There is limited evidence as to whether the immune protein profile is associated with a particular symptomatology pattern across the psychosis continuum.

We estimated two bifactor models of general and specific dimensions of psychotic experiences in unaffected siblings of patients (n = 52) and community controls (n = 200), and of psychotic symptoms in first-episode psychosis (FEP) patients (n = 110). We evaluated associations between these transdiagnostic dimensions and trait (TNF-α, IFN-γ), state (IL-6, IL-1β), and regulatory (TGF-β, IL-10, IL-4) cytokines. We explored whether schizophrenia genetic liability (schizophrenia polygenic risk score; SZ-PRS) modified the associations.

High levels of trait marker IFN-γ were associated with the severity of general psychosis dimension in the unaffected siblings and community controls, expanding to the depressive dimension in siblings and to the manic dimension in FEP. High TNF-α levels were associated with more positive psychotic experiences in unaffected siblings and manic symptoms in FEP. Low levels of state markers IL-6 and IL-1β were observed in unaffected siblings presenting more depressive experiences. Still, high levels of IL-6 and IL-1β were associated with the severity of the depressive and negative symptom dimensions at FEP. The severity of transdiagnostic dimension scores across the three groups was associated with lower regulatory cytokines. Exploratory analysis suggested that a high SZ-PRS contributed mostly to associations with psychotic dimensions.

IFN-γ mapped onto the multidimensional expression of psychosis, reinforcing the trait concept. State markers IL-6 and IL-1β may fluctuate along the spectrum. Dysfunction in the regulatory arm may disinhibit the inflammatory system. Associations with psychotic dimensions may be more prone to SZ-PRS susceptibility.

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.

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.

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.

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.

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.

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.

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 (χ2 = 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.

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’.

Child maltreatment (CM) and migrant status are independently associated with psychosis. We examined prevalence of CM by migrant status and tested whether migrant status moderated the association between CM and first-episode psychosis (FEP). We further explored whether differences in CM exposure contributed to variations in the incidence rates of FEP by migrant status.

We included FEP patients aged 18–64 years in 14 European sites and recruited controls representative of the local populations. Migrant status was operationalized according to generation (first/further) and region of origin (Western/non-Western countries). The reference population was composed by individuals of host country's ethnicity. CM was assessed with Childhood Trauma Questionnaire. Prevalence ratios of CM were estimated using Poisson regression. We examined the moderation effect of migrant status on the odds of FEP by CM fitting adjusted logistic regressions with interaction terms. Finally, we calculated the population attributable fractions (PAFs) for CM by migrant status.

We examined 849 FEP cases and 1142 controls. CM prevalence was higher among migrants, their descendants and migrants of non-Western heritage. Migrant status, classified by generation (likelihood test ratio:χ2 = 11.3, p = 0.004) or by region of origin (likelihood test ratio:χ2 = 11.4, p = 0.003), attenuated the association between CM and FEP. PAFs for CM were higher among all migrant groups compared with the reference populations.

The higher exposure to CM, despite a smaller effect on the odds of FEP, accounted for a greater proportion of incident FEP cases among migrants. Policies aimed at reducing CM should consider the increased vulnerability of specific subpopulations.

A history of childhood adversity is associated with psychotic disorder, with an increase in risk according to the number of exposures. However, it is not known why only some exposed individuals go on to develop psychosis. One possibility is pre-existing polygenic vulnerability. Here, we investigated, in the largest sample of first-episode psychosis (FEP) cases to date, whether childhood adversity and high polygenic risk scores for schizophrenia (SZ-PRS) combine synergistically to increase the risk of psychosis, over and above the effect of each alone.

We assigned a schizophrenia-polygenic risk score (SZ-PRS), calculated from the Psychiatric Genomics Consortium (PGC2), to all participants in a sample of 384 FEP patients and 690 controls from the case–control component of the EU-GEI study. Only participants of European ancestry were included in the study. A history of childhood adversity was collected using the Childhood Trauma Questionnaire (CTQ). Synergistic effects were estimated using the interaction contrast ratio (ICR) [odds ratio (OR)exposure and PRS − ORexposure − ORPRS + 1] with adjustment for potential confounders.

There was some evidence that the combined effect of childhood adversities and polygenic risk was greater than the sum of each alone, as indicated by an ICR greater than zero [i.e. ICR 1.28, 95% confidence interval (CI) −1.29 to 3.85]. Examining subtypes of childhood adversities, the strongest synergetic effect was observed for physical abuse (ICR 6.25, 95% CI −6.25 to 20.88).

Our findings suggest possible synergistic effects of genetic liability and childhood adversity experiences in the onset of FEP, but larger samples are needed to increase precision of estimates.

Cannabis consumption is a modifiable risk factor associated with psychosis, but not all cannabis users develop psychosis. Animal studies suggest that an antecedent active immune system interacts with subsequent cannabis exposure and moderates the cannabis–psychosis association, supporting the two-hit hypothesis. The clinical investigations are few, and it is unclear if the immune system is a biological candidate moderating the cannabis–psychosis association or whether cannabis increases inflammation, which in turn, augments psychosis likelihood.

