Disengagement from the Ribeirão Preto early intervention program for psychosis: A retrospective cohort study.

BACKGROUND: Treatment discontinuation within Early Intervention Services (EIS) for psychosis poses a significant challenge to achieving better outcomes in the early stages of psychotic disorders. Prevalence and predictors of early disengagement from EIS located in low- and middle-income countries (LMICs) remain poorly investigated. We aimed to examine the rates and predictors of disengagement from the Ribeirão Preto Early Intervention Program for Psychosis (Ribeirão Preto-EIP) in Brazil. METHODS: We conducted a retrospective cohort study using data from patients referred to the Ribeirão Preto-EIP between January 01, 2015, and December 31, 2018. Exclusion criteria were individuals with a single consultation, a diagnosis other than a psychotic disorder, and documented cases of death. RESULTS: Our sample comprised 234 patients, with an overall median follow-up time of 14.2 months. Early treatment disengagement was observed in 26.5 % (n=62), with a median time to disengagement of 5.25 months. Univariable analysis identified non-white skin color (HR=2.10, 95 %CI 1.26-3.49), positive THC screening (HR=2.22, 95 %CI 1.23-4.01), and substance-induced psychosis (HR=2.15, 95 %CI 1.10-4.21) as significant predictors. In multivariable analysis, only non-white skin color remained a significant predictor of early disengagement (HR=1.87, 95 %CI 1.08-3.27). CONCLUSIONS: The observed rates of early disengagement in our sample are similar to those reported in wealthy countries, but higher than previously reported for LMICs. Non-white skin color predicted early disengagement in our sample, probably due to social disadvantages. Our data highlights the need for enhanced research elucidating the specific features of EIS in LMICs.

Neurocognition and brain functional connectivity in a non-clinical population-based sample with psychotic experiences.

We characterized the neurocognitive profile of communed-based individuals and unaffected siblings of patients with psychosis from Brazil reporting psychotic experiences (PEs). We also analyzed associations between PEs and the intra and inter-functional connectivity (FC) in the Default Mode Network (DMN), the Fronto-Parietal Network (FPN) and the Salience Network (SN) measured by functional magnetic resonance imaging. The combined sample of communed-based individuals and unaffected siblings of patients with psychosis comprised 417 (neurocognition) and 85 (FC) volunteers who were divided as having low (<75th percentile) and high (≥75th percentile) PEs (positive, negative, and depressive dimensions) assessed by the Community Assessment of Psychic Experiences. The neurocognitive profile and the estimated current brief intellectual quotient (IQ) were assessed using the digit symbol (processing speed), arithmetic (working memory), block design (visual learning) and information (verbal learning) subtests of Wechsler Adult Intelligence Scale-third edition. Logistic regression models were performed for neurocognitive analysis. For neuroimaging, we used the CONN toolbox to assess FC between the specified regions, and ROI-to-ROI analysis. In the combined sample, high PEs (all dimensions) were related to lower processing speed performance. High negative PEs were related to poor visual learning performance and lower IQ, while high depressive PEs were associated with poor working memory performance. Those with high negative PEs presented FPN hypoconnectivity between the right and left lateral prefrontal cortex. There were no associations between PEs and the DMN and SN FC. Brazilian individuals with high PEs showed neurocognitive impairments like those living in wealthier countries. Hypoconnectivity in the FPN in a community sample with high PEs is coherent with the hypothesis of functional dysconnectivity in schizophrenia.

Transdiagnostic dimensions of symptoms and experiences associated with immune proteins in the continuity of psychosis.

BACKGROUND: There is limited evidence as to whether the immune protein profile is associated with a particular symptomatology pattern across the psychosis continuum. METHODS: We estimated two bifactor models of general and specific dimensions of psychotic experiences in unaffected siblings of patients (n = 52) and community controls (n = 200), and of psychotic symptoms in first-episode psychosis (FEP) patients (n = 110). We evaluated associations between these transdiagnostic dimensions and trait (TNF-α, IFN-γ), state (IL-6, IL-1ß), and regulatory (TGF-ß, IL-10, IL-4) cytokines. We explored whether schizophrenia genetic liability (schizophrenia polygenic risk score; SZ-PRS) modified the associations. RESULTS: High levels of trait marker IFN-γ were associated with the severity of general psychosis dimension in the unaffected siblings and community controls, expanding to the depressive dimension in siblings and to the manic dimension in FEP. High TNF-α levels were associated with more positive psychotic experiences in unaffected siblings and manic symptoms in FEP. Low levels of state markers IL-6 and IL-1ß were observed in unaffected siblings presenting more depressive experiences. Still, high levels of IL-6 and IL-1ß were associated with the severity of the depressive and negative symptom dimensions at FEP. The severity of transdiagnostic dimension scores across the three groups was associated with lower regulatory cytokines. Exploratory analysis suggested that a high SZ-PRS contributed mostly to associations with psychotic dimensions. CONCLUSIONS: IFN-γ mapped onto the multidimensional expression of psychosis, reinforcing the trait concept. State markers IL-6 and IL-1ß may fluctuate along the spectrum. Dysfunction in the regulatory arm may disinhibit the inflammatory system. Associations with psychotic dimensions may be more prone to SZ-PRS susceptibility.

