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The European Community’s Seventh Framework Programme under grant agreement No. HEALTH-F2-2010-241909 (EUGEI); The Spanish sample was supported by the Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (SAM16PE07CP1, PI16/02012, PI19/024) (...), Velthorst, E., Mollon, J., Murray, R.M., de Haan, L., Germeys, I.M., Glahn, D.C., Arango, C., van der Ven, E., Di Forti, M., Bernardo, M., Guloksuz, S., Delespaul, P., Mezquida, G., Amoretti, S., Bobes, J., Saiz, P.A., García-Portilla, M.P., Santos, J.L., Jiménez-López, E., Sanjuan, J., Aguilar, E.J., Arrojo, M., Carracedo, A., López, G., González-Peñas, J., Parellada, M., Atbaşoğlu, C., Saka, M.C., Üçok, A., Alptekin, K., Akdede, B., Binbay, T., Altınyazar, V., Ulaş, H., Yalınçetin, B., Gümüş-Akay, G., Beyaz, B.C., Soygür, H., Cankurtaran, E.Ş., Kaymak, S.U., Maric, N.P., Mihaljevic, M.M., Petrovic, S.A., Mirjanic, T., Del-Ben, C.M., Ferraro, L., Gayer-Anderson, C., Jones, P.B., Jongsma, H.E., Kirkbride, J.B., La Cascia, C., Lasalvia, A., Tosato, S., Llorca, P.-M., Menezes, P.R., Morgan, C., Quattrone, D., Menchetti, M., Selten, J.-P., Szöke, A., Tarricone, I., Tortelli, A., McGuire, P., Valmaggia, L., Kempton, M.J., van der Gaag, M., Riecher-Rössler, A., Bressan, R.A., Barrantes-Vidal, N., Nelson, B., McGorry, P., Pantelis, C., Krebs, M.-O., Ruhrmann, S., Sachs, G., Rutten, B.P.F., van Os, J., Alizadeh, B.Z., van Amelsvoort, T., Bartels-Velthuis, A.A., Bruggeman, R., van Beveren, N.J., Luykx, J.J., Cahn, W., Simons, C.J.P., Kahn, R.S., Schirmbeck, F., van Winkel, R., Calem, M., Tognin, S., Modinos, G., Pisani, S., Kraan, T.C., van Dam, D.S., Burger, N., Amminger, G.P., Politis, A., Goodall, J., Borgwardt, S., Studerus, E., Gadelha, A., Brietzke, E., Asevedo, G., Asevedo, E., Zugman, A., Domínguez-Martínez, T., Monsonet, M., Cristóbal-Narváez, P., Racioppi, A., Kwapil, T.R., Kazes, M., Daban, C., Bourgin, J., Gay, O., Mam-Lam-Fook, C., Nordholm, D., Rander, L., Krakauer, K., Glenthøj, L.B., Glenthøj, B., Gebhard, D., Arnhold, J., Klosterkötter, J., Lasser, I., Winklbaur, B., Reichenberg, A., EU-GEI High Risk Study

The work was supported by: Clinician Scientist Medical Research Council fellowship (project reference MR/M008436/1) to MDF; the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care South London at King’s College Hospital NHS Foundation Trust to DQ; DFG Heisenberg professorship (no. 389624707) to UR. National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. 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). The Brazilian study was funded by the São Paulo Research Foundation under grant number 2012/0417-0., Quattrone, D., Ferraro, L., Tripoli, G., La Cascia, C., Quigley, H., Quattrone, A., Jongsma, H.E., Del Peschio, S., Gatto, G., Gayer-Anderson, C., Jones, P.B., Kirkbride, J.B., La Barbera, D., Tarricone, I., Berardi, D., Tosato, S., Lasalvia, A., Szöke, A., Arango, C., Bernardo, M., Bobes, J., Del Ben, C.M., Menezes, P.R., Llorca, P.-M., Santos, J.L., Sanjuán, J., Tortelli, A., Velthorst, E., De Haan, L., Rutten, B.P.F., Lynskey, M.T., Freeman, T.P., Sham, P.C., Cardno, A.G., Vassos, E., Van Os, J., Morgan, C., Reininghaus, U., Lewis, C.M., Murray, R.M., Di Forti, M.

