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Childhood adversity is associated with various clinical dimensions in psychosis; however, how genetic vulnerability shapes the adversity-associated psychopathological signature is yet to be studied. We studied data of 583 First Episode Psychosis (FEP) cases from the EU-GEI FEP case-control study, including Polygenic risk scores for major depressive disorder (MDD-PRS), bipolar disorder (BD-PRS) and schizophrenia (SZ-PRS); childhood adversity measured with the total score of the Childhood Trauma Questionnaire (CTQ); and positive, negative, depressive and manic psychopathological domains from a factor model of transdiagnostic dimensions. Genes and environment interactions were explored as a departure from a multiplicative effect of PRSs and total CTQ on each dimension. Analyses were adjusted for age, sex, 10 PCA, site of recruitment and for medication. A childhood adversity and PRS multiplicative interaction was observed between A) the CTQ and MDD-PRS on the predominance of positive (β = 0.42, 95% CI = [0.155, 0.682], p = 0.004); and depressive (β = 0.33, 95% CI = [0.071, 0.591], p = 0.013) dimensions; B) between the CTQ and BD-PRS on the positive dimension (β = 0.45, 95% CI = [0.106, 0.798], p = 0.010), and C) with the CTQ and SZ-PRS on the positive dimension (β = -0.34, 95% CI = [-0.660, -0.015], p = 0.040). Bonferroni corrected p-value of significance was set at 0.0125. In conclusion, despite being underpowered, this study suggests that genetic liability for MDD and BD may have a moderating effect on the sensibility of childhood adversity on depressive and positive psychotic dimensions. This supports the hypothesis of an affective pathway to psychosis in those exposed to childhood adversity., (© 2024. The Author(s).)

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.

Background: While cannabis use is a well-established risk factor for psychosis, little is known about any association between reasons for first using cannabis (RFUC) and later patterns of use and risk of psychosis., Methods: We used data from 11 sites of the multicentre European Gene-Environment Interaction (EU-GEI) case-control study. 558 first-episode psychosis patients (FEPp) and 567 population controls who had used cannabis and reported their RFUC.We ran logistic regressions to examine whether RFUC were associated with first-episode psychosis (FEP) case-control status. Path analysis then examined the relationship between RFUC, subsequent patterns of cannabis use, and case-control status., Results: Controls (86.1%) and FEPp (75.63%) were most likely to report 'because of friends' as their most common RFUC. However, 20.1% of FEPp compared to 5.8% of controls reported: 'to feel better' as their RFUC (χ 2 = 50.97; p < 0.001). RFUC 'to feel better' was associated with being a FEPp (OR 1.74; 95% CI 1.03-2.95) while RFUC 'with friends' was associated with being a control (OR 0.56; 95% CI 0.37-0.83). The path model indicated an association between RFUC 'to feel better' with heavy cannabis use and with FEPp-control status., Conclusions: Both FEPp and controls usually started using cannabis with their friends, but more patients than controls had begun to use 'to feel better'. People who reported their reason for first using cannabis to 'feel better' were more likely to progress to heavy use and develop a psychotic disorder than those reporting 'because of friends'.

Background: Childhood adversity and cannabis use are considered independent risk factors for psychosis, but whether different patterns of cannabis use may be acting as mediator between adversity and psychotic disorders has not yet been explored. The aim of this study is to examine whether cannabis use mediates the relationship between childhood adversity and psychosis., Methods: Data were utilised on 881 first-episode psychosis patients and 1231 controls from the European network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) study. Detailed history of cannabis use was collected with the Cannabis Experience Questionnaire. The Childhood Experience of Care and Abuse Questionnaire was used to assess exposure to household discord, sexual, physical or emotional abuse and bullying in two periods: early (0-11 years), and late (12-17 years). A path decomposition method was used to analyse whether the association between childhood adversity and psychosis was mediated by (1) lifetime cannabis use, (2) cannabis potency and (3) frequency of use., Results: The association between household discord and psychosis was partially mediated by lifetime use of cannabis (indirect effect coef. 0.078, s.e. 0.022, 17%), its potency (indirect effect coef. 0.059, s.e. 0.018, 14%) and by frequency (indirect effect coef. 0.117, s.e. 0.038, 29%). Similar findings were obtained when analyses were restricted to early exposure to household discord., Conclusions: Harmful patterns of cannabis use mediated the association between specific childhood adversities, like household discord, with later psychosis. Children exposed to particularly challenging environments in their household could benefit from psychosocial interventions aimed at preventing cannabis misuse.

