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Background: Cannabis use and familial vulnerability to psychosis have been associated with social cognition deficits. This study examined the potential relationship between cannabis use and cognitive biases underlying social cognition and functioning in patients with first episode psychosis (FEP), their siblings, and controls., Methods: We analyzed a sample of 543 participants with FEP, 203 siblings, and 1168 controls from the EU-GEI study using a correlational design. We used logistic regression analyses to examine the influence of clinical group, lifetime cannabis use frequency, and potency of cannabis use on cognitive biases, accounting for demographic and cognitive variables., Results: FEP patients showed increased odds of facial recognition processing (FRP) deficits (OR = 1.642, CI 1.123-2.402) relative to controls but not of speech illusions (SI) or jumping to conclusions (JTC) bias, with no statistically significant differences relative to siblings. Daily and occasional lifetime cannabis use were associated with decreased odds of SI (OR = 0.605, CI 0.368-0.997 and OR = 0.646, CI 0.457-0.913 respectively) and JTC bias (OR = 0.625, CI 0.422-0.925 and OR = 0.602, CI 0.460-0.787 respectively) compared with lifetime abstinence, but not with FRP deficits, in the whole sample. Within the cannabis user group, low-potency cannabis use was associated with increased odds of SI (OR = 1.829, CI 1.297-2.578, FRP deficits (OR = 1.393, CI 1.031-1.882, and JTC (OR = 1.661, CI 1.271-2.171) relative to high-potency cannabis use, with comparable effects in the three clinical groups., Conclusions: Our findings suggest increased odds of cognitive biases in FEP patients who have never used cannabis and in low-potency users. Future studies should elucidate this association and its potential implications.

Introduction: Obsessive compulsive disorder is associated with affected executive functioning, including memory, cognitive flexibility, and organizational strategies. As it was reported in previous studies, patients with preserved executive functions respond better to pharmacological treatment, while others need to keep trying different pharmacological strategies., Material and Methods: In this work we used machine learning techniques to predict pharmacological response (OCD patients' symptomatology reduction) based on executive functioning and clinical variables. Among those variables we used anxiety, depression and obsessive-compulsive symptoms scores by applying State-Trait Anxiety Inventory, Hamilton Depression Rating Scale and Yale-Brown Obsessive Compulsive Scale respectively, while Rey-Osterrieth Complex Figure Test was used to assess organisation skills and non-verbal memory; Digits' subtests from Wechsler Adult Intelligence Scale-IV were used to assess short-term memory and working memory; and Raven's Progressive Matrices were applied to assess problem solving and abstract reasoning., Results: As a result of our analyses, we created a reliable algorithm that predicts Y-BOCS score after 12 weeks based on patients' clinical characteristics (sex at birth, age, pharmacological strategy, depressive and obsessive-compulsive symptoms, years passed since diagnostic and Raven's Progressive Matrices score) and Digits' scores. A high correlation (0.846) was achieved in predicted and true values., Conclusions: The present study proves the viability to predict if a patient would respond or not to a certain pharmacological strategy with high reliability based on sociodemographics, clinical variables and cognitive functions as short-term memory and working memory. These results are promising to develop future prediction models to help clinical decision making., (Copyright © 2024 The Authors. Published by Elsevier España S.L.U. All rights reserved.)

