The synergetic effect of childhood trauma and recent stressful events in psychosis: associated neurocognitive dysfunction.

BACKGROUND: A higher incidence of childhood trauma (CT) has been reported in first episode of psychosis (FEP). There is, however, a lack of knowledge about the synergetic effect between CT and recent stressful events (RSE). METHODS: Information on specific types of CT (under 17 years) and RSE (within the past 3 years) was available for 290 FEP patients and 52 healthy controls (HC). Cognitive function at baseline was assessed through a comprehensive neuropsychological test battery. RESULTS: While 45.2% of FEP patients and 25% of HC reported at least one CT event, 62.7% of FEP and 21.2% of HC reported an RSE. Meanwhile, 36.2% of FEP patients and 9.6% of HC encountered both childhood and recent stressful events. The patients that just reported CT showed normality in all but the verbal memory cognitive domain; those with additive CT and RSE presented worse general cognitive function, specifically on working memory, processing speed, and executive function. RSE and general cognitive dysfunction were significant determinants of psychosis onset. CONCLUSIONS: These results support a synergetic influence of trauma and stressful events on brain function and allow a better understanding of mediators for psychotic disorders useful in the design of specific strategies based on stress-targeted therapies.

Widespread white matter microstructural differences in schizophrenia across 4322 individuals: results from the ENIGMA Schizophrenia DTI Working Group.

The regional distribution of white matter (WM) abnormalities in schizophrenia remains poorly understood, and reported disease effects on the brain vary widely between studies. In an effort to identify commonalities across studies, we perform what we believe is the first ever large-scale coordinated study of WM microstructural differences in schizophrenia. Our analysis consisted of 2359 healthy controls and 1963 schizophrenia patients from 29 independent international studies; we harmonized the processing and statistical analyses of diffusion tensor imaging (DTI) data across sites and meta-analyzed effects across studies. Significant reductions in fractional anisotropy (FA) in schizophrenia patients were widespread, and detected in 20 of 25 regions of interest within a WM skeleton representing all major WM fasciculi. Effect sizes varied by region, peaking at (d=0.42) for the entire WM skeleton, driven more by peripheral areas as opposed to the core WM where regions of interest were defined. The anterior corona radiata (d=0.40) and corpus callosum (d=0.39), specifically its body (d=0.39) and genu (d=0.37), showed greatest effects. Significant decreases, to lesser degrees, were observed in almost all regions analyzed. Larger effect sizes were observed for FA than diffusivity measures; significantly higher mean and radial diffusivity was observed for schizophrenia patients compared with controls. No significant effects of age at onset of schizophrenia or medication dosage were detected. As the largest coordinated analysis of WM differences in a psychiatric disorder to date, the present study provides a robust profile of widespread WM abnormalities in schizophrenia patients worldwide. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.

The prognostic role of catatonia, hallucinations, and symptoms of schizophrenia in acute and transient psychosis.

OBJECTIVES: To examine the prospective temporal stability of acute and transient psychotic disorders (ATPDs) and analyze whether there are clinical, psychopathological, or sociodemographic characteristics that predict ATPD diagnostic stability. METHOD: We conducted a prospective, 2-year, observational study of patients presenting a first-episode ATPD. A multivariate logistic regression model was developed to identify independent variables associated with ATPD diagnostic stability. Well-established predictive factors of diagnostic stability, as well as all the psychopathological features included in the ICD-10 Diagnostic Criteria for Research (DCR) descriptions of ATPD, were analyzed. RESULTS: Sixty-eight patients with a first episode of ATPD completed the study with a diagnostic stability rate as high as 55.9% (n = 38) at the end of the follow-up period. Multivariate analysis revealed that diagnostic stability was independently significantly associated with the baseline presence of motility disturbances (OR = 6.86, 95% CI = 1.10-42.62; P = 0.039), the absence of hallucinations (OR = 5.75, 95% CI = 1.51-21.98; P = 0.010), and the absence of schizophrenic features (OR = 7.13, 95% CI = 1.38-36.90; P = 0.019). CONCLUSION: A symptom checklist assessing these psychopathological features would enable early identification of those subjects whose initial ATPD diagnosis will remain stable over time.

