Effectiveness of family metacognitive training in mothers with psychosis and their adolescent children: a multicenter study protocol.

Background: More than half of women with psychosis take care of their children despite the difficulties caused by the disease. Additionally, these kids have a higher risk of developing a mental health disorder. However, no interventions have been developed to meet these needs. Metacognitive Training (MCT) is a psychological intervention that has demonstrated its efficacy in improving cognitive insight, symptom management and social cognition in people with first-episode psychosis (FEP). Additionally, MCT has shown better results in women than men with FEP. This study aims to adapt and evaluate the efficacy of MCT-F in mothers and adolescent children in an online group context with the main purpose of improving family relationships, cognitive awareness and symptoms in women with psychosis and increase their children's knowledge of the disease and their functioning. As secondary objectives, it also aims to evaluate improvements in metacognition, social cognition, symptoms, protective factors and self-perception of stigma. Materials and methods: A quasi-experimental design with participants acting as their own control will be carried out. Forty-eight mothers with psychosis and their adolescent children (between 12 and 20 years old) recruited from a total of 11 adult mental health care centers will receive MCT-F. Participants will be evaluated 11 weeks before the intervention (T1), at baseline (T2), and post-intervention (T3) with a cognitive insight scale, as a primary outcome. Measures of metacognitive and social cognition, symptoms, cognitive functioning, family and social functioning, protective factors (self-esteem, resilience, and coping strategies) and self-perceived stigma will be addressed as secondary outcomes. Assessment will also address trauma and attachment in mothers and, lastly, the feasibility and acceptability of MCT-F in both participant groups. Discussion: This will be the first investigation of the efficacy, acceptability, and viability of the implementation of MCT-F. The results of this study may have clinical implications, contributing to improving mothers' with psychosis and adolescents' functioning and better understanding of the disease, in addition to the possible protective and preventive effect in adolescents, who are known to be at higher risk of developing severe mental disorders.Clinical trial registration:https://clinicaltrials.gov/, identifier [NCT05358457].

Exploring parenthood in first episode of psychosis: the potential role of the offspring in the outcome of women.

PURPOSE: The study aimed to explore the role of parenthood at first episode of psychosis (FEP) on recovery, with a focus on potential sex differences. METHODS: Sociodemographic, clinical, and neurocognitive information was considered on 610 FEP patients form the PAFIP cohort (Spain). Baseline and three-year follow-up comparisons were carried out. Chi-square tests and ANCOVA analysis were performed controlling for the effect of age and years of education. RESULTS: Men comprised 57.54% of the sample, with only 5.41% having offspring when compared to 36.29% of women. Parenthood was related to shorter duration of untreated illness (DUI) in women with children (12.08 months mothers vs. 27.61 months no mothers), showing mothers better premorbid adjustment as well. Childless men presented the worst premorbid adjustment and the highest cannabis and tobacco consumption rates. Mothers presented better global cognitive function, particularly in attention, motor dexterity and executive function at three-year follow-up. CONCLUSIONS: Diminished parental rates among FEP men could be suggested as a consequence of a younger age of illness onset. Sex roles in caregiving may explain the potential role of parenthood on premorbid phase, with a better and heathier profile, and a more favorable long-term outcome in women. These characteristics may be relevant when adjusting treatment specific needs in men and women with and without offspring.

Studying the relationship between intelligence quotient and schizophrenia polygenic scores in a family design with first-episode psychosis population.

BACKGROUND: The intelligence quotient (IQ) of patients with first-episode psychosis (FEP) and their unaffected relatives may be related to the genetic burden of schizophrenia (SCZ). The polygenic score approach can be useful for testing this question. AIM: To assess the contribution of the polygenic risk scores for SCZ (PGS-SCZ) and polygenic scores for IQ (PGS-IQ) to the individual IQ and its difference from the mean IQ of the family (named family-IQ) through a family-based design in an FEP sample. METHODS: The PAFIP-FAMILIES sample (Spain) consists of 122 FEP patients, 131 parents, 94 siblings, and 176 controls. They all completed the WAIS Vocabulary subtest for IQ estimation and provided a DNA sample. We calculated PGS-SCZ and PGS-IQ using the continuous shrinkage method. To account for relatedness in our sample, we performed linear mixed models. We controlled for covariates potentially related to IQ, including age, years of education, sex, and ancestry principal components. RESULTS: FEP patients significantly deviated from their family-IQ. FEP patients had higher PGS-SCZ than other groups, whereas the relatives had intermediate scores between patients and controls. PGS-IQ did not differ between groups. PGS-SCZ significantly predicted the deviation from family-IQ, whereas PGS-IQ significantly predicted individual IQ. CONCLUSIONS: PGS-SCZ discriminated between different levels of genetic risk for the disorder and was specifically related to patients' lower IQ in relation to family-IQ. The genetic background of the disorder may affect neurocognition through complex pathological processes interacting with environmental factors that prevent the individual from reaching their familial cognitive potential.