Evidence on the impact of the COVID-19 pandemic on psychotic disorders is so far scarce. We conducted an incidence study to ascertain rates of first-episode psychosis (FEP) before and during the COVID-19 pandemic in South London. We screened clinical records of individuals living in the London boroughs of Southwark and Lambeth who were referred to the early intervention services before (from 1/3/2019 to 28/2/2020) and during (from 1/3/2020 to 28/2/2021) the COVID-19 pandemic. We used the Office for National Statistics to determine the population at risk. We computed crude and sex-age standardised FEP incidence per 100,000 person-years. We used Poisson regression to calculate the incidence rate ratio (IRR) across the COVID-19 pandemic. A total of 321 incident cases of FEP were identified during the COVID-19 pandemic, accounting for a crude rate of 69.8 (95% CI 62.1-77.4) per 100,000 person-years. The crude rate for the year before was 47.5 (95% CI 41.2-53.8). The incidence variation between the two years accounted for an adjusted IRR of 1.45 (95% CI 1.22-1.72). The pandemic was accompanied by a 45% spike in the rates of first-episode psychosis. This finding should inform public health research and demonstrate the need for adequate resources for secondary care., Competing Interests: Declaration of Competing Interest None in relation to the present research., (Copyright © 2023. Published by Elsevier B.V.)

Background: 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 EUropean Network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) first episode 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)., Methods: Participants (842 cases, 1284 controls) from 16 European EU-GEI sites were successfully genotyped following standard quality control procedures. The sample was stratified based on genomic ancestry and analyses were done only on the subsample representing the European population (573 cases, 1005 controls). Using 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., Results: In case-control comparisons PRS-SZ, PRS-BD and PRS-D distributed differentially across psychotic subcategories. In case-case comparisons, both PRS-SZ [odds ratio (OR) = 0.7, 95% confidence interval (CI) 0.54-0.92] and PRS-D (OR = 1.31, 95% CI 1.06-1.61) differentiated AP from SSD; and within AP categories, only PRS-SZ differentiated BD from psychotic depression (OR = 2.14, 95% CI 1.23-3.74)., Conclusions: 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 the potential usefulness of PRSs in specific populations such as high-risk or early psychosis phases.

Objectives: The liberalisation of cannabis laws, the increasing availability and potency of cannabis has renewed concern about the risk of psychosis with cannabis., Methods: The objective of the WFSBP task force was to review the literature about this relationship., Results: Converging lines of evidence suggest that exposure to cannabis increases the risk for psychoses ranging from transient psychotic states to chronic recurrent psychosis. The greater the dose, and the earlier the age of exposure, the greater the risk. For some psychosis outcomes, the evidence supports some of the criteria of causality. However, alternate explanations including reverse causality and confounders cannot be conclusively excluded. Furthermore, cannabis is neither necessary nor sufficient to cause psychosis. More likely it is one of the multiple causal components. In those with established psychosis, cannabis has a negative impact on the course and expression of the illness. Emerging evidence also suggests alterations in the endocannabinoid system in psychotic disorders., Conclusions: Given that exposure to cannabis and cannabinoids is modifiable, delaying or eliminating exposure to cannabis or cannabinoids, could potentially impact the rates of psychosis related to cannabis, especially in those who are at high risk for developing the disorder.

Diagnostic categories do not completely reflect the heterogeneous expression of psychosis. Using data from the EU-GEI study, we evaluated the impact of schizophrenia polygenic risk score (SZ-PRS) and patterns of cannabis use on the transdiagnostic expression of psychosis. We analysed first-episode psychosis patients (FEP) and controls, generating transdiagnostic dimensions of psychotic symptoms and experiences using item response bi-factor modelling. Linear regression was used to test the associations between these dimensions and SZ-PRS, as well as the combined effect of SZ-PRS and cannabis use on the dimensions of positive psychotic symptoms and experiences. We found associations between SZ-PRS and (1) both negative (B = 0.18; 95%CI 0.03-0.33) and positive (B = 0.19; 95%CI 0.03-0.35) symptom dimensions in 617 FEP patients, regardless of their categorical diagnosis; and (2) all the psychotic experience dimensions in 979 controls. We did not observe associations between SZ-PRS and the general and affective dimensions in FEP. Daily and current cannabis use were associated with the positive dimensions in FEP (B = 0.31; 95%CI 0.11-0.52) and in controls (B = 0.26; 95%CI 0.06-0.46), over and above SZ-PRS. We provide evidence that genetic liability to schizophrenia and cannabis use map onto transdiagnostic symptom dimensions, supporting the validity and utility of the dimensional representation of psychosis. In our sample, genetic liability to schizophrenia correlated with more severe psychosis presentation, and cannabis use conferred risk to positive symptomatology beyond the genetic risk. Our findings support the hypothesis that psychotic experiences in the general population have similar genetic substrates as clinical disorders., (© 2021. The Author(s).)

