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The EU-GEI Project was funded by grant agreement Health-F2-2010-241909 from the European Community’s Seventh Framework program. The Brazilian study was funded by grant 2012-0417-0 from the São Paulo Research Foundation, D'Andrea, Giuseppe; Lal, Jatin; Tosato, Sarah;Gayer-Anderson, Charlotte;Jongsma, Hannah E.;Stilo, Simona A.; van der Ven, Els;Quattrone, Diego;Velthorst, Eva;Berardi, Domenico;Rossi Menezes, Paulo; Arango, Celso; Parellada, Mara; Lasalvia, Antonio; La Cascia, Caterina; Ferraro, Laura; La Barbera, Daniele; Sideli, Lucia; Bobes, Julio; Bernardo, Miguel; Sanjuan, Julio; Santos, Jose Luis; Arrojo, Manuel; Marta Del-Ben, Cristina; Tripoli, Giada; Llorca, Pierre-Michel; de Haan, Lieuwe; Selten, Jean-Paul; Tortelli, Andrea; Szoke, Andrei; Muratori, Roberto; Rutten, Bart P.; van Os, Jim; Jones, Peter B.; Kirkbride, James B.; Murray, Robin M.; di Forti, Marta; Tarricone, Ilaria; Morgan, Craig

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 =

Introduction The neural correlates of the cognitive dysfunction in first-episode psychosis (FEP) are still unclear. The present review and meta-analysis provide an update of the location of the abnormalities in the fMRI-measured brain response to cognitive processes in individuals with FEP. Methods Systematic review and voxel-based meta-analysis of cross-sectional fMRI studies comparing neural responses to cognitive tasks between individuals with FEP and healthy controls (HC) according to PRISMA guidelines. Results Twenty-six studies were included, comprising 598 individuals with FEP and 567 HC. Individual studies reported statistically significant hypoactivation in the dorsolateral prefrontal cortex (6 studies), frontal lobe (8 studies), cingulate (6 studies) and insula (5 studies). The meta-analysis showed statistically significant hypoactivation in the left anterior insula, precuneus and bilateral striatum. Conclusions While the studies tend to highlight frontal hypoactivation during cognitive tasks in FEP, our meta-analytic results show that the left precuneus and insula primarily display aberrant activation in FEP that may be associated with salience attribution to external stimuli and related to deficits in perception and regulation.

Background To date, a large number of functional magnetic resonance imaging (fMRI) studies have been conducted on psychosis. However, little is known about changes in brain functioning in psychotic patients using an emotional auditory paradigm at different stages of the disease. Such knowledge is important for advancing our understanding of the disorder and thus creating more targeted interventions. This study aimed to investigate whether individuals with first-episode psychosis (FEP) and chronic schizophrenia show abnormal brain responses to emotional auditory processing and to compare the responses between FEP and chronic schizophrenia. Methods Patients with FEP (n = 31) or chronic schizophrenia (n = 23) and healthy controls (HCs, n = 31) underwent an fMRI scan while presented with both emotional and nonemotional words. Results Using HC as a reference, patients with FEP showed decreased right temporal activation, while patients with chronic schizophrenia showed increased bilateral temporal activation. When comparing the patient groups, individuals with FEP showed lower frontal lobe activation. Conclusion To the best of our knowledge, this is the first study with an emotional auditory paradigm used in psychotic patients at different stages of the disease. Our results suggested that the temporal lobe might be a key issue in the physiopathology of psychosis, although abnormal activation could also be derived from a connectivity problem. There is lower activation in the early stage and evolution to greater activation when patients become chronic. This study highlights the relevance of using emotional paradigms to better understand brain activation at different stages of psychosis.

The EUGEI project was supported by the European Community's Seventh Framework Program under grant agreement No. HEALTH-F2-2009-241909 (Project EU-GEI). Dr O'Donovan is supported by MRC programme grant (G08005009) and an MRC Centre grant (MR/L010305/1), Henquet, C., Van Os, J., Pries, L.K., Rauschenberg, C., Delespaul, P., Kenis, G., Luykx, J.J., Lin, B.D., Richards, A.L., Akdede, B., Binbay, T., Altlnyazar, V., Yallnçetin, B., Gümüş-Akay, G., Cihan, B., Soygür, H., Ulaş, H., Cankurtaran, E.S., Kaymak, S.U., Mihaljevic, M.M., Petrovic, S.S., Mirjanic, T., Bernardo, M., Mezquida, G., Amoretti, S., Bobes, J., Saiz, P.A., Garciá-Portilla, M.P., Sanjuan, J., Aguilar, E.J., Santos, J.L., Jiménez-López, E., Arrojo, M., Carracedo, A., López, G., González-Penãs, J., Parellada, M., Maric, N.P., Atbaşoelu, C., Ucok, A., Alptekin, K., Saka, M.C., Arango, C., O'Donovan, M., Rutten, B.P.F., Gülöksüz, S.

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.

BackgroundThere is evidence that environmental and genetic risk factors for schizophrenia spectrum disorders are transdiagnostic and mediated in part through a generic pathway of affective dysregulation.MethodsWe analysed to what degree the impact of schizophrenia polygenic risk (PRS-SZ) and childhood adversity (CA) on psychosis outcomes was contingent on co-presence of affective dysregulation, defined as significant depressive symptoms, in (i) NEMESIS-2 (n = 6646), a representative general population sample, interviewed four times over nine years and (ii) EUGEI (n = 4068) a sample of patients with schizophrenia spectrum disorder, the siblings of these patients and controls.ResultsThe impact of PRS-SZ on psychosis showed significant dependence on co-presence of affective dysregulation in NEMESIS-2 [relative excess risk due to interaction (RERI): 1.01, p = 0.037] and in EUGEI (RERI = 3.39, p = 0.048). This was particularly evident for delusional ideation (NEMESIS-2: RERI = 1.74, p = 0.003; EUGEI: RERI = 4.16, p = 0.019) and not for hallucinatory experiences (NEMESIS-2: RERI = 0.65, p = 0.284; EUGEI: −0.37, p = 0.547). A similar and stronger pattern of results was evident for CA (RERI delusions and hallucinations: NEMESIS-2: 3.02, p < 0.001; EUGEI: 6.44, p < 0.001; RERI delusional ideation: NEMESIS-2: 3.79, p < 0.001; EUGEI: 5.43, p = 0.001; RERI hallucinatory experiences: NEMESIS-2: 2.46, p < 0.001; EUGEI: 0.54, p = 0.465).ConclusionsThe results, and internal replication, suggest that the effects of known genetic and non-genetic risk factors for psychosis are mediated in part through an affective pathway, from which early states of delusional meaning may arise.

