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Background Little is known on whether associations between childhood autistic traits and psychotic experiences persist into adulthood and whether genetic confounding and childhood trauma influence them. Here we investigate the associations between childhood autistic traits and psychotic experiences until young adulthood and assess the influence of schizophrenia polygenic risk and childhood traumatic experiences, using the Avon Longitudinal Study of Parents and Children (ALSPAC) population-based birth cohort. Study design We used a measure of broad autistic traits (autism factor mean score), and four dichotomised measures of autistic traits capturing social communication difficulties (age 7), repetitive behaviours (age 5), sociability (age 3), and pragmatic language (age 9). Psychotic experiences were assessed at ages 18 and 24 using the semi-structured Psychosis-Like Symptoms interview (PLIKSi). Traumatic experiences between ages 5 and 11 were assessed with questionnaires and interviews administered to children and parents at multiple ages. Study results Broad autistic traits, as well as social communication difficulties, were associated with psychotic experiences that were distressing and/or frequent until age 24 (autism factor mean score, n = 3707: OR 1.19, 95%CI 1.01–1.39; social communication difficulties, n = 3384: OR 1.54, 95%CI 0.97–2.45). Childhood trauma mediated a substantial proportion of the identified associations (~28% and 36% respectively, maximum n = 3577). Schizophrenia polygenic risk did not appear to confound the associations. Multiple imputation analyses (maximum n = 13 105) yielded comparable results. Conclusions Childhood trauma may be an important, potentially modifiable pathway between autistic features and later onset of psychotic psychopathology.

Dysregulation of striatal dopamine is considered to be an important driver of pathophysiological processes in schizophrenia. Despite being one of the main origins of dopaminergic input to the striatum, the (dys)functioning of the substantia nigra (SN) has been relatively understudied in schizophrenia. Hence, this paper aims to review different molecular aspects of nigral function-ing in patients with schizophrenia compared to healthy controls by integrating post-mortem and molecular imaging studies. We found evidence for hyperdopaminergic functioning in the SN of patients with schizophrenia (i.e. increased AADC activity in antipsychotic-free/-naive patients and elevated neuromelanin accumulation). Reduced GABAergic inhibition (i.e. decreased den-sity of GABAergic synapses, lower VGAT mRNA levels and lower mRNA levels for GABAA receptor subunits), excessive glutamatergic excitation (i.e. increased NR1 and Glur5 mRNA levels and a reduced number of astrocytes), and several other disturbances implicating the SN (i.e. immune functioning and copper concentrations) could potentially underlie this nigral hyperactivity and associated striatal hyperdopaminergic functioning in schizophrenia. These results highlight the importance of the SN in schizophrenia pathology and suggest that some aspects of molecular functioning in the SN could potentially be used as treatment targets or biomarkers.(c) 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

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 =

Background: This study tested the hypotheses that (i) the relationship between a history of childhood abuse and severity of psychosis is mediated by loneliness; (ii) the relationship between loneliness and psychosis is mediated by within-person fluctuations in depressive and anxious feelings.Methods: Fifty-nine individuals with non-affective psychotic disorder rated the intensity of loneliness, positive symptoms, and depressive and anxious feelings during repeated moments in daily life (Experience Sampling Method). Childhood abuse was assessed retrospectively using the 'Childhood Experience of Care and Abuse' interview. To test the mediation hypotheses, a multilevel structural equation modeling paradigm was used.Results: As predicted, the relationship between severity of childhood abuse and positive symptoms was mediated by loneliness (b = 0.08, 95% CI [0.02, 0.13], p = 0.005). In turn, the relationship between loneliness and positive symptoms was mediated by within-person fluctuations in both depressive (b = 0.04, 95% CI [0.02, 0.06], p < 0.001) and anxious (b = 0.02, 95% CI [0.01, 0.03], p = 0.002) symptomatology. Depression was a stronger mediator than anxiety (b = 0.02, 95% CI [0.00, 0.04], p = 0.027).Conclusions: Our findings highlight the role of childhood abuse and loneliness in the severity of psychosis in daily life.(c) 2019 Elsevier B.V. All rights reserved.