Background: Urbanicity is a well-established risk factor for psychosis. Our recent multi-national study found an association between urbanicity and clinical psychosis in Northern Europe but not in Southern Europe. In this study, we hypothesized that the effect of current urbanicity on variation of schizotypy would be greater in North-western Europe countries than in Southern Europe ones., Methods: We recruited 1080 individuals representative of the populations aged 18-64 of 14 different sites within 5 countries, classified as either North-western Europe (England, France, and The Netherlands) with Southern Europe (Spain and Italy). Our main outcome was schizotypy, assessed through the Structured Interview for Schizotypy-Revised. Our main exposure was current urbanicity, operationalized as local population density. A priori confounders were age, sex, ethnic minority status, childhood maltreatment, and social capital. Schizotypy variation was assessed using multi-level regression analysis. To test the differential effect of urbanicity between North-western and Southern European, we added an interaction term between population density and region of recruitment., Results: Population density was associated with schizotypy (β = 0.248,95%CI = 0.122-0.375;p < 0.001). The addition of the interaction term improved the model fit (likelihood test ratio:χ 2  = 6.85; p = 0.009). The effect of urbanicity on schizotypy was substantially stronger in North-western Europe (β = 0.620,95%CI = 0.362-0.877;p < 0.001) compared with Southern Europe (β = 0.190,95%CI = 0.083-0.297;p = 0.001)., Conclusions: The association between urbanicity and both subclinical schizotypy and clinical psychosis, rather than being universal, is context-specific. Considering that urbanization is a rapid and global process, further research is needed to disentangle the specific factors underlying this relationship., (© 2024 The Author(s). Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

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).)

The rising prevalence and legalisation of cannabis worldwide have underscored the need for a comprehensive understanding of its biological impact, particularly on mental health. Epigenetic mechanisms, specifically DNA methylation, have gained increasing recognition as vital factors in the interplay between risk factors and mental health. This study aimed to explore the effects of current cannabis use and high-potency cannabis on DNA methylation in two independent cohorts of individuals experiencing first-episode psychosis (FEP) compared to control subjects. The combined sample consisted of 682 participants (188 current cannabis users and 494 never users). DNA methylation profiles were generated on blood-derived DNA samples using the Illumina DNA methylation array platform. A meta-analysis across cohorts identified one CpG site (cg11669285) in the CAVIN1 gene that showed differential methylation with current cannabis use, surpassing the array-wide significance threshold, and independent of the tobacco-related epigenetic signature. Furthermore, a CpG site localised in the MCU gene (cg11669285) achieved array-wide significance in an analysis of the effect of high-potency (THC = > 10%) current cannabis use. Pathway and regional analyses identified cannabis-related epigenetic variation proximal to genes linked to immune and mitochondrial function, both of which are known to be influenced by cannabinoids. Interestingly, a model including an interaction term between cannabis use and FEP status identified two sites that were significantly associated with current cannabis use with a nominally significant interaction suggesting that FEP status might moderate how cannabis use affects DNA methylation. Overall, these findings contribute to our understanding of the epigenetic impact of current cannabis use and highlight potential molecular pathways affected by cannabis exposure., (© 2024. The Author(s).)

Introduction: Bipolar disorder (BD) has been reconceptualised as a progressive disorder that develops from mild to severe presentations. An empirical staging model - the Empirically Developed Clinical Staging Model for BD (EmDe-5) - was developed in a previous study. This study aims to further validate that model using a larger and more representative Spanish sample., Material and Methods: 183 BD outpatients were recruited at 11 sites in Spain. Assessment included clinical characteristics of the BD (number of hospitalisations, number of suicide attempts, comorbid personality disorders), physical health (BMI, metabolic syndrome, number of physical illnesses), cognition (SCIP), functioning (permanently disabled due to BD, FAST), and quality of life (SF-36). The CGI-S, VAS-S, and psychopharmacological treatment pattern were used as external validators., Results: Ten patients (51.5%) were classified as stage 1, 33 (18%) as stage 2, 93 (508%) as stage 3, 37 (202%) as stage 4, and 10 (55%) as stage 5. All profilers, other than number of suicide attempts (p=0.311) and comorbid personality disorder (p=0.061), exhibited worse scores from stage 1 to 5. As expected, VAS-S and CGI-S scores were worse in the later stages. Regarding treatment, early stages (1-2) were associated with the use of one to three drugs while late stages (4-5) were associated with four or more drugs (p=0.002)., Conclusions: We confirm the EmDe-5 staging model's construct validity. The ease of obtaining the profilers, together with the operational criteria provided to quantify them, will facilitate the use of the EmDe-5 staging model in daily clinical practice., (Copyright © 2021. Published by Elsevier España S.L.U.)