Family Metacognitive Training (MCT-F): Adapting MCT to Mothers with Psychosis and Their Adolescent Children.

Over half of women with psychosis are mothers. Research suggests that mothers with psychosis face unique challenges affecting both their mental health prognosis and their relationship with their children. Moreover, those children have a higher risk of developing a mental disorder. Notwithstanding, interventions specifically tailored to these families remain largely uncovered. Metacognitive Training (MCT) has demonstrated its efficacy in improving cognitive insight, symptom management, and social cognition in people with psychosis. However, there is no evidence of the efficacy of MCT in a family setting (MCT-F). This study describes the first adaptation of MCT for mothers with psychosis and their adolescent children in an online group setting. The phases (assessment, decision, adaptation, production, topical experts' integration) of the ADAPT-ITT model were systematically applied through a participatory approach (n = 22), including a first-person perspective and involving qualitative (e.g., topical expert literature review and consensus groups, interviews, thematic analyses) and quantitative methods. While MCT's core components were retained, participants guided adaptations both in content and delivery. The findings suggest the importance of community engagement and sharing decision-making processes to demonstrate the acceptability and feasibility of the adapted intervention. Employing a structured approach such as the ADAPT-ITT model ensures readiness of the new training for efficacy trials.

Processing speed in first episode of psychosis and first-degree relatives: A candidate endophenotype of spectrum schizophrenia disorders.

OBJECTIVE: The processing speed (PS) is highly impacted in individuals experiencing their first episode of psychosis (FEP). Conducting family studies can help to determine whether PS can serve as an endophenotype of schizophrenia spectrum disorders (SSDs), offering valuable insights into the prevention and diagnosis of SSDs. METHOD: A comprehensive cognitive battery, encompassing tests for PS, verbal memory, visual memory, working memory, executive functions, motor dexterity, and attention, was administered to a sample consisting of 133 FEP patients, 146 parents, 98 siblings, and 202 healthy controls (HCs). Univariate analyses (analysis of covariance [ANCOVA]) were conducted to compare the different cognitive domains between groups, utilizing sex, age, and years of education as covariates and Bonferroni corrections. Effect sizes (ESs) were calculated for estimating the magnitude of differences between groups. RESULTS: Group comparisons revealed significant differences in all cognitive domains. PS was the most impaired function in patients. Parents and siblings had intermediate PS performance between FEP patients and HC. Large ES were observed in PS between FEP versus siblings, FEP versus controls, parents versus controls, and parents versus siblings. CONCLUSIONS: Despite not meeting all the necessary criteria, the PS observed in FEP patients and their first-degree relatives suggests its potential as a promising endophenotype of SSDs. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Cognitive insight in first-episode psychosis: Exploring the complex relationship between executive functions and social cognition.

Social cognition (SC) and executive function (EF) have been described as important variables for social functioning and recovery of patients with psychosis. However, the relationship between SC and EF in first-episode psychosis (FEP) deserves further investigation, especially focusing on gender differences. AIMS: To investigate the relationship between EF and different domains of SC in FEP patients and to explore gender differences in the relationship between these domains. METHODS: A cross-sectional study of 191 patients with new-onset psychosis recruited from two multicenter clinical trials. A comprehensive cognitive battery was used to assess SC (Hinting Task, Face Test and IPSAQ) and EF (TMT, WSCT, Stroop Test and digit span - WAIS-III). Pearson correlations and linear regression models were performed. RESULTS: A correlation between Theory of Mind (ToM), Emotional Recognition (ER) and EF was found using the complete sample. Separating the sample by gender showed different association profiles between these variables in women and men. CONCLUSIONS: A relationship between different domains of SC and EF is found. Moreover, women and men presented distinct association profiles between EF and SC. These results should be considered in order to improve the treatment of FEP patients and designing personalized interventions by gender.

