Variation of subclinical psychosis across 16 sites in Europe and Brazil: findings from the multi-national EU-GEI study.

BACKGROUND: Incidence of first-episode psychosis (FEP) varies substantially across geographic regions. Phenotypes of subclinical psychosis (SP), such as psychotic-like experiences (PLEs) and schizotypy, present several similarities with psychosis. We aimed to examine whether SP measures varied across different sites and whether this variation was comparable with FEP incidence within the same areas. We further examined contribution of environmental and genetic factors to SP. METHODS: We used data from 1497 controls recruited in 16 different sites across 6 countries. Factor scores for several psychopathological dimensions of schizotypy and PLEs were obtained using multidimensional item response theory models. Variation of these scores was assessed using multi-level regression analysis to estimate individual and between-sites variance adjusting for age, sex, education, migrant, employment and relational status, childhood adversity, and cannabis use. In the final model we added local FEP incidence as a second-level variable. Association with genetic liability was examined separately. RESULTS: Schizotypy showed a large between-sites variation with up to 15% of variance attributable to site-level characteristics. Adding local FEP incidence to the model considerably reduced the between-sites unexplained schizotypy variance. PLEs did not show as much variation. Overall, SP was associated with younger age, migrant, unmarried, unemployed and less educated individuals, cannabis use, and childhood adversity. Both phenotypes were associated with genetic liability to schizophrenia. CONCLUSIONS: Schizotypy showed substantial between-sites variation, being more represented in areas where FEP incidence is higher. This supports the hypothesis that shared contextual factors shape the between-sites variation of psychosis across the spectrum.

Duration of Untreated Psychosis in First-Episode Psychosis is not Associated With Common Genetic Variants for Major Psychiatric Conditions: Results From the Multi-Center EU-GEI Study.

Duration of untreated psychosis (DUP) is associated with clinical outcomes in people with a diagnosis of first-episode psychosis (FEP), but factors associated with length of DUP are still poorly understood. Aiming to obtain insights into the possible biological impact on DUP, we report genetic analyses of a large multi-center phenotypically well-defined sample encompassing individuals with a diagnosis of FEP recruited from 6 countries spanning 17 research sites, as part of the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) study. Genetic propensity was measured using polygenic scores for schizophrenia (SZ-PGS), bipolar disorder (BD-PGS), major depressive disorder (MDD-PGS), and intelligence (IQ-PGS), which were calculated based on the results from the most recent genome-wide association meta-analyses. Following imputation for missing data and log transformation of DUP to handle skewedness, the association between DUP and polygenic scores (PGS), adjusting for important confounders, was investigated with multivariable linear regression models. The sample comprised 619 individuals with a diagnosis of FEP disorders with a median age at first contact of 29.0 years (interquartile range [IQR] = 22.0-38.0). The median length of DUP in the sample was 10.1 weeks (IQR = 3.8-30.8). One SD increases in SZ-PGS, BD-PGS, MDD-PGS or IQ-PGS were not significantly associated with the length of DUP. Our results suggest that genetic variation does not contribute to the DUP in patients with a diagnosis of FEP disorders.

The EUropean Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI): Incidence and First-Episode Case-Control Programme.

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

The contribution of cannabis use to variation in the incidence of psychotic disorder across Europe (EU-GEI): a multicentre case-control study.

BACKGROUND: Cannabis use is associated with increased risk of later psychotic disorder but whether it affects incidence of the disorder remains unclear. We aimed to identify patterns of cannabis use with the strongest effect on odds of psychotic disorder across Europe and explore whether differences in such patterns contribute to variations in the incidence rates of psychotic disorder. METHODS: We included patients aged 18-64 years who presented to psychiatric services in 11 sites across Europe and Brazil with first-episode psychosis and recruited controls representative of the local populations. We applied adjusted logistic regression models to the data to estimate which patterns of cannabis use carried the highest odds for psychotic disorder. Using Europe-wide and national data on the expected concentration of Δ9-tetrahydrocannabinol (THC) in the different types of cannabis available across the sites, we divided the types of cannabis used by participants into two categories: low potency (THC <10%) and high potency (THC ≥10%). Assuming causality, we calculated the population attributable fractions (PAFs) for the patterns of cannabis use associated with the highest odds of psychosis and the correlation between such patterns and the incidence rates for psychotic disorder across the study sites. FINDINGS: Between May 1, 2010, and April 1, 2015, we obtained data from 901 patients with first-episode psychosis across 11 sites and 1237 population controls from those same sites. Daily cannabis use was associated with increased odds of psychotic disorder compared with never users (adjusted odds ratio [OR] 3·2, 95% CI 2·2-4·1), increasing to nearly five-times increased odds for daily use of high-potency types of cannabis (4·8, 2·5-6·3). The PAFs calculated indicated that if high-potency cannabis were no longer available, 12·2% (95% CI 3·0-16·1) of cases of first-episode psychosis could be prevented across the 11 sites, rising to 30·3% (15·2-40·0) in London and 50·3% (27·4-66·0) in Amsterdam. The adjusted incident rates for psychotic disorder were positively correlated with the prevalence in controls across the 11 sites of use of high-potency cannabis (r = 0·7; p=0·0286) and daily use (r = 0·8; p=0·0109). INTERPRETATION: Differences in frequency of daily cannabis use and in use of high-potency cannabis contributed to the striking variation in the incidence of psychotic disorder across the 11 studied sites. Given the increasing availability of high-potency cannabis, this has important implications for public health. FUNDING SOURCE: Medical Research Council, the European Community's Seventh Framework Program grant, São Paulo Research Foundation, National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust and King's College London and the NIHR BRC at University College London, Wellcome Trust.

Treated Incidence of Psychotic Disorders in the Multinational EU-GEI Study.

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.