Schizophrenia (SZ), Bipolar Disorder (BD) and Depression (D) run in families. This susceptibility is partly due to hundreds or thousands of common genetic variants, each conferring a fractional risk. The cumulative effects of the associated variants can be summarised as a polygenic risk score (PRS). Using data from the EUGEI case-control study, we aimed to test whether PRSs for three major psychiatric disorders (SZ, BD, D) and for intelligent quotient (IQ) as a neurodevelopmental proxy, can discriminate affective psychosis (AP) from schizophrenia-spectrum disorder (SSD). Participants (573 cases, 1005 controls) of european ancestry from 17 sites as part of the EUGEI study were successfully genotyped following standard quality control procedures. Using standardised PRS for SZ, BD, D, and IQ built from the latest available summary statistics, we performed simple or multinomial logistic regression models adjusted for 10 principal components for the different clinical comparisons. In case-control comparisons PRS-SZ, PRS-BD and PRS-D distributed differentially across psychotic subcategories. In case-case comparison, both PRS-SZ (OR=0.7, 95 %CI 0.53-0.92) and PRS-D (OR=1.29, 95%CI 1.05-1.6) differentiated global AP from SSD; and within AP categories, only PRS-SZ differentiated BD from psychotic depression (OR=2.38, 95%CI 1.32-4.29). Combining PRS for severe psychiatric disorders in prediction models for psychosis phenotypes can increase discriminative ability and improve our understanding of these phenotypes. Our results point towards potential usefulness of PRSs for diagnostic prediction in specific populations such as high-risk or early psychosis phases.

People with psychosis have a reduced life expectancy of 10–20 years, largely due to cardiovascular disease. This trial aimed to determine the effectiveness of a modular health promotion intervention (IMPaCT Therapy) in improving health and reducing cardiovascular risk in psychosis. A multicentre, two arm, parallel cluster RCT was conducted across five UK mental health NHS trusts. Community care coordinators (CC) were randomly assigned to training and supervision in delivering IMPaCT Therapy or treatment as usual (TAU) to current patients with psychosis (cluster). The primary outcome was the physical and mental health subscales of the Short form-36 (SF-36) questionnaire. Of 104 care coordinators recruited, 52 (with 213 patients) were randomised to deliver IMPaCT therapy and 52 (with 193 patients) randomised to TAU. Of 406 patients, 318 (78%) and 301 (74%) attended 12- and 15-month follow-up respectively. IMPaCT therapy showed no significant effect on the physical or mental health component SF-36 scores versus TAU at 12 or 15 months. No effect was observed for cardiovascular risk indicators, except for HDL cholesterol, which improved more with IMPACT therapy than TAU (Treatment effect (95% CI); 0.085 (0.007 to 0.16); p = 0.034). The 22% of patients who received >180 min of IMPACT Therapy in addition to usual care achieved a greater reduction in waist circumference than did controls, which was clinically significant. Training and supervising community care coordinators to use IMPaCT therapy in patients with psychosis is insufficient to significantly improve physical or mental health quality of life. The search for effective, pragmatic interventions deliverable in health care services continues. The trial was retrospectively registered with ISRCTN registry on 23/4/2010 at ISRCTN58667926 ; recruitment started on 01/03/2010 with first randomization on 09.08.2010 ISRCTN58667926 .

BackgroundDiagnostic categories within the psychosis spectrum are widely used in clinical practice, however psychosis may occur on a continuum. Therefore, we explored whether the continuous distribution of psychotic symptoms across categories is a function of genetic as well as environmental risk factors, such as polygenic risk scores (PRSs) and cannabis use.MethodsAs part of the EU-GEI study, we genotyped first episode psychosis patients (FEP) and population controls, for whom transdiagnostic dimensions of psychotic symptoms or experiences were generated using item response bi-factor modelling. Linear regression was used, separately in patients and controls, to test the associations between these dimensions and schizophrenia (SZ) PRSs, as well as the combined effect of SZ-PRS and cannabis use on the positive symptom/experience dimensions.ResultsSZ-PRS was associated with negative (B=0.18; 95%CI 0.03 to 0.34) and positive (B=0.19; 95%CI 0.03 to 0.36) symptom dimensions in 617 FEP, and with all the psychotic experience dimensions in 979 controls. The putative effect of SZ-PRS on either symptom or experience dimensions was of a small magnitude. Cannabis use was additionally associated with the positive dimensions both in FEP (B=0.31; 95%CI 0.11 to 0.52) and in controls (B=0.26; 95%CI 0.06 to 0.46), independently from SZ-PRS.ConclusionsWe report two validators to the latent dimensional structure of psychosis. SZ risk variants and cannabis use independently map onto specific dimensions, contributing to variation across the psychosis continuum. Findings support the hypothesis that psychotic experiences have similar biological substrates as clinical disorders.