The social defeat hypothesis of schizophrenia, which proposes that the chronic experience of outsider status or subordinate position leads to increased striatal dopamine activity and thereby to increased risk, has been criticized. The aims of this paper are to improve the definition of defeat and to integrate the social defeat hypothesis with the neurodevelopmental hypothesis. Marmot advanced the idea that low status is pathogenic in that it is associated with a lack of social participation and a lack of autonomy. Given the similarity with outsider status and subordinate position, we re-define social defeat as low status. From this new perspective it is also likely that pre-schizophrenic impairments (of neurodevelopmental origin or not) are pathogenic in that they contribute to low status. The effect of low status may be enhanced by repeated exposure to humiliation, but few studies have measured this variable. Since most individuals exposed to low status do not develop schizophrenia, we propose that this risk factor increases the risk of disorder in the presence of a poor homeostatic control of dopamine neurons in midbrain and dorsal striatum. This is consistent with studies of healthy subjects which report a negative association between low socio-economic status and dopamine D2/D3 receptor availability in the dorsal striatum. In this new version of the social defeat hypothesis we propose that the combination of low status, repeated humiliation and poor homeostatic control of dopamine neurons in midbrain and dorsal striatum leads to increased striatal dopamine activity and thereby to an increased risk of schizophrenia.

Background: Several studies have observed that mentalization-based treatment (MBT) is an effective treatment for borderline personality disorder (BPD), but its effectiveness for other personality disorders (PDs) has hardly been examined. Additionally, the evidence supporting the claim that MBT improves mentalizing capacity is scarce. The present study examined whether (i) patients with a broad range of PDs would profit from MBT (ii) mentalizing capacity would improve over time; (iii) patients with BPD would profit more from MBT than those with non-borderline PDs Method: Personality disorders, psychiatric symptoms, social functioning, maladaptive personality functioning and mentalizing capacity were measured in a group of individuals with various PDs (n = 46) that received MBT. Assessments were made at baseline and after 6, 12, and 18 months of treatment. The severity of psychiatric symptoms, measured using the Outcome Questionnaire 45, was the primary outcome variable. Results: Overall, enrollment in the MBT program was associated with a decrease in psychiatric symptoms and an improvement of personality functioning, social functioning for a mixed group of PDs (all p’s ≤ .01). Bigger effect sized were observed for BPD patients (n=25) than for patients with non-BPD (n=21), but the difference failed to reach statistical significance (p=0.06). A primary analysis showed that the decrease in psychiatric symptoms was significant in BPD patients (p=0.01), not in non-BPD (p=0.19) patients. However, a sufficiently powered secondary analysis with imputed data showed that non-BPD patients reported a significant decrease in psychiatric symptoms too (p=0.01). Mentalizing capacity of the whole group improved over time (dvaried between .68 and 1.46). Discussion: These results suggest that MBT is effective for a broad range of PDs and shows that MBT is associated with improvements in mentalizing capacity. As the study is not experimental in design, we cannot make causal claims. Trial Registration: The study design was approved by the Leiden University Ethical Committee. Conclusion: Mentalization-based treatment seems to be an effective treatment for patients with a broad range of PDs.

Studies 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. Polyvictimization 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), then 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 = 3.09; p =

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.

Alterations in dopamine signalling have been implied in autism spectrum disorder (ASD), and these could be associated with the risk of developing a psychotic disorder in ASD adults. Negative social experiences and feelings of social defeat might result in an increase in dopamine functioning. However, few studies examined dopamine functioning in vivo in ASD. Here we examine whether striatal dopamine synthesis capacity is increased in ASD and associated with social defeat. Forty-four unmedicated, non-psychotic adults diagnosed with ASD and 22 matched controls, aged 18–30 years, completed a dynamic 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine positron emission tomography/computed tomography ([18F]-FDOPA PET/CT) scan to measure presynaptic dopamine synthesis capacity in the striatum. We considered unwanted loneliness, ascertained using the UCLA Loneliness Scale, as primary measure of social defeat. We found no statistically significant difference in striatal dopamine synthesis capacity between ASD and controls (F1,60 = 0.026, p = 0.87). In ASD, striatal dopamine synthesis capacity was not significantly associated with loneliness (β = 0.01, p = 0.96). Secondary analyses showed comparable results when examining the associative, limbic, and sensorimotor sub-regions of the striatum (all p-values > 0.05). Results were similar before and after adjusting for age, sex, smoking-status, and PET/CT-scanner-type. In conclusion, in unmedicated, non-psychotic adults with ASD, striatal dopamine synthesis capacity is not increased and not associated with social defeat.

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.

Social functioning can be severely impaired in non-affective psychotic disorder (NAPD). Current models of psychosis pathogenesis do not tend to focus on social dysfunction and pharmacological treatment fails to ameliorate it. In this article, we propose that mentalization theory provides a valuable contribution to the understanding and treatment of NAPD. Impaired mentalizing may contribute to both positive and negatives symptoms as well as social dysfunction observed in NAPD. Furthermore, impaired mentalizing may help explain the relation between childhood abuse, insecure attachment and psychosis. Mentalization based treatment may contribute to the functional recovery of NAPD patients as it targets the social cognitive processes underlying social interaction. The article includes a description of the principles of MBT in general, specific characteristics of using MBT with patients with NAPD and a clinical vignette to illustrate these principles.