Protocol for the Psychosis Immune Mechanism Stratified Medicine (PIMS) trial: a randomised double-blind placebo-controlled trial of single-dose tocilizumab in patients with psychosis.

INTRODUCTION: Evidence suggests a potentially causal role of interleukin 6 (IL-6), a pleiotropic cytokine that generally promotes inflammation, in the pathogenesis of psychosis. However, no interventional studies in patients with psychosis, stratified using inflammatory markers, have been conducted to assess the therapeutic potential of targeting IL-6 in psychosis and to elucidate potential mechanism of effect. Tocilizumab is a humanised monoclonal antibody targeting the IL-6 receptor to inhibit IL-6 signalling, licensed in the UK for treatment of rheumatoid arthritis. The primary objective of this study is to test whether IL-6 contributes to the pathogenesis of first episode psychosis and to examine potential mechanisms by which IL-6 affects psychotic symptoms. A secondary objective is to examine characteristics of inflammation-associated psychosis. METHODS AND ANALYSIS: A proof-of-concept study employing a randomised, parallel-group, double-blind, placebo-controlled design testing the effect of IL-6 inhibition on anhedonia in patients with psychosis. Approximately 60 participants with a diagnosis of schizophrenia and related psychotic disorders (ICD-10 codes F20, F22, F25, F28, F29) with evidence of low-grade inflammation (IL-6≥0.7 pg/mL) will receive either one intravenous infusion of tocilizumab (4.0 mg/kg; max 800 mg) or normal saline. Psychiatric measures and blood samples will be collected at baseline, 7, 14 and 28 days post infusion. Cognitive and neuroimaging data will be collected at baseline and 14 days post infusion. In addition, approximately 30 patients with psychosis without evidence of inflammation (IL-6<0.7 pg/mL) and 30 matched healthy controls will be recruited to complete identical baseline assessments to allow for comparison of the characteristic features of inflammation-associated psychosis. ETHICS AND DISSEMINATION: The study is sponsored by the University of Bristol and has been approved by the Cambridge East Research Ethics Committee (reference: 22/EE/0010; IRAS project ID: 301682). Study findings will be published in peer-review journals. Findings will also be disseminated by scientific presentation and other means. TRIAL REGISTRATION NUMBER: ISRCTN23256704.

Lifetime cannabis use and childhood trauma associated with CNR1 genetic variants increase the risk of psychosis: findings from the STREAM study.

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.

Rethinking Immunity and Cognition in Clinical High Risk for Psychosis.

It is well known that schizophrenia is associated with cognitive impairment, reduced cortical grey matter and increased circulating concentrations of inflammatory cytokines. However, the relationship between these findings is not clear. We outline the influential neuroinflammatory hypotheses that raised cytokines provoke a damaging immune response in microglia that results in reduced grey matter and associated cognitive performance. We investigated whether such an interaction might be detectable in the prodromal period as illness emerges from the Clinical High Risk for Psychosis (CHR-P). Meta-analyses suggest that compared with controls, impaired cognition and reduced grey matter are already present by the prodrome and that greater decrements are present in those who later develop symptoms. In contrast, the few cytokine studies report no abnormalities in CHR-P except that interleukin-6 (IL-6) levels were raised versus controls and to a greater extent in the future patients, in one study. We noted that cognitive impairment and less cortical grey matter are more severe in schizophrenia than in affective disorders, but that increased cytokine levels are similarly prevalent across disorders. We found no studies correlating cytokine levels with cognitive impairment in CHR-P but such correlations seem unlikely given the minimal relationship reported in a recent meta-analysis of the many cytokine-cognition studies in established illness. From this and other evidence, we conclude that neuroinflammation is not a core feature of schizophrenia nor a substrate for reduced grey matter volume or cognitive function. We draw attention instead to the emerging evidence that brain-resident immune cells and signalling molecules such as Tregs and IL-6, which are influenced by schizophrenia risk genes, regulate and are necessary for the development and function of neuron-glia interaction. We suggest that cognitive impairment in schizophrenia can be seen as a convergence of genetic and immune-neurodevelopmental dysregulation whereas raised cytokines are a consequence of impaired Tregs control of systemic inflammation.