Background: Some recent studies have challenged the direction of causality for the association between cannabis use and psychotic disorder, suggesting that cannabis use initiation is explained by common genetic variants associated with risk of schizophrenia. We used data from the European Union Gene-Environment Interaction consortium (EUGEI) case-control study to test for the independent and combined effect of heavy cannabis use, and of Schizophrenia Polygenic risk score (SZ PRS), on risk for psychotic disorder. Methods: Genome-wide data were obtained from 492 first episode psychosis patients (FEPp) and from 787 controls of European Ancestry, and used to generate SZ PRS from the summary results of an independent meta-analysis. Information on pattern of cannabis use was used to build a 7-level frequency-type composite cannabis use measure that we previously found was a strong predictor of psychotic disorder. Results: SZ PRS did not predict cannabis initiation (b=0.027; p=0.51) or how frequently controls (b=0.027; p=0.06) or FEPp (b=0.006; p=0.91) used it, or the type of cannabis they used (Controls: b = 0.032; p=0.31); FEPp: b= 0.005; p=0.89). The frequency-type composite cannabis use measure (OR=1.32; 95% CI 1.22-1.44) and SZ PRS (OR=2.29; 95%CI 1.71-3.05) showed independent effects from each other on the OR for psychotic disorder. Conclusion: SZ PRS does not predict an individual s propensity to try cannabis, frequency of use, or the potency of the cannabis used. Our findings provide the first evidence that SZ PRS and heavy cannabis use exert effects independent from each other on the risk for psychotic disorder.

BACKGROUND: There is increasing evidence for shared genetic susceptibility between schizophrenia and bipolar disorder. Although genetic variants only convey subtle increases in risk individually, their combination into a polygenic risk score constitutes a strong disease predictor.AimsTo investigate whether schizophrenia and bipolar disorder polygenic risk scores can distinguish people with broadly defined psychosis and their unaffected relatives from controls. METHOD: Using the latest Psychiatric Genomics Consortium data, we calculated schizophrenia and bipolar disorder polygenic risk scores for 1168 people with psychosis, 552 unaffected relatives and 1472 controls. RESULTS: Patients with broadly defined psychosis had dramatic increases in schizophrenia and bipolar polygenic risk scores, as did their relatives, albeit to a lesser degree. However, the accuracy of predictive models was modest. CONCLUSIONS: Although polygenic risk scores are not ready for clinical use, it is hoped that as they are refined they could help towards risk reduction advice and early interventions for psychosis.Declaration of interestR.M.M. has received honoraria for lectures from Janssen, Lundbeck, Lilly, Otsuka and Sunovian. Funding: This work was funded by the Medical Research Council (G0901310), the Wellcome Trust (grants 085475/B/08/Z, 085475/Z/08/Z), the European Union’s Seventh Framework Programme for research, technological development and demonstration (grant 602450). This study was also supported by the NIHR Biomedical Research Centre at University College London (mental health theme) and by the NIHR Biomedical Research Centre at the South London and Maudsley NHS Foundation Trust and Institute of Psychiatry – Kings College London. Further support: NHIR Academic Clinical fellowship awarded to M.S.C.. E.B. acknowledges research funding from: 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 and the NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and Institute of Psychiatry Kings College London. The Brain and Behaviour Research foundation’s (NARSAD’s) Young Investigator Award (Grant 22604, awarded to C.I.). The BMA Margaret Temple grant 2016 to J. H.T. European Research Council Marie Curie award to A.D.-R. 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 healthcare organisations. Amsterdam: Academic Psychiatric Centre of the Academic Medical Center and the mental health institutions: GGZ Ingeest, Arkin, Dijk en Duin, GGZ Rivierduinen, Erasmus Medical Centre, GGZ Noord Holland Noord. 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 Zorggroep, Prins Clauscentrum Sittard, RIAGG Roermond, Universitair Centrum Sint-Jozef Kortenberg, CAPRI University of Antwerp, PC Ziekeren Sint-Truiden, PZ Sancta Maria Sint-Truiden, GGZ Overpelt, OPZ Rekem. Groningen: University Medical Center Groningen and the mental health institutions: Lentis, GGZ Friesland, GGZ Drenthe, Dimence, Mediant, GGNet Warnsveld, Yulius Dordrecht and Parnassia psychomedical center (The Hague). Utrecht: University Medical Center Utrecht and the mental health institutions Altrecht, GGZ Centraal, Riagg Amersfoort and Delta. The sample from Spain was collected at the Hospital Universitario Marqués de Valdecilla, University of Cantabria, Santander, Spain, under the following grant support: Carlos III Health Institute PI020499, PI050427, PI060507, Plan Nacional de Drugs Research Grant 2005- Orden sco/3246/2004, SENY Fundació Research Grant CI 2005-0308007 and Fundación Marqués de Valdecilla API07/011. The present data were obtained at the Hospital Marqués de Valdecilla, University of Cantabria, Santander, Spain, under the following grant support: MINECO Exp.: SAF2013-46292-R.