Stopping cannabis use benefits outcome in psychosis: findings from 10-year follow-up study in the PAFIP-cohort.

OBJECTIVE: To examine the long-term (up to 10 years) patterns related to cannabis use in a sample of patients with first episode of psychosis (FEP) and the effect that consumption might have on clinical, functioning, and neurocognition at long-term. METHODS: Cannabis use was described in 209 FEP patients. Patients were divided into three groups according to cannabis use: persistent users, ex-users, and never-users. Groups were longitudinally (baseline and 10-year follow-up) compared on clinical, functional, and cognitive variables. RESULTS: Clinical differences at 10-year follow-up were observed between persistent cannabis users and the other two groups (ex-users and never-users), showing persistent users more severe symptoms (BPRS: x2  = 15.583, P ≤ 0.001; SAPS: x2  = 12.386, P = 0.002) and poorer functionality (DAS: x2  = 6.067, P = 0.048; GAF: x2  = 6.635, P = 0.033). Patients who stopped cannabis use prior to the reassessment showed a similar pattern to those who had never consumed. CONCLUSION: The use of cannabis could negatively affect the evolution of the psychotic disorder. Perhaps the negative effects caused by cannabis use could be reversed with the cessation of consumption. It is necessary to make an effort in the intervention toward an early withdrawal from the use of cannabis, since this could play an important role in the prognosis of the disease.

Associations between psychosis endophenotypes across brain functional, structural, and cognitive domains.

BACKGROUND: A range of endophenotypes characterise psychosis, however there has been limited work understanding if and how they are inter-related. METHODS: This multi-centre study includes 8754 participants: 2212 people with a psychotic disorder, 1487 unaffected relatives of probands, and 5055 healthy controls. We investigated cognition [digit span (N = 3127), block design (N = 5491), and the Rey Auditory Verbal Learning Test (N = 3543)], electrophysiology [P300 amplitude and latency (N = 1102)], and neuroanatomy [lateral ventricular volume (N = 1721)]. We used linear regression to assess the interrelationships between endophenotypes. RESULTS: The P300 amplitude and latency were not associated (regression coef. -0.06, 95% CI -0.12 to 0.01, p = 0.060), and P300 amplitude was positively associated with block design (coef. 0.19, 95% CI 0.10-0.28, p 0.38). All the cognitive endophenotypes were associated with each other in the expected directions (all p < 0.001). Lastly, the relationships between pairs of endophenotypes were consistent in all three participant groups, differing for some of the cognitive pairings only in the strengths of the relationships. CONCLUSIONS: The P300 amplitude and latency are independent endophenotypes; the former indexing spatial visualisation and working memory, and the latter is hypothesised to index basic processing speed. Individuals with psychotic illnesses, their unaffected relatives, and healthy controls all show similar patterns of associations between endophenotypes, endorsing the theory of a continuum of psychosis liability across the population.

Prefrontal cortical thinning links to negative symptoms in schizophrenia via the ENIGMA consortium.

BACKGROUND: Our understanding of the complex relationship between schizophrenia symptomatology and etiological factors can be improved by studying brain-based correlates of schizophrenia. Research showed that impairments in value processing and executive functioning, which have been associated with prefrontal brain areas [particularly the medial orbitofrontal cortex (MOFC)], are linked to negative symptoms. Here we tested the hypothesis that MOFC thickness is associated with negative symptom severity. METHODS: This study included 1985 individuals with schizophrenia from 17 research groups around the world contributing to the ENIGMA Schizophrenia Working Group. Cortical thickness values were obtained from T1-weighted structural brain scans using FreeSurfer. A meta-analysis across sites was conducted over effect sizes from a model predicting cortical thickness by negative symptom score (harmonized Scale for the Assessment of Negative Symptoms or Positive and Negative Syndrome Scale scores). RESULTS: Meta-analytical results showed that left, but not right, MOFC thickness was significantly associated with negative symptom severity (ß std = -0.075; p = 0.019) after accounting for age, gender, and site. This effect remained significant (p = 0.036) in a model including overall illness severity. Covarying for duration of illness, age of onset, antipsychotic medication or handedness weakened the association of negative symptoms with left MOFC thickness. As part of a secondary analysis including 10 other prefrontal regions further associations in the left lateral orbitofrontal gyrus and pars opercularis emerged. CONCLUSIONS: Using an unusually large cohort and a meta-analytical approach, our findings point towards a link between prefrontal thinning and negative symptom severity in schizophrenia. This finding provides further insight into the relationship between structural brain abnormalities and negative symptoms in schizophrenia.

Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium.

The profile of brain structural abnormalities in schizophrenia is still not fully understood, despite decades of research using brain scans. To validate a prospective meta-analysis approach to analyzing multicenter neuroimaging data, we analyzed brain MRI scans from 2028 schizophrenia patients and 2540 healthy controls, assessed with standardized methods at 15 centers worldwide. We identified subcortical brain volumes that differentiated patients from controls, and ranked them according to their effect sizes. Compared with healthy controls, patients with schizophrenia had smaller hippocampus (Cohen's d=-0.46), amygdala (d=-0.31), thalamus (d=-0.31), accumbens (d=-0.25) and intracranial volumes (d=-0.12), as well as larger pallidum (d=0.21) and lateral ventricle volumes (d=0.37). Putamen and pallidum volume augmentations were positively associated with duration of illness and hippocampal deficits scaled with the proportion of unmedicated patients. Worldwide cooperative analyses of brain imaging data support a profile of subcortical abnormalities in schizophrenia, which is consistent with that based on traditional meta-analytic approaches. This first ENIGMA Schizophrenia Working Group study validates that collaborative data analyses can readily be used across brain phenotypes and disorders and encourages analysis and data sharing efforts to further our understanding of severe mental illness.

Positive symptoms associate with cortical thinning in the superior temporal gyrus via the ENIGMA Schizophrenia consortium.

OBJECTIVE: Based on the role of the superior temporal gyrus (STG) in auditory processing, language comprehension and self-monitoring, this study aimed to investigate the relationship between STG cortical thickness and positive symptom severity in schizophrenia. METHOD: This prospective meta-analysis includes data from 1987 individuals with schizophrenia collected at seventeen centres around the world that contribute to the ENIGMA Schizophrenia Working Group. STG thickness measures were extracted from T1-weighted brain scans using FreeSurfer. The study performed a meta-analysis of effect sizes across sites generated by a model predicting left or right STG thickness with a positive symptom severity score (harmonized SAPS or PANSS-positive scores), while controlling for age, sex and site. Secondary models investigated relationships between antipsychotic medication, duration of illness, overall illness severity, handedness and STG thickness. RESULTS: Positive symptom severity was negatively related to STG thickness in both hemispheres (left: ßstd = -0.052; P = 0.021; right: ßstd = -0.073; P = 0.001) when statistically controlling for age, sex and site. This effect remained stable in models including duration of illness, antipsychotic medication or handedness. CONCLUSION: Our findings further underline the important role of the STG in hallmark symptoms in schizophrenia. These findings can assist in advancing insight into symptom-relevant pathophysiological mechanisms in schizophrenia.

No progression of the alterations in the cortical thickness of individuals with schizophrenia-spectrum disorder: a three-year longitudinal magnetic resonance imaging study of first-episode patients.