BackgroundIn Europe, the incidence of psychotic disorder is high in certain migrant and minority ethnic groups (hence: ‘minorities’). However, it is unknown how the incidence pattern for these groups varies within this continent. Our objective was to compare, across sites in France, Italy, Spain, the UK and the Netherlands, the incidence rates for minorities and the incidence rate ratios (IRRs, minorities v. the local reference population).MethodsThe European Network of National Schizophrenia Networks Studying Gene–Environment Interactions (EU-GEI) study was conducted between 2010 and 2015. We analyzed data on incident cases of non-organic psychosis (International Classification of Diseases, 10th edition, codes F20–F33) from 13 sites.ResultsThe standardized incidence rates for minorities, combined into one category, varied from 12.2 in Valencia to 82.5 per 100 000 in Paris. These rates were generally high at sites with high rates for the reference population, and low at sites with low rates for the reference population. IRRs for minorities (combined into one category) varied from 0.70 (95% CI 0.32–1.53) in Valencia to 2.47 (95% CI 1.66–3.69) in Paris (test for interaction: p = 0.031). At most sites, IRRs were higher for persons from non-Western countries than for those from Western countries, with the highest IRRs for individuals from sub-Saharan Africa (adjusted IRR = 3.23, 95% CI 2.66–3.93).ConclusionsIncidence rates vary by region of origin, region of destination and their combination. This suggests that they are strongly influenced by the social context.

Common genetic variants ofFOXP2may contribute to schizophrenia vulnerability, but controversial results have been reported for this proposal. Here we evaluated the potential impact of the commonFOXP2rs2396753 polymorphism in schizophrenia. It was previously reported to be part of a risk haplotype for this disease and to have significant effects on gray matter concentration in the patients. We undertook the first examination into whether rs2396753 affects the brain expression ofFOXP2and a replication study of earlier neuroimaging findings of the influence of this genetic variant on brain structure.FOXP2expression levels were measured in postmortem prefrontal cortex samples of 84 male subjects (48 patients and 36 controls) from the CIBERSAM Brain and the Stanley Foundation Array Collections. High-resolution anatomical magnetic resonance imaging was performed on 79 male subjects (61 patients, 18 controls) using optimized voxel-based morphometry. We found differences inFOXP2expression and brain morphometry depending on the rs2396753, relating lowFOXP2mRNA levels with reduction of gray matter density. We detected an interaction between rs2396753 and the clinical groups, showing that heterozygous patients for this polymorphism have gray matter density decrease and lowFOXP2expression comparing with the heterozygous controls. This study shows the importance of independent replication of neuroimaging genetic studies ofFOXP2as a candidate gene in schizophrenia. Furthermore, our results suggest that theFOXP2rs2396753 affects mRNA levels, thus providing new knowledge about its significance as a potential susceptibility polymorphism in schizophrenia. The genomic DNA and RNA samples corresponding to the Array Collection were donated by the Stanley Medical Research Institute Brain Collection courtesy of Drs. Michael B. Knable, E. Fuller Torrey, Maree J. Webster, and Robert H. Yolken. The postmortem human brain tissues were donated by the Brain Collections of the Spanish National Network for Research in Mental Health CIBERSAM. The authors also thank the collaboration of the staff members of the Basque Institute of Legal Medicine, Sant Joan de Deu Foundation and the Psychiatry Unit of Hospital Clinico of Valencia. XHC was supported by a postdoctoral fellowship from CONACYT, Mexico; NSO and JGJ were recipients of research contracts from CIBERSAM, Spain.

BackgroundMotor abnormalities (MAs) are the primary manifestations of schizophrenia. However, the extent to which MAs are related to alterations of subcortical structures remains understudied.MethodsWe aimed to investigate the associations of MAs and basal ganglia abnormalities in first-episode psychosis (FEP) and healthy controls. Magnetic resonance imaging was performed on 48 right-handed FEP and 23 age-, gender-, handedness-, and educational attainment-matched controls, to obtain basal ganglia shape analysis, diffusion tensor imaging techniques (fractional anisotropy and mean diffusivity), and relaxometry (R2*) to estimate iron load. A comprehensive motor battery was applied including the assessment of parkinsonism, catatonic signs, and neurological soft signs (NSS). A fully automated model-based segmentation algorithm on 1.5T MRI anatomical images and accurate corregistration of diffusion and T2* volumes and R2* was used.ResultsFEP patients showed significant local atrophic changes in left globus pallidus nucleus regarding controls. Hypertrophic changes in left-side caudate were associated with higher scores in sensory integration, and in right accumbens with tremor subscale. FEP patients showed lower fractional anisotropy measures than controls but no significant differences regarding mean diffusivity and iron load of basal ganglia. However, iron load in left basal ganglia and right accumbens correlated significantly with higher extrapyramidal and motor coordination signs in FEP patients.ConclusionsTaken together, iron load in left basal ganglia may have a role in the emergence of extrapyramidal signs and NSS of FEP patients and in consequence in the pathophysiology of psychosis.

