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Schizophrenia (SCZ) is a severe psychiatric disorder with unclear pathophysiology. Moreover, there is no specific biological marker to help clinicians to define a diagnosis, and medication is decided according to the psychiatrist's experience. In this scenario, microRNAs (miRNAs), which are small noncoding RNA molecules that regulate several genes, emerge as potential peripheral biomarkers to help not only the evaluation of the disease state but also the treatment response. Here, we systematically reviewed indexed literature and evaluated follow-up studies investigating the changes in miRNA expression due to antipsychotic treatment. We also assessed target genes and performed pathway enrichment analysis of miRNAs listed in this systematic review. A total of 11 studies were selected according to research criteria, and we observed that 28 miRNAs play a relevant role in schizophrenia pathogenesis or response to antipsychotic treatment, seven of those of extreme interest as possible biomarkers either for condition or treatment. Predicted targets of the miRNAs reviewed here were previously associated with schizophrenia in genome-wide studies, and pathway analysis showed enrichment for genes related to neural processes. With this review, we expect to highlight the importance of miRNAs in schizophrenia pathogenesis and its treatment and point out interesting miRNAs to future studies., Competing Interests: Declaration of competing interest The authors have nothing to disclose., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Patient response to antipsychotic drugs varies and may be related to clinical and genetic heterogeneity. This study aimed to determine the performance of clinical, genetic, and hybrid models to predict the response of first episode of psychosis (FEP). patients to the antipsychotic risperidone. We evaluated 141 antipsychotic-naïve FEP patients before and after 10 weeks of risperidone treatment. Patients who had a response rate equal to or higher than 50% on the Positive and Negative Syndrome Scale were considered responders (n = 72; 51%). Analyses were performed using a support vector machine (SVM), k-nearest neighbors (kNN), and random forests (RF). Clinical and genetic (with single-nucleotide variants [SNVs]) models were created separately. Hybrid models (clinical+genetic factors) with and without feature selection were created. Clinical models presented greater balanced accuracy 63.3% (confidence interval [CI] 0.46-0.69) with the SVM algorithm than the genetic models (balanced accuracy: 58.5% [CI 0.41-0.76] - kNN algorithm). The hybrid model, which included duration of untreated psychosis, Clinical Global Impression-Severity scale scores, age, cannabis use, and 406 SNVs, showed the best performance (balanced accuracy: 72.9% [CI 0.62-0.84] - RF algorithm). A hybrid model, including clinical and genetic predictors, can provide enhanced predictions of response to antipsychotic treatment., Competing Interests: RAB declares personal fees and non-financial support from Janssen and Ache Laboratórios Farmacêuticos, grants, and personal fees from Roche, outside the submitted work. AG declares personal fees and non-financial support from Janssen, Daiichi Sankyo, Lundbeck, Teva, Cristalia, and Ache Laboratórios Farmacêuticos outside the submitted work. CN declares personal fees and non-financial support from Janssen, Daiichi Sankyo, Lundbeck, Teva, and Ache Laboratórios Farmacêuticos outside the submitted work. No other conflicts of interest declared concerning the publication of this article.

Traumatic brain injury (TBI) is a prevalent and debilitating condition, which often leads to the development of post-traumatic epilepsy (PTE), a condition that yet lacks preventive strategies. Biperiden, an anticholinergic drug, is a promising candidate that has shown efficacy in murine models of PTE. MicroRNAs (miRNAs), small regulatory RNAs, can help in understanding the biological basis of PTE and act as TBI- and PTE-relevant biomarkers that can be detected peripherally, as they are present in extracellular vesicles (EVs) that cross the blood-brain barrier. This study aimed to investigate miRNAs in serum EVs from patients with TBI, and their association with biperiden treatment and PTE. Blood samples of 37 TBI patients were collected 10 days after trauma and treatment initiation in a double-blind clinical trial. A total of 18 patients received biperiden, with three subjects developing PTE, and 19 received placebo, with two developing PTE. Serum EVs were characterized by size distribution and protein profiling, followed by high-throughput sequencing of the EV miRNome. Differential expression analysis revealed no significant differences in miRNA expression between TBI patients with and without PTE. Interestingly, miR-9-5p displayed decreased expression in biperiden-treated patients compared to the placebo group. This miRNA regulates genes enriched in stress response pathways, including axonogenesis and neuronal death, relevant to both PTE and TBI. These findings indicate that biperiden may alter miR-9-5p expression in serum EVs, which may play a role in TBI resolution., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The pathophysiology of many neuropsychiatric disorders is still poorly understood. Identification of biomarkers for these diseases could benefit patients due to better classification and stratification. Exosomes excreted into the circulatory system can cross the blood-brain barrier and carry a cell type-specific set of molecules. Thus, exosomes are a source of potential biomarkers for many diseases, including neuropsychiatric disorders. Here, we investigated exosomal proteins produced from human-induced pluripotent stem cells (iPSCs) and iPSC-derived neural stem cells, neural progenitors, neurons, astrocytes, microglia-like cells, and brain capillary endothelial cells. Of the 31 exosome surface markers analyzed, a subset of biomarkers were significantly enriched in astrocytes (CD29, CD44, and CD49e), microglia-like cells (CD44), and neural stem cells (SSEA4). To identify molecular fingerprints associated with disease, circulating exosomes derived from healthy control (HC) individuals were compared against schizophrenia (SCZ) patients and late-onset Alzheimer's disease (LOAD) patients. A significant epitope pattern was identified for LOAD (CD1c and CD2) but not for SCZ compared to HC. Thus, analysis of cell type- and disease-specific exosome signatures of iPSC-derived cell cultures may provide a valuable model system to explore proteomic biomarkers for the identification of novel disease profiles.

Objective: Post-traumatic stress disorder (PTSD) is triggered by traumatic events, but genetic vulnerability and a history of childhood trauma are additional factors that may increase the risk of PTSD. Thus, our study focused on exploring the interaction between genetic susceptibility, as assessed by polygenic risk score (PRS), and traumatic events., Methods: We evaluated 68 women with PTSD who had been sexually assaulted and 63 healthy controls without a history of sexual assault. DNA was genotyped using the Infinium Global Screening Array (Illumina), and PRS analysis was performed using PRSice. Furthermore, logistic regression models were employed to examine the interaction between childhood trauma, traumatic life events, and PTSD-PRS and how they contribute to the risk of developing PTSD., Results: We found a significant association between PRS, childhood trauma (p = 0.03; OR = 1.241), and PTSD. Additionally, an interaction was observed between PRS, traumatic life events, and childhood trauma, particularly relating to physical and emotional neglect (p = 0.028; OR = 1.010). When examining neglect separately, we found a modest association between emotional neglect and PTSD (p = 0.014; OR = 1.086)., Conclusions: Our findings highlight the importance of considering genetic vulnerability and traumatic experiences in understanding the etiology of PTSD., Competing Interests: The authors report no conflicts of interest.

Objectives: Gene-environment interactions increase the risk of psychosis. The objective of this study was to investigate gene-gene and gene-environment interactions in psychosis, including single nucleotide variants (SNVs) of dopamine-2 receptor (D2R), N-methyl-d-aspartate receptor (NMDAR), and cannabinoid receptor type 1 (CB1R), lifetime cannabis use, and childhood trauma., Methods: Twenty-three SNVs of genes encoding D2R (DRD2: rs1799978, rs7131056, rs6275), NMDAR (GRIN1: rs4880213, rs11146020; GRIN2A: rs1420040, rs11866328; GRIN2B: rs890, rs2098469, rs7298664), and CB1R (CNR1: rs806380, rs806379, rs1049353, rs6454674, rs1535255, rs2023239, rs12720071, rs6928499, rs806374, rs7766029, rs806378, rs10485170, rs9450898) were genotyped in 143 first-episode psychosis patients (FEPp) and 286 community-based controls by Illumina HumanCoreExome-24 BeadChip. Gene-gene and gene-environment associations were assessed using nonparametric Multifactor Dimensionality Reduction software., Results: Single-locus analyses among the 23 SNVs for psychosis and gene-gene interactions were not significant (p > 0.05 for all comparisons); however, both environmental risk factors showed an association with psychosis (p < 0.001). Moreover, gene-environment interactions were significant for an SNV in CNR1 and cannabis use. The best-performing model was the combination of CNR1 rs12720071 and lifetime cannabis use (p < 0.001), suggesting an increased risk of psychosis., Conclusion: Our study supports the hypothesis of gene-environment interactions for psychosis involving T-allele carriers of CNR1 SNVs, childhood trauma, and cannabis use., Competing Interests: GPR has received honoraria for lectures and/or advisory panel membership from Janssen, Lundbeck, Otsuka, and Sunovion, and a research grant from Sunovion. The other authors report no conflicts of interest..