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

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

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

To compare the incidence of psychosis among migrants with the incidence among the native Dutch in Amsterdam, Gouda and Voorhout.We identified patients with a first treated episode of psychosis (ICD-10 codes F20-F33) in 2010-2013 as part of the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) study. Information on the composition of the population made it possible to calculate incidence rates.We analyzed the Incidence Rate Ratios (IRR) of psychosis among various ethnic groups compared to the native Dutch using a Poisson model.The standardized rates in Amsterdam were 55.3/ 100,000 person-years (py) for migrants and 24.9/ 100,000py for native Dutch. In Gouda and Voorhout, these rates were 28.5 en 20.0/ 100,000py. We found increased rates among Moroccan males of the first (IRR=4.07 [95%-CI: 1.76-9.42]) and second generation (IRR=6.48 [3.30-12.68]) in Amsterdam. In Gouda and Voorhout, we found increased rates both among Moroccan males (IRR=3.37 [1.17-9.74]) of the first generation and Moroccan females of the second generation (IRR=7.10 [2.79-18.06]). High rates were also found in Amsterdam for male migrants from Eastern Europe (IRR=4.52 [2.24-9.11]), migrants from sub-Saharan Africa (IRR=3.15 [1.68-5.91]) and first-generation migrants, both males and females, from Surinam and the Netherlands Antilles. We found a decreased incidence for Western migrants.We found an increased incidence of psychosis among non-Western migrants and in Amsterdam also among Eastern-European migrants. The variation by region of origin and destination generation, and gender suggests that this risk is strongly influenced by the societal context.

BackgroundTo provide an overview of epidemiological studies of dementia among migrant groups in Europe and to estimate their pooled odds ratio (OR) v. the reference population.MethodsSearch for articles reporting on incidence or prevalence of dementia among ethnic minorities and migrants in Europe, published before 21 December 2018. We performed several meta-analyses, using a random-effects model, and, when there was no evidence of heterogeneity, a fixed-effects model. We distinguished between all migrants, African-Europeans and Asian-Europeans.ResultsWe retrieved five population-based surveys and two health care record studies. The latter included one incidence study, the remainder were prevalence studies. The meta-analysis of all studies yielded a pooled OR, adjusted for age and sex, of 1.73 (95% CI 1.42–2.11) for dementia in all migrant groups. However, the pooled OR of population surveys (3.10; 95% CI 2.12–4.51) was significantly higher than that for the health care record studies (OR 0.94; 95% CI 0.80–1.11). The pooled ORs for African-Europeans and Asian-Europeans, based on population surveys, were 2.54 (95% CI 1.70–3.80) and 5.36 (95% CI 2.78–10.31), respectively.ConclusionsThe discrepancy between health care record studies and population surveys suggests that many migrants remain undiagnosed. Migrants from Asia and Africa seem to be at significantly increased risk of dementia in Europe. Since the prevalence rates in their countries of origin are generally not higher than those for natives in Europe, there may be a parallel with the epidemiology of schizophrenia.

Introduction: There is increasing evidence that autistic traits are associated with psychotic experiences. However, the mechanisms underlying such associations are still unknown. In this longitudinal birth cohort study, we examine the relationship between childhood autistic traits and psychotic experiences in adolescence and young adulthood, and the influence of childhood trauma on this association.Methods: We analysed data from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. We used four dichotomized measures of autistic traits (social communication difficulties at age 7, repetitive behaviour at age 5, sociability at age 3, and pragmatic language at age 9). Psychotic experiences were assessed at ages 18 and 24 using the semi-structured Psychosis-Like Symptoms interview. Traumatic experiences between ages 5 to 11 were assessed with questionnaires and interviews administered to children and parents.Results: The maximum sample with complete data was 3410 for the autistic traits-psychotic experiences analyses and 3327 for the mediation analyses. The corresponding maximum sample sizes for the imputed data analysis were 10,053 and 8121, respectively. Social communication difficulties were associated with psychotic experiences (odds ratio [OR] = 1.43, 95% confidence interval [CI] 1.01–2.02), including those that were distressing and/or frequent (OR = 1.60, 95% CI 1.02–2.52). Childhood trauma mediated approximately 40% of this association. Other autistic traits showed no consistent relationship with psychotic experiences. Results were similar when we adjusted for schizophrenia polygenic risk scores (PRS).Discussion: Childhood social communication difficulties are associated with psychotic experiences by age 24. This association does not appear to be explained by genetic risk as captured by current schizophrenia PRS. The experience of trauma may be an important, potentially modifiable pathway between autistic features and later onset of psychotic psychopathology where interventions could be targeted.