BackgroundA range of endophenotypes characterise psychosis, however there has been limited work understanding if and how they are inter-related.MethodsThis multi-centre study includes 8754 participants: 2212 people with a psychotic disorder, 1487 unaffected relatives of probands, and 5055 healthy controls. We investigated cognition [digit span (N= 3127), block design (N= 5491), and the Rey Auditory Verbal Learning Test (N= 3543)], electrophysiology [P300 amplitude and latency (N= 1102)], and neuroanatomy [lateral ventricular volume (N= 1721)]. We used linear regression to assess the interrelationships between endophenotypes.ResultsThe P300 amplitude and latency were not associated (regression coef. −0.06, 95% CI −0.12 to 0.01,p= 0.060), and P300 amplitude was positively associated with block design (coef. 0.19, 95% CI 0.10–0.28,p< 0.001). There was no evidence of associations between lateral ventricular volume and the other measures (allp> 0.38). All the cognitive endophenotypes were associated with each other in the expected directions (allp< 0.001). Lastly, the relationships between pairs of endophenotypes were consistent in all three participant groups, differing for some of the cognitive pairings only in the strengths of the relationships.ConclusionsThe P300 amplitude and latency are independent endophenotypes; the former indexing spatial visualisation and working memory, and the latter is hypothesised to index basic processing speed. Individuals with psychotic illnesses, their unaffected relatives, and healthy controls all show similar patterns of associations between endophenotypes, endorsing the theory of a continuum of psychosis liability across the population.

Reduced fecundity, associated with severe mental disorders, places negative selection pressure on risk alleles and may explain, in part, why common variants have not been found that confer risk of disorders such as autism, schizophrenia and mental retardation. Thus, rare variants may account for a larger fraction of the overall genetic risk than previously assumed. In contrast to rare single nucleotide mutations, rare copy number variations (CNVs) can be detected using genome-wide single nucleotide polymorphism arrays. This has led to the identification of CNVs associated with mental retardation and autism. In a genome-wide search for CNVs associating with schizophrenia, we used a population-based sample to identify de novo CNVs by analysing 9,878 transmissions from parents to offspring. The 66 de novo CNVs identified were tested for association in a sample of 1,433 schizophrenia cases and 33,250 controls. Three deletions at 1q21.1, 15q11.2 and 15q13.3 showing nominal association with schizophrenia in the first sample (phase I) were followed up in a second sample of 3,285 cases and 7,951 controls (phase II). All three deletions significantly associate with schizophrenia and related psychoses in the combined sample. The identification of these rare, recurrent risk variants, having occurred independently in multiple founders and being subject to negative selection, is important in itself. CNV analysis may also point the way to the identification of additional and more prevalent risk variants in genes and pathways involved in schizophrenia. ©2008 Macmillan Publishers Limited. All rights reserved., link_to_OA_fulltext

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.

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.

Funder: FP7 Ideas: European Research Council; doi: http://dx.doi.org/10.13039/100011199; Grant(s): HEALTH-F2-2010-241909, Purpose: The EUropean Network of National Schizophrenia Networks Studying Gene–Environment Interactions (EU-GEI) study contains an unparalleled wealth of comprehensive data that allows for testing hypotheses about (1) variations in incidence within and between countries, including by urbanicity and minority ethnic groups; and (2) the role of multiple environmental and genetic risk factors, and their interactions, in the development of psychotic disorders. Methods: Between 2010 and 2015, we identified 2774 incident cases of psychotic disorders during 12.9 million person-years at risk, across 17 sites in 6 countries (UK, The Netherlands, France, Spain, Italy, and Brazil). Of the 2774 incident cases, 1130 cases were assessed in detail and form the case sample for case–control analyses. Across all sites, 1497 controls were recruited and assessed. We collected data on an extensive range of exposures and outcomes, including demographic, clinical (e.g. premorbid adjustment), social (e.g. childhood and adult adversity, cannabis use, migration, discrimination), cognitive (e.g. IQ, facial affect processing, attributional biases), and biological (DNA via blood sample/cheek swab). We describe the methodology of the study and some descriptive results, including representativeness of the cohort. Conclusions: This resource constitutes the largest and most extensive incidence and case–control study of psychosis ever conducted.