Premorbid adjustment as predictor of long-term functionality: Findings from a 10-year follow-up study in the PAFIP-cohort.

The literature indicates that patients with schizophrenia spectrum disorders often show deficits in premorbid adjustment. Additionally, these impairments have been correlated with critical disease parameters, evident in both early and advanced stages. The principal objective of this study was to investigate the association between premorbid adjustment and functional outcomes a decade following the initial episode of psychosis. A cluster analysis was performed to group patients according to their premorbid adjustment scores as assessed with the Premorbid Adjustment Scale (PAS). The measurements of The Disability Assessment Scale (DAS), The Global Assessment of Function (GAF) scale, ​​and The Quality of Life Scale (QLS) were used to compare the functionality of the groups at a 10-year follow-up. A total of 231 patients were classified into three groups based on their premorbid adjustment: "good PAS", "deteriorating PAS", and "chronically poor PAS". The three groups differed significantly in their sociodemographic and cognitive baseline characteristics. At the 10-year follow-up, "good PAS" group had better scores than the other groups in the variables of functionality and quality of life. The relationship found between premorbid adjustment and long-term functional results in patients with psychosis can help us predict the evolution of patients and act accordingly.

Normative Modeling of Brain Morphometry Across the Lifespan Using CentileBrain: Algorithm Benchmarking and Model Optimization.

We present an empirically benchmarked framework for sex-specific normative modeling of brain morphometry that can inform about the biological and behavioral significance of deviations from typical age-related neuroanatomical changes and support future study designs. This framework was developed using regional morphometric data from 37,407 healthy individuals (53% female; aged 3-90 years) following a comparative evaluation of eight algorithms and multiple covariate combinations pertaining to image acquisition and quality, parcellation software versions, global neuroimaging measures, and longitudinal stability. The Multivariate Factorial Polynomial Regression (MFPR) emerged as the preferred algorithm optimized using nonlinear polynomials for age and linear effects of global measures as covariates. The MFPR models showed excellent accuracy across the lifespan and within distinct age-bins, and longitudinal stability over a 2-year period. The performance of all MFPR models plateaued at sample sizes exceeding 3,000 study participants. The model and scripts described here are freely available through CentileBrain (https://centilebrain.org/).

Biomarkers as proxies for cognitive reserve: The role of high density lipoprotein cholesterol in first episode of psychosis.

INTRODUCTION: The proxies used to compose cognitive reserve (CR) for patients of a first episode of psychosis (FEP) have varied in the literature. The development of FEP is linked to peripheral pathways of the central nervous system, yet despite this knowledge, no research has considered the introduction of biomarkers as proxies for CR. Meanwhile, schizophrenia has been linked to the metabolic system, indicating that alterations in the levels of biological parameters, in particular high-density lipoproteins (HDL), cause worse global functioning and cognitive impairment. For these reasons, the present study aimed to create a quantifiable and objective CR index that adjusts for the multifactorial nature of FEP. MATERIALS AND METHODS: We included 668 FEP patients and 217 healthy controls. Participants were assessed for sociodemographic information, years of education, employment status, premorbid IQ and biological parameters: waist circumference, hypertension, and levels of HDL, triglycerides, and glucose. RESULTS: The findings suggest that the years of education proxy showed correlational and higher relationship with HDL levels for both FEP patients (r=0.23, b=0.185) and controls (r=0.31, b=0.342). We found that the CR index composed of years of education and HDL levels showed a higher explanatory power for the phenomenon than the classic CR index composed of years of education, employment status and premorbid IQ. CONCLUSIONS: This article proposes an objective and quantifiable method to measure CR that is more the multifactorial nature of FEP.

Just Play Cognitive Modern Board and Card Games, It's Going to Be Good for Your Executive Functions: A Randomized Controlled Trial with Children at Risk of Social Exclusion.

