Showing papers by "Robin M. Murray published in 2018"

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

Abstract: 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 Sao 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.

Effect of Cannabidiol on Medial Temporal, Midbrain, and Striatal Dysfunction in People at Clinical High Risk of Psychosis: A Randomized Clinical Trial.

Abstract: Importance Cannabidiol (CBD) has antipsychotic effects in humans, but how these are mediated in the brain remains unclear Objective To investigate the neurocognitive mechanisms that underlie the therapeutic effects of CBD in psychosis Design, Setting, and Participants In this parallel-group, double-blind, placebo-controlled randomized clinical trial conducted at the South London and Maudsley NHS Foundation Trust in London, United Kingdom, 33 antipsychotic medication–naive participants at clinical high risk (CHR) of psychosis and 19 healthy control participants were studied Data were collected from July 2013 to October 2016 and analyzed from November 2016 to October 2017 Interventions A total of 16 participants at CHR of psychosis received a single oral dose of 600 mg of CBD, and 17 participants at CHR received a placebo Control participants were not given any drug All participants were then studied using functional magnetic resonance imaging (fMRI) while performing a verbal learning task Main Outcomes and Measures Brain activation during verbal encoding and recall, indexed using the blood oxygen level–dependent hemodynamic response fMRI signal Results Of the 16 participants in the CBD group, 6 (38%) were female, and the mean (SD) age was 2243 (495) years; of 17 in the placebo group, 10 (59%) were female, and the mean (SD) age was 2535 (524) years; and of 19 in the control group, 8 (42%) were female, and the mean (SD) age was 2389 (414) years Brain activation (indexed using the median sum of squares ratio of the blood oxygen level–dependent hemodynamic response effects model component to the residual sum of squares) was analyzed in 15 participants in the CBD group, 16 in the placebo group, and 19 in the control group Participants receiving placebo had reduced activation relative to controls in the right caudate during encoding (placebo: median, −0027; interquartile range [IQR], −0041 to −0016; control: median, 0020; IQR, −0022 to 0056;P Conclusions and Relevance Cannabidiol may partially normalize alterations in parahippocampal, striatal, and midbrain function associated with the CHR state As these regions are critical to the pathophysiology of psychosis, the influence of CBD at these sites could underlie its therapeutic effects on psychotic symptoms Trial Registration isrctnorg Identifier:ISRCTN46322781

A polygenic risk score analysis of psychosis endophenotypes across brain functional, structural, and cognitive domains.

Abstract: This large multi-center study investigates the relationships between genetic risk for schizophrenia and bipolar disorder, and multi-modal endophenotypes for psychosis. The sample included 4,242 individuals; 1,087 patients with psychosis, 822 unaffected first-degree relatives of patients, and 2,333 controls. Endophenotypes included the P300 event-related potential (N = 515), lateral ventricular volume (N = 798), and the cognitive measures block design (N = 3,089), digit span (N = 1,437), and the Ray Auditory Verbal Learning Task (N = 2,406). Data were collected across 11 sites in Europe and Australia; all genotyping and genetic analyses were done at the same laboratory in the United Kingdom. We calculated polygenic risk scores for schizophrenia and bipolar disorder separately, and used linear regression to test whether polygenic scores influenced the endophenotypes. Results showed that higher polygenic scores for schizophrenia were associated with poorer performance on the block design task and explained 0.2% (p = 0.009) of the variance. Associations in the same direction were found for bipolar disorder scores, but this was not statistically significant at the 1% level (p = 0.02). The schizophrenia score explained 0.4% of variance in lateral ventricular volumes, the largest across all phenotypes examined, although this was not significant (p = 0.063). None of the remaining associations reached significance after correction for multiple testing (with alpha at 1%). These results indicate that common genetic variants associated with schizophrenia predict performance in spatial visualization, providing additional evidence that this measure is an endophenotype for the disorder with shared genetic risk variants. The use of endophenotypes such as this will help to characterize the effects of common genetic variation in psychosis.