Lifetime cannabis use and childhood trauma increase risk of psychosis in carriers of CNR1 genetic variants: findings from the STREAM study

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.

Increased blood neutrophil extracellular traps (NETs) associated with early life stress: translational findings in recent-onset schizophrenia and rodent model.

Higher levels of interleukin (IL)-6 and elevated neutrophil counts are consistently reported in the blood of patients with schizophrenia. Stressors during childhood and/or adolescence are major socioenvironmental risk factors for schizophrenia and may contribute to immune dysregulation. Previous studies using blood cytokines to stratify patients with schizophrenia suggest that only a subset presents a low-grade inflammatory state. However, these studies have not addressed whether environmental factors such as childhood maltreatment contributed to identifying inflammatory clusters. Moreover, a neutrophil-related mechanism (Neutrophil Extracellular Traps; NETs) central to both the initiation and chronicity of autoimmune and inflammatory diseases has never been investigated in psychiatry. Elevated NETs in schizophrenia may predispose patients to inflammatory and autoimmune diseases resulting in reduced life expectancy. We, therefore, investigated NETs as a novel mechanism and biological target in early schizophrenia and their role together with IL-6 and childhood maltreatment in identifying cluster subgroups. We found increased NETs in the plasma of patients with early schizophrenia (n = 78) compared to both their unaffected siblings (n = 25) and community controls (n = 78), irrespective of sex, body mass index, psychoactive drug use, or tobacco smoking. Increased NETs in patients were unrelated to antipsychotic treatment, which was further tested in vitro using fresh neutrophils. By applying unsupervised two-step clustering analysis, we integrated values of NETs, IL-6, and childhood maltreatment scores. We identified two main clusters; childhood maltreatment scores and NETs were the most important variables contributing to cluster separation (high-CL1 and low-CL2), while IL-6 was the least contributor. Patients allocated in the high-CL1 (61.5%) had significantly higher childhood maltreatment scores, NETs, and IL-6 levels than the remaining groups (patients low-CL2, siblings, and controls high-CL1 and low-CL2). We complemented these findings with a rat model based on stress exposure during adolescence that results in several schizophrenia-like changes in adulthood. We found that adolescent stressed rats had higher NETs and IL-6 levels in serum compared to non-stressed rats with a tendency to produce more NETs from the bone marrow. Altogether, this study brings a novel cellular-based mechanism in schizophrenia that, combined with early-stress, could be useful to identify subgroups for more personalised treatments.

T regulatory cells as a potential therapeutic target in psychosis? Current challenges and future perspectives.

Many studies have reported that patients with psychosis, even before drug treatment, have mildly raised levels of blood cytokines relative to healthy controls. In contrast, there is a remarkable scarcity of studies investigating the cellular basis of immune function and cytokine changes in psychosis. The few flow-cytometry studies have been limited to counting the proportion of the major classes of monocyte and lymphocytes without distinguishing their pro- and anti-inflammatory subsets. Moreover, most of the investigations are cross-sectional and conducted with patients on long-term medication. These features make it difficult to eliminate confounding of illness-related changes by lifestyle factors, disease duration, and long exposure to antipsychotics. This article focuses on regulatory T cells (Tregs), cornerstone immune cells that regulate innate and adaptive immune forces and neuro-immune interactions between astrocytes and microglia. Tregs are also implicated in cardio-metabolic disorders that are common comorbidities of psychosis. We have recently proposed that Tregs are hypofunctional ('h-Tregs') in psychosis driven by our clinical findings and other independent research. Our h-Treg-glial imbalance hypothesis offers a new account for the co-occurrence of systemic immune dysregulation and mechanisms of psychosis development. This article extends our recent review, the h-Treg hypothesis, to cover new discoveries on Treg-based therapies from pre-clinical findings and their clinical implications. We provide a detailed characterisation of Treg studies in psychosis, identifying important methodological limitations and perspectives for scientific innovation. The outcomes presented in this article reaffirms our proposed h-Treg state in psychosis and reveals emerging preclinical research suggesting the potential benefit of Treg-enhancing therapies. There is a clear need for longitudinal studies conducted with drug-naïve or minimally treated patients using more sophisticated techniques of flow-cytometry, CyTOF expression markers, and in vitro co-culture assays to formally test the suppressive capacity of Tregs. Investment in Treg research offers major potential benefits in targeting emerging immunomodulatory treatment modalities on person-specific immune dysregulations.

