Connectome architecture shapes large-scale cortical alterations in schizophrenia: a worldwide ENIGMA study.

Schizophrenia is a prototypical network disorder with widespread brain-morphological alterations, yet it remains unclear whether these distributed alterations robustly reflect the underlying network layout. We tested whether large-scale structural alterations in schizophrenia relate to normative structural and functional connectome architecture, and systematically evaluated robustness and generalizability of these network-level alterations. Leveraging anatomical MRI scans from 2439 adults with schizophrenia and 2867 healthy controls from 26 ENIGMA sites and normative data from the Human Connectome Project (n = 207), we evaluated structural alterations of schizophrenia against two network susceptibility models: (i) hub vulnerability, which examines associations between regional network centrality and magnitude of disease-related alterations; (ii) epicenter mapping, which identifies regions whose typical connectivity profile most closely resembles the disease-related morphological alterations. To assess generalizability and specificity, we contextualized the influence of site, disease stages, and individual clinical factors and compared network associations of schizophrenia with that found in affective disorders. Our findings show schizophrenia-related cortical thinning is spatially associated with functional and structural hubs, suggesting that highly interconnected regions are more vulnerable to morphological alterations. Predominantly temporo-paralimbic and frontal regions emerged as epicenters with connectivity profiles linked to schizophrenia's alteration patterns. Findings were robust across sites, disease stages, and related to individual symptoms. Moreover, transdiagnostic comparisons revealed overlapping epicenters in schizophrenia and bipolar, but not major depressive disorder, suggestive of a pathophysiological continuity within the schizophrenia-bipolar-spectrum. In sum, cortical alterations over the course of schizophrenia robustly follow brain network architecture, emphasizing marked hub susceptibility and temporo-frontal epicenters at both the level of the group and the individual. Subtle variations of epicenters across disease stages suggest interacting pathological processes, while associations with patient-specific symptoms support additional inter-individual variability of hub vulnerability and epicenters in schizophrenia. Our work outlines potential pathways to better understand macroscale structural alterations, and inter- individual variability in schizophrenia.

Mapping gray and white matter volume abnormalities in early-onset psychosis: an ENIGMA multicenter voxel-based morphometry study.

INTRODUCTION: Regional gray matter (GM) alterations have been reported in early-onset psychosis (EOP, onset before age 18), but previous studies have yielded conflicting results, likely due to small sample sizes and the different brain regions examined. In this study, we conducted a whole brain voxel-based morphometry (VBM) analysis in a large sample of individuals with EOP, using the newly developed ENIGMA-VBM tool. METHODS: 15 independent cohorts from the ENIGMA-EOP working group participated in the study. The overall sample comprised T1-weighted MRI data from 482 individuals with EOP and 469 healthy controls. Each site performed the VBM analysis locally using the standardized ENIGMA-VBM tool. Statistical parametric T-maps were generated from each cohort and meta-analyzed to reveal voxel-wise differences between EOP and healthy controls as well as the individual-based association between GM volume and age of onset, chlorpromazine (CPZ) equivalent dose, and other clinical variables. RESULTS: Compared with healthy controls, individuals with EOP showed widespread lower GM volume encompassing most of the cortex, with the most marked effect in the left median cingulate (Hedges' g = 0.55, p = 0.001 corrected), as well as small clusters of lower white matter (WM), whereas no regional GM or WM volumes were higher in EOP. Lower GM volume in the cerebellum, thalamus and left inferior parietal gyrus was associated with older age of onset. Deficits in GM in the left inferior frontal gyrus, right insula, right precentral gyrus and right superior frontal gyrus were also associated with higher CPZ equivalent doses. CONCLUSION: EOP is associated with widespread reductions in cortical GM volume, while WM is affected to a smaller extent. GM volume alterations are associated with age of onset and CPZ equivalent dose but these effects are small compared to case-control differences. Mapping anatomical abnormalities in EOP may lead to a better understanding of the role of psychosis in brain development during childhood and adolescence.

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.

In vivo white matter microstructure in adolescents with early-onset psychosis: a multi-site mega-analysis.