The effects of cannabidiol on persecutory ideation and anxiety in a high trait paranoid group.

Abstract: Background:Previous studies have suggested that cannabidiol has anxiolytic and antipsychotic properties, raising hopes that cannabidiol will translate to the psychiatric clinic. Cannabidiol may be particularly useful for anxiety and paranoia in those at-risk of major mental illness.Methods:Immersion in a controlled 3D virtual-reality scenario was used to assay persecutory ideation and anxiety in a sample of non-clinical volunteers (n=32) pre-selected for high paranoid traits. Participants were randomised to receive oral cannabidiol (600 mg) or placebo 130 min prior to entering virtual-reality. Well-validated rating scales were used to assay persecutory thinking and anxiety. Salivary cortisol concentration, heart rate and blood pressure were measured over the course of the experimental session.Results:Immersion in the virtual-reality session elicited anxiety as indexed by the Beck’s anxiety inventory (p<0.005), and increased cortisol concentration (p=0.05), heart rate (p<0.05) and systolic blood pressure (...

Cannabis and psychosis: what do we know and what should we do?

Abstract: It is now incontrovertible that heavy use of cannabis increases the risk of psychosis. There is a dose-response relationship and high potency preparations and synthetic cannabinoids carry the greatest risk. It would be wise to await the outcome of the different models of legalisation that are being introduced in North America, before deciding whether or not to follow suit. Declaration of interest None.

Use of schizophrenia and bipolar disorder polygenic risk scores to identify psychotic disorders.

Abstract: BACKGROUND: There is increasing evidence for shared genetic susceptibility between schizophrenia and bipolar disorder. Although genetic variants only convey subtle increases in risk individually, their combination into a polygenic risk score constitutes a strong disease predictor.AimsTo investigate whether schizophrenia and bipolar disorder polygenic risk scores can distinguish people with broadly defined psychosis and their unaffected relatives from controls. METHOD: Using the latest Psychiatric Genomics Consortium data, we calculated schizophrenia and bipolar disorder polygenic risk scores for 1168 people with psychosis, 552 unaffected relatives and 1472 controls. RESULTS: Patients with broadly defined psychosis had dramatic increases in schizophrenia and bipolar polygenic risk scores, as did their relatives, albeit to a lesser degree. However, the accuracy of predictive models was modest. CONCLUSIONS: Although polygenic risk scores are not ready for clinical use, it is hoped that as they are refined they could help towards risk reduction advice and early interventions for psychosis.Declaration of interestR.M.M. has received honoraria for lectures from Janssen, Lundbeck, Lilly, Otsuka and Sunovian.

Interaction between cannabis consumption and childhood abuse in psychotic disorders: preliminary findings on the role of different patterns of cannabis use.

Abstract: Aim Several studies have suggested that lifetime cannabis consumption and childhood abuse synergistically contribute to the risk for psychotic disorders. This study aimed to extend existing findings regarding an additive interaction between childhood abuse and lifetime cannabis use by investigating the moderating role of type and frequency of cannabis use. Methods Up to 231 individuals presenting for the first time to mental health services with psychotic disorders and 214 unaffected population controls from South London, United Kingdom, were recruited as part of the Genetics and Psychosis study. Information about history of cannabis use was collected using the Cannabis Experiences Questionnaire. Childhood physical and sexual abuse was assessed using the Childhood Experience of Care and Abuse Questionnaire. Results Neither lifetime cannabis use nor reported exposure to childhood abuse was associated with psychotic disorder when the other environmental variable was taken into account. Although the combination of the two risk factors raised the odds for psychosis by nearly three times (adjusted OR = 2.94, 95% CI: 1.44–6.02, P = 0.003), no evidence of interaction was found (adjusted OR = 1.46, 95% CI: −0.54 to 3.46, P = 0.152). Furthermore, the association of high-potency cannabis and daily consumption with psychosis was at least partially independent of the effect of childhood abuse. Conclusions The heavy use of high-potency cannabis increases the risk of psychosis but, in addition, smoking of traditional resin (hash) and less than daily cannabis use may increase the risk for psychosis when combined with exposure to severe childhood abuse.