Objective: The aim of this systematic review and meta-analysis was to study the association between specific environmental risk factors (ERF) and later development of Bipolar disorder and Psychotic depression., Methods: A systematic search of prospective studies was conducted in MEDLINE, EMBASE and PsycINFO databases, and supplemented by hand searching, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (registration number: CRD42018092253). Selected ERF included: pre-/peri-natal factors-paternal age at birth, maternal infection, obstetric complications, perinatal stress; early childhood factors-urbanicity at birth, childhood infection, childhood adversity; later life factors-substance misuse, ethnic minority and migration, urbanicity later in life, stressful life events, and traumatic head injury. Pooled effect sizes of the association between these ERF and affective psychoses were calculated from systematically selected studies. When studies examining each ERF were insufficient for meta-analysis, results were presented narratively., Results: Forty-six studies were included for quantitative analyses among selected ERF for affective psychosis, with significant association found for paternal age >40 years (OR 1.17, 95%CI 1.12-1.23), early (OR 1.52, 95%CI 1.07-2.17) and late (OR 1.32, 95%CI 1.05-1.67) gestational age, childhood adversity (OR 1.33, 95%CI 1.18-1.50), substance misuse (OR 2.87, 95%CI 1.63-5.50), and being from an ethnic minority (OR 1.99, 95%CI 1.39-2.84)., Conclusions: These results suggest some shared environmental load between non-affective and affective psychosis, implying generalized risks for psychosis rather than for specific diagnostic categories. Nonetheless, published studies for some ERF in the affective psychoses are scarce, and further longitudinal studies are needed., (© 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.)

Despite the accepted link between childhood abuse and positive psychotic symptoms, findings between other adversities, such as neglect, and the remaining dimensions in people with psychosis have been inconsistent, with evidence not yet reviewed quantitatively. The aim of this study was to systematically examine quantitatively the association between broadly defined childhood adversity (CA), abuse (sexual/physical/emotional), and neglect (physical/emotional) subtypes, with positive, negative, depressive, manic, and disorganized dimensions in those with psychosis. A search was conducted across EMBASE, MEDLINE, PsychINFO, and Cochrane Libraries using search terms related to psychosis population, CA, and psychopathological dimensions. After reviewing for relevance, data were extracted, synthesized, and meta-analyzed. Forty-seven papers were identified, including 7379 cases across 40 studies examining positive, 37 negative, 20 depressive, 9 disorganized, and 13 manic dimensions. After adjustment for publication bias, general adversity was positively associated with all dimensions (ranging from r = 0.08 to r = 0.24). Most forms of abuse were associated with depressive (ranging from r = 0.16 to r = 0.32), positive (ranging from r = 0.14 to r = 0.16), manic (r = 0.13), and negative dimensions (ranging from r = 0.05 to r = 0.09), while neglect was only associated with negative (r = 0.13) and depressive dimensions (ranging from r = 0.16 to r = 0.20). When heterogeneity was found, it tended to be explained by one specific study. The depressive dimension was influenced by percentage of women (ranging from r = 0.83 to r = 1.36) and poor-quality scores (ranging from r = -0.21 and r = -0.059). Quality was judged as fair overall. Broadly defined adversity and forms of abuse increase transdimensional severity. Being exposed to neglect during childhood seems to be exclusively related to negative and depressive dimensions suggesting specific effects., (© 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.)

Various psychological and biological pathways have been proposed as mediators between childhood adversity (CA) and psychosis. A systematic review of the evidence in this domain is needed. Our aim is to systematically review the evidence on psychological and biological mediators between CA and psychosis across the psychosis spectrum. This review followed PRISMA guidelines. Articles published between 1979 and July 2019 were identified through a literature search in OVID (PsychINFO, Medline and Embase) and Cochrane Libraries. The evidence by each analysis and each study is presented by group of mediator categories found. The percentage of total effect mediated was calculated. Forty-eight studies were included, 21 in clinical samples and 27 in the general population (GP) with a total of 82 352 subjects from GP and 3189 from clinical studies. The quality of studies was judged as 'fair'. Our results showed (i) solid evidence of mediation between CA and psychosis by negative cognitive schemas about the self, the world and others (NS); by dissociation and other post-traumatic stress disorder symptoms; and through an affective pathway in GP but not in subjects with disorder; (iii) lack of studies exploring biological mediators. We found evidence suggesting that various overlapping and not competing pathways involving post-traumatic and mood symptoms, as well as negative cognitions contribute partially to the link between CA and psychosis. Experiences of CA, along with relevant mediators should be routinely assessed in patients with psychosis. Evidence testing efficacy of interventions targeting such mediators through cognitive behavioural approaches and/or pharmacological means is needed in future.