BackgroundIndividuals with autism spectrum disorder (ASD) appear to be at increased risk of non-affective psychotic disorder (NAPD) and bipolar disorder (BD). However, most previous studies examined the co-occurrence of ASD and NAPD or BD, ignoring possible diagnostic bias and selection bias. We used longitudinal data from Dutch psychiatric case registers to assess the risk of NAPD or BD among individuals with ASD, and compared the results to those obtained for the Dutch population in earlier studies.MethodsIndividuals with ASD (n = 17 234) were followed up between 16 and 35 years of age. Kaplan–Meier estimates were used to calculate the risk of NAPD or BD. We conducted separate analyses to reduce possible bias, including an analysis among individuals diagnosed with ASD before age 16 years (n = 8337).ResultsOf the individuals with ASD, 23.50% (95% confidence interval 21.87–25.22) were diagnosed with NAPD and 3.79% (3.06–4.69) with BD before age 35 years. The corresponding figures for the general population were 0.91% (0.63–1.28) and 0.13% (0.08–0.20). Risk estimates were substantially lower, but still higher than general population estimates, when we restricted our analyses to individuals diagnosed with ASD before age 16, with 1.87% (1.33–2.61) being diagnosed with NAPD and 0.57% (0.21–1.53) with BD before age 25 years. The corresponding figures for the general population were 0.63% (0.44–0.86) and 0.08% (0.05–0.12).ConclusionsIndividuals with ASD are at increased risk of NAPD or BD. This is likely not the result of diagnostic or selection bias.

BackgroundThe aims of this meta-analysis are (i) to estimate the pooled relative risk (RR) of developing non-affective psychotic disorder (NAPD) and affective psychotic disorder (APD) among migrants and their children; (ii) to adjust these results for socioeconomic status (SES); (iii) to examine the sources of heterogeneity that underlie the risk of NAPD.MethodsWe included population-based incidence studies that reported an age-adjusted RR with 95% confidence interval (CI) published 1 January 1977–12 October 2017 and used a random-effects model.ResultsWe retrieved studies performed in Europe (n= 43), Israel (n= 3), Canada (n= 2) and Australia (n= 1). The meta-analysis yielded a RR, adjusted for age and sex, of 2.13 (95% CI 1.99–2.27) for NAPD and 2.94 (95% CI 2.28–3.79) for APD. The RRs diminished, but persisted after adjustment for SES. With reference to NAPD: a personal or parental history of migration to Europe from countries outside Europe was associated with a higher RR (RR = 2.94, 95% CI 2.63–3.29) than migration within Europe (RR = 1.88, 95% 1.62–2.18). The corresponding RR was lower in Israel (RR = 1.22; 0.99–1.50) and Canada (RR = 1.21; 0.85–1.74). The RR was highest among individuals with a black skin colour (RR = 4.19, 95% CI 3.42–5.14). The evidence of a difference in risk between first and second generation was insufficient.ConclusionsPositive selection may explain the low risk in Canada, while the change from exclusion to inclusion may do the same in Israel. Given the high risks among migrants from developing countries in Europe, social exclusion may have a pathogenic role.

Objective: The aim of this study was to establish the specificity and sensitivity of a simplified screening test based on diastolic blood pressure and waist circumference for predicting metabolic syndrome. Method: Demographic, anthropometric (waist circumference and systolic and diastolic blood pressure) and laboratory (triglyceride, high-density lipoprotein and fasting glucose) data were collected from a large cohort of Dutch patients with a schizophrenia spectrum disorder in order to determine whether patients fulfilled the Western criteria of the International Diabetes Federation (IDF) for metabolic syndrome. The sensitivity, specificity, likelihood ratio of a positive or negative test outcome and positive and negative predictive values of the simplified test (only waist circumference and diastolic blood pressure) were calculated. Results: Of 252 recruited patients, 55% met the IDF criteria for metabolic syndrome. The sensitivity and the specificity of the simplified test were 65% and 85%, respectively. The likelihood ratios of positive and negative test outcomes were 4.35 and 0.41, respectively, and the positive and negative predictive values were 87% and 67%, respectively. Conclusion: This simplified screening test did not have diagnostic validity for metabolic syndrome in a Dutch cohort of patients with schizophrenia spectrum disorder.

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.