Different types of childhood adversity and 5-year outcomes in a longitudinal cohort of first-episode psychosis patients

Abstract: Little is known about the impact of different forms of childhood adversity on outcomes in first-episode psychosis (FEP) patients beyond the first year of treatment. We investigated associations between different types of childhood adversity and outcomes of FEP patients over the 5 years following their first contact with mental health services for psychosis. 237 FEP cases aged 18-65 years were followed on average for 5 years after first presentation to psychiatric services in South London, UK. Childhood adversity prior to 17 years of age was assessed at baseline using the Childhood Experience of Care and Abuse Questionnaire (CECA.Q). The results showed that exposure to at least one type of childhood adversity was significantly associated with a lower likelihood of achieving symptomatic remission, longer inpatient stays, and compulsory admission over the 5-year follow-up. There was no evidence though of a dose-response effect. Some specificity was evident. Childhood parental separation was associated with significantly greater likelihood of non-compliance with antipsychotic medications, compulsory admission, and substance dependence. Institutional care was significantly associated with longer total length of inpatient stays; and parental death was significantly associated with compulsory admissions. Clinicians should screen FEP patients for childhood adversity and tailor interventions accordingly to improve outcomes.

The Representativeness of Participants With Severe Mental Illness in a Psychosocial Clinical Trial.

Abstract: Introduction: Cardiovascular morbidity and mortality are increased in severe mental illnesses (SMI). Trials of psychosocial health interventions to improve physical health in SMI, including in treatment-resistant schizophrenia, have shown some benefit. However, the representativeness of participants in such trials has not been determined. Method: We utilized an anonymised case register to determine if participants in a randomized controlled trial (RCT) of a novel psychosocial health intervention aiming to improve physical health in SMI had similar severity of illness to eligible non-participants. A retrospective database analysis was performed, using Health of the Nation Outcome Scale (HoNOS) data from the sample of patients participating in the IMPaCT (Improving Physical health and reducing substance use in Psychosis) RCT (n = 293) compared to all eligible participants with a psychotic illness (n = 774). Results: The mean total HoNOS score in the eligible comparator population (Mean = 9.09, SD = 5.8, range = 0-30) was significantly greater than that of the IMPaCT RCT participants (Mean = 7.16, SD = 4.7, range = 0-26), (t = 3.810, p = 0.006), as was the degree of overall illness severity and functional impairment, as measured by HoNOS. Conclusion: This study shows for the first time that the patient population participating in an RCT of a lifestyle intervention for those with SMI had a better mental health status at entry to the trial, than the total eligible population, although there was no difference in physical health needs. This has relevance to the applicability of RCTs of lifestyle interventions in service planning and suggests that when people are more unwell, greater effort may be needed to include them in psychosocial interventions. A more careful and focused recruitment approach should be followed to improve the participation of the more severely ill patients in psychosocial interventions in order to enhance the external validity of such studies.

Tobacco smoking is associated with psychotic experiences in the general population of South London.

Abstract: BACKGROUND: The association between cigarette smoking and psychosis remains unexplained, but could relate to causal effects in both directions, confounding by socioeconomic factors, such as ethnicity, or use of other substances, including cannabis. Few studies have evaluated the association between cigarettes and psychotic experiences (PEs) in diverse, inner-city populations, or relationships with number of cigarettes consumed. METHODS: We assessed associations and dose-response relationships between cigarette smoking and PEs in a cross-sectional survey of household residents (n = 1680) in South East London, using logistic regression to adjust for cannabis use, other illicit substances, and socioeconomic factors, including ethnicity. RESULTS: We found association between any PEs and daily cigarette smoking, which remained following adjustment for age, gender, ethnicity, cannabis and use of illicit stimulant drugs (fully adjusted odds ratio 1.47, 95% confidence interval 1.01-2.15). Fully adjusted estimates for the association, and with number of PEs, increased with number of cigarettes smoked daily, implying a dose-response effect (p = 0.001 and <0.001, respectively). Odds of reporting any PEs in ex-smokers were similar to never-smokers. CONCLUSIONS: In this diverse epidemiological sample, association between smoking and PEs was not explained by confounders such as cannabis or illicit drugs. Daily cigarette consumption showed a dose-response relationship with the odds of reporting PEs, and of reporting a greater number of PEs. There was no difference in odds of reporting PEs between ex-smokers and never-smokers, raising the possibility that the increase in PEs associated with smoking may be reversible.