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 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., Tarricone, I., D'Andrea, G., Jongsma, H.E., Tosato, S., Gayer-Anderson, C., Stilo, S.A., Suprani, F., Iyegbe, C., Van Der Ven, E., Quattrone, D., Di Forti, M., Velthorst, E., Rossi Menezes, P., Arango, C., Parellada, M., Lasalvia, A., La Cascia, C., Ferraro, L., Bobes, J., Bernardo, M., Sanjuán, I., Santos, J.L., Arrojo, M., Del-Ben, C.M., Tripoli, G., Llorca, P.-M., De Haan, L., Selten, J.-P., Tortelli, A., Szöke, A., Muratori, R., Rutten, B.P., Van Os, J., Jones, P.B., Kirkbride, J.B., Berardi, D., Murray, R.M., Morgan, C.

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 work was supported by Guarantors of Brain post-doctoral clinical fellowship to DQ; Clinician Scientist Medical Research Council fellowship (project reference MR/M008436/1) to MDF; Heisenberg professorship from the German Research Founda- tion (grant no. 389624707) to UR; the National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. 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). The Brazilian study was funded by the São Paulo Research Foundation under grant number 2012/0417-0., Quattrone D., Reininghaus U., Richards A.L., Tripoli G., Ferraro L., Quattrone A., Marino P., Rodriguez V., Spinazzola E., Gayer-Anderson C., Jongsma H.E., Jones P.B., La Cascia C., La Barbera D., Tarricone I., Bonora E., Tosato S., Lasalvia A., Szöke A., Arango C., Bernardo M., Bobes J., Del Ben C.M., Menezes P.R., Llorca P.-M., Santos J.L., Sanjuán J., Arrojo M., Tortelli A., Velthorst E., Berendsen S., de Haan L., Rutten B.P.F., Lynskey M.T., Freeman T.P., Kirkbride J.B., Sham P.C., O’Donovan M.C., Cardno A.G., Vassos E., van Os J., Morgan C., Murray R.M., Lewis C.M., Di Forti M., Hubbard K., Beards S., Stilo S.A., Parellada M., Fraguas D., Castro M.R., Andreu-Bernabeu Á., López G., Matteis M., González E., Durán-Cutilla M., Díaz-Caneja C.M., Cuadrado P., Rodríguez Solano J.J., Carracedo A., Costas J., Sánchez E., Amoretti S., Lorente-Rovira E., Garcia-Portilla P., Jiménez-López E., Franke N., van Dam D., Termorshuizen F., van der Ven E., Messchaart E., Leboyer M., Schürhoff F., Jamain S., Baudin G., Ferchiou A., Pignon B., Richard J.-R., Charpeaud T., Tronche A.-M., Frijda F., Marrazzo G., Sideli L., Sartorio C., Seminerio F., Loureiro C.M., Shuhama R., Ruggeri M., Bonetto C., Cristofalo D., Berardi D., Seri M., D’Andrea G.

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 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.

The GAP multidisciplinary study carried out in South London, recruited 410 first episode of psychosis patients and 370 controls; the aim was to elucidate the multiple genetic and environmental factors influencing the onset and outcome of psychosis. The study demonstrated the risk increasing effect of adversity in childhood (especially parental loss, abuse, and bullying) on onset of psychosis especially positive symptoms. Adverse life events more proximal to onset, being from an ethnic minority, and cannabis use also played important roles; indeed, one quarter of new cases of psychosis could be attributed to use of high potency cannabis. The “jumping to conclusions” bias appeared to mediate the effect of lower IQ on vulnerability to psychosis. We confirmed that environmental factors operate on the background of polygenic risk, and that genetic and environment act together to push individuals over the threshold for manifesting the clinical disorder. The study demonstrated how biological pathways involved in the stress response (HPA axis and immune system) provide important mechanisms linking social risk factors to the development of psychotic symptoms. Further evidence implicating an immune/inflammatory component to psychosis came from our finding of complement dysregulation in FEP. Patients also showed an upregulation of the antimicrobial alpha-defensins, as well as differences in expression patterns of genes involved in NF-κB signaling and Cytokine Production. Being of African origin not only increased risk of onset but also of a more difficult course of illness. The malign effect of childhood adversity predicted a poorer outcome as did continued use of high potency cannabis.