Objective To compare the mortality in people using clozapine to that of people using other antipsychotics. Methods Danish incidence cohort of 22 110 patients with a first diagnosis of non-affective psychotic disorder (1995-2013) and a prevalence cohort of 50 881 patients ever diagnosed with such a disorder (1969-2013). Hazard ratios (HR) were calculated for the antipsychotic drug used at the time of death (?current use?: incidence and prevalence cohort), and for the drug used for the longest at that moment (?cumulative use?: incidence cohort), using a Cox model with adjustment for somatic comorbidity. Clozapine was the reference drug. Results As for current drug use, the risk of suicide was higher among users of other antipsychotics in the incidence (HRadj=1.76; 95% CI 0.72-4.32) and prevalence (HRadj=2.20; 95% CI 1.35-3.59) cohorts. There was no significant difference in all-cause or cardiovascular mortality in the two cohorts. Cumulative use of clozapine was not associated with an increased cardiovascular mortality. Cumulative use of other antipsychotics for up to 1 year was associated with a lower all-cause mortality and suicide risk than a similar period of clozapine use (all-cause: HRadj=0.73; 95% CI 0.63-0.85, suicide; HRadj=0.65; 95% CI 0.46-0.91). Conclusion The results indicate that the use of clozapine is not associated with increased cardiovascular mortality. We found opposing trends towards a lower risk of suicide during current use of clozapine and a higher risk of suicide associated with cumulative use up to 1 year. This suggests that clozapine cessation marks a period of high risk of suicide. ObjectiveTo compare the mortality in people using clozapine to that of people using other antipsychotics.Methods Danish incidence cohort of 22 110 patients with a first diagnosis of non‐affective psychotic disorder (1995‐2013) and a prevalence cohort of 50 881 patients ever diagnosed with such a disorder (1969‐2013). Hazard ratios (HR) were calculated for the antipsychotic drug used at the time of death (‘current use’: incidence and prevalence cohort), and for the drug used for the longest at that moment (‘cumulative use’: incidence cohort), using a Cox model with adjustment for somatic comorbidity. Clozapine was the reference drug.Results As for current drug use, the risk of suicide was higher among users of other antipsychotics in the incidence (HRadj=1.76; 95% CI 0.72‐4.32) and prevalence (HRadj=2.20; 95% CI 1.35‐3.59) cohorts. There was no significant difference in all‐cause or cardiovascular mortality in the two cohorts. Cumulative use of clozapine was not associated with an increased cardiovascular mortality. Cumulative use of other antipsychotics for up to 1 year was associated with a lower all‐cause mortality and suicide risk than a similar period of clozapine use (all‐cause: HRadj=0.73; 95% CI 0.63‐0.85, suicide; HRadj=0.65; 95% CI 0.46‐0.91).Conclusion The results indicate that the use of clozapine is not associated with increased cardiovascular mortality. We found opposing trends towards a lower risk of suicide during current use of clozapine and a higher risk of suicide associated with cumulative use up to 1 year. This suggests that clozapine cessation marks a period of high risk of suicide.

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.

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

The European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) Project 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.

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.

It is likely that the chronic stress of social defeat or exclusion contributes to the increased psychosis risk among members of ethnic minorities. Is this idea compatible with the dopamine or neurodevelopmental hypothesis, two dominant hypotheses with regard to pathogenesis? Defeated animals show clear evidence of dopamine sensitization. As for humans, one study showed elevated striatal dopamine function in migrants and their children. Other studies have shown this in other excluded groups, namely, adults with hearing impairment and individuals with a history of childhood trauma. Of note, the perigenual anterior cingulate cortex may play a major role in the processing of social stress and regulates dopaminergic areas implicated in stress sensitization. The authors are not aware of studies in humans that examined whether (proxies for) social exclusion contribute(s) to structural brain changes present at psychosis onset. Animal studies, however, reported that long-term isolation may lead to reductions in brain volume and that social defeat can reduce neurogenesis.

BackgroundImpaired mentalizing ability – an impaired ability to understand one's own and other people's behavior in terms of mental states – is associated with social dysfunction in non-affective psychotic disorder (NAPD). We tested whether adding mentalization-based treatment for psychotic disorder (MBTp) to treatment as usual (TAU) results in greater improvement in social functioning.MethodsMulticenter, rater-blinded, randomized controlled trial. Eighty-four patients with NAPD were assigned to TAU or MBTp plus TAU. Patients in the MBTp group received 18 months of MBTp, consisting of weekly group sessions and one individual session per 2 weeks. Social functioning was measured using the Social Functioning Scale. We conducted ANCOVAs to examine the difference between treatment conditions directly after treatment and at 6-month follow-up and performed moderation and mediation analyses.ResultsIntention-to-treat analyses showed no significant differences between groups post-treatment (p = 0.31) but revealed the MBTp group to be superior to TAU at follow-up (p = 0.03). Patients in the MBTp group also seemed to perform better on measures of mentalizing ability, although evidence of a mediation effect was limited (p = 0.06). Lastly, MBTp treatment was less effective in chronic patients than in recent-onset patients (p = 0.049) and overall symptoms at baseline were mild, which may have reduced the overall effectiveness of the intervention.ConclusionThe results suggest that MBTp plus TAU may lead to more robust improvements in social functioning compared to TAU, especially for patients with a recent onset of psychosis.