Age at first birth in women is genetically associated with increased risk of schizophrenia

Abstract: Previous studies have shown an increased risk for mental health problems in children born to both younger and older parents compared to children of average-aged parents. We previously used a novel design to reveal a latent mechanism of genetic association between schizophrenia and age at first birth in women (AFB). Here, we use independent data from the UK Biobank (N = 38,892) to replicate the finding of an association between predicted genetic risk of schizophrenia and AFB in women, and to estimate the genetic correlation between schizophrenia and AFB in women stratified into younger and older groups. We find evidence for an association between predicted genetic risk of schizophrenia and AFB in women (P-value = 1.12E-05), and we show genetic heterogeneity between younger and older AFB groups (P-value = 3.45E-03). The genetic correlation between schizophrenia and AFB in the younger AFB group is -0.16 (SE = 0.04) while that between schizophrenia and AFB in the older AFB group is 0.14 (SE = 0.08). Our results suggest that early, and perhaps also late, age at first birth in women is associated with increased genetic risk for schizophrenia in the UK Biobank sample. These findings contribute new insights into factors contributing to the complex bio-social risk architecture underpinning the association between parental age and offspring mental health.

The antipsychotic landscape: dopamine and beyond.

Abstract: Until recently, the actions of antipsychotic and pro-psychotic drugs have largely been evaluated in the framework of neuronal doctrine - namely, that neurons communicate by releasing transmitters, and that psychiatric disorders are caused by neurotransmitter imbalances. Moreover, the majority of studies have focused on single transmitter systems - neglecting the fact that in the nervous system, different transmitter systems work in concert and impact on not only their immediate receptors but also downstream pathways that shape structural plasticity. In this review, we discuss the history of understanding the antipsychotic and pro-psychotic actions of drugs, recent developments and future perspectives.

A dimensional approach to assessing psychiatric risk in adults born very preterm.

Abstract: Background Individuals who were born very preterm have higher rates of psychiatric diagnoses compared with term-born controls; however, it remains unclear whether they also display increased sub-clinical psychiatric symptomatology. Hence, our objective was to utilize a dimensional approach to assess psychiatric symptomatology in adult life following very preterm birth. Methods We studied 152 adults who were born very preterm (before 33 weeks’ gestation; gestational range 24–32 weeks) and 96 term-born controls. Participants’ clinical profile was examined using the Comprehensive Assessment of At-Risk Mental States (CAARMS), a measure of sub-clinical symptomatology that yields seven subscales including general psychopathology, positive, negative, cognitive, behavioural, motor and emotional symptoms, in addition to a total psychopathology score. Intellectual abilities were examined using the Wechsler Abbreviated Scale of Intelligence. Results Between-group differences on the CAARMS showed elevated symptomatology in very preterm participants compared with controls in positive, negative, cognitive and behavioural symptoms. Total psychopathology scores were significantly correlated with IQ in the very preterm group only. In order to examine the characteristics of participants’ clinical profile, a principal component analysis was conducted. This revealed two components, one reflecting a non-specific psychopathology dimension, and the other indicating a variance in symptomatology along a positive-to-negative symptom axis. K -means ( k = 4) were used to further separate the study sample into clusters. Very preterm adults were more likely to belong to a high non-specific psychopathology cluster compared with controls. Conclusion and Relevance Very preterm individuals demonstrated elevated psychopathology compared with full-term controls. Their psychiatric risk was characterized by a non-specific clinical profile and was associated with lower IQ.