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

Smoking prevalence in schizophrenia is considerably larger than in general population, playing an important role in early mortality. We compared the polygenic contribution to smoking in schizophrenic patients and controls to assess if genetic factors may explain the different prevalence. Polygenic risk scores (PRSs) for smoking initiation and four genetically correlated traits were calculated in 1108 schizophrenic patients (64.4% smokers) and 1584 controls (31.1% smokers). PRSs for smoking initiation, educational attainment, body mass index and age at first birth were associated with smoking in patients and controls, explaining a similar percentage of variance in both groups. Attention-deficit hyperactivity disorder (ADHD) PRS was associated with smoking only in schizophrenia. This association remained significant after adjustment by psychiatric cross-disorder PRS. A PRS combining all the traits was more explanative than smoking initiation PRS alone, indicating that genetic susceptibility to the other traits plays an additional role in smoking behaviour. Smoking initiation PRS was also associated with schizophrenia in the whole sample, but the significance was lost after adjustment for smoking status. This same pattern was observed in the analysis of specific SNPs at the CHRNA5-CHRNA3-CHRNB4 cluster associated with both traits. Overall, the results indicate that the same genetic factors are involved in smoking susceptibility in schizophrenia and in general population and are compatible with smoking acting, directly or indirectly, as a risk factor for schizophrenia that contributes to the high prevalence of smoking in these patients. The contrasting results for ADHD PRS may be related to higher ADHD symptomatology in schizophrenic patients.

Resumen Objetivos Evaluar si los inhibidores de la colinesterasa pueden inducir mania, y determinar si este efecto puede estar relacionado con estados u otras caracteristicas previas de los pacientes. Metodo Se realizo una revision sistematica, incluyendo articulos publicados en ISI Web of Knowledge y PubMed, desde enero de 1990 a marzo de 2018, siguiendo criterios PRISMA. Resultados De 326 estudios identificados, se incluyeron en la revision 16. En los casos comunicados hay una correlacion entre la introduccion de un inhibidor de la colinesterasa y la aparicion de un episodio maniaco/hipomaniaco. El riesgo parece ser mayor si el paciente tiene antecedentes de trastorno afectivo y si esta tomando medicacion antidepresiva. Conclusiones Los inhibidores de la colinesterasa pueden inducir mania en algunos pacientes. Mas estudios son necesarios para una mejor comprension de este fenomeno; se deben tomar precauciones al prescribir estos farmacos en pacientes de riesgo.

Background Auditory hallucinations (AH) are a core symptom of psychosis. The brain abnormalities responsible for AH remain controversial due to inconsistent and conflicting findings across studies, with substantial confounding factors, such as chronicity. Few studies have examined the pathological changes that occur in the gray matter (GM) of patients with first-episode psychosis (FEP) and AH. The present study aims to validate the presence and characteristics of these structural abnormalities in relation to the intensity of psychotic symptoms and AH in a larger homogeneous sample than those of previous studies. Methods A magnetic resonance voxel-based morphometric analysis was applied to a group of 215 patients with FEP (93 patients with AH and 122 patients without AH) and 177 healthy controls. The patients were evaluated using the PANSS scale. Results: Patients with FEP exhibited greater reductions in GM concentrations in the temporal, frontal, cingulate and insular areas than the healthy controls did. No specific differences were found between the patients with FEP and AH and the patients without AH. In addition, total scores on the PANSS were negatively correlated with GM reductions in the FEP group. No correlations were found between the severity of the AH and the GM volumes. Conclusions As in previous studies, reductions in the GM concentrations in patients with FEP suggest that alterations are present in the early stages of psychosis, and these alterations are correlated with the severity of the illness. The GM reductions were not found to be related to the presence or severity of AH.

Objective Neurological correlates of impaired insight in non-affective psychosis remain unclear. This study aimed to review and meta-analyze the studies assessing the grey matter volumetric correlates of impaired insight in non-affective psychosis. Methods This study consisted of a systematic review of 23 studies, and a meta-analysis with SDM-PSI of the 11 studies that were whole-brain and reported maps or peaks of correlation of studies investigating the grey matter volumetric correlates of insight assessments of non-affective psychosis, PubMed and OVID datasets were independently reviewed for articles reporting neuroimaging correlates of insight in non-affective psychosis. Quality assessment was realized following previous methodological approaches for the ABC quality assessment test of imaging studies, based on two main criteria: the statistical power and the multidimensional assessment of insight. Study peaks of correlation between grey matter volume and insight were used to recreate brain correlation maps. Results A total of 418 records were identified through database searching. Of these records, twenty-three magnetic resonance imaging (MRI) studies that used different insight scales were included. The quality of the evidence was high in 11 studies, moderate in nine, and low in three. Patients with reduced insight showed decreases in the frontal, temporal (specifically in superior temporal gyrus), precuneus, cingulate, insula, and occipital lobes cortical grey matter volume. The meta-analysis indicated a positive correlation between grey matter volume and insight in the right insula (i.e., the smaller the grey matter, the lower the insight). Conclusion Several brain areas might be involved in impaired insight in patients with non-affective psychoses. The methodologies employed, such as the applied insight scales, may have contributed to the considerable discrepancies in the findings.

European Community's Seventh Framework Program, European Commission [HEALTH-F2-2009-241909]; Scientific and Technological Research Council of Turkey, 2219 International Postdoctoral Research Fellowship Program; Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (SAM16PE07CP1, PI16/02012, and PI19/024)..., Erzin, G., Pries, L.-K., van Os, J., Fusar-Poli, L., Delespaul, P., Kenis, G., Luykx, J.J., Lin, B.D., Richards, A.L., Akdede, B., Binbay, T., Altınyazar, V., Yalınçetin, B., Gümüş-Akay, G., Cihan, B., Soygür, H., Ulaş, H., Cankurtaran, E.Ş., Kaymak, S.U., Mihaljevic, M.M., Andric-Petrovic, S., Mirjanic, T., Bernardo, M., Mezquida, G., Amoretti, S., Bobes, J., Saiz, P.A., García-Portilla, M.P., Sanjuan, J., Aguilar, E.J., Santos, J.L., Jiménez-López, E., Arrojo, M., Carracedo, A., López, G., González-Peñas, J., Parellada, M., Maric, N.P., Atbaşoğlu, C., Ucok, A., Alptekin, K., Saka, M.C., Arango, C., O'Donovan, M.C., Rutten, B.P.F., Guloksuz, S., Genetic Risk and Outcome of Psychosis (GROUP) investigators

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.

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.