Background: Individuals with bipolar disorder (BD) often have co-occurring substance use disorders (SUDs), which substantially impoverish the course of illness. Despite the importance of this dual diagnosis, the evidence of the efficacy and safety of adjuvant treatments is mostly unknown., Objective: To perform a meta-analysis to evaluate the efficacy and safety of adjuvant drugs in patients with co-occurring BD and SUD., Methods: We searched PubMed, Scopus, and Web of Knowledge until 30th April 2022 for randomized clinical trials (RCT) evaluating the efficacy and safety of adjuvant drugs compared to placebo in patients with a dual diagnosis of BD and SUD. We meta-analyzed the effect of adjuvant drugs on general outcomes (illness severity, mania, depression, anxiety, abstinence, substance craving, substance use, gamma-GT, adherence, and adverse events) and used the results to objectively assess the quality of the evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. For completeness, we also report the specific effects of specific adjuvant drugs in patients with specific substance disorders., Results: We included 15 RCT studies (9 alcohol, 3 cocaine, 2 nicotine, and 1 cannabis) comprising 628 patients allocated to treatment and 622 to placebo. There was low-quality evidence that adjuvant drugs may reduce illness severity (g=-0.25, 95% CI: -0.44, -0.06), and very-low quality evidence that they may decrease substance use (g=-0.23, 95% CI: -0.44, -0.02) and increase substance abstinence (g=0.21, 95% CI: 0.04, 0.38)., Discussion: There is low-quality evidence that adjuvant drugs may help reduce illness severity, probably via facilitating abstinence and lower substance use. However, the evidence is weak; thus, these results should be considered cautiously until better evidence exists., (Copyright © 2023 SEP y SEPB. Published by Elsevier España S.L.U. All rights reserved.)

Schizophrenia diagnosis and admission history were associated with a polygenic score (PGS) for schizophrenia based on a subset of variants that act by modifying the expression of genes whose expression is also modified by antipsychotics. This gene set was enriched in cytokine production. Interleukin-6 (IL-6) is the only cytokine whose plasma levels were associated both with schizophrenia diagnosis and with acute decompensations in the largest meta-analysis. Therefore, we hypothesized that an IL-6 PGS, but not other cytokines PGSs, would be associated with schizophrenia chronicity/psychiatric admissions. Using the IL-6 PGS model from The PGS Catalog, IL-6 PGS was calculated in 427 patients with schizophrenia and data regarding admission history. Association between IL-6 PGS and chronicity, measured as number and duration of psychiatric admissions, or ever readmission was analyzed by multivariate ordinal and logistic regression, respectively. Specificity of results was assessed by analysis of PGSs from the other cytokines at The PGS Catalog with meta-analytic evidence of association with schizophrenia diagnosis or acute decompensations, IL-1RA, IL-4, IL-8, and IL-12. IL-6 PGS was associated with schizophrenia chronicity, explaining 1.51% of variability (OR = 1.29, 95% CI 1.07-1.55, P = 0.007). There was no association with ever readmission. Other cytokines PGSs were not associated with chronicity. Association with IL-6 PGS was independent of association with schizophrenia PGS. Our results provide evidence that genetically regulated higher levels of IL-6 are involved in schizophrenia chronicity, highlighting the relevance of immunity processes for a subgroup of patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Suicide is a major public health problem, especially among individuals over 50 years old. Despite the suitability of this life stage for prevention, research on the efficacy of psychological interventions is scarce and methodologically limited, affecting their clinical utility and efficacy. Brief, flexible interventions that can be applied both in-person and remotely are needed. This study aims to evaluate the efficacy of a brief problem-solving-based suicide prevention program applied through various modalities to individuals over 50 years old., Methods: A randomized controlled trial will be conducted. A sample of 212 adults aged 50 or older with suicidal ideation will be randomly assigned to a problem-solving-based psychological intervention administered face-to-face (PSPI-P; n = 53), by telephone multiconference (PSPI-M; n = 53), via a smartphone app (PSPI-A; n = 53), or to a usual care control group (UCCG; n = 53). The intervention will be delivered in 7 sessions or modules of 90 min each. Blind trained evaluators will conduct assessments at pre-intervention, post-intervention, and follow-ups at 3, 6, and 12 months. The primary outcome will be suicidal ideation evaluated using the Suicidal Ideation Scale (SSI) and the Columbia Suicide Severity Rating Scale (C-SSRS). Secondary outcomes will include hopelessness, anxiety and depression symptoms, reasons for living, impulsivity, problem-solving skills, social support, anger syndrome, gratitude, personality, dropouts, treatment adherence, and satisfaction with the intervention., Discussion: This study will provide evidence of the efficacy of a brief problem-solving-based intervention for suicide prevention in individuals over 50 years old, administered face-to-face, by telephone multiconference, and via a smartphone app. If results are favorable, it will indicate that an effective, accessible, clinically and socially useful suicide prevention intervention has been developed for affected individuals, families, and communities., Trial Registration: ClinicalTrials.gov NCT06338904. Registered April 1, 2024., (© 2024. The Author(s).)