The relationship of childhood trauma and DNA methylation of NMDA receptor genes in first-episode schizophrenia.

Aim: We investigated GRIN1, GRIN2A, GRIN2B and LINE-1 DNA methylation in first-episode schizophrenia patients, their nonaffected siblings and age- and sex-matched controls testing for associations between DNA methylation and exposition to childhood trauma. Materials & methods: The Childhood Trauma Questionnaire evaluated the history of childhood trauma. Genomic DNA was bisulfite converted and pyrosequencing was employed to quantify DNA methylation. Results:GRIN2A, GRIN2B and LINE-1 DNA methylation was not associated with childhood trauma in patients, siblings and controls. Siblings with childhood trauma had hypermethylation at CpG1 of GRIN1 compared with siblings without trauma. Conclusion: Childhood trauma may influence GRIN1 methylation in subjects with liability to psychosis, but not in frank schizophrenia or controls.

Lay abstract Schizophrenia results from a combination of genetic and environmental influences. We investigated how some changes in genes can be silenced by a process named DNA methylation and may be linked to schizophrenia. For this reason, we hypothesized that childhood trauma, an environmental risk factor, would be associated with DNA methylation in schizophrenia patients compared with their unaffected siblings and controls. Our research has shown that altered blood DNA methylation of one candidate gene for psychiatric disorders may be associated with childhood trauma in the unaffected siblings of schizophrenia patients, but not in frank schizophrenia or controls. We believe that this gene plays an important role in helping identify vulnerable as well as resilient individuals to schizophrenia disorder.

Impaired regulatory T cell control of astroglial overdrive and microglial pruning in schizophrenia.

It is widely held that schizophrenia involves an active process of peripheral inflammation that induces or reflects brain inflammation with activation of microglia, the brain's resident immune cells. However, recent in vivo radioligand binding studies and large-scale transcriptomics in post-mortem brain report reduced markers of microglial inflammation. The findings suggest a contrary hypothesis; that microglia are diverted into their non-inflammatory synaptic remodelling phenotype that interferes with neurodevelopment and perhaps contributes to the relapsing nature of schizophrenia. Recent discoveries on the regulatory interactions between micro- and astroglial cells and immune regulatory T cells (Tregs) cohere with clinical omics data to suggest that: i) disinhibited astrocytes mediate the shift in microglial phenotype via the production of transforming growth factor-beta, which also contributes to the disturbances of dopamine and GABA function in schizophrenia, and ii) systemically impaired functioning of Treg cells contributes to the dysregulation of glial function, the low-grade peripheral inflammation, and the hitherto unexplained predisposition to auto-immunity and reduced life-expectancy in schizophrenia, including greater COVID-19 mortality.

The independent and combined effects of cannabis use and systemic inflammation during the early stages of psychosis: exploring the two-hit hypothesis.

BACKGROUND: Cannabis consumption is a modifiable risk factor associated with psychosis, but not all cannabis users develop psychosis. Animal studies suggest that an antecedent active immune system interacts with subsequent cannabis exposure and moderates the cannabis-psychosis association, supporting the two-hit hypothesis. The clinical investigations are few, and it is unclear if the immune system is a biological candidate moderating the cannabis-psychosis association or whether cannabis increases inflammation, which in turn, augments psychosis likelihood. METHODS: We explored the mediating and moderating role of blood inflammation using PROCESS macro. We used data from a cross-sectional study, including 153 first-episode psychosis patients and 256 community-based controls. Participants answered the Cannabis Experience Questionnaire (cannabis frequency, age of onset, and duration), and plasma cytokines were measured [interleukin (IL)-1ß, IL-6, IL-4, IL-10, tumour necrosis factor-α (TNF-α), interferon-γ (IFN-γ), transforming growth factor-ß (TGF-ß); multiplex]. We computed an inflammatory composite score (ICS) to represent the systemic inflammatory state. Confounders included sex, age, ethnicity, educational level, body mass index, tobacco smoking, lifetime use of other drugs, and antipsychotic treatment. RESULTS: Mediation: Cannabis consumption was not associated with increased inflammation, thus not supporting a mediating effect of inflammation. Moderation: Daily use and age of onset <17 interacted significantly with the ICS to increase the odds of psychosis beyond their individual effects and were only associated with psychosis among those scoring medium-high in the ICS. CONCLUSIONS: Immune dysregulation might be part of the pathophysiology of psychosis, not explained by cannabis use or other confounders. We provide the first and initial evidence that immune dysregulation modifies the cannabis-psychosis association, in line with a two-hit hypothesis.

