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Background: Previous studies identified clusters of first-episode psychosis (FEP) patients based on cognition and premorbid adjustment. This study examined a range of socio-environmental risk factors associated with clusters of FEP, aiming a) to compare clusters of FEP and community controls using the Maudsley Environmental Risk Score for psychosis (ERS), a weighted sum of the following risks: paternal age, childhood adversities, cannabis use, and ethnic minority membership; b) to explore the putative differences in specific environmental risk factors in distinguishing within patient clusters and from controls., Methods: A univariable general linear model (GLS) compared the ERS between 1,263 community controls and clusters derived from 802 FEP patients, namely, low (n = 223) and high-cognitive-functioning (n = 205), intermediate (n = 224) and deteriorating (n = 150), from the EU-GEI study. A multivariable GLS compared clusters and controls by different exposures included in the ERS., Results: The ERS was higher in all clusters compared to controls, mostly in the deteriorating ( β =2.8, 95% CI 2.3 3.4 , η 2 = 0.049) and the low-cognitive-functioning cluster ( β =2.4, 95% CI 1.9 2.8, η 2 = 0.049) and distinguished them from the cluster with high-cognitive-functioning. The deteriorating cluster had higher cannabis exposure (mean difference = 0.48, 95% CI 0.49 0.91) than the intermediate having identical IQ, and more people from an ethnic minority (mean difference = 0.77, 95% CI 0.24 1.29) compared to the high-cognitive-functioning cluster., Conclusions: High exposure to environmental risk factors might result in cognitive impairment and lower-than-expected functioning in individuals at the onset of psychosis. Some patients' trajectories involved risk factors that could be modified by tailored interventions.

Background: Studies of salivary cortisol levels in psychosis have yielded inconsistent findings, which may be attributable to heterogeneity in cortisol measurement, illness stage, and approaches to dealing with sampling factors and potential confounders. To address these issues, we performed an individual participant data (IPD) meta-analysis comparing individuals at different stages of psychosis to controls using five different salivary cortisol measures and explored potential effect modifiers., Methods: Salivary cortisol data from five London-based cohorts were used to derive the cortisol awakening response, total daytime cortisol output, basal cortisol, and diurnal slope measures (wake-to-evening and peak-to-evening). Linear regression models were first performed to obtain standardised beta coefficients (β), representing the difference in each cortisol metric between each clinical stage group (cases) and healthy individuals (controls) after accounting for relevant sampling factors; we then used random-effects meta-analyses and meta-regression models to investigate the effect of psychosis stage and sample characteristics on effect sizes., Results: Data were available for 352 individuals distributed across psychosis clinical stages (1a - distress disorder: N = 35; 1b - clinical high-risk for psychosis: N = 90; 2a - first-episode psychosis: N = 197; 2b - single episode remitted: N = 5; 3 - relapsing/remitting illness: N = 18; 4 - severe and persistent illness: N = 7) and 292 controls. A significant overall main effect of clinical stage on peak-to-evening diurnal slope was observed (χ 2 =12.83, p = 0.025), with both the clinical high-risk (β=0.21, 95 % CI: 0.06, 0.36) and first-episode psychosis (β=0.20, 95 % CI: 0.10, 0.31) groups characterised by flatter slopes than controls. The clinical stage groups and controls did not differ on any other cortisol measure. Several sample characteristics were significantly associated with diurnal slope effect sizes, but after accounting for clinical stage, only the association between mean age in cases and wake-to-evening diurnal slope retained significance., Conclusion: Clinical high-risk and first-episode psychosis participants differed from healthy controls in the peak-to-evening diurnal cortisol slope. This measure has not been examined in these populations before, and its potential predictive and prognostic utility for psychotic disorders merits further investigation., Competing Interests: Declaration of Competing Interest Dr Cullen has received consultancy fees from Stratenym Inc and Symmetron Ltd. RMM has received honoraria giving lectures/seminars at meetings supported by Janssen, Lundbeck, Recordati, Otsuka, and Sunovian. Dr Alameda has received honoraria giving a non promotional lecture at a meeting organised by Otsuka-Lundbeck alliance. All other authors have no conflict/competing interests to declare., (Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.)