Gene-environment interactions (GxE) have been increasingly explored in psychiatry but with low replication rates. Attention-deficit/hyperactivity disorder (ADHD) is a suitable candidate for studying GxE due to its high heritability and well-defined environmental risk factors. Here, we explored GxE using polygenic risk score (PRS) to represent the genetic liability to ADHD (ADHD-PRS) and environmental risk score (ERS) to represent the combined effects of environmental risk factors. We analyzed longitudinal data of 2,046 individuals (6-14 years of age at baseline and 14-23 at the last follow-up) from the Brazilian High-Risk Cohort Study for Psychiatric Disorders. Psychiatric evaluation included the Child Behavior Checklist and the Strength and Difficulties Questionnaire. Statistical analyses were performed using mixed-effects models. We observed statistically significant interactions between ADHD-PRS and ERS, suggesting that environmental and genetic factors act synergistically in the development of ADHD symptoms. These effects were not present for depression or anxiety symptoms. No evidence of GxE correlation was detected. Mechanistically, our findings suggest that environmental stressors modulate the genetic risk for ADHD. Future studies should investigate whether the reduction of environmental risks can prevent the development of symptoms of ADHD, especially in children with a family history of the disorder.

Introduction: Long interspersed nuclear elements (LINEs) are endogenous retrotransposable elements. A few studies have linked the methylation pattern of LINE-1 to different mental disorders (e.g., post-traumatic stress disorder [PTSD], autism spectrum disorder [ASD], panic disorder [PD]). We sought to unify the existing knowledge in the field and provide a better understanding of the association between mental disorders and LINE-1 methylation., Methods: A systematic review was executed with 12 eligible articles according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines., Results: For psychotic disorders, PTSD, ASD, and PD, lower LINE-1 methylation levels were detected, whereas for mood disorders, the findings are controversial. The studies were conducted with subjects aged 18-80 years. Peripheral blood samples were utilized in 7/12 articles., Conclusion: Although most studies have shown that LINE-1 hypomethylation was associated with mental disorders, there were still some divergences (i.e., hypermethylation associated with mental disorders). These studies suggest that LINE-1 methylation may be an important factor related to the development of mental disorders and highlight the need to better comprehend the biological mechanisms underlying the role of LINE-1 in mental disorders pathophysiology., Competing Interests: The authors declare that they have no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 S. Karger AG, Basel.)

Background: Specific pathways of intergenerational transmission of behavioral traits remain unclear. Here, we aim to investigate how parental genetics influence offspring cognition, educational attainment, and psychopathology in youth., Methods: Participants for the discovery sample were 2,189 offspring (aged 6-14 years), 1898 mothers and 1,017 fathers who underwent genotyping, psychiatric, and cognitive assessments. We calculated polygenic scores (PGS) for cognition, educational attainment, attention-deficit hyperactivity disorder (ADHD), and schizophrenia for the trios. Phenotypes studied included educational and cognitive measures, ADHD and psychotic symptoms. We used a stepwise approach and multiple mediation models to analyze the effect of parental PGS on offspring traits via offspring PGS and parental phenotype. Significant results were replicated in a sample of 1,029 adolescents, 363 mothers, and 307 fathers., Results: Maternal and paternal PGS for cognition influenced offspring general intelligence and executive function via offspring PGS (genetic pathway) and parental education (phenotypic pathway). Similar results were found for parental PGS for educational attainment and offspring reading and writing skills. These pathways fully explained associations between parental PGS and offspring phenotypes, without residual direct association. Associations with maternal, but not paternal, PGS were replicated. No associations were found between parental PGS for psychopathology and offspring specific symptoms., Conclusions: Our findings indicate that parental genetics influences offspring cognition and educational attainment by genetic and phenotypic pathways, suggesting the expression of parental phenotypes partially explain the association between parental genetic risk and offspring outcomes. Multiple mediations might represent an effective approach to disentangle distinct pathways for intergenerational transmission of behavioral traits., (© 2022 Association for Child and Adolescent Mental Health.)

Introduction: Sexual assault and a history of childhood sexual abuse (CSA) are related to posttraumatic stress disorder (PTSD) development. Long interspersed nuclear elements (LINE-1) are transposable elements, and their methylation is used to infer DNA global methylation. DNA methylation can be affected by trauma exposition which in turn would be associated with PTSD. Thus, we investigated if the LINE-1 methylation pattern is related to PTSD symptoms in females with a history of CSA., Methods: This is a case-control study that examined, at baseline (W1), 64 women victims of sexual assault diagnosed with PTSD and 31 patients with PTSD who completed the 1-year follow-up (W2). Participants were categorized into two groups according to the presence of CSA (PTSDCSA+: NW1 = 19, NW2 = 10; PTSDCSA-: NW1 = 45, NW2 = 21). PTSD symptoms (re-experiencing, avoidance, hyperarousal, alterations in cognition/mood) were assessed using the Clinician-Administered PTSD Scale, and the history of CSA was assessed by the Childhood Trauma Questionnaire. LINE-1 methylation was measured in three sites (CpG1, CpG2, CpG3) located in the 5'UTR region using bisulfite conversion followed by pyrosequencing. Linear regression models were performed to test the relation between LINE-1 CpG sites methylation and PTSD symptoms., Results: We found a negative association between CpG2 methylation and hyperarousal symptoms among those in the PTSDCSA+ group in W1 (adjusted p = 0.003) compared to the PTSDCSA- group ( p > 0.05). Still, no association was observed between other PTSD symptoms and other CpG sites. Further, in the longitudinal analysis, LINE-1 hypomethylation was no longer observed in PTSD participants exposed to CSA., Conclusion: Our findings suggest that LINE-1 methylation may help understand the relationship between trauma and PTSD. However, more studies are needed to investigate LINE-1 as an epigenetic marker of psychiatric disorders., Competing Interests: The authors have no conflicts of interest to declare., (© 2023 S. Karger AG, Basel.)

Telomeres are short tandem repeats of "TTAGGG" that protect the chromosome ends from deterioration or fusion of chromosomes. Their repeat length shortens with cell division acting as a biomarker of cellular aging. Traumatic stress events during adulthood or childhood have been associated with posttraumatic stress disorder (PTSD) and short leukocyte telomere length (LTL). This study investigated whether LTL was associated with PTSD in a Brazilian sample of sexually assaulted civilian women at two time points: baseline and 1-year follow-up. At baseline, we assessed 64 women with PTSD following sexual assault (cases) and 60 women with no previous history of sexual trauma or mental disorders (healthy controls - HC). At follow-up visit, 13 persistent PTSD cases, 11 HCs, and 11 PTSD remitters patients were evaluated. PTSD diagnosis and severity were assessed using Mini International Neuropsychiatric Interview (Diagnostic and Statistical Manual of Mental Disorders III/IV criteria) and Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), respectively. LTL was measured using multiplex real-time polymerase chain reaction (PCR). In the baseline analysis, we observed that LTL was associated with re-experiencing symptoms ( B = -0.16; confidence interval (CI) 95% = -0.027--0.005; Bonferroni-adjusted p -value = 0.02), but no association was observed between other PTSD symptoms and LTL. In the longitudinal analysis, telomere shortening was no longer observed in patients with PTSD and PTSD remitters. In conclusion, our findings indicate that shorter baseline LTL is associated with early stage of PTSD re-experiencing symptoms in recently sexually assaulted women., Competing Interests: RP is paid for their editorial work on the journal Complex Psychiatry. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Carvalho, Coimbra, Xavier, Bugiga, Fonseca, Olff, Polimanti, Mello, Ota, Mello and Belangero.)