BACKGROUND: Cortical thickness measurement offers an index of brain development processes. In healthy individuals, cortical thickness is reduced with increasing age and is related to cognitive decline. Cortical thinning has been reported in schizophrenia. Whether cortical thickness changes differently over time in patients and its impact on outcome remain unanswered. METHOD: Data were examined from 109 patients and 76 healthy controls drawn from the Santander Longitudinal Study of first-episode schizophrenia for whom adequate structural magnetic resonance imaging (MRI) data were available (n = 555 scans). Clinical and cognitive assessments and MRIs were acquired at three regular time points during a 3-year follow-up period. We investigated likely progressive cortical thickness changes in schizophrenia during the first 3 years after initiating antipsychotic treatment. The effects of cortical thickness changes on cognitive and clinical variables were also examined along with the impact of potential confounding factors. RESULTS: There were significant diagnoses × scan time interaction main effects for total cortical thickness (F 1,309.1 = 4.60, p = 0.033) and frontal cortical thickness (F 1,310.6 = 5.30, p = 0.022), reflecting a lesser thinning over time in patients. Clinical and cognitive outcome was not associated with progressive cortical changes during the early years of the illness. CONCLUSIONS: Cortical thickness abnormalities do not unswervingly progress, at least throughout the first years of the illness. Previous studies have suggested that modifiable factors may partly account for cortical thickness abnormalities. Therefore, the importance of implementing practical actions that may modify those factors and improve them over the course of the illness should be highlighted.

Trajectories of symptom dimensions in short-term response to antipsychotic treatment in patients with a first episode of non-affective psychosis.

BACKGROUND: Trajectory patterns of positive, disorganized and negative dimension symptoms during antipsychotic treatment in drug-naive patients with first-episode psychosis have yet to be examined by using naturalistic data. METHOD: This pragmatic clinical trial randomized 161 drug-naive patients with a first episode of psychosis to olanzapine, risperidone or haloperidol. Patients were assessed with the Scale for the Assessment of Negative Symptoms (SANS) and Positive Symptoms (SAPS) at baseline and at the end of weeks 1, 2, 3, 4 and 6 of antipsychotic treatment. Censored normal models of response trajectories were developed with three dimensions of the SAPS-SANS scores (positive, disorganized and negative) in order to identify the different response trajectories. Diagnosis, cannabis use, duration of untreated psychosis (DUP), smoking and antipsychotic class were examined as possible predictive variables. RESULTS: Patients were classified in five groups according to the positive dimension, three groups according to the disorganized dimension and five groups according to the negative dimension. Longer DUPs and cannabis use were associated with higher scores and poorer responses in the positive dimension. Cannabis use was associated with higher scores and poorer responses in the disorganized dimension. Only schizophrenia diagnosis was associated with higher scores and poorer responses in the negative dimension. CONCLUSIONS: Our results illustrate the heterogeneity of short-term response to antipsychotics in patients with a first episode of psychosis and highlight markedly different patterns of response in the positive, disorganized and negative dimensions. DUP, cannabis use and diagnosis appeared to have a prognostic value in predicting treatment response with different implications for each dimension.

Three-year longitudinal population-based volumetric MRI study in first-episode schizophrenia spectrum patients.

BACKGROUND: Schizophrenia is a chronic brain disorder associated with structural brain abnormalities already present at the onset of the illness. Whether these brain abnormalities might progress over time is still under debate. METHOD: The aim of this study was to investigate likely progressive brain volume changes in schizophrenia during the first 3 years after initiating antipsychotic treatment. The study included 109 patients with a schizophrenia spectrum disorder and a control group of 76 healthy subjects. Subjects received detailed clinical and cognitive assessment and structural magnetic resonance imaging (MRI) at regular time points during a 3-year follow-up period. The effects of brain changes on cognitive and clinical variables were examined along with the impact of potential confounding factors. RESULTS: Overall, patients and healthy controls exhibited a similar pattern of brain volume changes. However, patients showed a significant lower progressive decrease in the volume of the caudate nucleus than control subjects (F 1,307.2 = 2.12, p = 0.035), with healthy subjects showing a greater reduction than patients during the follow-up period. Clinical and cognitive outcomes were not associated with progressive brain volume changes during the early years of the illness. CONCLUSIONS: Brain volume abnormalities that have been consistently observed at the onset of non-affective psychosis may not inevitably progress, at least over the first years of the illness. Taking together with clinical and cognitive longitudinal data, our findings, showing a lack of brain deterioration in a substantial number of individuals, suggest a less pessimistic and more reassuring perception of the illness.