We explored the mediating and moderating role of blood inflammation using PROCESS macro. We used data from a cross-sectional study, including 153 first-episode psychosis patients and 256 community-based controls. Participants answered the Cannabis Experience Questionnaire (cannabis frequency, age of onset, and duration), and plasma cytokines were measured [interleukin (IL)-1β, IL-6, IL-4, IL-10, tumour necrosis factor-α (TNF-α), interferon-γ (IFN-γ), transforming growth factor-β (TGF-β); multiplex]. We computed an inflammatory composite score (ICS) to represent the systemic inflammatory state. Confounders included sex, age, ethnicity, educational level, body mass index, tobacco smoking, lifetime use of other drugs, and antipsychotic treatment.

Mediation: Cannabis consumption was not associated with increased inflammation, thus not supporting a mediating effect of inflammation. Moderation: Daily use and age of onset <17 interacted significantly with the ICS to increase the odds of psychosis beyond their individual effects and were only associated with psychosis among those scoring medium–high in the ICS.

Immune dysregulation might be part of the pathophysiology of psychosis, not explained by cannabis use or other confounders. We provide the first and initial evidence that immune dysregulation modifies the cannabis–psychosis association, in line with a two-hit hypothesis.

Perceived discrimination is associated with worse mental health. Few studies have assessed whether perceived discrimination (i) is associated with the risk of psychotic disorders and (ii) contributes to an increased risk among minority ethnic groups relative to the ethnic majority.

We used data from the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions Work Package 2, a population-based case−control study of incident psychotic disorders in 17 catchment sites across six countries. We calculated odds ratios (OR) and 95% confidence intervals (95% CI) for the associations between perceived discrimination and psychosis using mixed-effects logistic regression models. We used stratified and mediation analyses to explore differences for minority ethnic groups.

Reporting any perceived experience of major discrimination (e.g. unfair treatment by police, not getting hired) was higher in cases than controls (41.8% v. 34.2%). Pervasive experiences of discrimination (≥3 types) were also higher in cases than controls (11.3% v. 5.5%). In fully adjusted models, the odds of psychosis were 1.20 (95% CI 0.91–1.59) for any discrimination and 1.79 (95% CI 1.19–1.59) for pervasive discrimination compared with no discrimination. In stratified analyses, the magnitude of association for pervasive experiences of discrimination appeared stronger for minority ethnic groups (OR = 1.73, 95% CI 1.12–2.68) than the ethnic majority (OR = 1.42, 95% CI 0.65–3.10). In exploratory mediation analysis, pervasive discrimination minimally explained excess risk among minority ethnic groups (5.1%).

Pervasive experiences of discrimination are associated with slightly increased odds of psychotic disorders and may minimally help explain excess risk for minority ethnic groups.

Psychosis rates are higher among some migrant groups. We hypothesized that psychosis in migrants is associated with cumulative social disadvantage during different phases of migration.

We used data from the EUropean Network of National Schizophrenia Networks studying Gene-Environment Interactions (EU-GEI) case–control study. We defined a set of three indicators of social disadvantage for each phase: pre-migration, migration and post-migration. We examined whether social disadvantage in the pre- and post-migration phases, migration adversities, and mismatch between achievements and expectations differed between first-generation migrants with first-episode psychosis and healthy first-generation migrants, and tested whether this accounted for differences in odds of psychosis in multivariable logistic regression models.

In total, 249 cases and 219 controls were assessed. Pre-migration (OR 1.61, 95% CI 1.06–2.44, p = 0.027) and post-migration social disadvantages (OR 1.89, 95% CI 1.02–3.51, p = 0.044), along with expectations/achievements mismatch (OR 1.14, 95% CI 1.03–1.26, p = 0.014) were all significantly associated with psychosis. Migration adversities (OR 1.18, 95% CI 0.672–2.06, p = 0.568) were not significantly related to the outcome. Finally, we found a dose–response effect between the number of adversities across all phases and odds of psychosis (⩾6: OR 14.09, 95% CI 2.06–96.47, p = 0.007).

The cumulative effect of social disadvantages before, during and after migration was associated with increased odds of psychosis in migrants, independently of ethnicity or length of stay in the country of arrival. Public health initiatives that address the social disadvantages that many migrants face during the whole migration process and post-migration psychological support may reduce the excess of psychosis in migrants.

First 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.

We 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.

Caseness, 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).

FEP 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 ‘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.

A total of 817 first episode psychosis patients and 1294 population-based controls completed assessments of general intelligence (IQ), and JTC, and provided blood or saliva samples from which we extracted DNA and computed polygenic risk scores for IQ and schizophrenia.