Modern board and card games are usually used for leisure. Few studies have focused on the type of game played in vulnerable populations. Therefore, the main aim of this study was to test the effectiveness of playing modern board and card games to enhance updating, inhibition, and flexibility in children at risk of social exclusion using games that activated specific basic executive functions. We developed a quadruple-blind randomized clinical trial during the COVID-19 pandemic. Sixty-eight participants (7-12 years old) were divided into two experimental groups: 35 children played games that directly activated basic executive functions, and 33 played games that directly triggered other cognitive domains. The primary statistical analysis consisted of mixed models. We found significant time effects in cognitive flexibility and inhibition and, to a lesser extent, in working memory in both gaming groups. We analyzed the cognitive profile of the games and found that all the games activated basic executive functions significantly, irrespective of the experimental group. Therefore, it is possible that playing any type of modern board and card game (excluding games with a high incidence of luck) could be beneficial for children at risk of social exclusion.

A Proxy Approach to Family Involvement and Neurocognitive Function in First Episode of Non-Affective Psychosis: Sex-Related Differences.

Schizophrenia spectrum disorders (SSD) often show cognitive deficits (CD) impacting daily life. Family support has been shown to be protective against CD, yet the relationship between these in psychotic patients remains complex and not fully understood. This study investigated the association between a subdomain of family support, namely, family involvement (estimated through a proxy measure), cognitive functioning, and sex in first-episode psychosis (FEP) patients. The sample included 308 patients enrolled in the Program for Early Phases of Psychosis (PAFIP), divided into 4 groups based on their estimated family involvement (eFI) level and sex, and compared on various variables. Women presented lower rates of eFI than men (37.1% and 48.8%). Higher eFI was associated with better cognitive functioning, particularly in verbal memory. This association was stronger in women. The findings suggest that eFI may be an important factor in FEP patients' cognitive functioning. This highlights the importance of including families in treatment plans for psychotic patients to prevent CD. Further research is needed to better understand the complex interplay between family support, sex, and cognitive functioning in psychotic patients and develop effective interventions that target these factors.

Familiality of the Intelligence Quotient in First Episode Psychosis: Is the Degree of Family Resemblance Associated With Different Profiles?

BACKGROUND AND HYPOTHESIS: There is uncertainty about the relationship between the family intelligence quotient (IQ) deviation and the risk for schizophrenia spectrum disorders (SSD). This study tested the hypothesis that IQ is familial in first episode psychosis (FEP) patients and that their degree of familial resemblance is associated with different profiles. STUDY DESIGN: The participants of the PAFIP-FAMILIAS project (129 FEP patients, 143 parents, and 97 siblings) completed the same neuropsychological battery. IQ-familiality was estimated through the Intraclass Correlation Coefficient (ICC). For each family, the intra-family resemblance score (IRS) was calculated as an index of familial similarity. The FEP patients were subgrouped and compared according to their IRS and IQ. STUDY RESULTS: IQ-familiality was low-moderate (ICC = 0.259). A total of 44.9% of the FEP patients had a low IRS, indicating discordancy with their family-IQ. Of these patients, those with low IQ had more schizophrenia diagnosis and a trend towards poorer premorbid adjustment in childhood and early adolescence. Whereas FEP patients with low IQ closely resembling their family-IQ were characterized by having the lowest performance in executive functions. CONCLUSIONS: The deviation from the familial cognitive performance may be related to a particular pathological process in SSD. Individuals with low IQ who do not reach their cognitive familial potential show difficulties in adjustment since childhood, probably influenced by environmental factors. Instead, FEP patients with high phenotypic family resemblance might have a more significant genetic burden for the disorder.

Cognitive reserve as a moderator of outcomes in five clusters of first episode psychosis patients: a 10-year follow-up study of the PAFIP cohort.

BACKGROUND: Cognitive reserve (CR) has been associated with the development and prognosis of psychosis. Different proxies have been used to estimate CR among individuals. A composite score of these proxies could elucidate the role of CR at illness onset on the variability of clinical and neurocognitive outcomes. METHODS: Premorbid intelligence quotient (IQ), years of education and premorbid adjustment were explored as proxies of CR in a large sample (N = 424) of first-episode psychosis (FEP) non-affective patients. Clusters of patients were identified and compared based on premorbid, clinical and neurocognitive variables at baseline. Additionally, the clusters were compared at 3-year (N = 362) and 10-year (N = 150) follow-ups. RESULTS: The FEP patients were grouped into five CR clusters: C1 (low premorbid IQ, low education and poor premorbid) 14%; C2 (low premorbid IQ, low education and good premorbid adjustment) 29%; C3 (normal premorbid IQ, low education and poor premorbid adjustment) 17%; C4 (normal premorbid IQ, medium education and good premorbid adjustment) 25%; and C5 (normal premorbid IQ, higher education and good premorbid adjustment) 15%. In general, positive and negative symptoms were more severe in the FEP patients with the lowest CR at baseline and follow-up assessments, while those with high CR presented and maintained higher levels of cognitive functioning. CONCLUSIONS: CR could be considered a key factor at illness onset and a moderator of outcomes in FEP patients. A high CR could function as a protective factor against cognitive impairment and severe symptomatology. Clinical interventions focused on increasing CR and documenting long-term benefits are interesting and desirable.