Background: Dimensional approaches can decompose a construct in a set of continuous variables, improving the characterization of complex phenotypes, such as schizophrenia. However, the five-factor model of the Positive and Negative Syndrome Scale (PANSS), the most used instrument in schizophrenia research, yielded poor fits in most confirmatory factor analysis (CFA) studies, raising concerns about its applications. Thus, we aimed to identify dimensional PANSS CFA models with good psychometric properties by comparing the traditional CFA with three methodological approaches: Bayesian CFA, multilevel modeling, and Multiple Indicators Multiple Causes (MIMIC) modeling., Methods: Clinical data of 700 schizophrenia patients from four centers were analyzed. We first performed a traditional CFA. Next, we tested the three techniques: 1) a Bayesian CFA; 2) a multilevel analysis using the centers as level; and 3) a MIMIC modeling to evaluate the impact of clinical staging on PANSS factors and items., Results: CFA and Bayesian CFA produced poor fit models. However, when adding a multilevel structure to the CFA model, a good fit model emerged. MIMIC modeling yielded significant differences in the factor structure between the clinical stages of schizophrenia. Sex, age, age of onset, and duration of illness did not significantly affect the model fit., Conclusion: Our comparison of different CFA methods highlights the need for multilevel structure to achieve a good fit model and the potential utility of staging models (rather than the duration of illness) to deal with clinical heterogeneity in schizophrenia. Large prospective samples with biological data should help to understand the interplay between psychometrics concerns and neurobiology research., (Copyright © 2018. Published by Elsevier B.V.)

Treatment-resistant schizophrenia (TRS) occurs in one-third of the patients, but the molecular determinants of poor antipsychotic response remain unclear. We compared genetic data of patients with TRS (n = 63) with non-TRS (n = 111) by polygenic risk scores (PRS) calculated by PRSice software using PGC2&#95;SCZ (Psychiatric Genomics Consortium - Schizophrenia) data. TRS criteria followed the International Psychopharmacology Algorithm Project SCZ algorithm. Statistical clustering and functional enrichment analyses of genes harboring TRS-linked variants were performed. Individuals on the top three deciles of schizophrenia PRS distribution exhibited higher odds of being refractory to antipsychotics than those on the bottom three deciles. Clusters of interacting variant-harboring genes were identified among the association signals. They are upregulated in the dorsolateral prefrontal, orbitofrontal, temporal, and inferior parietal areas during adolescence and early adulthood. Similar gene modules were found using transcriptional data from the same brain regions in individuals with schizophrenia. Genes were enriched among markers of cortical interneurons and somatosensory pyramidal cells. Finally, the enrichment of the clustered genes in drug-response expression signatures revealed compounds that could be employed to identify novel antipsychotic targets. In conclusion, we identified variant-harboring genes that may predispose SCZ patients to poor antipsychotic response and found statistically enriched clusters which provided functional and spatiotemporal context for TRS, suggesting that genotypic variation may converge to biological alterations at the interplay between actin dynamics and synaptic organization., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Schizophrenia has a heritability of 60-80% 1 , much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Human brain structure changes throughout the lifespan. Altered brain growth or rates of decline are implicated in a vast range of psychiatric, developmental and neurodegenerative diseases. In this study, we identified common genetic variants that affect rates of brain growth or atrophy in what is, to our knowledge, the first genome-wide association meta-analysis of changes in brain morphology across the lifespan. Longitudinal magnetic resonance imaging data from 15,640 individuals were used to compute rates of change for 15 brain structures. The most robustly identified genes GPR139, DACH1 and APOE are associated with metabolic processes. We demonstrate global genetic overlap with depression, schizophrenia, cognitive functioning, insomnia, height, body mass index and smoking. Gene set findings implicate both early brain development and neurodegenerative processes in the rates of brain changes. Identifying variants involved in structural brain changes may help to determine biological pathways underlying optimal and dysfunctional brain development and aging., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

A growing body of research demonstrates the association between neighborhood context and health. The underlying biological mechanisms of this association are not fully understood. We conducted a systematic review of studies that investigated the association between neighborhood context and telomere length (TL), a DNA-protein complex that shortens after cell division. Short TL is linked to age-related diseases and may be impacted by chronic stress. Nineteen eligible articles identified through PubMed and Scopus met inclusion criteria. Results demonstrated inconsistent support for the relationship between neighborhood disadvantage and short TL. However, findings across several studies provide evidence for an inverse association between perceived neighborhood problems and TL, suggesting that TL may be an important factor in understanding health vulnerabilities associated specifically with negative perceptions of the neighborhood context., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Lack of diversity regarding genetic and environmental backgrounds weakens the generalization and clinical applicability of research findings on psychotic disorders. Notably, Latin Americans have been generally neglected in genetic studies, comprising less than 2% of genome-wide association study samples. But Latin American populations represent a unique opportunity for research, given the exceptionally high ethnic admixture of this group. Increasing genetic diversity is essential to improve the fine mapping of known regions associated with psychotic disorders, discover novel genetic associations, and replicate studies. Additionally, Latin America is characterized by massive social, political, and economic inequalities, all known risk factors for mental health issues, including psychotic disorders. This article aims to 1) discuss the challenges and advantages of studying Latin America's particular genetic makeup and environmental context; 2) review previous studies conducted in the region; and 3) describe three Latin American research initiatives in progress: the Neuropsychiatric Genetics of Psychosis in Mexican Populations (NeuroMEX), the Paisa, and the Latin American Network for the Study of Early Psychosis (ANDES) studies.

Psychotic experiences (PE) are forms of hallucinations and delusions neither reaching the intensity and functional impairment required to be regarded as full psychotic symptoms nor a psychotic disorder. Here we investigated the ability to predict PE using multiple models (regressions, mediation and moderation) using polygenic risk score for psychotic experiences (PE-PRS), polygenic risk score for schizophrenia (SCZ-PRS), and polyenvironmental risk score (PERS) in youth from a Brazilian sample. The scores were not able to predict outcome, either when both scores were combined (PERS + PE-PRS and PERS + SCZ-PRS) or separately. Our results show that there is no association between PE and PRS or PERS among adolescents in our Brazilian sample. The lack of association may be a result of the absence of better representativeness regarding genetic and environmental factors of our population., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Schizophrenia is a severe and multifactorial disorder with an unknown causative pathophysiology. Abnormalities in neurodevelopmental and aging processes have been reported. Relative telomere length (RTL) and DNA methylation age (DMA), well-known biomarkers for estimating biological age, are both commonly altered in patients with schizophrenia compared to healthy controls. However, few studies investigated these aging biomarkers in first-episode psychosis (FEP) and in antipsychotic-naïve patients. To cover the existing gap regarding DMA and RTL in FEP and antipsychotic treatment, we aimed to verify whether those aging markers could be associated with psychosis and treatment response. Thus, we evaluated these measures in the blood of FEP antipsychotic-naïve patients and healthy controls (HC), as well as the response to antipsychotics after 10 weeks of treatment with risperidone. RTL was measured in 392 subjects, being 80 FEP and 312 HC using qPCR, while DMA was analyzed in a subset of 60 HC, 60 FEP patients (antipsychotic-naïve) and 59 FEP-10W (after treatment) using the "Multi-tissue Predictor"and the Infinium HumanMethylation450 BeadChip Kit. We observed diminished DMA and longer RTL in FEP patients before treatment compared to healthy controls, indicating a decelerated aging process in those patients. We found no statistical difference between responder and non-responder patients at baseline for both markers. An increased DMA was observed in patients after 10 weeks of treatment, however, after adjusting for blood cell composition, no significant association remained. Our findings indicate a decelerated aging process in the early phases of the disease., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Resistance to antipsychotic treatment affects up to 30% of patients with schizophrenia. Although the time course of development of treatment-resistant schizophrenia (TRS) varies from patient to patient, the reasons for these variations remain unknown. Growing evidence suggests brain dysconnectivity as a significant feature of schizophrenia. In this study, we compared fractional anisotropy (FA) of brain white matter between TRS and non-treatment-resistant schizophrenia (non-TRS) patients. Our central hypothesis was that TRS is associated with reduced FA values., Methods: TRS was defined as the persistence of moderate to severe symptoms after adequate treatment with at least two antipsychotics from different classes. Diffusion-tensor brain MRI obtained images from 34 TRS participants and 51 non-TRS. Whole-brain analysis of FA and axial, radial, and mean diffusivity were performed using Tract-Based Spatial Statistics (TBSS) and FMRIB's Software Library (FSL), yielding a contrast between TRS and non-TRS patients, corrected for multiple comparisons using family-wise error (FWE) < 0.05., Results: We found a significant reduction in FA in the splenium of corpus callosum (CC) in TRS when compared to non-TRS. The antipsychotic dose did not relate to the splenium CC., Conclusion: Our results suggest that the focal abnormality of CC may be a potential biomarker of TRS.

