p>0.001). In the multinomial regression, both PRS SZ (RRR=2.09 95% CI 1.0 4- 2.5, p

BACKGROUND: Although the association between psychotic illness and cigarette smoking is well known, it is not clear why people with psychosis are more likely to smoke than are the general population. First, we carried out a systematic review and meta-analysis aimed to test the hypothesis that a) daily tobacco use is associated with an increased risk of psychotic illness in both case-control and prospective studies, and b) smoking is associated with an earlier age at onset of psychotic illness. Secondly, we carried out two case-control studies aimed to derive an estimate of the prevalence of smoking in patients presenting with their first episode of psychosis. The first was the GAP study carried out in South London, the second was the EU-GEI multi-site study carried out across 16 sites in Europe and Brazil. METHODS: First, we searched Embase, Medline, and PsycINFO and selected observational studies in which rates of smoking were reported in people with psychotic disorders, compared with controls. We calculated the weighted mean difference for age at onset of psychosis and age at initiation of smoking. For categorical outcomes, we calculated odds ratios from cross-sectional studies and risk ratios from prospective studies. Secondly, in the GAP study, we interviewed 596 people with their first episode of psychosis and 333 healthy controls representative of the local population. In the EU-GEI study, we interviewed 1,150 patients with first episode psychosis and 1,350 healthy controls. In both all subjects were interviewed in detail about their recreational drug use including tobacco use. In the EU-GEI study approximately one half of the cases and controls also underwent an EWAS examination of epigenetics in peripheral blood. RESULTS: 61 studies met inclusion criteria for the systematic review, and the overall sample included 14,555 tobacco users and 273,162 non-users. The prevalence of smoking in patients presenting with their first episode of psychosis was 0·57 (95% CI 0·52-0·62; p

BACKGROUND: Epigenetic mechanisms are emerging as potential important players that underlie the interactions between genetic and environmental risk factors in the aetiology of psychiatric disorders. Cannabis is the most widely used recreational drug and its use, with a dose relationship pattern, has consistently been associated with an increased risk to develop Psychotic Disorders. Consistent with animal data, it has been shown that regular cannabis users show higher levels of CB1 mRNA expression and promoter methylation status in peripheral blood cells than non-users. We are the first to investigate if cannabis use leaves a distinct DNA methylation signature across the genome and if this overlaps with biological pathways already associated with Psychotic Disorders. METHODS: Genome-wide DNA methylomic (EWAS) profiling using the Illumina Infinium MethylationEPIC array in human peripheral blood tissue from 413 First episode Psychosis and 521 healthy population controls part of the EUGEI (European network of national schizophrenia networks studying Gene-Environment Interactions) study. Samples were randomized with respect to phenotypic status, age, sex and study site to avoid batch effects. Stringent QC pipeline checks (i.e. signal intensity, duplicates, sex, bisulphite conversion, genotypes) with cross-reactive and non-reliable probes removed. Our analyses focused on probes with a minimum range of methylation values of 5% within the middle 80% of samples, resulting in 618,048 probes5. Covariates: 1) tobacco smoking score; 2) age; 3) cell type proportions and 4) study sites Linear model was used to compare across the DNA methylomic profiling of a) Lifetime cannabis users (YES) and b) daily cannabis users with never users. RESULTS: Our preliminary analyses revealed regular cannabis use-associated dysregulation of DNA methylation at multiple loci across the epigenome that also include CpGs previously associated with Schizophrenia. Downstream pathway analysis revealed enrichment of genomic regions that are highly disease relevant. CONCLUSIONS: Our preliminary findings in a sample of healthy controls suggest: Difference in DNA Methylation profiling between individuals who have tried cannabis at some point in their life and more significantly so in daily users compared to never users; 2) these differences were detected taking into account important confounders including the epigenetic tobacco scoring. Most of these DMS are in protein coding genes including BDNF,SHANK2 and CACNA2D2, which are involved in important neurodevelopmental processes. BDNF and CACNA2D2 have also been indicated as susceptibility genes for Schizophrenia and Bipolar Disorders. Finally, our pathway analysis indicated significant enrichment for these DMSs in pathways involved in biological processing such as neuronal migration and development and glutamate receptor binding, a possible hint towards the unravelling of the biology linking adolescence cannabis use with psychosis.