Background: Schizophrenia is a highly heritable disorder characterized by increased cortical thinning throughout the life span. Studies have reported a shared genetic basis between schizophrenia and cortical thickness. However, no genes whose expression is related to abnormal cortical thinning in schizophrenia have been identified., Methods: We conducted linear mixed models to estimate the rates of accelerated cortical thinning across 68 regions from the Desikan-Killiany atlas in individuals with schizophrenia compared with healthy control participants from a large longitudinal sample (n cases  = 169 and n controls  = 298, ages 16-70 years). We studied the correlation between gene expression data from the Allen Human Brain Atlas and accelerated thinning estimates across cortical regions. Finally, we explored the functional and genetic underpinnings of the genes that contribute most to accelerated thinning., Results: We found a global pattern of accelerated cortical thinning in individuals with schizophrenia compared with healthy control participants. Genes underexpressed in cortical regions that exhibit this accelerated thinning were downregulated in several psychiatric disorders and were enriched for both common and rare disrupting variation for schizophrenia and neurodevelopmental disorders. In contrast, none of these enrichments were observed for baseline cross-sectional cortical thickness differences., Conclusions: Our findings suggest that accelerated cortical thinning, rather than cortical thickness alone, serves as an informative phenotype for neurodevelopmental disruptions in schizophrenia. We highlight the genetic and transcriptomic correlates of this accelerated cortical thinning, emphasizing the need for future longitudinal studies to elucidate the role of genetic variation and the temporal-spatial dynamics of gene expression in brain development and aging in schizophrenia., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background and Hypothesis: Recent findings suggest the incidence of first-episode psychotic disorders (FEP) varies according to setting-level deprivation and cannabis use, but these factors have not been investigated together. We hypothesized deprivation would be more strongly associated with variation in FEP incidence than the prevalence of daily or high-potency cannabis use between settings., Study Design: We used incidence data in people aged 18-64 years from 14 settings of the EU-GEI study. We estimated the prevalence of daily and high-potency cannabis use in controls as a proxy for usage in the population at-risk; multiple imputations by chained equations and poststratification weighting handled missing data and control representativeness, respectively. We modeled FEP incidence in random intercepts negative binomial regression models to investigate associations with the prevalence of cannabis use in controls, unemployment, and owner-occupancy in each setting, controlling for population density, age, sex, and migrant/ethnic group., Study Results: Lower owner-occupancy was independently associated with increased FEP (adjusted incidence rate ratio [aIRR]: 0.76, 95% CI: 0.61-0.95) and non-affective psychosis incidence (aIRR: 0.68, 95% CI: 0.55-0.83), after multivariable adjustment. Prevalence of daily cannabis use in controls was associated with the incidence of affective psychoses (aIRR: 1.53, 95% CI: 1.02-2.31). We found no association between FEP incidence and unemployment or high-potency cannabis use prevalence. Sensitivity analyses supported these findings., Conclusions: Lower setting-level owner-occupancy and increased prevalence of daily cannabis use in controls independently contributed to setting-level variance in the incidence of different psychotic disorders. Public health interventions that reduce exposure to these harmful environmental factors could lower the population-level burden of psychotic disorders., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

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.