The EUGEI project was supported by the European Community’s Seventh Framework Program under grant agreement No. HEALTH-F2- 2009-241909 (Project EU-GEI). Dr. Arango was supported by the Spanish Ministry of Science and Innovation; Instituto de Salud Carlos III (SAM16-PE07CP1, PI16/02012, PI19/024); CIBERSAM (...), Fusar-Poli, L; Pries, LK; van Os, J; Erzin, G; Delespaul, P; Kenis, G; Luykx, JJ; Lin, BCD; Richards, AL; Akdede, B; Binbay, T; Altinyazar, V; Yalincetin, B; Gumus-Akay, G; Cihan, B; Soygur, H; Ulas, H; Cankurtaran, ES; Kaymak, SU; Mihaljevic, MM; Andric-Petrovic, S; Mirjanic, T; Bernardo, M; Mezquida, G; Amoretti, S; Bobes, J; Saiz, PA; Garcia-Portilla, MP; Sanjuan, J; Aguilar, EJ; Santos, JL; Jimenez-Lopez, E; Arrojo, M; Carracedo, A; Lopez, G; Gonzalez-Penas, J; Parellada, M; Maric, NP; Atbasoglu, C; Ucok, A; Alptekin, K; Saka, MC; Aguglia, E; Arango, C; O'Donovan, M; Rutten, BPF; Guloksuz, S

Importance: Psychotic disorders contribute significantly to the global disease burden, yet the latest international incidence study of psychotic disorders was conducted in the 1980s. Objectives: To estimate the incidence of psychotic disorders using comparable methods across 17 catchment areas in 6 countries and to examine the variance between catchment areas by putative environmental risk factors. Design, Setting, and Participants: An international multisite incidence study (the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions) was conducted from May 1, 2010, to April 1, 2015, among 2774 individuals from England (2 catchment areas), France (3 catchment areas), Italy (3 catchment areas), the Netherlands (2 catchment areas), Spain (6 catchment areas), and Brazil (1 catchment area) with a first episode of nonorganic psychotic disorders (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] codes F20-F33) confirmed by the Operational Criteria Checklist. Denominator populations were estimated using official national statistics. Exposures: Age, sex, and racial/ethnic minority status were treated as a priori confounders. Latitude, population density, percentage unemployment, owner-occupied housing, and single-person households were treated as catchment area-level exposures. Main Outcomes and Measures: Incidence of nonorganic psychotic disorders (ICD-10 codes F20-F33), nonaffective psychoses (ICD-10 codes F20-F29), and affective psychoses (ICD-10 codes F30-F33) confirmed by the Operational Criteria Checklist. Results: A total of 2774 patients (1196 women and 1578 men; median age, 30.5 years [interquartile range, 23.0-41.0 years]) with incident cases of psychotic disorders were identified during 12.9 million person-years at risk (crude incidence, 21.4 per 100 000 person-years; 95% CI, 19.4-23.4 per 100 000 person-years). A total of 2183 patients (78.7%) had nonaffective psychotic disorders. After direct standardization for age, sex, and racial/ethnic minority status, an 8-fold variation was seen in the incidence of all psychotic disorders, from 6.0 (95% CI, 3.5-8.6) per 100 000 person-years in Santiago, Spain, to 46.1 (95% CI, 37.3-55.0) per 100 000 person-years in Paris, France. Rates were elevated in racial/ethnic minority groups (incidence rate ratio, 1.6; 95% CI, 1.5-1.7), were highest for men 18 to 24 years of age, and were lower in catchment areas with more owner-occupied homes (incidence rate ratio, 0.8; 95% CI, 0.7-0.8). Similar patterns were observed for nonaffective psychoses; a lower incidence of affective psychoses was associated with higher area-level unemployment (incidence rate ratio, 0.3; 95% CI, 0.2-0.5). Conclusions and Relevance: This study confirmed marked heterogeneity in risk for psychotic disorders by person and place, including higher rates in younger men, racial/ethnic minorities, and areas characterized by a lower percentage of owner-occupied houses., 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. The Brazilian study was funded by grant 2012/0417-0 from the São Paulo Research Foundation. Dr Kirkbride is funded by the Wellcome Trust and grant 101272/Z/13/Z from the Royal Society. Ms Jongsma and Dr Jones are funded by the National Institute of Health Research Collaboration of Leadership in Applied Health Research and Care East of England.

The EUGEI project was supported by the European Community’s Seventh Framework Program under grant agreement no. HEALTH-F2-2009-241909 (Project EU-GEI). Dr O’Donovan is supported by MRC programme grant (G08005009) and an MRC Centre grant (MR/ L010305/1). Dr Rutten was funded by a VIDI award number 91718336 from the Netherlands Scientific Organisation. Drs Guloksuz and van Os are supported by the Ophelia research project, ZonMw grant number: 636340001. Dr Arango was supported by the Spanish Ministry of Science and Innovation; Instituto de Salud Carlos III (SAM16PE07CP1, PI16/02012, PI19/024); CIBERSAM; Madrid Regional Government (B2017/BMD-3740, AGES-CM-2); Fundación Familia Alonso and Fundación Alicia Koplowitz., Pries, L.-K., Dal Ferro, G.A., Van Os, J., Delespaul, P., Kenis, G., Lin, B.D., Luykx, J.J., Richards, A.L., Akdede, B., Binbay, T., Altlnyazar, V., Yallnçetin, B., Gümüş-Akay, G., Cihan, B., Soygür, H., Ulaş, H., Åžahin Cankurtaran, E., Ulusoy Kaymak, S., Mihaljevic, M.M., Andric Petrovic, S., Mirjanic, T., Bernardo, M., Mezquida, G., Amoretti, S., Bobes, J., Saiz, P.A., Garciá-Portilla, M.P., Sanjuan, J., Aguilar, E.J., Santos, J.L., Jiménez-López, E., Arrojo, M., Carracedo, A., López, G., González-Penãs, J., Parellada, M., Maric, N.P., AtbaşoÄalu, C., Ucok, A., Alptekin, K., Can Saka, M., Arango, C., O'Donovan, M., Tosato, S., Rutten, B.P.F., Guloksuz, S., and Genetic Risk and Outcome of Psychosis (GROUP) investigators