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Purpose: The incidence of psychotic disorders varies in different geographical areas. As there have been no reports from Southern Italy, this study aimed to determine the incidence rate of first-episode psychosis in Palermo, Sicily. Methods: All patients, aged 18–65 years, presenting with a first episode of psychosis (FEP) (ICD-10 F20–29, F30–33) to mental health services in Palermo, were recorded over a 3-year period. Incidence rates of psychotic disorders and their 95% confidence intervals (95% CI) were estimated. Poisson regression was applied to estimate the differences in incidence rate ratio (IRR) by age, sex and migrant status. Results: Two hundred and four FEP participants were identified during the 3 years; 183 (89.7%, males n = 112) participants were native Italians and 21 were migrants (10.3%, males n = 14). The crude incidence of all psychoses was 15.9 (95% CI 13.7–18.1). As predicted, the risk of schizophrenia F20 was higher in males compared to females (adjusted IRR = 1.99, 95% CI 1.36–2.88) and in migrants compared to native Italians (adjusted IRR = 4.02, 95% CI 2.39–6.75). Conclusions: This study, the first from Sicily, confirms previous findings from Northern Italy that the risk of schizophrenia and other psychoses is much lower in Italian cities than those reported from cities in Northern Europe; the reasons for this disparity may provide important clues to the aetiology of psychosis.

Evidence for early parental death as a risk factor for psychosis in offspring is inconclusive. We analyzed data from a six-country, case-control study to examine the associations of early parental death, type of death (maternal, paternal, both), and child’s age at death with psychosis, both overall and by ethnic group. In fully adjusted multivariable mixed-effects logistic regression models, experiencing early parental death was associated with 1.54-fold greater odds of psychosis (95% confidence interval (CI): 1.23, 1.92). Experiencing maternal death had 2.27-fold greater odds (95% CI: 1.18, 4.37), paternal death had 1.14-fold greater odds (95% CI: 0.79, 1.64), and both deaths had 4.42-fold greater odds (95% CI: 2.57, 7.60) of psychosis compared with no early parental death. Experiencing parental death between 11 and 16 years of age had 2.03-fold greater odds of psychosis than experiencing it before five years of age (95% CI: 1.02, 4.04). In stratified analyses, experiencing the death of both parents had 9.22-fold greater odds of psychosis among minority ethnic groups (95% CI: 2.02−28.02) and no elevated odds among the ethnic majority (odds ratio (OR): 0.96; 95% CI: 0.10−8.97), which could be due in part to the higher prevalence of early parental death among minority ethnic groups but should be interpreted cautiously given the wide confidence intervals.

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

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.

The term “Psychosis,” from Greek ψυχή (psyche), “mind/soul,” and -ωσιζ (-osis), “abnormal condition or derangement,” indicates a mental state characterized by a set of positive and negative “psychotic” symptoms. Psychotic disorders have a multifactorial etiology. Many epidemiological studies have reported how rates of substance misuse, especially cannabis, are consistently higher in first episode psychosis patients. Another very important predictor of psychosis is migration history. It has been widely replicated that rates of schizophrenia are higher among migrant and ethnic minority groups. Little is known on the association between these two risk factors in the development of new-onset psychosis. One of the studies conducted so far have associated the use of cannabis to a greater risk of developing psychotic disorders for the second generation of migrants, but not with the first generation. Further studies are needed to emit light on the correlation of these two risk factors on the development of psychotic disorders.

Background—Despite increasing evidence suggesting that childhood maltreatment is significantly associated with psychosis, the specific role of bullying in the onset of psychotic disorders is still unclear. This study aimed to examine whether bullying was more prevalent amongst individuals presenting to services for the first time with a psychotic disorder than in unaffected community controls. Methods—Data on exposure to bullying, psychotic symptoms, cannabis use and history of conduct disorder were collected cross-sectionally from 222 first-presentation psychosis cases and 215 geographically-matched controls. Bullying victimisation was assessed retrospectively as part of the Brief Life Events schedule. Logistic regression was used to examine associations between exposure to bullying and case-control status, while controlling for potential confounders. Results—Psychosis cases were approximately twice as likely to report bullying victimisation when compared to controls. No significant interactions between bullying and either gender or cannabis use were found. Controls reporting being a victim of bullying were approximately twice as likely to also report at least one psychosis-like symptom. Conclusions—Our results extend previous research by suggesting that bullying victimisation may contribute to vulnerability to develop a psychotic disorder in some individuals.