Aripiprazole as protector against COVID-19 mortality.

The relation of antipsychotics with severe Coronavirus Disease 19 (COVID-19) outcomes is a matter of debate since the beginning of the pandemic. To date, controversial results have been published on this issue. We aimed to prove whether antipsychotics might exert adverse or protective effects against fatal outcomes derived from COVID-19. A population-based retrospective cohort study (January 2020 to November 2020) comprising inpatients (15,968 patients) who were at least 18 years old and had a laboratory-confirmed COVID-19 infection. Two sub-cohorts were delineated, comprising a total of 2536 inpatients: individuals who either had no prescription medication or were prescribed an antipsychotic within the 15 days preceding hospitalization. We conducted survival and odds ratio analyses to assess the association between antipsychotic use and mortality, reporting both unadjusted and covariate-adjusted results. We computed the average treatment effects, using the untreated group as the reference, and the average treatment effect on the treated, focusing solely on the antipsychotic-treated population. Among the eight antipsychotics found to be in use, only aripiprazole showed a significant decrease in the risk of death from COVID-19 [adjusted odds ratio (OR) = 0.86; 95% CI, 0.79-0.93, multiple-testing adjusted p-value < 0.05]. Importantly, these findings were consistent for both covariate-adjusted and unadjusted analyses. Aripiprazole has been shown to have a differentiated beneficial effect in protecting against fatal clinical outcome in COVID-19 infected individuals. We speculate that the differential effect of aripiprazole on controlling immunological pathways and inducible inflammatory enzymes, that are critical in COVID19 illness, may be associated with our findings herein.

The mediating role of reflective functioning in the association between childhood trauma and suicide attempt.

BACKGROUND: Childhood trauma is intimately related with suicidal behaviour. Patients who have suffered childhood trauma develop impaired Reflective Functioning (RF), which refers to the capacity to understand ourselves and others in terms of intentional mental states. An improvement in RF has been associated with a reduction in suicidal attempts, but the mediating role of RF between childhood trauma and suicidal behaviour has not been addressed so far. OBJECTIVE: We aim to examine the potential mediating effect of RF among childhood trauma and suicide attempts. METHOD: We included 748 patients who had attempted suicide at least once. They were asked to complete the Reflective Functioning Questionnaire (RFQ-8), the Columbia-Suicide Severity Rating scale (CSSRS), and the Childhood Trauma Questionnaire-Short Form (CTQ-SF). We conducted linear regressions by simple mediating model to examine the role of RF in the indirect association between childhood trauma and the number of suicide attempts. RESULTS: Our results show significant indirect effects through hypo and hypermentalizing between Emotional Abuse (EA) and Sexual Abuse (SA) in childhood and the number of suicide attempts in lifetime. These results indicate that ineffective RF significantly mediates the association between childhood trauma and suicidality. CONCLUSION: This is the first study supporting the mediational role of RF in the relationship between EA and SA, and the number of suicide attempt in lifetime. These findings have important implications for reducing suicide rates and preventing future re-attempts. Further studies analysing this mediating role and focusing efforts on increasing RF-based interventions are required.

Association and epistatic analysis of white matter related genes across the continuum schizophrenia and autism spectrum disorders: The joint effect of NRG1-ErbB genes.