To test whether: (1) psychiatrists will prescribe clozapine more often if they can delegate the monitoring tasks to an advanced nurse practitioner (ANP), (2) clozapine monitoring by an ANP is at least as safe as monitoring by a psychiatrist. Patients from 23 Dutch outpatient teams were assessed for an indication for clozapine. ANPs affiliated to these teams were randomized to Condition A: clozapine monitoring by an ANP, or Condition B: monitoring by the psychiatrist. The safety of monitoring was evaluated by determining whether the weekly neutrophil measurements were performed. Staff and patients were blinded regarding the first hypothesis. Of the 173 patients with an indication for clozapine at baseline, only seven in Condition A and four in Condition B were prescribed clozapine (Odds Ratio = 2.24, 95% CI 0.61–8.21; p = 0.225). These low figures affected the power of this study. When we considered all patients who started with clozapine over the 15-month period (N = 49), the Odds Ratio was 1.90 (95% CI 0.93–3.87; p = 0.078). With regard to the safety of the monitoring of the latter group of patients, 71.2% of the required neutrophil measurements were performed in condition A and 67.3% in condition B (OR = 0.98; CI = 0.16–3.04; p = 0.98). Identifying patients with an indication for clozapine does not automatically lead to improved prescription rates, even when an ANP is available for the monitoring. Clozapine-monitoring performed by an ANP seemed as safe as that by a psychiatrist. Electronic supplementary material The online version of this article (10.1007/s10488-020-01031-4) contains supplementary material, which is available to authorized users.

Reports of decreased mortality among patients with schizophrenia who use clozapine may be biased if clozapine is prescribed to relatively healthy patients and if intensive monitoring during its use prevents (under-treatment of) somatic disorder. We aimed to assess whether there is a difference in: (1) somatic comorbidity between patients who start with clozapine and those who start with other antipsychotics and (2) prescribed somatic medication, between patients using clozapine and those using olanzapine. Cohort study based on insurance claims (2010-2015). After selecting new users of antipsychotics and those who subsequently switched to clozapine (N = 158), aripiprazole (N = 295), olanzapine (N = 204) or first-generation antipsychotics (N = 295), we compared the clozapine starters to others on cardiovascular or diabetic comorbidity. Those using clozapine and olanzapine were compared on new prescriptions for cardiovascular or antidiabetic drugs. The OR(adj)of cardiovascular or diabetic comorbidity among other starters compared with clozapine starters was 0.77 [95% confidence interval (CI): 0.43-1.39], that is, a nonsignificantly increased prevalence associated with clozapine was found. Users of clozapine received significantly more new prescriptions for cardiovascular or antidiabetic medication (ORadj: 2.70, 95% CI: 1.43-5.08). Starters with clozapine were not cardiovascular/metabolic healthier than starters with other antipsychotics. During its use, they received more somatic treatment.

Reported childhood abuse has been linked to the severity of clinical symptoms and social dysfunction in non-affective psychotic disorder. Impaired mentalizing ability may be one of the mechanisms accounting for this effect. This study examined whether impaired mentalizing mediates the effect of reported childhood abuse on positive symptoms, negative symptoms, and social dysfunction. Eighty-seven patients with non-affective psychotic disorder were examined. Reported childhood abuse was measured using the Childhood Experience of Care and Abuse interview. Additionally, the Social Functioning Scale and the Positive and Negative Syndrome Scale were used. The Hinting Task was used to measure mentalizing impairment. Reported childhood abuse was significantly related to the severity of positive and negative symptoms, not to social dysfunction. Reported childhood abuse was also related to mentalizing impairment. Mentalizing impairment was related to negative symptoms, but not to positive symptoms or social dysfunction. Mentalizing impairment accounted for 40% of the association between reported childhood abuse and negative symptoms, indicating partial mediation. A sensitivity analysis revealed that the mediating effect was only observed in those who reported fairly severe childhood abuse.