IntroductionA number of authors have hypothesized that psychotic patients who consume cannabis constitute a differentiated subgroup of patients that have better cognitive and social skills, necessary to engage in illegal drug consumption, than non-using patients.ObjectivesGiven that the prevalence, and patterns, of cannabis use are culturally driven, we wanted to study first-episode psychosis (FEP) cannabis-using and non-using patients coming from different European countries as part of the EUGEI-STUDY.AimsWe tested the hypothesis of better premorbid social adjustment in cannabis-using FEP patients, by comparing them to FEP non cannabis users and to their respective healthy controls.MethodsA total of 1745 people (746 cases; 999 controls) completed the assessment for premorbid adjustment [Premorbid Adjustment Scale (PAS)] and cannabis use (CEQ-Revised). We first extracted the Premorbid Social Adjustment Factor (PSA) from PAS and then performedlinear mixed models with PSA as dependent variable and cannabis lifetime (Yes/No) and subject status (Cases/Controls) as independent variables. We then considered “Country” as random intercept.ResultsAcross all countries, PSA scores were better in patients who had smoked cannabis in their lifetime than patients who had not (P = 0.009). The difference in PSA score between cannabis users and non-users was significantly greater in cases than controls (P = 0.038). The relationship between PSA, cannabis lifetime (Yes/No) and subject status among nations (random intercept) is shown on Fig. 1.ConclusionsCannabis-using psychotic patients show better premorbid social adjustment than non-using patients, across 5 European countries.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Both substance use and poor medication adherence are associated with poor outcome in psychosis. To clarify the contributions of substance use and poor medication adherence to poor outcome in the year following a first episode of psychosis, 205 patients were evaluated for use of tobacco, alcohol, cannabis and stimulants at their psychosis onset, and in a 1-year follow-up. Data on medication adherence and symptom remission were also collected. Patients had high rates of overall substance use before (37-65%) and after psychosis onset (45-66%). 44% showed poor medication adherence and 55% did not reach remission from psychosis. Nicotine dependence and cannabis use after psychosis onset significantly predicted both poor medication adherence and non-remission, and poor medication adherence mediated the effects of these substances on non-remission. In conclusion, medication adherence lies on the causal pathway between nicotine dependence and cannabis on the one hand and non-remission on the other.

BackgroundMany studies have reported that cannabis use increases the risk of a first episode of psychosis (FEP). However, only a few studies have investigated the nature of cannabis-related experiences in FEP patients, and none has examined whether these experiences are similar in FEP and general populations. The aim of this study was to explore differences in self-reported cannabis experiences between FEP and non-psychotic populations.MethodA total of 252 subjects, who met International Classification of Diseases (ICD)-10 criteria for FEP, and 217 controls who reported cannabis use were selected from the Genetics and Psychosis (GAP) study. The Medical Research Council Social Schedule and the Cannabis Experience Questionnaire were used to collect sociodemographic data and cannabis use information, respectively.ResultsBoth ‘bad’ and ‘enjoyable’ experiences were more commonly reported by FEP subjects than controls. Principal components factor analysis identified four components which explained 62.3% of the variance. Linear regression analysis on the whole sample showed that the type of cannabis used and beliefs about the effect of cannabis on health all contributed to determining the intensity and frequency of experiences. Linear regression analysis on FEP subjects showed that the duration of cannabis use and amount of money spent on cannabis were strongly related to the intensity and frequency of enjoyable experiences in this population.ConclusionsThese results suggest a higher sensitivity to cannabis effects among people who have suffered their first psychotic episode; this hypersensitivity results in them reporting both more ‘bad’ and ‘enjoyable’ experiences. The greater enjoyment experienced may provide an explanation of why FEP patients are more likely to use cannabis and to continue to use it despite experiencing an exacerbation of their psychotic symptoms.