Maternal respiratory viral infections during pregnancy and offspring's neurodevelopmental outcomes: A systematic review.

Maternal infections during pregnancy, as cytomegalovirus and zika, have been consistently associated with severe newborn neurodevelopmental conditions, mainly related to vertical transmission and congenital infection. However, little is known about the neurodevelopmental consequences of maternal respiratory viral infections, which are the most prevalent infections during pregnancy. The recent COVID-19 pandemic has increased the interest in understanding the consequences of infections in offspring's development. This systematic review explores whether maternal gestational viral respiratory infections are associated with neurodevelopmental deviations in children below 10 years-old. The search was conducted in Pubmed, PsychInfo and Web of Science databases. 13 articles were revised, including information about maternal infection (Influenza, SARS-CoV-2 and unspecified respiratory infections) and offspring's neurodevelopment (global development, specific functions, temperament and behavioral/emotional aspects). Controversial results were reported regarding maternal respiratory infections during pregnancy and infants' neurodevelopment. Maternal infections seem to be associated with subtle alterations in some offspring's developmental subdomains, as early motor development, and attentional, behavioral/emotional minor problems. Further studies are needed to determine the impact of other psychosocial confounding factors.

Intelligence quotient changes over 10 years: Diversity of cognitive profiles in first episode of psychosis and healthy controls.

OBJECTIVE: This study aimed to analyse whether intelligence quotient (IQ) improves, declines, or remains stable over 10 years among FEP patients and healthy subjects. METHODS: A group of FEP patients enrolled in a Program of First Episode Psychosis in Spain called PAFIP, and a sample of Healthy Controls (HC) completed the same neuropsychological battery at baseline and approximately 10 years later, which included the WAIS vocabulary subtest to estimate premorbid IQ and 10-year IQ. Cluster analysis was performed separately in the patient group and the HC group to determine their profiles of intellectual change. RESULTS: One hundred and thirty-seven FEP patients were grouped into five clusters: "Improved low IQ" (9.49 % of patients), "Improved average IQ" (14.6 %), "Preserved low IQ" (17.52 %), "Preserved average IQ" (43.06 %), and "Preserved high IQ" (15.33 %). Ninety HC were grouped into three clusters: "Preserved low IQ" (32.22 % of the HC), "Preserved average IQ" (44.44 %), and "Preserved high IQ" (23.33 %). The first two clusters of FEP patients, characterized by a low IQ, earlier age at illness onset, and lower educational attainment, showed a substantial cognitive improvement. The remaining clusters demonstrated cognitive stability. CONCLUSIONS: The FEP patients showed intellectual improvement or stability, but no decline post-onset of psychosis. However, their profiles of intellectual change are more heterogeneous than that of HC over 10 years. Particularly, there is a subgroup of FEP patients with a significant potential for long-term cognitive enhancement.

Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium.

Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.

Exploring the impact of COVID-19 on newborn neurodevelopment: a pilot study.

The COVID-19 pandemic can seize the opportunity to explore the hypothesis of prenatal exposure to viral infections increases the risk for neurodevelopmental disorders. Advancing our knowledge in this regard would improve primary prevention of mental disorders in children. For this pilot study, six-week-old infants born to mothers exposed (n = 21) or unexposed (n = 21) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were assessed in Santander-Cantabria (Spain) using the Neonatal Behavioral Assessment Scale (NBAS). Groups comparisons were performed to explore the effects that infection and timing of exposure (in terms of the three trimesters of pregnancy). The infants' competencies and performances on the NBAS were generally similar in the exposed and unexposed to SARS-CoV-2 groups. The most significant difference found was a less optimally response to cuddliness (item on the state regulation domain) particularly in infants born to mothers exposed in the third trimester of pregnancy, and in pull-to-sit (item on the motor system domain). Although our interpretations must be careful, these preliminary results highlight the possible association between prenatal SARS-CoV-2 exposure and poorer development in motor skills and infant interactive behavior. Further longitudinal studies are needed to explore these relationships and disentangle the biological mechanisms implicated.