[EN] Background: eHealth interventions are widely used in clinical trials and increasingly in care settings as well; however, their efficacy in real-world contexts remains unknown. ReMindCare is a smartphone app that has been systematically implemented in a first episode of psychosis program (FEPP) for patients with early psychosis since 2018. Objective: The objective of this study was to assess the efficacy of ReMindCare after 19 months of use in the clinic and varying use by individual patients. Methods: The integration of the ReMindCare app into the FEPP started in October 2018. Patients with early psychosis self-selected to the app (ReMindCare group) or treatment as usual (TAU group). The outcome variables considered were adherence to the intervention and number of relapses, hospital admissions, and visits to urgent care units. Data from 90 patients with early psychosis were analyzed: 59 in the ReMindCare group and 31 in the TAU group. The mean age of the sample was 32.8 (SD 9.4) years, 73% (66/90) were males, 91% (83/90) were White, and 81% (74/90) were single. Results: Significant differences between the ReMindCare and TAU groups were found in the number of relapses, hospitalizations, and visits to urgent care units, with each showing benefits for the app. Only 20% (12/59) of patients from the ReMindCare group had a relapse, while 58% (18/31) of the TAU patients had one or more relapses (chi(2) =13.7, P=.001). Moreover, ReMindCare patients had fewer visits to urgent care units (chi(2) =7.4, P=.006) and fewer hospitalizations than TAU patients (chi(2) =4.6, P=.03). The mean of days using the app was 352.2 (SD 191.2; min/max: 18-594), and the mean of engagement was 84.5 (SD 16.04). Conclusions: To our knowledge, this is the first eHealth intervention that has preliminarily proven its benefits in the real-world treatment of patients with early psychosis., This study was supported by the Sanitary Research Institute of the University Clinic Hospital and the Mental Health Networking Biomedical Centre. It was also supported by the Generalitat Valenciana and the Program for Scientific Research, Technological Development, and Innovation in the Generalitat Valenciana of the European Union (2017/9830). It was also supported by grants from the Generalitat Valenciana (PROMETEO/2016/082, PROMETEO/2020/024), Carlos III Health Institute (PI13/00447; PI17/00402), and European Union through the European Regional Development Fund.

Auditory verbal hallucinations (AVHs) in schizophrenia have been characterized by their negative emotional valence. However, positive hallucinations have also been described. The objective of the current study is to explore the prevalence, course, characteristics, and associations of positive and useful voices. The Positive and Useful Voices Inquiry and some clinical and functioning instruments were administered to a sample of 68 patients with schizophrenia or schizoaffective disorder presenting with AVHs. Both the lifetime and current prevalences of positive and useful voices were high. Although AVHs tended to remain stable, there was a trend to decrease over time. The strongest positive attributions of such voices were that they help patients to feel important, amuse them, and help them to conduct their studies and carry out their profession. They seem to be mainly related to more grandiosity and to worse general functioning. Interference with biological and psychological treatments and the need for personalized formulations in patients with auditory hallucinations are discussed.

Suicidability has been associated with neuroticism and psychoticism, but its role during perinatal period has not been analyzed. We explore the association between personality dimensions, depressive symptoms, and other psychosocial variables in postpartum suicidal ideation. A cohort of 1795 healthy Spanish women from the general population was assessed for suicidal ideation (EPDS-Item10) in early postpartum, 8 and 32 weeks postpartum. Sociodemographic, obstetric, and reproductive variables, psychiatric history, social support, stressful life-events during pregnancy, depressive symptoms (EPDS), and the Eysenck's personality dimensions (EPQ-RS) were also assessed at baseline. A major depressive episode (DSM-IV) was confirmed in women with EPDS>10 at follow-up assessments. Descriptive, bivariate, and multivariate analyses were conducted. Adjusted logistic regression analysis was reported as odds ratio (ORs) with 95% confidence intervals (CIs). Seven percent of mothers reported suicidal ideation during the first 8 months postpartum. Sixty-two percent of women with suicidal ideation had a major depressive episode at 8 weeks, and 70% at 32 weeks postpartum. Neuroticism and psychoticism predicted suicidal ideation throughout the first 2 weeks after delivery (OR, 1.03; 95%CI 1.01-1.06; and OR, 1.03; 95%CI 1.01-1.05 respectively). Early postpartum depressive symptoms (OR 1.2; 95%CI 1.11-1.26), personal psychiatric history (OR 2.1; 95%CI 1.33-3.27), and stressful life events during pregnancy (OR 1.88; 95%CI 1.12-3.16) also emerged as predictors of postpartum suicidal ideation. Analysis of women for postpartum suicidal ideation should include not only psychiatric symptoms but also psychosocial assessment (i.e., covering psychiatric history, stressful events, or long-standing personality vulnerabilities) in order to identify those in need of early psychosocial or psychiatric care.

International audience

Resumen Hay un creciente interes en las intervenciones mobile Health (m-Health) en pacientes con psicosis. El objetivo de este estudio es realizar una revision sistematica para analizar el estado actual de la investigacion en este ambito. La busqueda de publicaciones se llevo a cabo siguiendo los criterios PRISMA, centrandose en aquellos estudios que utilizan tecnologias moviles en pacientes con psicosis durante el periodo de 1990 a 2016. Se selecciono un total de 20 articulos de los 431 estudios que se encontraron. Se diferencian 3 tipos de intervenciones: 1) analisis de calidad y usabilidad; 2) mejora de la adherencia, sintomas y reduccion de hospitalizaciones, y 3) analisis de la sintomatologia del paciente. Conclusion: Las intervenciones m-Health son viables y resultan faciles de utilizar para los pacientes con psicosis. Evaluan de forma mas eficiente la evolucion de los sintomas psicoticos y mejoran la adherencia al tratamiento, los sintomas y las hospitalizaciones. No se puede destacar una estrategia sobre las demas debido a que las diferencias en la metodologia las hace dificilmente comparables.