Emerging evidence suggests brain white matter alterations in adolescents with early-onset psychosis (EOP; age of onset <18 years). However, as neuroimaging methods vary and sample sizes are modest, results remain inconclusive. Using harmonized data processing protocols and a mega-analytic approach, we compared white matter microstructure in EOP and healthy controls using diffusion tensor imaging (DTI). Our sample included 321 adolescents with EOP (median age = 16.6 years, interquartile range (IQR) = 2.14, 46.4% females) and 265 adolescent healthy controls (median age = 16.2 years, IQR = 2.43, 57.7% females) pooled from nine sites. All sites extracted mean fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) for 25 white matter regions of interest per participant. ComBat harmonization was performed for all DTI measures to adjust for scanner differences. Multiple linear regression models were fitted to investigate case-control differences and associations with clinical variables in regional DTI measures. We found widespread lower FA in EOP compared to healthy controls, with the largest effect sizes in the superior longitudinal fasciculus (Cohen's d = 0.37), posterior corona radiata (d = 0.32), and superior fronto-occipital fasciculus (d = 0.31). We also found widespread higher RD and more localized higher MD and AD. We detected significant effects of diagnostic subgroup, sex, and duration of illness, but not medication status. Using the largest EOP DTI sample to date, our findings suggest a profile of widespread white matter microstructure alterations in adolescents with EOP, most prominently in male individuals with early-onset schizophrenia and individuals with a shorter duration of illness.

Precuneus and insular hypoactivation during cognitive processing in first-episode psychosis: Systematic review and meta-analysis of fMRI studies.

INTRODUCTION: The neural correlates of the cognitive dysfunction in first-episode psychosis (FEP) are still unclear. The present review and meta-analysis provide an update of the location of the abnormalities in the fMRI-measured brain response to cognitive processes in individuals with FEP. METHODS: Systematic review and voxel-based meta-analysis of cross-sectional fMRI studies comparing neural responses to cognitive tasks between individuals with FEP and healthy controls (HC) according to PRISMA guidelines. RESULTS: Twenty-six studies were included, comprising 598 individuals with FEP and 567 HC. Individual studies reported statistically significant hypoactivation in the dorsolateral prefrontal cortex (6 studies), frontal lobe (8 studies), cingulate (6 studies) and insula (5 studies). The meta-analysis showed statistically significant hypoactivation in the left anterior insula, precuneus and bilateral striatum. CONCLUSIONS: While the studies tend to highlight frontal hypoactivation during cognitive tasks in FEP, our meta-analytic results show that the left precuneus and insula primarily display aberrant activation in FEP that may be associated with salience attribution to external stimuli and related to deficits in perception and regulation.

Neuroimaging correlates of insight in non-affective psychosis: A systematic review and meta-analysis.

OBJECTIVE: Neurological correlates of impaired insight in non-affective psychosis remain unclear. This study aimed to review and meta-analyze the studies assessing the grey matter volumetric correlates of impaired insight in non-affective psychosis. METHODS: This study consisted of a systematic review of 23 studies, and a meta-analysis with SDM-PSI of the 11 studies that were whole-brain and reported maps or peaks of correlation of studies investigating the grey matter volumetric correlates of insight assessments of non-affective psychosis, PubMed and OVID datasets were independently reviewed for articles reporting neuroimaging correlates of insight in non-affective psychosis. Quality assessment was realized following previous methodological approaches for the ABC quality assessment test of imaging studies, based on two main criteria: the statistical power and the multidimensional assessment of insight. Study peaks of correlation between grey matter volume and insight were used to recreate brain correlation maps. RESULTS: A total of 418 records were identified through database searching. Of these records, twenty-three magnetic resonance imaging (MRI) studies that used different insight scales were included. The quality of the evidence was high in 11 studies, moderate in nine, and low in three. Patients with reduced insight showed decreases in the frontal, temporal (specifically in superior temporal gyrus), precuneus, cingulate, insula, and occipital lobes cortical grey matter volume. The meta-analysis indicated a positive correlation between grey matter volume and insight in the right insula (i.e., the smaller the grey matter, the lower the insight). CONCLUSION: Several brain areas might be involved in impaired insight in patients with non-affective psychoses. The methodologies employed, such as the applied insight scales, may have contributed to the considerable discrepancies in the findings.