Maternal influenza during pregnancy has been suggested to increase the psychosis risk for the offspring. This hypothesis has been tested using "ecological" studies, which examined the risk for individuals born after epidemics, and "serological" studies, based on serological evidence. A study of the latter type obtained an increased schizophrenia risk for individuals exposed during the first trimester. A second study found a relationship between influenza at any time during gestation and risk for bipolar disorder with psychotic features. The aims of this paper are to assess the validity of the serological studies and to evaluate the combined results of ecological and serological investigations using meta-analysis. The serological studies turned out to be of limited validity, because they utilized a single serum specimen. Since influenza antibodies can remain positive for years after infection, manymothers of casesmay have been infected before pregnancy. For an adequate timing of exposure one needs an acute and a convalescent specimen, obtained 10-20 days later. Meta-analysis with respect to schizophrenia: we pooled the results of the single serological investigation and 8 ecological studies related to the 1957 pandemic (with negative results) and found that the first investigation carried hardly any weight. Bipolar disorder: we pooled the results of the serological investigation and three other studies and obtained a mean, weighted odds ratio of 1.34 (95% CI 0.78-2.29) for individuals possibly exposed during prenatal life. The evidence for gestational influenza as psychosis risk factor is insufficient. (C) 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

The purpose of this review is to examine whether a contribution of social exclusion to the pathogenesis of psychosis is compatible with the dopamine hypothesis and/or the neurodevelopmental hypothesis. Humans experience social exclusion as defeating. An animal model for defeat is the resident-intruder paradigm. The defeated animal shows evidence of an increased sensitivity to amphetamine, increased dopamine release in the nucleus accumbens and prefrontal cortex, and increased firing of dopaminergic neurons in the ventral tegmental area. As for humans, one study showed that amphetamine-induced striatal dopamine release was significantly greater among nonpsychotic young adults with severe hearing impairment than among normal hearing controls. Two other studies reported an association between childhood trauma and increased dopamine function in striatal subregions. Several studies have suggested that the perigenual anterior cingulate cortex (pgACC) may play a role in the processing of social stress. Importantly, the pgACC regulates the activity of the ventral striatum through bidirectional interconnections. We are not aware of studies in humans that examined whether (proxies for) social exclusion contributes to the structural brain changes present at psychosis onset. Animal studies, however, reported that long-term isolation may lead to reductions in volume of the total brain, hippocampus, or medial prefrontal cortex. Other animal studies reported that social defeat can reduce neurogenesis. In conclusion, the answer to the question as to whether there are plausible mechanisms whereby social exclusion can contribute to the pathogenesis of psychosis is cautiously affirmative.

Purpose: Epidemiological studies in the Netherlands have reported an excessive gender gap in the risk for non-affective psychotic disorder (NAPD) among immigrants from Morocco with a higher risk elevation in males compared to females. We examined the consistency of these findings and their generalizability to immigrants from the Maghreb (Mauritania, Morocco, Algeria, Tunisia and Libya) in other European countries. Methods: Systematic review and meta-analysis. Medline, PsychINFO and EMBASE databases were searched for publications in the period from January 1970 to April 2014. We included incidence and prevalence studies of non-affective psychotic disorder (NAPD) among migrants from the Maghreb in Europe and studies of subclinical psychotic symptoms (SPS) in representative samples. A meta-analysis was performed on the subgroup of incidence studies. Results: Five incidence and three prevalence studies of NAPD, and two prevalence studies of SPS, conducted in the Netherlands (n=7), Belgium (n=1), France (n=1) and Italy (n=1) met our inclusion criteria. Across all research designs, the risks of NAPD and SPS were consistently increased among male, not female immigrants from the Maghreb. The meta-analysis of incidence studies of NAPD yielded male-to-female risk ratios of 5.1 [95 % confidence interval (CI) 3.1–8.4] for migrants from the Maghreb, 2.0 (95 % CI 1.6–2.5) for other migrant groups, and 1.8 (95 % CI 1.3–2.5) for non-migrant Europeans. Conclusions: The marked gender gap in psychosis risk among migrants from the Maghreb appears a consistent finding, foremost among the Moroccan-Dutch. The small number of studies limits the strength of conclusions that can be drawn about countries other than the Netherlands. Achievement–expectation mismatch, social marginalization and an increased prevalence of illicit drug use are possible explanations.

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.

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.

Mood and anxiety disorders are prevalent conditions affecting one out of four people during lifetime. The development of high validity animal models to study these disorders has been a major challenge in the past. When considering experimental approaches for studying affective disorders, the social defeat paradigm has been shown to have etiological, predictive and face validity. Here, we explain the general principle of social defeat stress paradigms, with a strong focus on the resident-intruder model and compare different experimental settings as published to date. We discuss behavioral changes described in defeated animals as well as changes in the animal's physiological parameters. In addition, we provide an overview of the molecular adaptations that are found in animals subjected to defeat stress, with special attention to neural circuits and neuroendocrine signaling. Defeat produces specific behaviors resembling the signs and symptoms of humans with affective disorders, such as anhedonia, social avoidance, despair and anxiety. These can be linked to a wide range of physiological changes-ranging from cardiovascular changes to alterations in the immune system- or by disturbances in specific neurotransmitter systems, in particular serotonin and dopamine. The defeat stress model thus impacts on several functional domains of behavior and may mimic cardinal features of a multitude of psychiatric disorders including depression, post-traumatic stress disorder and schizophrenia. This manuscript critically reviews the core findings, strengths and limitations of the range of animal studies in this field and provides future perspectives.