There is now sufficient evidence to support the importance of interventions in the early stages of psychosis. The delay in the detection and treatment of the first-episode psychosis is related to a lower and slower recovery, as well as a higher risk of relapse. Despite this fact, early intervention units or teams are still not regularly implemented in mental health service settings in Spain. In this opinion article, a review is presented of the main arguments for defending the need to implement these programmes and strategies in order to achieve this aim. There are a number of programmes for early intervention for psychosis currently working in other countries, with a therapeutic programme that includes pharmacological and psychosocial interventions, together with public awareness, information dissemination, and family-professional collaboration activities. Published literature on the experience of these programmes indicates that early intervention is not only effective in terms of the improvement of health status, but is also economically efficient. The main steps and recommendations needed to implement such early intervention programmes in our country are described.

Schizophrenia is a clinically heterogeneous syndrome affecting multiple dimensions of patients’ life. Therefore, its treatment might require a multidimensional approach that should take into account the efficacy (the ability of an intervention to get the desired result under ideal conditions), the effectiveness (the degree to which the intended effect is obtained under routine clinical practice conditions or settings) and the efficiency (value of the intervention as relative to its cost to the individual or society) of any therapeutic intervention. In a first step of the process, a group of 90 national experts from different areas of health-care and with a multidimensional and multidisciplinary perspective of the disease, defined the concepts of efficacy, effectiveness and efficiency of established therapeutic interventions within 7 key dimensions of the illness: symptomatology; comorbidity; relapse and adherence; insight and subjective experience; cognition; quality of life, autonomy and functional capacity; and social inclusion and associated factors. The main conclusions and recommendations of this stage of the work are presented herein.

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 Alterations in the structure and physiology of interneurons in the prefrontal cortex (PFC) are important factors in the etiopathology of different psychiatric disorders. Among the interneuronal subpopulations, parvalbumin (PV) expressing cells appear to be specially affected. Interestingly, during development and adulthood the connectivity of these interneurons is regulated by the presence of perineuronal nets (PNNs), specialized regions of the extracellular matrix, which are frequently surrounding PV expressing neurons. Previous reports have found anomalies in the density of PNNs in the PFC of schizophrenic patients. However, although some studies have described alterations in PNNs in some extracortical regions of bipolar disorder patients, there are no studies focusing on the prefrontocortical PNNs of bipolar or major depression patients. For this reason, we have analyzed the density of PNNs in post-mortem sections of the dorsolateral PFC (DLPFC) from the Stanley Neuropathology Consortium, which includes controls, schizophrenia, bipolar and major depression patients. Results We have not observed differences in the distribution of PV+ cells or PNNs, or in the percentage of PV+ interneurons surrounded by PNNs. The density of PV+ interneurons was similar in all the experimental groups, but there was a significantly lower density of PNNs in the DLPFC of bipolar disorder patients and a tendency towards a decrease in schizophrenic patients. No differences were found when evaluating the density of PV+ cells surrounded by PNNs. Interestingly, when assessing the influence of demographic data, we found an inverse correlation between the density of PNNs and the presence of psychosis. Conclusions The present results point to prefrontocortical PNNs and their role in the regulation of neuronal plasticity as putative players in the etiopathology of bipolar disorder and schizophrenia. Our findings also suggest a link between these specialized regions of the extracellular matrix and the presence of psychosis.

BackgroundFirst-degree relatives of patients with psychotic disorder have higher levels of polygenic risk (PRS) for schizophrenia and higher levels of intermediate phenotypes.MethodsWe conducted, using two different samples for discovery (n = 336 controls and 649 siblings of patients with psychotic disorder) and replication (n = 1208 controls and 1106 siblings), an analysis of association between PRS on the one hand and psychopathological and cognitive intermediate phenotypes of schizophrenia on the other in a sample at average genetic risk (healthy controls) and a sample at higher than average risk (healthy siblings of patients). Two subthreshold psychosis phenotypes, as well as a standardised measure of cognitive ability, based on a short version of the WAIS-III short form, were used. In addition, a measure of jumping to conclusion bias (replication sample only) was tested for association with PRS.ResultsIn both discovery and replication sample, evidence for an association between PRS and subthreshold psychosis phenotypes was observed in the relatives of patients, whereas in the controls no association was observed. Jumping to conclusion bias was similarly only associated with PRS in the sibling group. Cognitive ability was weakly negatively and non-significantly associated with PRS in both the sibling and the control group.ConclusionsThe degree of endophenotypic expression of schizophrenia polygenic risk depends on having a sibling with psychotic disorder, suggestive of underlying gene–environment interaction. Cognitive biases may better index genetic risk of disorder than traditional measures of neurocognition, which instead may reflect the population distribution of cognitive ability impacting the prognosis of psychotic disorder.

Background During last years, there has been an intensive search for blood biomarkers in schizophrenia to assist in diagnosis, prognosis and clinical management of the disease. Methods In this study, we first conducted a weighted gene coexpression network analysis to address differentially expressed genes in peripheral blood from patients with chronic schizophrenia (n?=?30) and healthy controls (n?=?15). The discriminating performance of the candidate genes was further tested in an independent cohort of patients with first-episode schizophrenia (n?=?124) and healthy controls (n?=?54), and in postmortem brain samples (cingulate and prefrontal cortices) from patients with schizophrenia (n?=?34) and healthy controls (n?=?35). Results The expression of the Eukaryotic Translation Initiation Factor 2D (EIF2D) gene, which is involved in protein synthesis regulation, was increased in the chronic patients of schizophrenia. On the contrary, the expression of the Thymocyte Selection-Associated High Mobility Group Box (TOX) gene, involved in immune function, was reduced. EIF2D expression was also altered in first-episode schizophrenia patients, but showing reduced levels. Any of the postmortem brain areas studied did not show differences of expression of both genes. Conclusions EIF2D and TOX are putative blood markers of chronic patients of schizophrenia, which expression change from the onset to the chronic disease, unraveling new biological pathways that can be used for the development of new intervention strategies in the diagnosis and prognosis of schizophrenia disease. Acknowledgments: This work was supported by Fondo de Investigación Sanitaria, Ministerio de Economía y Competitividad, Spain (PI10/01399, PI13/00447; PI17/00402, co-financed by FEDER) to J. Sanjuan and M.D. Moltó; Generalitat Valenciana PROMETEO Excellence Program, Spain (PROMETEO2016/082) to J Sanjuán. J Gilabert-Juan and N. Sebastiá-Ortega were recipients of research contracts from CIBERSAM, Spain. The RNA samples donated bythe Stanley Medical Research Institute Brain Collection were courtesy of Drs. Michael B. Knable, E. Fuller Torrey, Maree J. Webster, and Robert H. Yolken. The authors also thank the collaboration of the staff members of the hospitals.