Naturalistic study on the use of clozapine in the early phases of non-affective psychosis: A 10-year follow-up study in the PAFIP-10 cohort.

Clozapine is seldom prescribed in treatment-resistant schizophrenia (TRS) patients during early phases of the illness. We aimed to examine the pathway and patterns and the impact of clozapine use in patients with TRS who were followed up for 10 years after the first outbreak of the illness. Data were obtained retrospectively from an epidemiological cohort of first episode schizophrenia patients (n = 218) who had been treated in a specialized intervention program (PAFIP). Out of 218, 35 (16%) individuals were on clozapine at 10-year assessment, while 183 (84%) were taking other antipsychotics. Among those 183 psychosis subjects who were not on clozapine, 13 (7.1%) met criteria for TRS. In the clozapine group, ten (28.6%) met criteria for early-TR and twenty-five (71.4%) met criteria for late-TR. Before clozapine treatment was initiated, the median number of days under other antipsychotic treatment was 1551 days (IQR = 1715) and the median time that subjects remained on clozapine was 6.3 years (IC95%: 5.49-7.20). At 10 years, we found that those individuals taking clozapine had higher CGI total scores (F = 12.0, p = 0.001) and SANS total scores (F = 9.27, p = 0.003) than subjects taking other antipsychotics after correcting for baseline values. Interestingly, when performing these analyses at 10 years between subjects taking clozapine (n = 35) and subjects who despite meeting TRS criteria were not taking clozapine (n = 13), we found that subjects taking clozapine had significantly lower total scores on all clinical scales compared with subjects who met TRS criteria and were not taking clozapine (p values < 0.05). TRS patients who took the longest time to start clozapine (third tertile) showed significantly higher CGI scores at 10-year follow-up compared to those who initiated clozapine earlier (first tertile) (t = 2.60; p = 0.043). Our findings reinforce the need of a timely assessment of treatment-resistant criteria in early schizophrenia patients and highlight the long-term benefits of an early introduction of clozapine on those patients meeting treatment-resistant criteria.

Obesity and brain structure in schizophrenia - ENIGMA study in 3021 individuals.

Schizophrenia is frequently associated with obesity, which is linked with neurostructural alterations. Yet, we do not understand how the brain correlates of obesity map onto the brain changes in schizophrenia. We obtained MRI-derived brain cortical and subcortical measures and body mass index (BMI) from 1260 individuals with schizophrenia and 1761 controls from 12 independent research sites within the ENIGMA-Schizophrenia Working Group. We jointly modeled the statistical effects of schizophrenia and BMI using mixed effects. BMI was additively associated with structure of many of the same brain regions as schizophrenia, but the cortical and subcortical alterations in schizophrenia were more widespread and pronounced. Both BMI and schizophrenia were primarily associated with changes in cortical thickness, with fewer correlates in surface area. While, BMI was negatively associated with cortical thickness, the significant associations between BMI and surface area or subcortical volumes were positive. Lastly, the brain correlates of obesity were replicated among large studies and closely resembled neurostructural changes in major depressive disorders. We confirmed widespread associations between BMI and brain structure in individuals with schizophrenia. People with both obesity and schizophrenia showed more pronounced brain alterations than people with only one of these conditions. Obesity appears to be a relevant factor which could account for heterogeneity of brain imaging findings and for differences in brain imaging outcomes among people with schizophrenia.

The retinal ganglion cell layer reflects neurodegenerative changes in cognitively unimpaired individuals.