Purpose: To our knowledge, no study has examined in a structured way the extent of underprescription of clozapine in ambulatory patients with Non-Affective Psychotic Disorder (NAPD). In the Netherlands, psychiatric care for such patients is provided by Flexible Assertive Community Treatment (FACT) teams and by early intervention teams. In 20 FACT teams and 3 early intervention teams we assessed the proportion of patients who: use clozapine (type 1 patients), previously used this drug (type 2), have an unfulfilled indication for this drug, by type of indication (type 3), or were at least markedly psychotic, but had not yet received two adequate treatments with other antipsychotic drugs (type 4). We expected to find major differences between teams. To rule out that these differences are caused by differences in severity of psychopathology, we also calculated the proportions of patients who use clozapine given an indication at any time (number of type 1 patients divided by the sum of type 1, 2, and 3 patients). Materials and methods: The nurse practitioner of each team identified the patients already on clozapine. Next, using a highly-structured decision tree, the nurse practitioner and psychiatrist assessed whether the remaining patients had an indication for this drug. Indications were treatment-resistant positive symptoms, tardive dyskinesia, aggression and suicidality. The severity of positive symptoms was determined using the Clinical Global Impression-Schizophrenia Scale (CGI-SCH). Results: In the participating FACT-teams 2,286 NAPD patients were assessed. The range among teams in proportions was: type 1: 8.8-34.7% (mean: 23.0%), type 2: 0-8.2% (mean: 3.5%), type 3: 1.7-15.6% (mean: 6.9%), type 4: 1.8-16.3% (mean: 8.6%). The range in proportions of patients using this drug given an indication was 49.0-90.9% (mean: 68.8%). These figures were lower in early intervention teams. Conclusions: The proportion of patients in FACT-teams who have an unfulfilled indication for clozapine is 6.9%. There were considerable differences between teams with respect to this proportion. Almost a third of the outpatients had at any time an indication for clozapine. If one takes type 4 patients into account, this proportion may be higher. Registration number: NTR5135 http://www.trialregister.nl/trialreg/index.asp.

Purpose of reviewArguably, the strongest evidence of an environmental contribution to the cause of psychosis is the increased risk for certain groups of migrants and ethnic minorities. This article summarizes findings published since 2016.Recent findingsTwo studies suggested that migration or minority status are proxies for exposure to an inferior social status. A study from Bologna, Italy, showed that the psychosis risk for internal migrants from Southern Italy was as much increased as that for international migrants. A report from New Zealand reported a higher risk for Maoris than for the remainder of the population.Furthermore, a Danish investigation showed that own-group ethnic density of the neighbourhood at age 15 strongly modified the psychosis risk at adult age. This rules out differential mobility during the prodromal phase as an explanation for the ethnic density effect. Preliminary evidence suggests that the psychotogenic effect of migration may be mediated by elevated dopamine in the striatum.SummaryAn increasing body of evidence suggests that the higher psychosis risk for certain migrant or ethnic minority groups is due to an inferior social status. Neuroimaging of the dopamine system appears to be a promising avenue for research into pathogenesis.

BACKGROUND: The incidence of psychotic disorder is increased among various migrant and ethnic minority populations in Europe. Consistent evidence shows that risk estimates are moderated by ethnic background, but there may also be moderation by host country (1,2). We therefore aimed to study the risk of psychotic disorder in first- and second-generation immigrants in areas with varying levels of urbanicity across 5 European countries using uniform methods (3). We were particularly interested in the variation in psychosis risk among immigrants in different host countries. METHODS: The European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) study was conducted between 2010 and 2015. We analyzed data of individuals with a standardized, first diagnosis of nonorganic psychosis (International Classification of Disease, 10th edition (ICD-10) codes F20-F33) from 13 sites across the United Kingdom, the Netherlands, France, Spain and Italy. Age- and sex-adjusted incidence rate ratios (IRRadj) for immigrants compared to the non-migrant, reference population from the same country were calculated using Poisson regression models. Denominator data were obtained from national statistics offices. RESULTS: We identified 775 migrant and 1111 non-migrant cases during the study period. The IRRadj for immigrants varied from 1.15 (95% confidence interval (CI) 0.66–2.00) in Spain to 2.85 (95% CI 2.03–3.99) in the UK. We found a significant difference in risk estimates (p