There is a well-known association of traumatic experiences and posttraumatic stress disorder (PTSD) with body size and composition, including consistent differences between sexes. However, the biology underlying these associations is unclear. To understand the genetic underpinnings of this complex relationship, we investigated genome-wide datasets informative of African and European ancestries from the Psychiatric Genomic Consortium, the UK Biobank, the GIANT Consortium, and the Million Veteran Program. We used genome-wide association statistics to estimate sex-specific genetic correlations ( r g ) of traumatic experiences, social support, and PTSD with multiple anthropometric traits. After multiple testing corrections (false discovery rate, FDR q < 0.05), we observed 58 significant r g relationships in females (e.g., childhood physical abuse and body mass index, BMI r g  = 0.245, p = 3.88 × 10 -10 ) and 21 significant r g relationships in males (e.g., been involved in combat or exposed to warzone and leg fat percentage; r g  = 0.405, p = 4.42 × 10 -10 ). We performed causal inference analyses of these genetic overlaps using Mendelian randomization and latent causal variable approaches. Multiple female-specific putative causal relationships were observed linking body composition/size with PTSD (e.g., leg fat percentage→PTSD; beta = 0.319, p = 3.13 × 10 -9 ), traumatic experiences (e.g., childhood physical abuse→waist circumference; beta = 0.055, p = 5.07 × 10 -4 ), and childhood neglect (e.g., "someone to take you to doctor when needed as a child"→BMI; beta = -0.594, p = 1.09 × 10 -5 ). In males, we observed putative causal effects linking anthropometric-trait genetic liabilities to traumatic experiences (e.g., BMI→childhood physical abuse; beta = 0.028, p = 8.19 × 10 -3 ). Some of these findings were replicated in individuals of African descent although the limited sample size available did not permit us to conduct a sex-stratified analysis in this ancestry group. In conclusion, our findings provide insights regarding sex-specific causal networks linking anthropometric traits to PTSD, traumatic experiences, and social support ., Competing Interests: D.J.S. received personal fees from Lundbeck and Sun Pharmaceutical Industries. R.P. and J.G. are paid for their editorial work on the journal Complex Psychiatry. The other authors declare no competing interests., (© 2021 The Authors.)

Brain-derived neurotrophic factor (BDNF) and the immune-inflammatory response system (IRS) have been implicated in the pathophysiology of schizophrenia. However, no research examined the associations between BDNF and immune activation both before and after treatment in antipsychotic-naïve first episode psychosis (AN-FEP). This study aims to examine serum BDNF levels and their association with IRS and the compensatory immune-regulatory reflex system (CIRS) in AN-FEP before and after risperidone treatment. We included 31 AN-FEP and 22 healthy controls. AN-FEP showed reduced levels of BDNF as compared to controls, and BDNF levels normalized after treatment with risperidone. BDNF levels were inversely correlated with a greater IRS response. Higher levels of IRS/CIRS biomarkers were associated with lower levels of BDNF including M1 macrophage, T-helper (Th)-1, Th-2, and Th-17, and T-regulatory (Treg) cell responses. Our findings indicate that AN-FEP is characterized by decreased levels of BDNF, which are normalized after treatment with risperidone. BDNF levels were inversely associated with activated immune-inflammatory pathways. The findings support the hypothesis that, increased IRS is linked to neurotoxicity, and that a decrease in BDNF may be part of the IRS/CIRS responses in FEP and, thus, be involved in the development of psychosis., (Copyright © 2021. Published by Elsevier Ltd.)

The core features of obstructive sleep apnea (OSA) can potentially contribute to the acceleration of telomere shortening mechanisms. Other factor associated with telomeres is Klotho gene as it can negatively regulates telomerase activity. Noteworthy, KLOTHO protein level has recently been associated with OSA. In this sense, it was plausible to hypothesize that OSA would be associated with short telomere length and those with OSA plus risk single nucleotide polymorphisms (SNPs) in Klotho gene would present even shorter telomere length. As part of the EPISONO cohort, 1042 individuals answered questionnaires, underwent polysomnography and had blood collected for DNA extraction. OSA was defined according to AHI≥ 15 events/hour. Leukocyte telomere length (LTL) was measured through real-time polymerase chain reaction (qPCR) and Klotho SNPs were genotyped by array. Mediation analyses considered the presence of SNPs in Klotho gene and how this interaction can affect OSA and its consequence in telomere length. All the analyses were corrected for multiple comparisons. LTL was significantly shorter in OSA compared to controls in a severity-dependent manner (B = 0.055; CI = 0.007-0.102; p = 0.02). Among the 43 Klotho SNPs analyzed, we observed that 4 SNPs (rs525014, rs7982726, rs685417 and rs9563124) significantly mediated the association between OSA and short LTL. Klotho gene opens a new venue in OSA research since it can contribute in the increase of knowledge of the mechanisms involved in the consequences of short telomeres in individuals with OSA., (Copyright © 2021. Published by Elsevier B.V.)

Background: Thalamic volume measures have been linked to obsessive-compulsive disorder (OCD) in children and adolescents. However, it is unclear if alterations in thalamic volumes occur before or after symptom onset and if there is a relation to the presence of sub-clinical obsessive-compulsive symptoms (OCS). Here, we explore the relationship between OCS and the rate of thalamic volume change in a cohort of children and youth at high risk to develop a mental disorder. A secondary aim was to determine if there is a relationship between OCS and the individual's OCD polygenic risk score (OCD-PRS) and between the rate of thalamic volume change and the OCD-PRS. Methods: The sample included 378 children enrolled in the longitudinal Brazilian High-Risk Cohort for Mental Conditions. Participants were assessed for OCS and the symmetrized percent change (SPC) of thalamic volume across two time-points separated by 3 years, along with the OCD-PRS. Zero-altered negative binomial models were used to analyze the relationship between OCS and thalamic SPC. Multiple linear regressions were used to examine the relationship between thalamic SPC and OCD-PRS. Results: A significant relationship between OCS and the right thalamus SPC ( p = 0.042) was found. There was no significant relationship between changes in thalamic volume SPC and OCD-PRS. Conclusions: The findings suggest that changes in the right thalamic volume over the course of 3 years in children may be associated to OCS. Future studies are needed to confirm these results and further characterize the specific nature of OCS symptoms associated with thalamic volumes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ravagnani Salto, Santoro, Hoexter, Jackowski, Pan, Rosário, Belangero, Alvarenga, Doretto, Fumo, Batistuzzo, Macul Ferreira de Barros, Timpano, Ota, Rohde, Miguel, Leckman and Zugman.)