BACKGROUND: To evaluate a wide range of optical coherence tomography (OCT) parameters for possible application as a screening tool for cognitively healthy individuals at risk of Alzheimer's disease (AD), assessing the potential relationship with established cerebrospinal fluid (CSF) core AD biomarkers and magnetic resonance imaging (MRI). METHODS: We studied 99 participants from the Valdecilla Study for Memory and Brain Aging. This is a prospective cohort for multimodal biomarker discovery and validation that includes participants older than 55 years without dementia. Participants received a comprehensive neuropsychological battery and underwent structural 3-T brain MRI, lumbar puncture for CSF biomarkers (phosphorylated-181-Tau (pTau), total Tau (tTau), beta-amyloid 1-42 (Aß 1-42), and beta-amyloid 1-40 (Aß 1-40)). All individuals underwent OCT to measure the retinal ganglion cell layer (GCL), the retinal nerve fiber layer (RFNL), the Bruch's membrane opening-minimum rim width (BMO-MRW), and choroidal thickness (CT). In the first stage, we performed a univariate analysis, using Student's t-test. In the second stage, we performed a multivariate analysis including only those OCT parameters that discriminated at a nominal level, between positive/negative biomarkers in stage 1. RESULTS: We found significant differences between the OCT measurements of pTau- and tTau-positive individuals compared with those who were negative for these markers, most notably that the GCL and the RNFL were thinner in the former. In stage 2, our dependent variables were the quantitative values of CSF markers and the hippocampal volume. The Aß 1-42/40 ratio did not show a significant correlation with OCT measurements while the associations between pTau and tTau with GCL were statistically significant, especially in the temporal region of the macula. Besides, the multivariate analysis showed a significant correlation between hippocampal volume with GCL and RNFL. However, after false discovery rate correction, only the associations with hippocampal volume remained significant. CONCLUSIONS: We found a significant correlation between Tau (pTau) and neurodegeneration biomarkers (tTau and hippocampus volume) with GCL degeneration and, to a lesser degree, with damage in RFNL. OCT analysis constitutes a non-invasive and unexpensive biomarker that allows the detection of neurodegeneration in cognitively asymptomatic individuals.

A meta-analysis of deep brain structural shape and asymmetry abnormalities in 2,833 individuals with schizophrenia compared with 3,929 healthy volunteers via the ENIGMA Consortium.

Schizophrenia is associated with widespread alterations in subcortical brain structure. While analytic methods have enabled more detailed morphometric characterization, findings are often equivocal. In this meta-analysis, we employed the harmonized ENIGMA shape analysis protocols to collaboratively investigate subcortical brain structure shape differences between individuals with schizophrenia and healthy control participants. The study analyzed data from 2,833 individuals with schizophrenia and 3,929 healthy control participants contributed by 21 worldwide research groups participating in the ENIGMA Schizophrenia Working Group. Harmonized shape analysis protocols were applied to each site's data independently for bilateral hippocampus, amygdala, caudate, accumbens, putamen, pallidum, and thalamus obtained from T1-weighted structural MRI scans. Mass univariate meta-analyses revealed more-concave-than-convex shape differences in the hippocampus, amygdala, accumbens, and thalamus in individuals with schizophrenia compared with control participants, more-convex-than-concave shape differences in the putamen and pallidum, and both concave and convex shape differences in the caudate. Patterns of exaggerated asymmetry were observed across the hippocampus, amygdala, and thalamus in individuals with schizophrenia compared to control participants, while diminished asymmetry encompassed ventral striatum and ventral and dorsal thalamus. Our analyses also revealed that higher chlorpromazine dose equivalents and increased positive symptom levels were associated with patterns of contiguous convex shape differences across multiple subcortical structures. Findings from our shape meta-analysis suggest that common neurobiological mechanisms may contribute to gray matter reduction across multiple subcortical regions, thus enhancing our understanding of the nature of network disorganization in schizophrenia.

Comparison of aripiprazole and risperidone effectiveness in first episode non-affective psychosis: Rationale and design of a prospective, randomized, 3-phase, investigator-initiated study (PAFIP-3).