[EN] Aim Despite the potential benefits of e-health interventions for patients with psychosis, the integration of these applications into the clinical workflow and analysis of their long-term effects still face significant challenges. To address these issues, we developed the ReMindCare app. This app aims to improve the treatment quality for patients with psychosis. We chose to study the app in real world and pragmatic manner to ensure results will be generalizable. Methods This is a naturalistic empirical study of patients in a first episode of psychosis programme. The app was purpose-designed based on two previous studies, and it offers the following assessments: (a) three daily questions regarding anxiety, sadness and irritability; and (b) 18 weekly questions about medication adherence, medication side effects, medication attitudes and prodromal symptoms. The app offers preset alerts, reminders and the ability for patients to reach out to their clinicians. Data captured by the app are linked to the electronic medical record of the patient. Patients will use the app as part of their ongoing care for a maximum period of 5 years, and assessments will occur at baseline and at the end of the first, second and fifth years of app use. Results Recruitment started in October 2018 and is still ongoing. Conclusions The ReMindCare app represents early real-world use of digital mental health tools that offer direct integration into clinical care. High retention and compliance rates are expected, and this will in turn lead to improved quality of assessments and communication between patients and clinicians., Centro de Investigacion Biomedica en Red de Salud Mental; European Social Fund, Grant/Award Number: 2017/9830; Generalitat Valenciana, Grant/Award Number: PROMETEO/2016/082; Instituto de Salud Carlos III, Grant/Award Numbers: PI01399, PI13/00447, PI17/00402

BackgroundThe “jumping to conclusions” (JTC) bias is associated with both psychosis and general cognition but their relationship is unclear. In this study, we set out to clarify the relationship between the JTC bias, IQ, psychosis and polygenic liability to schizophrenia and IQ.Methods817 FEP patients and 1294 population-based controls completed assessments of general intelligence (IQ), and JTC (assessed by the number of beads drawn on the probabilistic reasoning “beads” task) and provided blood or saliva samples from which we extracted DNA and computed polygenic risk scores for IQ and schizophrenia.ResultsThe estimated proportion of the total effect of case/control differences on JTC mediated by IQ was 79%. Schizophrenia Polygenic Risk Score (SZ PRS) was non-significantly associated with a higher number of beads drawn (B= 0.47, 95% CI −0.21 to 1.16, p=0.17); whereas IQ PRS (B=0.51, 95% CI 0.25 to 0.76, pp=0.006), but did not relate to delusions in patients.Conclusionsthe JTC reasoning bias in psychosis is not a specific cognitive deficit but is rather a manifestation or consequence, of general cognitive impairment. Whereas, in the general population, the JTC bias is related to psychotic-like experiences, independent of IQ. The work has potential to inform interventions targeting cognitive biases in early psychosis.

BACKGROUND: Recently there has been an increasing interest in the use of machine learning techniques to neuroimaging data, in order to discriminate patients with schizophrenia from healthy control. However, until now, these tools have not been useful enough to be integrated into the clinical practice (Arbabshirani MR et al 2016). In the last 10 years we have been using an fMRI auditory emotional paradigm specifically designed for psychosis (Sanjuan et al 2007). This paradigm showed sensitivity to detect changes in brain activation after CBT treatment in patients with persistent auditory hallucinations (Aguilar et al 2018). Objective: Discriminate patients with Non-affective Psychosis from healthy controls employing Machine Learning in a fMRI database (with the Emotional Auditory Paradigm). METHODS: Sample: 122 patients with the diagnosis of Non-affective psychosis according to DSM-IV criteria, and 49 healthy controls, from two different samples of Valencia Clinic Hospital (Spain) and Barcelona San Pau Hospital (Spain). 37 patients and 21 healthy controls come from Valencia, and 85 patients and 28 healthy controls come from Barcelona. fMRI Paradigm: Four blocks of stimuli, 20 s each, interleaved with another four blocks of rest of 20 s each, were presented to patients and controls. Each block had 13 words, 2 with emotional content and 2 with 13 emotional neutral words (Sanjuan 2007). Machine Learning Method: Several measures were extracted from the fMR images for a total of 312 characteristics. These characteristics are statistical parameters extracted from the percentage of brain activation change for all anatomical areas: amygdala, lower front, medium frontal, superior front, insula, lower temporary, temporary average, superior temporary, cingular, hippocampus. The following statistical descriptors were collected for each area and zone: mean, median, standard deviation, asymmetry, kurtosis and others related to these ones. Machine learning techniques were applied, in particular, Support Vector Machines (SVM) (Schölkopf and Smola, 2018), to this data. An exhaustive scanning of the parameters C and Gamma of the Radial Basis Function kernel SVM was performed. RESULTS: The obtained accuracy for an experiment using all data with a cross validation with 25 splits was 77%. If we separate samples from each hospital, we obtained an accuracy of 84% for Barcelona and 71% for Valencia. DISCUSSION: These preliminary results with a very passive, simple, short paradigm in different samples suggested, this method combining the emotional auditory paradigm with machine learning technique may be useful as clinical state biomarker in daily diagnosis practice. Although other Machine Learning Machine Techniques and replications in different larger samples are needed before filling the gap between research and clinical practice. Furthermore, these results indicate that this methodology may help elucidate pathophysiological mechanisms in psychoses. References: Arbabshirani MR, S P J Sui, V D. Calhoun Single subject prediction of brain disorders in neuroimaging: Promises and pitfalls NeuroImage 145 (2017) 137–165 Sanjuan J; Lull JJ; Aguilar EJ; Martí-Bonmatí L; Moratal D; Gonzalez JC; Robles M; Keshavan MS.Emotional words induce enhanced brain activity in schizophrenic patients with auditory hallucinations. Psychiatry Research. 2007, 154, pp. 21 - 29. Aguilar EJ, et al Emotional fMR auditory paradigm demonstrates normalization of limbic hyperactivity after cognitive behavior therapy for auditory hallucinations. Schizophr Res. 2018;193:304–312. Schölkopf B, Smola A. Learning with Kernels: Support Vector Machines, Regularization, Optimization, and Beyond, MIT Press, 2018.