Inflammatory markers like C-reactive protein (CRP) have been associated with post-traumatic stress disorder (PTSD) and traumatic experiences, but the underlying mechanisms are unclear. We investigated the relationship among serum CRP, PTSD, and traits related to traumatic events and social support using genetic association data from the Psychiatric Genomics Consortium (23,185 PTSD cases and 151,309 controls), the UK Biobank (UKB; up to 117,900 individuals), and the CHARGE study (Cohorts for Heart and Aging Research in Genomic Epidemiology, 148,164 individual). Linkage disequilibrium score regression, polygenic risk scoring, and two-sample Mendelian randomization (MR) analyses were used to investigate genetic overlap and causal relationships. Genetic correlations of CRP were observed with PTSD (rg = 0.16, p = 0.026) and traits related to traumatic events, and the presence of social support (-0.28 < rg < 0.20; p < 0.008). We observed a bidirectional association between CRP and PTSD (CRP → PTSD: β = 0.065, p = 0.015; PTSD → CRP: β = 0.008, p = 0.009). CRP also showed a negative association with the "felt loved as a child" trait (UKB, β = -0.017, p = 0.008). Owing to the known association of socioeconomic status (SES) on PTSD, a multivariable MR was performed to investigate SES as potential mediator. We found that household income (univariate MR: β = -0.22, p = 1.57 × 10 -7 ; multivariate MR: β = -0.17, p = 0.005) and deprivation index (univariate MR: β = 0.38, p = 1.63 × 10 -9 ; multivariate MR: β = 0.27, p = 0.016) were driving the causal estimates of "felt loved as a child" and CRP on PTSD. The present findings highlight a bidirectional genetic association between PTSD and CRP, also suggesting a potential role of SES in the interplay between childhood support and inflammatory processes with respect to PTSD risk.

Objective: Mental disorders can have a major impact on brain development. Peripheral blood concentrations of brain-derived neurotrophic factor (BDNF) are lower in adult psychiatric disorders. Serum BDNF concentrations and BDNF genotype have been associated with cortical maturation in children and adolescents. In 2 large independent samples, this study tests associations between serum BDNF concentrations, brain structure, and psychopathology, and the effects of BDNF genotype on BDNF serum concentrations in late childhood and early adolescence., Methods: Children and adolescents (7-14 years old) from 2 cities (n = 267 in Porto Alegre; n = 273 in São Paulo) were evaluated as part of the Brazilian high-risk cohort (HRC) study. Serum BDNF concentrations were quantified by sandwich ELISA. Genotyping was conducted from blood or saliva samples using the SNParray Infinium HumanCore Array BeadChip. Subcortical volumes and cortical thickness were quantified using FreeSurfer. The Development and Well-Being Behavior Assessment was used to identify the presence of a psychiatric disorder., Results: Serum BDNF concentrations were not associated with subcortical volumes or with cortical thickness. Serum BDNF concentration did not differ between participants with and without mental disorders, or between Val homozygotes and Met carriers., Conclusions: No evidence was found to support serum BDNF concentrations as a useful marker of developmental differences in brain and behavior in early life. Negative findings were replicated in 2 of the largest independent samples investigated to date.

Background: Posttraumatic stress disorder (PTSD) is a prevalent, chronic, and severe disorder related to traumatic events. Women are disproportionately affected by PTSD than men and are more at risk in the occurrence of sexual assault victimization. Estimates suggest that 50% of women develop PTSD following sexual assault and successful clinical management can be challenging. Growing evidence has implicated neural, immune, and endocrine alterations underpinning PTSD, but only few studies have assessed the evolution of acute PTSD in women., Objective: This study aims to measure whether the onset of PTSD is associated with accelerated aging in women following sexual assault. We hypothesize that the increase of allostatic load caused by PTSD leads to neuroprogression. We will implement a randomized clinical trial to compare responses to treatment with either interpersonal psychotherapy adapted for PTSD (IPT-PTSD) or the selective serotonin reuptake inhibitor sertraline., Methods: We will include women between 18 and 45 years of age, who experienced sexual assault from 1 to 6 months before the initial evaluation, and present with a Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) diagnosis of PTSD. Baseline evaluation will comprise clinical and psychometric assessments, structural and functional magnetic resonance imaging, neuropsychological testing, polysomnography, evaluation of immune and endocrine parameters, and genetic analyses. Age-matched female healthy controls will be included and subjected to the same evaluation. Patients will be randomized for treatment in 1 of the 2 arms of the study for 14 weeks; follow-up will continue until 1 year after inclusion via treatment as usual. The researchers will collect clinical and laboratory data during periodic clinical assessments up to 1-year follow-up., Results: Data collection started in early 2016 and will be completed by the end of the first semester of 2020. Analyses will be performed soon afterward, followed by the elaboration of several articles. Articles will be submitted in early 2021. This research project has obtained a grant from the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP 2014/12559-5)., Conclusions: We expect to provide insight into the consequences of recent sexual assault exposure in women by investigating the degree of neuroprogression developing from an early stage of PTSD. We also expect to provide important evidence on the efficacy of a non-exposure psychotherapy (IPT-PTSD) to mitigate PTSD symptoms in recently sexually assaulted women. Further, we aim to obtain evidence on how treatment outcomes are associated with neuroprogression measures., Trial Registration: Brazilian Clinical Trials Registry RBR-3z474z; http://www.ensaiosclinicos.gov.br/rg/RBR-3z474z/., International Registered Report Identifier (irrid): DERR1-10.2196/19162., (©Bruno Messina Coimbra, Mary Yeh, Ana Teresa D'Elia, Mariana Rangel Maciel, Carolina Muniz Carvalho, Ana Carolina Milani, Adriana Mozzambani, Mario Juruena, Sintia Iole Belangero, Andrea Parolin Jackowski, Dalva Poyares, Andrea Feijo Mello, Marcelo Feijo Mello. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 18.11.2020.)

Discrimination is unfair treatment against a certain group based on race, age, gender, sexual orientation, or other social identities. Discrimination is pervasive in society, elevates psychosocial stress, and is associated with negative mental and physical health outcomes. However, more research is needed to understand the biological mechanisms underlying discrimination-related health disparities. Telomere science may contribute to elucidate some of these aspects. Telomeres are protein-DNA complexes that shorten after cell division and are valuable markers of cellular aging. Short telomeres have been associated with the onset of age-related diseases. Evidence shows that chronic psychological stress may accelerate telomere shortening. Since discrimination can lead to psychological strain with cumulative impact on general health, we hypothesized that groups that report more discrimination show reduced telomere length (TL) as a consequence of psychosocial stress elevation. Through a systematic review of the literature we found 12 articles that met our criteria. Eligible studies measured racial, gender, unfair policing, and multiple forms of discrimination in association with TL. Our review showed mixed results, suggesting that there is weak evidence of a main association between discrimination and TL. However, discrimination may interact with several variables (such as depressive symptoms, acculturation, higher socioeconomic status, internalization of negative racial bias, and not discussing discrimination experiences with others) and contribute to shorten telomeres. Discrimination is a complex social construct composed of a vast sum of experiences, impressions, and contexts that in combination with other sources of stress may have an impact on TL. Telomeres may be a plausible pathway to investigate health discrepancies in discriminated groups in society, but more evidence is needed to investigate the potential harm of discrimination on cells., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Our previous studies showed increased angiotensin I-converting enzyme (ACE) activity in chronic schizophrenia (SCZ) patients compared to healthy control (HC) volunteers, and the relevance of combining ACE genotype and activity for predicting SCZ was suggested., Methods: ACE activity was measured in plasma of ACE insertion/deletion (I/D) genotyped HC volunteers (N = 53) and antipsychotic-naïve first-episode psychosis (FEP) patients (N = 45), assessed at baseline (FEB-B) and also after 2-months (FEP-2M) of treatment with the atypical antipsychotic risperidone., Results: ACE activity measurements showed significant differences among HC, FEP-B and FEP-2M groups (F = 5.356, df = 2, p = 0.005), as well as between HC and FEP-2M (post-hoc Tukey's multiple comparisons test, p = 0.004). No correlation was observed for ACE activity increases and symptom severity reductions in FEP as assessed by total PANSS (r = -0.131, p = 0.434). FEP subgrouped by ACE I/D genotype showed significant ACE activity increases, mainly in the DD genotype subgroup. No correlation between ACE activity and age was observed in FEP or HC groups separately (r = 0.210, p = 0.392), but ACE activity levels differences observed between these groups were influenced by age., Conclusions: The importance of measuring the ACE activity in blood plasma, associated to ACE I/D genotyping to support the follow-up of FEP patients did not show correlation with general symptoms amelioration in the present study. However, new insights into the influence of age and I/D genotype for ACE activity changes in FEP individuals upon treatment was demonstrated., (© The Author(s) 2020. Published by Oxford University Press on behalf of CINP.)