Substance use and at-risk mental state for psychosis in 2102 prisoners: the case for early detection and early intervention in prison.

Abstract: AIM: Prisoners exhibit high rates of substance use and mental health problems. In the present study, we sought to gain a detailed understanding of substance use amongst young prisoners to inform early detection and early intervention strategies in a prison setting. METHODS: This is a cross-sectional study of 2102 prisoners who were screened by the London Early Detection and Prevention in Prison Team (LEAP). Data on the use of substances were collected including age of first use, recent use, duration of use and poly-drug use. The Prodromal Questionnaire - Brief Version was used to screen for the at-risk mental state. RESULTS: We found high rates of lifetime and recent use and low age of first use of a number of substances. We also found strong associations between substance use and screening positive for an at-risk mental state. Logistic regression analysis confirmed that use of any drug in the last year, poly-drug and early use, as well as heavy alcohol use, were related to an increased risk of screening positive. CONCLUSIONS: Substance use in the prison population is not only widespread and heavy but is also strongly linked with a higher risk of developing mental health problems. The need for early detection and early intervention in prison is discussed.

Only a small proportion of patients with first episode psychosis come via prodromal services: a retrospective survey of a large UK mental health programme.

Abstract: Background Little is known about patients with a first episode of psychosis (FEP) who had first presented to prodromal services with an “at risk mental state” (ARMS) before making the transition to psychosis. We set out to identify the proportion of patients with a FEP who had first presented to prodromal services in the ARMS state, and to compare these FEP patients with FEP patients who did not have prior contact with prodromal services. Methods In this study information on 338 patients aged ≤37 years who presented to mental health services between 2010 and 2012 with a FEP was examined. The data on pathways to care, clinical and socio-demographic characteristics were extracted from the Biomedical Research Council Case Register for the South London and Maudsley NHS Trust. Results Over 2 years, 14 (4.1% of n = 338) young adults presented with FEP and had been seen previously by the prodromal services. These ARMS patients were more likely to enter their pathway to psychiatric care via referral from General Practice, be born in the UK and to have had an insidious mode of illness onset than FEP patients without prior contact with the prodromal services. Conclusions In the current pathways to care configuration, prodromal services are likely to prevent only a few at-risk individuals from transitioning to psychosis even if effective preventative treatments become available.

The Maudsley Environmental Risk Score for Psychosis

Abstract: Risk prediction algorithms have long been used in health research and practice (e.g., in prediction of cardiovascular disease, diabetes, etc.) However, similar tools have not been developed for mental health problems, despite extensive research on risk factors. For example, for psychotic disorders, attempts to sum environmental risk are rare, usually unsystematic and dictated by available data. In light of this, we sought to develop a valid, easy to use measure of the total environmental risk for psychotic disorders, which can be used in research and clinical practice. We first reviewed the literature to identify well-replicated and validated environmental risk factors for psychosis and, then, used the largest available meta-analyses to derive current best estimates of risk. We devised a method of scoring individuals based on the level of exposure to each risk factor, using odds ratios from the meta-analyses, to produce an Environmental Risk Score (ERS). Six risk factors (ethnic minority status, urbanicity, high paternal age, obstetric complications, cannabis use, and childhood adversity) were used to generate the ERS. A distribution for different levels of risk based on permuted data showed that most of population would be at low/moderate risk with a small minority at increased environmental risk for psychosis. This is the first systematic approach to develop an aggregate measure of environmental risk for psychoses. This can be used as a continuous measure of liability to disease or transformed to a relative risk. Its predictive ability will improve with the collection of additional, population specific data.