Longitudinal trajectories in negative symptoms and changes in brain cortical thickness: 10-year follow-up study.

BACKGROUND: Understanding the evolution of negative symptoms in first-episode psychosis (FEP) requires long-term longitudinal study designs that capture the progression of this condition and the associated brain changes. AIMS: To explore the factors underlying negative symptoms and their association with long-term abnormal brain trajectories. METHOD: We followed up 357 people with FEP over a 10-year period. Factor analyses were conducted to explore negative symptom dimensionality. Latent growth mixture modelling (LGMM) was used to identify the latent classes. Analysis of variance (ANOVA) was conducted to investigate developmental trajectories of cortical thickness. Finally, the resulting ANOVA maps were correlated with a wide set of regional molecular profiles derived from public databases. RESULTS: Three trajectories (stable, decreasing and increasing) were found in each of the three factors (expressivity, experiential and attention) identified by the factor analyses. Patients with an increasing trajectory in the expressivity factor showed cortical thinning in caudal middle frontal, pars triangularis, rostral middle frontal and superior frontal regions from the third to the tenth year after the onset of the psychotic disorder. The F-statistic map of cortical thickness expressivity differences was associated with a receptor density map derived from positron emission tomography data. CONCLUSIONS: Stable and decreasing were the most common trajectories. Additionally, cortical thickness abnormalities found at relatively late stages of FEP onset could be exploited as a biomarker of poor symptom outcome in the expressivity dimension. Finally, the brain areas with less density of receptors spatially overlap areas that discriminate the trajectories of the expressivity dimension.

Bridging Big Data: Procedures for Combining Non-equivalent Cognitive Measures from the ENIGMA Consortium.

Investigators in neuroscience have turned to Big Data to address replication and reliability issues by increasing sample sizes, statistical power, and representativeness of data. These efforts unveil new questions about integrating data arising from distinct sources and instruments. We focus on the most frequently assessed cognitive domain - memory testing - and demonstrate a process for reliable data harmonization across three common measures. We aggregated global raw data from 53 studies totaling N = 10,505 individuals. A mega-analysis was conducted using empirical bayes harmonization to remove site effects, followed by linear models adjusting for common covariates. A continuous item response theory (IRT) model estimated each individual's latent verbal learning ability while accounting for item difficulties. Harmonization significantly reduced inter-site variance while preserving covariate effects, and our conversion tool is freely available online. This demonstrates that large-scale data sharing and harmonization initiatives can address reproducibility and integration challenges across the behavioral sciences.

Brain ageing in schizophrenia: evidence from 26 international cohorts via the ENIGMA Schizophrenia consortium.

Schizophrenia (SZ) is associated with an increased risk of life-long cognitive impairments, age-related chronic disease, and premature mortality. We investigated evidence for advanced brain ageing in adult SZ patients, and whether this was associated with clinical characteristics in a prospective meta-analytic study conducted by the ENIGMA Schizophrenia Working Group. The study included data from 26 cohorts worldwide, with a total of 2803 SZ patients (mean age 34.2 years; range 18-72 years; 67% male) and 2598 healthy controls (mean age 33.8 years, range 18-73 years, 55% male). Brain-predicted age was individually estimated using a model trained on independent data based on 68 measures of cortical thickness and surface area, 7 subcortical volumes, lateral ventricular volumes and total intracranial volume, all derived from T1-weighted brain magnetic resonance imaging (MRI) scans. Deviations from a healthy brain ageing trajectory were assessed by the difference between brain-predicted age and chronological age (brain-predicted age difference [brain-PAD]). On average, SZ patients showed a higher brain-PAD of +3.55 years (95% CI: 2.91, 4.19; I2 = 57.53%) compared to controls, after adjusting for age, sex and site (Cohen's d = 0.48). Among SZ patients, brain-PAD was not associated with specific clinical characteristics (age of onset, duration of illness, symptom severity, or antipsychotic use and dose). This large-scale collaborative study suggests advanced structural brain ageing in SZ. Longitudinal studies of SZ and a range of mental and somatic health outcomes will help to further evaluate the clinical implications of increased brain-PAD and its ability to be influenced by interventions.