Aim: We investigated the DNA methylation profile over LINE-1 in antipsychotic-naive, first-episode psychosis-patients (n = 69) before and after 2 months of risperidone treatment and in healthy controls (n = 62). Materials & methods: Patients were evaluated using standardized scales and classified as responders and nonresponders. DNA from blood was bisulfite converted and LINE-1 fragments were amplified and pyrosequencing was performed. Results: Lower LINE-1 methylation was observed in antipsychotic-naive first-episode psychosis patients than in healthy controls. Lower DNA methylation levels before treatment were associated with poor risperidone responses. A positive correlation was observed between LINE-1 methylation levels and positive symptoms response. Conclusion: Our study brings new insight regarding how epigenomic studies and clinical correlation studies can supplement psychosis treatment.

We aimed to identify blood gene expression patterns associated to psychopathological trajectories retrieved from a large community, focusing on the emergence and remission of general psychiatric symptoms. Hundred and three individuals from the Brazilian High-Risk Cohort Study (BHRCS) for mental disorders were classified in four groups according to Child Behavior Checklist (CBCL) total score at the baseline (w0) and after 3 years (w1): low-high (L-H) (N = 27), high-low (H-L) (N = 12), high-high (H-H) (N = 34) and low-low (L-L) groups (N = 30). Blood gene expression profile was measured using Illumina HT-12 Beadchips, and paired analyses comparing w0 and w1 were performed for each group. Results: 98 transcripts were differentially expressed comparing w0 and w1 in the L-H, 33 in the H-L, 177 in the H-H and 273 in the L-L. Of these, 66 transcripts were differentially expressed exclusively in the L-H; and 6 only in the H-L. Cross-Lagged Panel Models analyses revealed that RPRD2 gene expression at w1 might be influenced by the CBCL score at w0. Moreover, COX5B, SEC62, and NDUFA2 were validated with another technique and were also differentially regulated in postmortem brain of subjects with mental disorders, indicating that they might be important not only to specific disorders, but also to general psychopathology and symptoms trajectories. Whereas genes related to metabolic pathways seem to be associated with the emergence of psychiatric symptoms, mitochondrial inner membrane genes might be important over the course of normal development. These results suggest that changes in gene expression can be detected in blood in different psychopathological trajectories.

To investigate the causal relationship between blood metabolites and traits related to trauma-response, we combined genome-wide and metabolome-wide datasets generated from large-scale cohorts. Five trauma-response traits ascertained in the UK Biobank (52,816 < N < 117,900 individuals) were considered: (i) "Avoided activities/situations because of previous stressful experience" (Avoidance); (ii) "Felt distant from other people" (Distant); (iii) "Felt irritable/had angry outbursts" (Irritable); (iv) "Felt very upset when reminded of stressful experience" (Upset); (v) "Repeated disturbing thoughts of stressful experience". These were investigated with respect to 52 blood metabolites tested in a previous genome-wide-association study (N = 24,925 European-ancestry individuals). Linkage disequilibrium score regression, polygenic risk scoring (PRS), and Mendelian randomization were applied to the datasets. We observed that 14 metabolites were genetically correlated with trauma-response traits (p < 0.05). High-resolution PRS of 4 metabolites (citrate; glycoprotein acetyls; concentration of large very-low-density lipoproteins (VLDL) particles (LVLDLP); total cholesterol in medium particles of VLDL (MVLDLC)) were associated with trauma-response traits (false discovery rate Q < 10%). These genetic associations were partially due to causal relationships (Citrate→Upset β = - 0.058, p = 9.1 × 10 -4 ; Glycoproteins→Avoidance β = 0.008, p = 0.003; LVLDLP→Distant β = 0.008, p = 0.022; MVLDLC→Avoidance β = 0.019, p = 3 × 10 -4 ). No reverse associations were observed. In conclusion, our study supports causal relationships between certain blood metabolites and emotional and behavioral responses to traumatic experiences.

Objective: German psychiatrist Kurt Schneider proposed the concept of first-rank symptoms (FRS) of schizophrenia in 1959. However, their relevance for diagnosis and prediction of treatment response are still unclear. Most studies have investigated FRS in chronic or medicated patients. The present study sought to evaluate whether FRS predict remission, response, or improvement in functionality in antipsychotic-naive first-episode psychosis., Methods: Follow-up study of 100 patients at first episode of psychosis (FEP), with no previous treatment, assessed at baseline and after 2 months of treatment. The participants were evaluated with the standardized Positive and Negative Syndrome Scale (PANSS) and Global Assessment of Functioning (GAF) and for presence of FRS., Results: Logistic regression analysis showed that, in this sample, up to three individual FRS predicted remission: voices arguing, voices commenting on one's actions, and thought broadcasting., Conclusion: Specific FRS may predict remission after treatment in FEP patients. This finding could give new importance to Kurt Schneider's classic work by contributing to future updates of diagnostic protocols and improving estimation of prognosis.

The impact of early life stress on mental health and telomere length shortening have been reported. Changes in brain default mode network (DMN) were found to be related to a myriad of psychiatric conditions in which stress may play a role. In this context, family environment and adverse childhood experiences (ACEs) are potential causes of stress. This is a hypothesis-driven study focused on testing two hypotheses: (i) there is an association between telomere length and the function of two main hubs of DMN: the posterior cingulate cortex (PCC) and the medial prefrontal cortex (mPFC); (ii) this association is modulated by family environment and/or ACEs. To the best of our knowledge, this is the first study investigating these hypotheses. Resting-state functional magnetic resonance imaging data and blood sample were collected from 389 subjects (6-15 age range). We assessed DMN fractional amplitude of low-frequency fluctuations (fALFF) and leukocyte telomere length (LTL). We fitted general linear models to test the main effects of LTL on DMN hubs and the interaction effects with Family Environment Scale (FES) and ACEs. The results did not survive a strict Bonferroni correction. However, uncorrected p-values suggest that LTL was positively correlated with fALFF in PCC and a FES interaction between FES and LTL at mPFC. Although marginal, our results encourage further research on the interaction between DMN hubs, telomere length and family environment, which may play a role on the biological embedding of stress., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Psychiatric symptomatology during late childhood and early adolescence tends to persist later in life. In the present longitudinal study, we aimed to identify changes in genome-wide DNA methylation patterns that were associated with the emergence of psychopathology in youths from the Brazilian High-Risk Cohort (HRC) for psychiatric disorders. Moreover, for the differentially methylated genes, we verified whether differences in DNA methylation corresponded to differences in mRNA transcript levels by analyzing the gene expression levels in the blood and by correlating the variation of DNA methylation values with the variation of mRNA levels of the same individuals. Finally, we examined whether the variations in DNA methylation and mRNA levels were correlated with psychopathology measurements over time., Methods: We selected 24 youths from the HRC who presented with an increase in dimensional psychopathology at a 3-year follow-up as measured by the Child Behavior Checklist (CBCL). The DNA methylation and gene expression data were compared in peripheral blood samples (n = 48) obtained from the 24 youths before and after developing psychopathology. We implemented a methodological framework to reduce the effect of chronological age on DNA methylation using an independent population of 140 youths and the effect of puberty using data from the literature., Results: We identified 663 differentially methylated positions (DMPs) and 90 differentially methylated regions (DMRs) associated with the emergence of psychopathology. We observed that 15 DMPs were mapped to genes that were differentially expressed in the blood; among these, we found a correlation between the DNA methylation and mRNA levels of RB1CC1 and a correlation between the CBCL and mRNA levels of KMT2E. Of the DMRs, three genes were differentially expressed: ASCL2, which is involved in neurogenesis; HLA-E, which is mapped to the MHC loci; and RPS6KB1, the gene expression of which was correlated with an increase in the CBCL between the time points., Conclusions: We observed that changes in DNA methylation and, consequently, in gene expression in the peripheral blood occurred concurrently with the emergence of dimensional psychopathology in youths. Therefore, epigenomic modulations might be involved in the regulation of an individual's development of psychopathology.