Objectives Substance abuse is a well established risk factor for First-Episode Psychosis (FEP), but its influence on FEP course is less clear. Starting from our baseline observation that substance users were younger than non-users at the psychosis onset, we hypothesized that substance use at baseline could be an independent risk factor for a worse clinical course. Methods An incidence cohort of patients with FEP collected in an 8 year period (2002–2009) at the Bologna West Community Mental Health Centers (CMHCs) was assessed at baseline and at 12 month follow-up. Drop-out, hospitalizations and service utilization were used as clinical outcomes. Results Most of the patients were still in contact with CMHC at 12 month follow up. Substance users had a significantly higher rate of hospitalizations during the follow-up after adjusting for age, gender and other potential confounders (OR 5.84, 95% CI 2.44–13.97, p ≤ 0.001). Conclusions This study adds to previous evidence showing the independent effect of substance use on FEP course. The identification of a “potentially modifiable” environmental predictor of the course of the illness such as substance use at psychosis onset allows us to envisage the possibility of ameliorating the course of the illness by managing this factor.

UNLABELLED: Cannabis use is associated with an earlier age of onset of psychosis (AOP). However, the reasons for this remain debated. METHODS: We applied a Cox proportional hazards model to 410 first-episode psychosis patients to investigate the association between gender, patterns of cannabis use, and AOP. RESULTS: Patients with a history of cannabis use presented with their first episode of psychosis at a younger age (mean years = 28.2, SD = 8.0; median years = 27.1) than those who never used cannabis (mean years = 31.4, SD = 9.9; median years = 30.0; hazard ratio [HR] = 1.42; 95% CI: 1.16-1.74; P < .001). This association remained significant after controlling for gender (HR = 1.39; 95% CI: 1.11-1.68; P < .001). Those who had started cannabis at age 15 or younger had an earlier onset of psychosis (mean years = 27.0, SD = 6.2; median years = 26.9) than those who had started after 15 years (mean years = 29.1, SD = 8.5; median years = 27.8; HR = 1.40; 95% CI: 1.06-1.84; P = .050). Importantly, subjects who had been using high-potency cannabis (skunk-type) every day had the earliest onset (mean years = 25.2, SD = 6.3; median years = 24.6) compared to never users among all the groups tested (HR = 1.99; 95% CI: 1.50- 2.65; P < .0001); these daily users of high-potency cannabis had an onset an average of 6 years earlier than that of non-cannabis users. CONCLUSIONS: Daily use, especially of high-potency cannabis, drives the earlier onset of psychosis in cannabis users.

Background: A number of studies have reported that patients with psychosis who use cannabis have better cognitive performance than those who do not. This is surprising as cannabis can impair cognition in healthy subjects. An obvious question is whether the better current performance of psychotic patients who have used cannabis is a reflection of their having a higher premorbid IQ than those psychotic patients who haven't used cannabis. Aim: In a sample of patients at their first episode of psychosis, we tested the hypothesis that patients who smoked cannabis would have a higher premorbid IQ than patients who did not. Methodology: 279 participants (119 patients and 160 healthy controls) were assessed in order to obtain current and premorbid IQ measures and detailed information on cannabis use. We examined the association between cannabis use and both premorbid and current IQ in patients and controls. Results: Patients who had ever smoked cannabis had significantly higher current (p < .001) and premorbid IQ (p = .004) compared to patients who had never used cannabis. This difference was not found among controls. Conclusions: These findings suggest that the better cognitive performance of patients with their first episode of psychosis who have used cannabis compared with those who haven't is due to the better premorbid IQ of the former.

Background Cannabis use is associated with an increased risk of psychosis. One study has suggested that genetic variation in the AKT1 gene might influence this effect. Methods In a case-control study of 489 first-episode psychosis patients and 278 control subjects, we investigated the interaction between variation at the AKT1 rs2494732 single nucleotide polymorphism and cannabis use in increasing the risk of psychosis. Results The rs2494732 locus was not associated with an increased risk of a psychotic disorder, with lifetime cannabis use, or with frequency of use. We did, however, find that the effect of lifetime cannabis use on risk of psychosis was significantly influenced by the rs2494732 locus (likelihood ratio statistic for the interaction=8.54; p = .014). Carriers of the C/C genotype with a history of cannabis use showed a greater than twofold increased likelihood of a psychotic disorder (odds ratio=2.18 [95% confidence interval: 1.12, 4.31]) when compared with users who were T/T carriers. Moreover, the interaction between the rs2494732 genotype and frequency of use was also significant at the 5% level (likelihood ratio=13.39; p = .010). Among daily users, C/C carriers demonstrated a sevenfold increase in the odds of psychosis compared with T/T carriers (odds ratio=7.23 [95% confidence interval: 1.37, 38.12]). Conclusions Our findings provide strong support for the initial report that genetic variation at rs2494732 of AKT1 influences the risk of developing a psychotic disorder in cannabis users.