Background: The role of insight dimensions – illness recognition (IR), symptoms relabelling (SR), treatment compliance (TC) - in suicide risk in first-episode psychosis (FEP) remains unclear. Method: The AESOP (n=181) and GAP (n=112) FEP cohorts were followed-up over 10- and 5 years. Survival analysis modelled time to first suicidal event in relation to baseline scores on the Schedule for the Assessment of Insight, whilst adjusting for demographic, clinical, psychopathological and neuropsychological variables., This work represents independent research which was supported by the UK Medical Research Council (grant number G0500817) and partly-funded by the UK Department of Health via the National Institute for Health Research (NIHR) Specialist Biomedical Research Centre for Mental Health award to the South London and Maudsley NHS Foundation Trust (SLaM) and the Institute of Psychiatry, Psychology and Neuroscience at Kings College London. JDLM was funded by the British Medical Association via the Margaret Temple Research Award for Schizophrenia. PBJ received funding support from the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research & Care (CLAHRC), East of England. RMM was supported by the Medical Research Council and Lord Leverhulme Trust. CM is funded by grants from the Medical Research Council (grant number MR/P025927/1) and EU (grant number ERC Ref: 648837 REACH). RD is funded by a Clinician Scientist Fellowship awarded by the Academy of Medical Sciences in partnership with The Health Foundation. ASD is supported by National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and Kings College London.

Aims: Cognitive impairment is a possible indicator of neurodevelopmental impairment, but not all psychotic patients are cognitively compromised. It has been suggested that heavy cannabis use may precipitate psychosis in those who show no such compromise. This study compares two samples of patients with first-episode psychosis and their respective non-psychotic controls, in London (UK) and Palermo (Italy), and examines whether different patterns of cannabis use are reflected in differences in IQ. Methods: The two studies used the same inclusion/exclusion criteria and instruments. The sample comprised 249 subjects from London (106 patients and 143 controls) and 247 subjects from Palermo (120 patients and 127 controls). ANCOVA was performed with IQ as the dependent variable and city and frequency of cannabis use as predictors. This was then repeated with the case group only, by adjusting for relevant confounders. Results: We found a greater amount of cannabis use in the London sample, compared to Palermo and patients from London had higher IQ than patients from Palermo, a difference that was more significant than that reflected between controls (Fjavax.xml.bind.JAXBElement@68a50fa4(1, 402) = 7.6, p = 0.006). Once corrected for symptomatology and treatment, patients from London who had never used cannabis were similar to patients from Palermo regarding IQ. Thus the higher IQ of patients from London was mainly due to the subgroup of cannabis-using patients (Fcannabis*city(2,145) = 4.6, p = 0.011). Conclusions: We can speculate that a greater amount of cannabis-use may have contributed by precipitating psychosis in patients with a higher IQ in London but less so in patients from Palermo.

Experimental and epidemiological studies implicate the cannabinoid 1 receptor (CB1R) in the pathophysiology of psychosis. However, whether CB1R levels are altered in the early stages of psychosis and whether they are linked to cognitive function or symptom severity remain unknown.To investigate CB1R availability in first-episode psychosis (FEP) without the confounds of illness chronicity or the use of illicit substances or antipsychotics.This cross-sectional, case-control study of 2 independent samples included participants receiving psychiatric early intervention services at 2 independent centers in Turku, Finland (study 1) and London, United Kingdom (study 2). Study 1 consisted of 18 volunteers, including 7 patients with affective or nonaffective psychoses taking antipsychotic medication and 11 matched controls; study 2, 40 volunteers, including 20 antipsychotic-naive or antipsychotic-free patients with schizophrenia or schizoaffective disorder and 20 matched controls. Data were collected from January 5, 2015, through September 26, 2018, and analyzed from June 20, 2016, through February 12, 2019.The availability of CB1R was indexed using the distribution volume (VT, in milliliters per cubic centimeter) of 2 CB1R-selective positron emission tomography radiotracers: fluoride 18-labeled FMPEP-d2 (study 1) and carbon 11-labeled MePPEP (study 2). Cognitive function was measured using the Wechsler Digit Symbol Coding Test. Symptom severity was measured using the Brief Psychiatric Rating Scale for study 1 and the Positive and Negative Syndrome Scale for study 2.A total of 58 male individuals were included in the analyses (mean [SD] age of controls, 27.16 [5.93] years; mean [SD] age of patients, 26.96 [4.55] years). In study 1, 7 male patients with FEP (mean [SD] age, 26.80 [5.40] years) were compared with 11 matched controls (mean [SD] age, 27.18 [5.86] years); in study 2, 20 male patients with FEP (mean [SD] age, 27.00 [5.06] years) were compared with 20 matched controls (mean [SD] age, 27.15 [6.12] years). In study 1, a significant main effect of group on [18F]FMPEP-d2 VT was found in the anterior cingulate cortex (ACC) (t16 = -4.48; P .001; Hedges g = 1.2), hippocampus (t16 = -2.98; P = .006; Hedges g = 1.4), striatum (t16 = -4.08; P = .001; Hedges g = 1.9), and thalamus (t16 = -4.67; P .001; Hedges g = 1.4). In study 2, a significant main effect of group on [11C]MePPEP VT was found in the ACC (Hedges g = 0.8), hippocampus (Hedges g = 0.5), striatum (Hedges g = 0.4), and thalamus (Hedges g = 0.7). In patients, [11C]MePPEP VT in the ACC was positively associated with cognitive functioning (R = 0.60; P = .01), and [11C]MePPEP VT in the hippocampus was inversely associated with Positive and Negative Syndrome Scale total symptom severity (R = -0.50; P = .02).The availability of CB1R was lower in antipsychotic-treated and untreated cohorts relative to matched controls. Exploratory analyses indicated that greater reductions in CB1R levels were associated with greater symptom severity and poorer cognitive functioning in male patients. These findings suggest that CB1R may be a potential target for the treatment of psychotic disorders.