A New Machine Learning Framework for Understanding the Link Between Cannabis Use and First-Episode Psychosis

Abstract: Lately, several studies started to investigate the existence of links between cannabis use and psychotic disorders. This work proposes a refined Machine Learning framework for understanding the links between cannabis use and 1st episode psychosis. The novel framework concerns extracting predictive patterns from clinical data using optimised and post-processed models based on Gaussian Processes, Support Vector Machines, and Neural Networks algorithms. The cannabis use attributes' predictive power is investigated, and we demonstrate statistically and with ROC analysis that their presence in the dataset enhances the prediction performance of the models with respect to models built on data without these specific attributes.

T132. assessment of cross-national equivalence of the community assessment of psychic experiences (cape)

Abstract: Abstract Background The Community Assessment of Psychic Experiences (CAPE) is a self-report questionnaire that has been developed to measure the dimensions of psychosis in the general population. The cross-national equivalence of a questionnaire allows the comparability of a scale across different populations in different countries, i.e., using different versions of the scale according to the considered language. In this study, our aim was to investigate the equivalence of the CAPE across different countries. Methods Data were drawn from the European Union Gene-Environment Interaction (EU-GEI) study. Participants (incident case of psychotic disorder, controls and siblings of cases) were recruited across in six countries: United Kingdom, the Netherlands, Italy, Spain, Brazil and France. To analyse the cross-national equivalence of the dichotomised version of the CAPE, we used the multigroup categorical confirmatory factory analysis (MCCFA). The cross-national equivalence can be stated after the establishment of three invariances characterised by increased constraints: the configural invariance, the metric invariance and the scalar invariance across the multiples groups. Results The configural invariance model fits well, providing evidence for identical factor structure across countries. The assumption that factor loadings are identical across countries is granted based on the negligible change in the fit indices in the metric invariance model. Moreover, the fit indices suggest that the CAPE shows scalar invariance across countries. Discussion These findings suggest that comparisons across countries of factor and observed means of the CAPE are possible. Thus, differences observed in scores between samples from different countries can be considered as different levels of psychosis.

Can Artificial Neural Networks Predict Psychiatric Conditions Associated with Cannabis Use

Abstract: This data-driven computational psychiatry research proposes a novel machine learning approach to developing predictive models for the onset of first-episode psychosis, based on artificial neural networks. The performance capabilities of the predictive models are enhanced and evaluated by a methodology consisting of novel model optimisation and testing, which integrates a phase of model tuning, a phase of model post-processing with ROC optimisation based on maximum accuracy, Youden and top-left methods, and a model evaluation with the k-fold cross-testing methodology. We further extended our framework by investigating the cannabis use attributes’ predictive power, and demonstrating statistically that their presence in the dataset enhances the prediction performance of the neural network models. Finally, the model stability is explored via simulations with 1000 repetitions of the model building and evaluation experiments. The results show that our best Neural Network model’s average accuracy of predicting first-episode psychosis, which is evaluated with Monte Carlo, is above 80%.

O12.4. some of the individual differences in risk to develop psychosis among cannabis users can be explained by where they live and by their age at first use

Abstract: Abstract Background Cannabis use remains the most widely used recreational drug worldwide. Following from several USA states legalisation policies, European countries are reconsidering their cannabis laws. While a significant amount of Epidemiological evidence has reported that cannabis use increases the risk of psychosis it is still unclear: 1) what underpins individual differences in developing a psychotic disorder following cannabis use; 2) if variations in availability of cannabis have affected rate of Psychotic disorders across Europe. Methods Using detailed data on lifetime pattern of cannabis use from the EUGEI first episode case-control study (N=2300) and the available Incidence rates of Psychosis calculated for each European site of the same study, we aim 1) to estimate if differences in age at first use, especially of high potency cannabis among cannabis users resulted in differences in their probability to develop psychosis across the study sites; 2) to calculate the proportion of new cases of psychosis attributable to early adolescence-high Potency cannabis in the 5 countries; 3) to relate data on prevalence of cannabis use in each study site with the corresponding Incidence rates for psychotic disorders. Results Cannabis users starting using cannabis at age 15 and younger who live in those EU countries where high potency cannabis is available have the highest probability to develop psychosis, compared to never users (Adj ORs from 2.6–5.9; p<0.01). Moreover, the proportion of new cases of Psychosis attributable to heavy use started in adolescence was between 20% and 37%. Finally, the correlation between lifetime use of cannabis in population controls from the study sites was significantly correlated with the corresponding incidence rates for Psychosis (r=0.6; p<0.001) Discussion Before Europe rushes into the USA legalisation “moda” more public education effort might need to be invested in reducing the use of high potency type of cannabis among young adolescents. The latter could lead to a significant reduction in the proportion of new cases of psychosis across Europe.