Research suggested accumulation of tau proteins might lead to the degeneration of functional networks. Studies investigating the impact of genetic risk for Alzheimer's disease (AD) on early brain connections might shed light on mechanisms leading to AD development later in life. Here, we aim to investigate whether the polygenic risk score for Alzheimer's disease (AD-PRS) influences the connectivity among regions susceptible to tau pathology during childhood and adolescence. Participants were youth, aged 6-14 years, and recruited in Porto Alegre (discovery sample, n = 332) and São Paulo (replication sample, n = 304), Brazil. Subjects underwent genotyping and 6-min resting state funcional magnetic resonance imaging. Connections between the local maxima of tau pathology networks were used as dependent variables. The AD-PRS was associated with the connectivity between the right precuneus and the right superior temporal gyrus (discovery sample: β = 0.180, p adjusted  = 0.036; replication sample: β = 0.202, p = 0.031). This connectivity was also associated with inhibitory control (β = 0.157, p adjusted  = 0.035) and moderated the association between the AD-PRS and both immediate and delayed recall. These findings suggest the AD-PRS may affect brain connectivity in youth, which might impact memory performance and inhibitory control in early life., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Our previous studies showed reduced Ndel1 enzyme activity in patients with chronic schizophrenia (SCZ), and only a subtle NDEL1 mRNA increases in antipsychotic-naïve first-episode psychosis (FEP) individuals compared to matched healthy controls (HC). Aiming to refine the evaluation of Ndel1 enzyme activity in early stages of psychosis, we compared 3 groups composed by (1) subjects at ultra-high-risk (UHR) for psychosis, (2) a cohort comprising antipsychotic-naïve FEP individuals (assessed in three moments, at baseline (FEP-0), and after 2 months (FEP-2 M) and one year (FEP-1Y) of treatment with risperidone), and (3) a HC group. There was no significant difference in Ndel1 enzyme activity between UHR and HC, but this activity was significantly lower in FEP compared to HC. Conversely, Ndel1 activity in HC groups was higher than in FEP even before (FEP-0) or after the treatment with risperidone (FEP-2 M and FEP-1Y), and with progressive decrease of Ndel1 activity and significant improvement of symptoms observed after this treatment. In addition, a positive correlation was observed for Ndel1 activity with clinical symptoms as assessed by PANSS, while a negative correlation was seen for GAF scores. Our results suggest that reductions in Ndel1 activity in FEP may be possibly related to responses to the illness, rather than to the pharmacological effects of antipsychotics, which might be acting essentially in the symptoms suppression. This hypothesis might be further evaluated in prospective long-term follow-up studies with a larger sample cohort., (Copyright © 2019 Elsevier B.V. All rights reserved.)

We investigated the role of DGCR2, a corticogenesis-related gene, on schizophrenia (SZ) and its subphenotypes, including brain morphology. A total of 221 SZ patients, 263 controls and 70 antipsychotic-naïve first episode of psychosis (FEP) were genotyped for 17 DGCR2 polymorphisms. While no association between DGCR2 polymorphisms and SZ was found, the missense variant rs2072123 was associated to left rostral anterior cingulate thickness, showing that DGCR2 seems not to be associated directly with the SZ but might be influencing the brain morphology. We also showed a DGCR2 downregulation in SZ patients when compared to controls and FEP., (Copyright © 2019. Published by Elsevier B.V.)

The study of patients with schizophrenia (SZ) at different clinical stages may help clarify what effects could be due to the disease itself, to the pharmacological treatment, or to the disease progression. We compared expression levels of targeted genes in blood from individuals in different stages of SZ: clinical high risk for psychosis (CHR), first episode of psychosis (FEP), and chronic SZ (CSZ). Then, we further verified whether single-nucleotide polymorphisms (SNPs) could be related to gene expression differences. We investigated 12 genes in 394 individuals (27 individuals with CHR, 70 antipsychotic-naive individuals with FEP, 157 CSZ patients, and 140 healthy controls (HCs)). For a subsample, genotype data were also available, and we extracted SNPs that were previously associated with the expression of selected genes in whole blood or brain tissue. We generated a mediation model in which a putative cause (SNP) is related to a presumed effect (disorder) via an intermediate variable (gene expression). MBP and NDEL1 were upregulated in FEP compared to all other groups; DGCR8 was downregulated in FEP compared to HC and CHR; DGCR2 was downregulated in CSZ compared to FEP and HCs; DISC1 was upregulated in schizophrenia compared to controls or FEP, possibly induced by the rs3738398 and rs10864693 genotypes, which were associated with DISC1 expression; and UFD1 was upregulated in CSZ and CHR compared to FEP and HC. Our results indicated changes in gene expression profiles throughout the different clinical stages of SZ, reinforcing the need for staging approaches to better capture SZ heterogeneity.

We evaluated the effects of the interaction between child maltreatment (CM) and single nucleotide polymorphisms (SNPs) on development of mental disorders (MD) and psychopathology. We genotyped 720 individuals from a Brazilian community school-based prospective study, focusing on SNPs in 21 genes known to be associated with mental disorders. CM was assessed via a multi-informant-measure, which was previously validated. To test G × CM, we used linear or logistic models depending on variable evaluated (MD or dimensional psychopathology). After Bonferroni multiple comparison correction, we did not find any statistically significant association of G × CM with either MD or psychopathology., (Copyright © 2019. Published by Elsevier B.V.)

Psychotic disorders are accompanied by activation of the immune inflammatory response system (IRS). The compensatory immune-regulatory system (CIRS) is a regulatory immune response that is induced by the IRS but exerts negative feedback through increased levels of anti-inflammatory cytokines such as interleukin (IL)-4, IL-13 and IL-10. This study aims to examine the IRS and CIRS components, including macrophagic M1, T-helper (Th)-1, Th-2, Th-17 and T-regulatory (Treg) phenotypes, in antipsychotic-naïve first episode psychosis (AN-FEP) before and after risperidone treatment. We included 31 AN-FEP and 22 healthy controls. AN-FEP showed increments in M1, Th-1, Th-2, Th-17 and Treg phenotypes and a relatively greater IRS response (especially granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-6 and IL-12) as compared with the CIRS response. Inflammatory markers, especially IL-6 and IL-8, were significantly correlated with negative, psychotic, affective and excitation symptom dimensions. Treatment with risperidone significantly suppressed the IRS and CIRS. Baseline levels of CIRS biomarkers, especially higher soluble tumor necrosis factor receptor-1 and IL-10 predicted clinical improvement after treatment. Our findings indicate that AN-FEP is characterized by robust IRS (M1 + Th-1 + Th-17) and CIRS responses, suggesting that monocytes, macrophages, Th-1, Th-2, Th-17 and Treg cells are activated. The findings indicate that (a) FEP patients are prone to the detrimental effects of M1, Th-1, Th-17 and Th-2 cells, which may contribute to long-lasting abnormalities in brain circuitry; and (b) in FEP, the CIRS may contribute to recovery from the acute phase of illness. Enhancing the CIRS might be a new drug target to treat FEP., (Copyright © 2018. Published by Elsevier B.V.)

Child maltreatment (CM) is a global issue with serious lifelong consequences. In fact, maltreatment during childhood might be an important risk factor for the development of psychiatric disorders. Furthermore, previous studies showed a strong relationship between telomere length (TL) and early life stress. Considering that only a few studies have evaluated this relationship in children and that even fewer considered the sex as a possible moderator, we investigated whether TL in the blood of both children and adolescents was associated with psychopathology and with a history of CM, and whether these associations were moderated by the sex. In this cross-sectional study, 561 individuals (ranging between 6 and 14 years of age) from a large prospective community school-based study, i.e., the Brazilian High-Risk Cohort (HRC), were evaluated. The Child Behavior Checklist (CBCL) score was used to assess psychopathology, whereas a latent variable encompassing some questions about history of adverse environment and trauma was employed to determine the CM history. TL was measured in blood cells using a multiplex quantitative polymerase chain reaction. Additionally, TL was inserted in two moderation models, in which the CBCL score/CM, TL and sex were the independent variables, the outcome, and the moderator variable, respectively. Although an association between psychiatric symptoms and TL was not observed, a relation between CM and TL moderated by the sex was seen, indicating that males with higher CM scores presented with shorter telomeres than did females. Our results suggest that child maltreatment could influence telomere length in both children and adolescents and that this effect is mediated by the sex., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree ( n  ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders., Competing Interests: G.B. has been a consultant in preclinical genomics and has received grant funding from Eli Lilly ltd within the last 3 years. A.G. has participated in advisory boards for Janssen-Cilag and Daiichi-Sankyo. The remaining authors declare no competing interests.