BACKGROUND: Selecting the most effective treatment represents a critical challenge with the potential of modifying the long-term prognosis of individuals suffering a first break of psychosis. Head-to-head clinical trials comparing effectiveness among antipsychotic drugs in individuals with a first-episode of non-affective psychosis (FEP) are scarce. METHODS: The rationale and design of a 3 phases clinical trial (PAFIP-3, NCT02305823) comparing the effectiveness of aripiprazole and risperidone, and to additionally assess the benefits of an early use of clozapine in primary treatment-resistant patients is reported. The design encompasses of 5 work packages (medication algorithm, cognitive functioning, psychoeducation/vocational functioning, imaging and biological markers) addressing critical issues and needs of first episode psychosis individuals and their cares. The primary outcome measure was treatment effectiveness assessed by all-cause treatment discontinuation rate. RESULTS: 266 individuals have been included in the randomization study phase I (risperidone vs. aripiprazole). At 3 months, the retention rate was of 94% (249/266), 48(19.3%) patients have gone through phase II (olanzapine treatment), and 7(2.8%) entered the clozapine phase (phase III). DISCUSSION: The PAFIP 3 clinical trial may provide relevant information about clinical guidelines to optimally treat patients with a first episode of non-affective psychosis and the benefits and risks of an early use of clozapine in treatment resistant patients. Clinicaltrials.gov: NCT02305823.

Neuroimaging correlates of insight in non-affective psychosis: A systematic review and meta-analysis.

OBJECTIVE: Neurological correlates of impaired insight in non-affective psychosis remain unclear. This study aimed to review and meta-analyze the studies assessing the grey matter volumetric correlates of impaired insight in non-affective psychosis. METHODS: This study consisted of a systematic review of 23 studies, and a meta-analysis with SDM-PSI of the 11 studies that were whole-brain and reported maps or peaks of correlation of studies investigating the grey matter volumetric correlates of insight assessments of non-affective psychosis, PubMed and OVID datasets were independently reviewed for articles reporting neuroimaging correlates of insight in non-affective psychosis. Quality assessment was realized following previous methodological approaches for the ABC quality assessment test of imaging studies, based on two main criteria: the statistical power and the multidimensional assessment of insight. Study peaks of correlation between grey matter volume and insight were used to recreate brain correlation maps. RESULTS: A total of 418 records were identified through database searching. Of these records, twenty-three magnetic resonance imaging (MRI) studies that used different insight scales were included. The quality of the evidence was high in 11 studies, moderate in nine, and low in three. Patients with reduced insight showed decreases in the frontal, temporal (specifically in superior temporal gyrus), precuneus, cingulate, insula, and occipital lobes cortical grey matter volume. The meta-analysis indicated a positive correlation between grey matter volume and insight in the right insula (i.e., the smaller the grey matter, the lower the insight). CONCLUSION: Several brain areas might be involved in impaired insight in patients with non-affective psychoses. The methodologies employed, such as the applied insight scales, may have contributed to the considerable discrepancies in the findings.

Differences between psychiatric disorders in the clinical and functional effectiveness of an acute psychiatric day hospital, for acutely ill psychiatric patients. / Diferencias en la efectividad clínica y funcional, entre trastornos psiquiátricos, de un hospital de día psiquiátrico de agudos para pacientes con enfermedad mental aguda.

INTRODUCTION: Intensive treatment in acute day-care psychiatric units may represent an efficient alternative to inpatient care. However, there is evidence suggesting that this clinical resource may not be equally effective for every psychiatric disorder. The primary aim of this study was to explore differences between main psychiatric diagnostic groups, in the effectiveness of an acute partial hospitalization program. And, to identify predictors of treatment response. MATERIAL AND METHODS: The study was conducted at an acute psychiatric day hospital. Clinical severity was assessed using BPRS, CGI, and the HoNOS scales. Main socio-demographic variables were also recorded. Patients were clustered into 4wide diagnostic groups (i.e.: non-affective psychosis; bipolar; depressive; and personality disorders) to facilitate statistical analyses. RESULTS: A total of 331 participants were recruited, 115 of whom (34.7%) were diagnosed with non-affective psychosis, 97 (28.3%) with bipolar disorder, 92 (27.8%) with affective disorder, and 27 (8.2%) with personality disorder. Patients with a diagnosis of bipolar disorder showed greater improvement in BPRS (F=5.30; P=0.001) and CGI (F=8.78; P<0.001) than those suffering from psychosis or depressive disorder. Longer length of stay in the day-hospital, and greater baseline BPRS severity, were identified as predictors of good clinical response. Thirty-day readmission rate was 3%; at long-term (6 months after discharge) only 11.8% (N=39) of patients were re-admitted to a psychiatric hospitalization unit, and no differences were observed between diagnostic groups. CONCLUSIONS: Intensive care in an acute psychiatric day hospital is feasible and effective for patients suffering from an acute mental disorder. However, this effectiveness differs between diagnostic groups.