INTRODUCTION: An updated summary of the most used instruments assessing auditory hallucinations in population with psychosis, allows us to underline the scarceness and need of Spanish versions of important instruments. The aim of the study is to examine the psychometric characteristics of two different and complementary instruments for assessing auditory hallucinations, the Spanish version of the Auditory Vocal Hallucination Scale (AVHRS) and the Spanish version of the Positive and Useful Voices Inquiry (PUVI).MATERIALS AND METHODS: A sample of 68 patients from four different centres, with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder presenting with auditory hallucinations were included. Apart from the AVHRS and the PUVI, the Psychotic Symptom Rating Scales-Auditory Hallucinations subscale (PSYRATS-AH) and the Positive and Negative Syndrome Scale (PANSS) were also administered to all patients, plus an acceptability questionnaire.RESULTS: The Spanish version of the AVHRS showed a good internal consistency, a moderate to high inter-rater reliability, a medium to moderate test-retest reliability, and a good convergent and discriminant validity. The Spanish version of the PUVI showed a good internal consistency and a heterogeneous, but in general moderate, test-retest reliability.CONCLUSIONS: The Spanish versions of the AVHRS and the PUVI have good psychometric properties and are well accepted among patients.

Background:Little is known about changes in brain functioning after first-episode psychosis (FEP). Such knowledge is important for predicting the course of disease and adapting interventions. Functional magnetic resonance imaging has become a promising tool for exploring brain function at the time of symptom onset and at follow-up.Method:A systematic review of longitudinal fMRI studies with FEP patients according to PRISMA guidelines. Resting-state and task-activated studies were considered together.Results:Eleven studies were included. These reported on a total of 236 FEP patients were evaluated by two fMRI scans and clinical assessments. Five studies found hypoactivation at baseline in prefrontal cortex areas, two studies found hypoactivation in the amygdala and hippocampus, and three others found hypoactivation in the basal ganglia. Other hypoactivated areas were the anterior cingulate cortex, thalamus and posterior cingulate cortex. Ten out of eleven studies reported (partial) normalization by increased activation after antipsychotic treatment. A minority of studies observed hyperactivation at baseline.Conclusions:This review of longitudinal FEP samples studies reveals a pattern of predominantly hypoactivation in several brain areas at baseline that may normalize to a certain extent after treatment. The results should be interpreted with caution given the small number of studies and their methodological and clinical heterogeneity.

DDR1 has been linked to schizophrenia (SZ) and myelination. Here, we tested whether DDR1 variants in people at risk for SZ influence white matter (WM) structural variations and cognitive processing speed (PS). First, following a case-control design (Study 1), SZ patients (N = 1193) and controls (N = 1839) were genotyped for rs1264323 and rs2267641 at DDR1, and the frequencies were compared. We replicated the association between DDR1 and SZ (rs1264323, adjusted P = 0.015). Carriers of the rs1264323AA combined with the rs2267641AC or CC genotype are at risk to develop SZ compared to the other genotype combinations. Second, SZ patients (Study 2, N = 194) underwent an evaluation of PS using the Trail Making Test (TMT) and DDR1 genotyping. To compare PS between DDR1 genotype groups, we conducted an analysis of covariance (including rs1264323 as a covariate) and found that SZ patients with the rs2267641CC genotype had decreased PS compared to patients with the AA and AC genotypes. Third, 54 patients (Study 3) from Study 2 were selected based on rs1264323 genotype to undergo reevaluation, including a DTI-MRI brain scan. To test for associations between PS, WM microstructure and DDR1 genotype, we first localized those WM regions where fractional anisotropy (FA) was correlated with PS and tested whether FA showed differences between the rs1264323 genotypes. SZ patients with the rs1264323AA genotype showed decreased FA in WM regions associated with decreased PS. We conclude that DDR1 variants may confer a risk of SZ through WM microstructural alterations leading to cognitive dysfunction.

Postpartum depression (PPD) is a common mood disorder that occurs after delivery with a prevalence of approximately 10%. Recent reports have related placental corticotropin-releasing hormone (pCRH) to postpartum depressive symptoms. The aim of this study was to determine whether pCRH, ACTH, and cortisol (measured 48 h after delivery) and glucocorticoid and mineralocorticoid receptor genotypes (NR3C1 and NR3C2) and their interaction are associated with PPD. A longitudinal 32-week prospective study of five hundred twenty-five Caucasian depression-free women that were recruited from obstetric units at two Spanish general hospitals immediately after delivery. Of the women included in the sample, forty-two (8%) developed PPD. A strong association between PPD and the interaction between the pCRH and NR3C2 rs2070951 genotype was observed. The mean level of pCRH in rs2070951GG carriers with PPD was 56% higher than the mean in the CG and CC genotype groups (P

In this study an anger induction laboratory task was applied to men with schizophrenia, and resulted in significant changes in different psychophysiological parameters that were measured in a pre-post design. We observed a significantly greater self-reported anger mood and negative affection, lower self-reported positive affection, an increase in cardiovascular reactivity (with blood pressure in deeper affection compared to controls), higher salivary testosterone levels, lower salivary cortisol levels, and an increase in right ear items reported in dichotic listening. Furthermore, clinical risk factors related to anger in our patients were analyzed by Stepwise Regression analyses. Trait anger was significantly associated with a higher level of delusional pathology and impulsivity. Regarding the resulted state of anger as an output of the induction, the most relevant finding was that anxiety consistently and significantly predicted the increasing in anger feelings, and, remarkably, it predicted also the increasing in T levels and the cardiovascular reactivity of the patients.