Background Psychotic symptoms can be conceptualised as dimensions of psychopathology cutting across diagnostic boundaries. Thus, they might be considered enhanced quantitative phenotypes to relate to genetic variants as summarised by Polygenic Risk Scores (PRSs) for Major Mental Disorders (MMDs), including Schizophrenia (SZ), Bipolar Disorder (BP), and Major Depressive Disorder (MDD). The objectives of this study were to: 1) identify the dimensional structure of symptoms at First Episode Psychosis (FEP), testing whether a bi-factor model statistically fits the conceptualization of psychosis as a single common construct (general psychosis factor) while also recognising multidimensionality (positive, negative, disorganized, manic, and depressive symptom factors); 2) examine the extent to which MMD PRSs indexed the phenotypic variance due to the general psychosis construct and to the specific symptom dimensions. Methods The sample included 1182 FEP patients recruited as part of the EUGEI study. The MRC Sociodemographic Schedule and the OPerational CRITeria (OPCRIT) were used to collect sociodemographic information and assess psychopathology. DNA was extracted from blood or saliva samples collected from 940 participants. The following analysis steps were performed: 1) OPCRIT psychopathology items were analysed using multidimensional item response modelling in Mplus to estimate unidimensional, multidimensional, and bi-factor models of psychosis. Models’ fit statistics were compared using Log-Likelihood, and Akaike and Bayesian Information Criteria. 2) SZ, BP, and MDD PRSs were built using the results from large mega-analyses from Working Groups of the Psychiatric Genomics Consortium. In PRSice, individuals’ number of risk alleles in the target sample was weighted by the log odds ratio from the discovery samples, and summed into the three PRSs. 3) For the best data fitting psychosis model, linear regressions were estimated to predict symptom dimensions as a continuous outcome from the three PRSs, accounting for population stratification. Results The best model fit statistics was observed for the bi-factor model including one general and five specific symptom factors compared with the other models. This indicated that there was a broad latent structure underlying the whole range of psychosis symptoms among five latent specific symptom dimensions. PRSs for SZ, BP, and MDD were calculated at the best model fitting P-value threshold. As expected, there was a substantial difference in discrimination of case-control status between SZ PRS and BP and MDD PRSs. A significant positive linear regression equation was observed for BP PRS and mania dimension severity (t(864)=2.74, p

Purpose of Review This systematic review aimed to investigate the relation between cannabis use and dissociation. Recent Findings Four analytical and 14 descriptive cross-sectional studies were included. There is no variation in the rates of cannabis use among individuals with dissociative experiences compared with the general population. In addition, the prevalence of dissociative disorders in subjects using cannabis is not different from those not using cannabis. The majority of the studies employed inadequate sampling procedures and a concurrent or retrospective assessment of the two variables, which might have increased the risk of bias, and only a few of them controlled for potential confounders. Summary The limited number of eligible studies, combined with the heterogeneity of study design and methodological limitations, do not support the association between cannabis and dissociative experiences and prevent from any inference about the direction of causality.