In this study, we aimed to test if the schizophrenia (SCZ) polygenic risk score (PRS) was associated with clinical symptoms in (a) the first episode of psychosis pre-treatment (FEP), (b) at nine weeks after initiation of risperidone treatment (FEP-9W) and (c) with the response to risperidone. We performed a detailed clinical assessment of 60 FEP patients who were antipsychotic-naive and, again, after nine weeks of standardized treatment with risperidone. After blood collection and DNA isolation, the samples were genotyped using the Illumina PsychArrayChip and then imputed. To calculate PRS, we used the latest available GWAS summary statistics from the Psychiatric Genomics Consortium wave-2 SCZ group as a training set. We used Poisson regression to test association between PRS and clinical measurements correcting for the four principal components (genotyping). We considered a p-value < 0.0014 (Bonferroni correction) as significant. First, we verified that the schizophrenia PRS was also able to distinguish cases from controls in this south-eastern Brazilian sample, with a similar variance explained to that seen in Northern European populations. In addition, within-cases analyses, we found that PRS is significantly correlated with baseline (pre-treatment) symptoms, as measured by lower clinical global assessment of functioning (-GAF), higher depressive symptoms and higher scores on a derived excitement factor. After standardized treatment for nine weeks, the correlation with GAF and the excitement factor disappeared while depressive symptoms became negatively associated with PRS. We conclude that drug (and other treatments) may confound attempts to understand the aetiological influence on symptomatology of polygenic risk scores. These results highlight the importance of studying schizophrenia, and other disorders, pre-treatment to understand the relationship between polygenic risk and phenotypic features.

In this study, we employed the Maximum Uncertainty Linear Discriminant Analysis (MLDA) to investigate whether the structural brain patterns in first episode psychosis (FEP) patients would be more similar to patients with chronic schizophrenia (SCZ) or healthy controls (HC), from a schizophrenia model perspective. Brain regions volumetric data were estimated by using MRI images of SCZ and FEP patients and HC. First, we evaluated the MLDA performance in discriminating SCZ from controls, which provided a score based on a model for changes in brain structure in SCZ. In the following, we compared the volumetric patterns of FEP patients with patterns of SCZ and healthy controls using these scores. The FEP group had a score distribution more similar to patients with schizophrenia (p-value = .461; Cohen's d=-.15) in comparison with healthy subjects (p-value=.003; Cohen's d = .62). Structures related to the limbic system and the circuitry involved in goal-directed behaviours were the most discriminant regions. There is a distinct pattern of volumetric changes in patients with schizophrenia in contrast to healthy controls, and this pattern seem to be detectable already in FEP., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Recent research has demonstrated that telomere maintenance might be a key integrating point for the cumulative effect of genetic and environmental factors in patients with first-episode psychosis (FEP) and schizophrenia (SCZ). Eighty-one participants with antipsychotic-naïve FEP, 173 with SCZ and 438 HC were enrolled in this study. Psychiatric diagnosis was assessed using the Semi-Structured Clinical Interview for DSM-IV Axis-I (SCID-I). The Positive and Negative Syndrome Scale (PANSS), Young Mania Rating Scale (YMRS) and Calgary Depression Scale for Schizophrenia (CDSS) were used to measure symptoms severity. Telomere length (TL) was determined using a multiplex qPCR assay. After adjustment for age, years of education, and smoking status, we found that patients with SCZ had longer TL (relative ratio (RR) = 1.08) than the HC group (RR = 1.00, Wald χ 2  = 12.48, p = 0.002). Further, non-remitted SCZ patients presented longer TL (RR = 1.00) compared to remitted SCZ (RR = 0.88, Wald χ 2  = 7.20, p = 0.007). TL in patients also correlated to psychopathology assessment in terms of total (p = 0.003) and positive PANSS scores (p = 0.001). No correlation with negative PANSS, YMRS, and CDSS or effects of medication was found on TL. Although the exact pathways underlying longer TL in SCZ patients remain unclear, these findings raise more questions than answers and suggest that TL may be of immense value on SCZ progression. Further studies are required to investigate the association of TL in FEP and SCZ., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: Cognitive impairment is a core feature of schizophrenia, related to dopaminergic dysfunction in the prefrontal cortex (PFC). It is hypothesized that functional single nucleotide polymorphism (SNP) rs4680 of the catechol-O-methyltransferase (COMT) gene could mediate the relationship between cognition and dopamine activity in the PFC. Other COMT SNPs could also play a role., Methods: We evaluated the role of three COMT SNPs (rs737865, rs165599, and rs4680) in schizophrenia and their impact on three working memory tasks. For genetic association analyses, 212 individuals with schizophrenia and 257 healthy controls (HCs) were selected. The Visual Working Memory (VWM) Task, Keep Track Task, and Letter Memory Task were administered to 133 schizophrenics and 93 HCs., Results: We found a significant association of rs737865, with the GG genotype exerting a protective effect and the GA haplotype (rs4680/rs165599) exerting a risk effect for schizophrenia. COMT rs4680 AA carriers and rs737865 AA carriers scored lowest on the Keep Track Task. When the genotype*group interaction effect was evaluated, rs165599 exerted opposite effects for VWM and Keep Track task performance in patients and controls, with AA carriers scoring lowest on both tests among controls, but highest among patients., Conclusion: These data support the hypothesis that COMT polymorphisms may be associated with schizophrenia and modulate cognition in patients and controls.

Posttraumatic stress disorder (PTSD) is a common psychiatric disorder. The etiology of PTSD is multifactorial, depending on many environmental and genetic risk factors, and the exposure to life or physical integrity-threatening events. Several studies have shown significant correlations of many neurobiological findings with PTSD. Hypothalamic-pituitary-adrenal (HPA) axis dysfunction is strongly correlated with this disorder. One hypothesis is that HPA axis dysfunction may precede the traumatic event, suggesting that genes expressed in the HPA axis may be involved in the development of PTSD. This article reviews molecular genetic studies related to PTSD collected through a literature search performed in PubMed, MEDLINE, ScienceDirect, and Scientific Electronic Library Online (SciELO). The results of these studies suggest that several polymorphisms in the HPA axis genes, including FKBP5, NR3C1, CRHR1, and CRHR2, may be risk factors for PTSD development or may be associated with the severity of PTSD symptoms., (© 2017 Wiley Periodicals, Inc.)

Telomeres are repetitive DNA sequences at the ends of chromatids that shorten following each cell replication. Once telomeres reach a critical length, DNA defense mechanisms can direct cells to either a state of arrest (senescence) or apoptosis. Stress induced by adversity is a probable cause of accelerated telomere shortening from an early age. However, few studies have examined the association between stress and telomere length in children, and it remains unclear whether young individuals may show signs of cellular aging early in life. Our aim was to examine whether adversity in childhood is associated with shortening of telomere length. We conducted a systematic review of studies that investigated the association between stress and telomere length in children from 3 to 15 years of age. Eleven studies met our selection criteria. We concluded that adversity in childhood (such as violence, low socioeconomic status, maternal depression, family disruption, and institutionalization) have an impact on telomere length. This suggests that exposed individuals show signs of accelerated erosion of telomeric ends from an early age. We discuss whether telomere shortening is related to negative health outcomes later in life or could be a biomarker predicting health outcomes. We believe that further large-scale longitudinal studies that repeatedly monitor telomere length are very important for providing a better assessment of telomere trajectory in psychologically stressed children. This will verify the extent to which adversity impacts upon the biological development of cell aging in childhood., (Copyright © 2017 Elsevier Ltd. All rights reserved.)