The estimated proportion of the total effect of case/control differences on JTC mediated by IQ was 79%. Schizophrenia polygenic risk score 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 0.25–0.76, p < 0.001) significantly predicted the number of beads drawn, and was thus associated with reduced JTC bias. The JTC was more strongly associated with the higher level of psychotic-like experiences (PLEs) in controls, including after controlling for IQ (B = −1.7, 95% CI −2.8 to −0.5, p = 0.006), but did not relate to delusions in patients.

Our findings suggest that the JTC reasoning bias in psychosis might not be a specific cognitive deficit but rather a manifestation or consequence, of general cognitive impairment. Whereas, in the general population, the JTC bias is related to PLEs, independent of IQ. The work has the potential to inform interventions targeting cognitive biases in early psychosis.

Daily use of high-potency cannabis has been reported to carry a high risk for developing a psychotic disorder. However, the evidence is mixed on whether any pattern of cannabis use is associated with a particular symptomatology in first-episode psychosis (FEP) patients.

We analysed data from 901 FEP patients and 1235 controls recruited across six countries, as part of the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) study. We used item response modelling to estimate two bifactor models, which included general and specific dimensions of psychotic symptoms in patients and psychotic experiences in controls. The associations between these dimensions and cannabis use were evaluated using linear mixed-effects models analyses.

In patients, there was a linear relationship between the positive symptom dimension and the extent of lifetime exposure to cannabis, with daily users of high-potency cannabis having the highest score (B = 0.35; 95% CI 0.14–0.56). Moreover, negative symptoms were more common among patients who never used cannabis compared with those with any pattern of use (B = −0.22; 95% CI −0.37 to −0.07). In controls, psychotic experiences were associated with current use of cannabis but not with the extent of lifetime use. Neither patients nor controls presented differences in depressive dimension related to cannabis use.

Our findings provide the first large-scale evidence that FEP patients with a history of daily use of high-potency cannabis present with more positive and less negative symptoms, compared with those who never used cannabis or used low-potency types.

Inflammation is a possible biological mechanism underlying the association between childhood maltreatment and psychosis. Previous investigations on this regard were mainly conducted on chronic schizophrenia and lacked control for confounders. We aim to investigate the role of familial liability, childhood maltreatment and recent stress in determining cytokine abnormalities at the onset of psychosis.

We recruited 114 first-episode psychosis (FEP) patients, 57 unaffected biological siblings of FEP patients, and 251 community-based controls. Plasma cytokines (IL-1β, IL-6, TNF-α, IFN-γ, IL-4, IL-10 and TGF-β) were measured and differences across the groups analysed after adjusting for potential confounders.

FEP had a higher pro- and anti-inflammatory cytokine profile (IL-1β, IL-6, TNF-α, IL-10 and TGF-β), which was not observed in unaffected siblings. Siblings presented decreased IL-1β when compared with patients and controls. Childhood maltreatment was associated with higher levels of TGF-β in both patients and siblings when compared with controls. Physical childhood abuse was associated with increased levels of TGF-β in FEP patients but with decreased levels in controls. Other childhood maltreatment subtypes or recent stressors did not affect cytokine levels in any of the groups.

Normal or reduced cytokines in siblings represent possibly a protective factor and suggest that the identified inflammatory profile in FEP can be a real pathophysiological component of psychosis. Experience of childhood maltreatment may contribute as long-term immune priming for the TGF-β pathway, and increased levels of this cytokine in both patients and siblings exposed to childhood maltreatment point to a possible biological candidate of familial risk for psychosis.

The value of the nosological distinction between non-affective and affective psychosis has frequently been challenged. We aimed to investigate the transdiagnostic dimensional structure and associated characteristics of psychopathology at First Episode Psychosis (FEP). Regardless of diagnostic categories, we expected that positive symptoms occurred more frequently in ethnic minority groups and in more densely populated environments, and that negative symptoms were associated with indices of neurodevelopmental impairment.

This study included 2182 FEP individuals recruited across six countries, as part of the EUropean network of national schizophrenia networks studying Gene–Environment Interactions (EU-GEI) study. Symptom ratings were analysed using multidimensional item response modelling in Mplus to estimate five theory-based models of psychosis. We used multiple regression models to examine demographic and context factors associated with symptom dimensions.

A bifactor model, composed of one general factor and five specific dimensions of positive, negative, disorganization, manic and depressive symptoms, best-represented associations among ratings of psychotic symptoms. Positive symptoms were more common in ethnic minority groups. Urbanicity was associated with a higher score on the general factor. Men presented with more negative and less depressive symptoms than women. Early age-at-first-contact with psychiatric services was associated with higher scores on negative, disorganized, and manic symptom dimensions.

Our results suggest that the bifactor model of psychopathology holds across diagnostic categories of non-affective and affective psychosis at FEP, and demographic and context determinants map onto general and specific symptom dimensions. These findings have implications for tailoring symptom-specific treatments and inform research into the mood-psychosis spectrum.