BACKGROUND: Schizophrenia-spectrum disorders (SSD) and Autism spectrum disorders (ASD) are neurodevelopmental disorders that share clinical, cognitive, and genetic characteristics, as well as particular white matter (WM) abnormalities. In this study, we aimed to investigate the role of a set of oligodendrocyte/myelin-related (OMR) genes and their epistatic effect on the risk for SSD and ASD. METHODS: We examined 108 SNPs in a set of 22 OMR genes in 1749 subjects divided into three independent samples (187 SSD trios, 915 SSD cases/control, and 91 ASD trios). Genetic association and gene-gene interaction analyses were conducted with PLINK and MB-MDR, and permutation procedures were implemented in both. RESULTS: Some OMR genes showed an association trend with SSD, while after correction, the ones that remained significantly associated were MBP, ERBB3, and AKT1. Significant gene-gene interactions were found between (i) NRG1*MBP (perm p-value = 0.002) in the SSD trios sample, (ii) ERBB3*AKT1 (perm p-value = 0.001) in the SSD case-control sample, and (iii) ERBB3*QKI (perm p-value = 0.0006) in the ASD trios sample. DISCUSSION: Our results suggest the implication of OMR genes in the risk for both SSD and ASD and highlight the role of NRG1 and ERBB genes. These findings are in line with the previous evidence and may suggest pathophysiological mechanisms related to NRG1/ERBBs signalling in these disorders.

Pattern of long-term weight and metabolic changes after a first episode of psychosis: Results from a 10-year prospective follow-up of the PAFIP program for early intervention in psychosis cohort.

BACKGROUND: People with psychosis are at higher risk of cardiovascular events, partly explained by a higher predisposition to gain weight. This has been observed in studies on individuals with a first-episode psychosis (FEP) at short and long term (mainly up to 1 year) and transversally at longer term in people with chronic schizophrenia. However, there is scarcity of data regarding longer-term (above 3-year follow-up) weight progression in FEP from longitudinal studies. The aim of this study is to evaluate the longer-term (10 years) progression of weight changes and related metabolic disturbances in people with FEP. METHODS: Two hundred and nine people with FEP and 57 healthy participants (controls) were evaluated at study entry and prospectively at 10-year follow-up. Anthropometric, clinical, and sociodemographic data were collected. RESULTS: People with FEP presented a significant and rapid increase in mean body weight during the first year of treatment, followed by less pronounced but sustained weight gain over the study period (Δ15.2 kg; SD 12.3 kg). This early increment in weight predicted longer-term changes, which were significantly greater than in healthy controls (Δ2.9 kg; SD 7.3 kg). Weight gain correlated with alterations in lipid and glycemic variables, leading to clinical repercussion such as increments in the rates of obesity and metabolic disturbances. Sex differences were observed, with women presenting higher increments in body mass index than men. CONCLUSIONS: This study confirms that the first year after initiating antipsychotic treatment is the critical one for weight gain in psychosis. Besides, it provides evidence that weight gain keep progressing even in the longer term (10 years), causing relevant metabolic disturbances.

Global and regional cortical thinning in first-episode psychosis patients: relationships with clinical and cognitive features.

BACKGROUND: The thickness of the cortical mantle is a sensitive measure for identifying alterations in cortical structure. We aimed to explore whether first episode schizophrenia patients already show a significant cortical thinning and whether cortical thickness anomalies may significantly influence clinical and cognitive features. METHOD: We investigated regional changes in cortical thickness in a large and heterogeneous sample of schizophrenia spectrum patients (n=142) at their first break of the illness and healthy controls (n=83). Magnetic resonance imaging brain scans (1.5 T) were obtained and images were analyzed by using brains2. The contribution of sociodemographic, cognitive and clinical characterictics was investigated. RESULTS: Patients showed a significant total cortical thinning (F=17.55, d=-0.62, p<0.001) and there was a diffuse pattern of reduced thickness (encompassing frontal, temporal and parietal cortices) (all p's<0.001, d's>0.53). No significant group×gender interactions were observed (all p's>0.15). There were no significant associations between the clinical and pre-morbid variables and cortical thickness measurements (all r's<0.12). A weak significant negative correlation between attention and total (r=-0.24, p=0.021) and parietal cortical thickness (r=-0.27, p=0.009) was found in patients (thicker cortex was associated with lower attention). Our data revealed a similar pattern of cortical thickness changes related to age in patients and controls. CONCLUSIONS: Cortical thinning is independent of gender, age, age of onset and duration of the illness and does not seem to significantly influence clinical and functional symptomatology. These findings support a primary neurodevelopment disorder affecting the normal cerebral cortex development in schizophrenia.