5.4 biological and epidemiological examination of transdiagnostic and specific symptom dimensions at psychosis onset: findings from the eugei study

Abstract: Abstract Background Current diagnostic models of psychosis have been questioned since Kraepelin’s original dichotomy of dementia praecox and manic depression. Indeed, increasing evidence has suggested that a dimensional approach might be a valid alternative platform for research. However, while an increasing number of studies have investigated how environmental risk factors for affective and non-affective psychosis map onto symptom dimensions, only a few have examined these dimensions in relation to genetic variants as summarised by Polygenic Risk Score (PRS). Furthermore, no studies have examined the putative effect of PRS for Schizophrenia (SZ), Bipolar Disorder (BP), and Major Depressive Disorder (MDD) on previously identified general and specific symptom dimensions. At the same time, only one study has investigated how symptoms vary according to epidemiological factors such as living in urban neighbourhoods. The objectives of this study were to: 1) test whether a bi-factor model statistically fits the conceptualization of psychosis as composed of general and specific dimensions; 2) examine the extent to which SZ, BP, and MDD PRSs explain the phenotypic variance due to general and specific dimensions; 3) test the hypothesis that the general psychosis dimension would be more severe in highly urban environments. Methods We used clinical and epidemiological data from the EUropean network of national schizophrenia networks studying Gene-Environment Interactions (EUGEI) study, including 2322 First Episode Psychosis (FEP) patients recruited in 17 sites across 6 countries. Genetic variants were collectively analyzed for 800 individuals. The following analysis steps were performed: 1) Psychopathology items were analysed using multidimensional item response modelling in MPlus to estimate unidimensional, multidimensional, and bi-factor models of psychosis. Model fit statistics included Log-Likelihood, and Akaike and Bayesian Information Criteria to compare these models. 2) SZ, BP, and MDD PRSs for general and specific dimensions were built using PRSice. Summary statistics from large case-control mega-analyses from the Psychiatric Genomics Consortium were used as base data sets and general and specific dimension scores were used as discovery data sets. Individuals’ number of risk alleles in the discovery sample was weighted by the log odds ratio from the base samples, accounting for population stratification, and summed into the three PRSs. 3) Multilevel regression analysis was used in STATA 14 to examine the variance in general dimension due to the population density levels across the sites. Results A bi-factor solution, composed of one general and five specific symptom dimensions, showed the best model fit statistics. Higher SZ PRS score was associated with higher scores on positive dimensions (β= 0.27, t=2.11, p<0.05); higher BP PRS was associated with higher scores on mania dimension (β= 0.17, t=2.11, p<0.05); higher MDD PRS was associated with lower scores on negative dimension (β= -0.31, t=-2.25, p<0.05). No trends of association were found for SZ, BP, or MDD PRSs and the general psychosis dimension. The transdiagnostic symptom dimension score was elevated in people living in more densely populated sites (η2=0.077, 95% CI 0.057–0.098). Discussion Our results suggest that a) symptom dimension structure at FEP is best represented by the bi-factor model; b) in FEP patients, there is a trend of associations between SZ PRS and positive dimension, and between BP PRS and mania dimension; and c) elevated level of transdiagnostic symptomatology was observed in more densely populated sites.