Dissecting the functional outcomes of first episode schizophrenia spectrum disorders: a 10-year follow-up study in the PAFIP cohort.

BACKGROUND: The aim of the current study was to examine the heterogeneity of functional outcomes in first episode psychosis (FEP) patients and related clinical, neurocognitive and sociodemographic factors using a cluster analytic approach. METHOD: A large sample of FEP patients (N = 209) was functionally reassessed 10 years after the first contact with an early intervention service. Multiple baseline, 3-year and 10-year follow-up variables were explored. RESULTS: The cluster analysis emphasized the existence of six independent clusters of functioning: one cluster was normal overall (42.16%), two clusters showed moderate interpersonal (9.63%) or instrumental (12.65%) deficits, two clusters showed more severe interpersonal (12.05%) or interpersonal and instrumental (13.85%) deficits and there was a significantly overall impaired cluster (9.63%). Cluster comparisons showed that several baseline and follow-up factors were differentially involved in functional outcomes. CONCLUSIONS: The current study demonstrated that distinct clusters of functioning in FEP patients can be identified. The fact that a variety of profiles was observed contributes to a better understanding of the nature of the heterogeneity characterizing FEP patients and has clinical implications for developing individualized treatment plans.

Neuroanatomical abnormalities in first-episode psychosis across independent samples: a multi-centre mega-analysis.

BACKGROUND: Neuroanatomical abnormalities in first-episode psychosis (FEP) tend to be subtle and widespread. The vast majority of previous studies have used small samples, and therefore may have been underpowered. In addition, most studies have examined participants at a single research site, and therefore the results may be specific to the local sample investigated. Consequently, the findings reported in the existing literature are highly heterogeneous. This study aimed to overcome these issues by testing for neuroanatomical abnormalities in individuals with FEP that are expressed consistently across several independent samples. METHODS: Structural Magnetic Resonance Imaging data were acquired from a total of 572 FEP and 502 age and gender comparable healthy controls at five sites. Voxel-based morphometry was used to investigate differences in grey matter volume (GMV) between the two groups. Statistical inferences were made at p < 0.05 after family-wise error correction for multiple comparisons. RESULTS: FEP showed a widespread pattern of decreased GMV in fronto-temporal, insular and occipital regions bilaterally; these decreases were not dependent on anti-psychotic medication. The region with the most pronounced decrease - gyrus rectus - was negatively correlated with the severity of positive and negative symptoms. CONCLUSIONS: This study identified a consistent pattern of fronto-temporal, insular and occipital abnormalities in five independent FEP samples; furthermore, the extent of these alterations is dependent on the severity of symptoms and duration of illness. This provides evidence for reliable neuroanatomical alternations in FEP, expressed above and beyond site-related differences in anti-psychotic medication, scanning parameters and recruitment criteria.

Treatment Discontinuation Impact on Long-Term (10-Year) Weight Gain and Lipid Metabolism in First-Episode Psychosis: Results From the PAFIP-10 Cohort.

BACKGROUND: Patients with a first episode of psychosis (FEP) are at higher risk of gaining weight and presenting metabolic disturbances, partly related to antipsychotic exposure. Previous studies suggest that treatment discontinuation might have a positive impact on weight in schizophrenia. The aim of this study was to evaluate the effect of treatment discontinuation on weight and metabolic changes in a FEP cohort. METHODS: A total of 209 FEP patients and 57 healthy controls were evaluated at study entry and prospectively at 10-year follow-up. Anthropometric measures and, clinical, metabolic, and sociodemographic data were collected. RESULTS: Patients discontinuing antipsychotic treatment presented a significantly lower increase in weight and better metabolic parameter results than those still on antipsychotic treatment at 10-year follow-up. CONCLUSIONS: Treatment discontinuation had a positive effect on the weight and metabolic changes observed in FEP patients; however, this effect was not sufficient to reaching a complete reversal to normal levels.

Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group.

DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc)-three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.