Sexual Regional Dimorphism of Post-Adolescent and Middle Age Brain Maturation. A Multi-center 3T MRI Study.

Sex-related differences are tied into neurodevelopmental and lifespan processes, beginning early in the perinatal and developmental phases and continue into adulthood. The present study was designed to investigate sexual dimorphism of changes in gray matter (GM) volume in post-adolescence, with a focus on early and middle-adulthood using a structural magnetic resonance imaging (MRI) dataset of healthy controls from the European Network on Psychosis, Affective disorders and Cognitive Trajectory (ENPACT). Three hundred and seventy three subjects underwent a 3.0 T MRI session across four European Centers. Age by sex effects on GM volumes were investigated using voxel-based morphometry (VBM) and the Automated Anatomical Labeling atlas regions (ROI). Females and males showed overlapping and non-overlapping patterns of GM volume changes during aging. Overlapping age-related changes emerged in bilateral frontal and temporal cortices, insula and thalamus. Both VBM and ROI analyses revealed non-overlapping changes in multiple regions, including cerebellum and vermis, bilateral mid frontal, mid occipital cortices, left inferior temporal and precentral gyri. These findings highlight the importance of accounting for sex differences in cross-sectional analyses, not only in the study of normative changes, but particularly in the context of psychiatric and neurologic disorders, wherein sex effects may be confounded with disease-related changes.

Classification of first-episode psychosis using cortical thickness: A large multicenter MRI study.

Machine learning classifications of first-episode psychosis (FEP) using neuroimaging have predominantly analyzed brain volumes. Some studies examined cortical thickness, but most of them have used parcellation approaches with data from single sites, which limits claims of generalizability. To address these limitations, we conducted a large-scale, multi-site analysis of cortical thickness comparing parcellations and vertex-wise approaches. By leveraging the multi-site nature of the study, we further investigated how different demographical and site-dependent variables affected predictions. Finally, we assessed relationships between predictions and clinical variables. 428 subjects (147 females, mean age 27.14) with FEP and 448 (230 females, mean age 27.06) healthy controls were enrolled in 8 centers by the ClassiFEP group. All subjects underwent a structural MRI and were clinically assessed. Cortical thickness parcellation (68 areas) and full cortical maps (20,484 vertices) were extracted. Linear Support Vector Machine was used for classification within a repeated nested cross-validation framework. Vertex-wise thickness maps outperformed parcellation-based methods with a balanced accuracy of 66.2% and an Area Under the Curve of 72%. By stratifying our sample for MRI scanner, we increased generalizability across sites. Temporal brain areas resulted as the most influential in the classification. The predictive decision scores significantly correlated with age at onset, duration of treatment, and positive symptoms. In conclusion, although far from the threshold of clinical relevance, temporal cortical thickness proved to classify between FEP subjects and healthy individuals. The assessment of site-dependent variables permitted an increase in the across-site generalizability, thus attempting to address an important machine learning limitation.

Prognostic value of cognitive functioning for global functional recovery in first-episode schizophrenia.

BACKGROUND: It has become widely accepted that cognitive deficits in schizophrenia are related to functional outcome. However, it remains to be seen whether these associations are relevant for predicting which cases will have a global functional recovery. In this study, we attempt to determine whether global functional recovery (integrating social and occupational outcomes) after first-episode schizophrenia (FES) can be predicted by cognitive variables. METHOD: A total of 131 FES patients with functional deficits (n=97) and functional recovery (n=34) as determined at 1-year follow-up were examined. Neuropsychological, sociodemographic, pre-morbid and clinical data at baseline were analysed using independent groups comparisons and a logistic regression method. RESULTS: Sustained attention and negative symptoms emerged as significant predictors of good global functional outcome. Although the model revealed a high accuracy (91%) in the classification of patients with functional deficits, it was unacceptably low (26%) in the classification of patients with global functional recovery. CONCLUSIONS: The limitations found in the prediction of a favourable global functional outcome may well be an indication for a need to address the role of other factors not commonly included in longitudinal studies of long-term outcomes in schizophrenia.