Plasma prevalence of anti-N-methyl-d-aspartate receptor IgG antibodies in early stages of psychosis.

We investigated the feasibility of including plasma anti-NMDAR antibody screening in the assessment of first-episode psychosis patients in an early intervention programme in the Southern hemisphere. Anti-NMDAR IgG antibodies were assessed by ELISA in 166 patients (64.0% men), 166 matched population-based controls and 76 patients' siblings (30.3% men). Fisher's exact test and ANOVA were performed. Positive anti-NMDAR antibody patients were more often observed in bipolar disorder (10.0%) than schizophrenia (2.4%) or psychotic depression (3.1%), although no significant differences were observed. Our results are not conclusive regarding the inclusion of plasma anti-NMDAR IgG antibodies in differential diagnostic protocols for psychosis.

Early-life stress effects on BDNF DNA methylation in first-episode psychosis and in rats reared in isolation.

Stressful events during early-life are risk factors for psychiatric disorders. Brain-derived neurotrophic factor (BDNF) is implicated in psychosis pathophysiology and deficits in BDNF mRNA in animal models of psychiatric disease are reported. DNA methylation can control gene expression and may be influenced by environmental factors such as early-life stress. We investigated BDNF methylation in first-episode psychosis (FEP) patients (n = 58), their unaffected siblings (n = 29) and community-based controls (n = 59), each of whom completed the Childhood Trauma Questionnaire (CTQ); BDNF methylation was also tested in male Wistar rats housed isolated or grouped from weaning. DNA was extracted from human blood and rat brain (prefrontal cortex and hippocampus), bisulphite-converted and the methylation of equivalent sequences within BDNF exon IV determined by pyrosequencing. BDNF methylation did not differ significantly between diagnostic groups; however, individuals who had experienced trauma presented higher levels of methylation. We found association between the mean BDNF methylation and total CTQ score in FEP, as well as between individual CpG sites and subtypes of trauma. No significant correlations were found for controls or siblings with child trauma. These results were independent of age, gender, body mass index, BDNF genotype or LINE-1, a measure of global methylation, which showed no significant association with trauma. Isolation rearing resulted in increased BDNF methylation in both brain regions compared to group-housed animals, a correlate of previously reported changes in gene expression. Our results suggest that childhood maltreatment may result in increased BDNF methylation, providing a mechanism underlying the association between early-life stress and psychosis.

Neuroinflammation as measured by positron emission tomography in patients with recent onset and established schizophrenia: implications for immune pathogenesis.

Positron emission tomography (PET) imaging of the 18 kDa translocator protein (TSPO), which is upregulated in activated microglia, is a method for investigating whether immune activation is evident in the brain of adults with schizophrenia. This study aimed to measure TSPO availability in the largest patient group to date, and to compare it between patients with recent onset (ROS) and established (ES) schizophrenia. In total, 20 ROS patients (14 male), 21 ES (13 male), and 21 healthy controls completed the study. Patients were predominantly antipsychotic-medicated. Participants underwent a PET scan using the TSPO-specific radioligand [11C](R)-PK11195. The primary outcome was binding potential (BPND) in the anterior cingulate cortex (ACC). Secondary outcomes were BPND in six other regions. Correlations were investigated between TSPO availability and symptom severity. Data showed that mean BPND was higher in older (ES and controls) compared with younger (ROS and controls) individuals, but did not significantly differ between ROS or ES and their respective age-matched controls (ACC; ANOVA main effect of diagnosis: F1,58 = 0.407, p = 0.526). Compared with controls, BPND was lower in antipsychotic-free (n = 6), but not in medicated, ROS patients. BPND in the ES group was negatively correlated with positive symptoms, and positively correlated with negative symptom score. Our data suggest ageing is associated with higher TSPO but a diagnosis of schizophrenia is not. Rather, subnormal TSPO levels in drug-free recent-onset patients may imply impaired microglial development and/or function, which is counteracted by antipsychotic treatment. The development of novel radioligands for specific immune-mechanisms is needed for further clarification.

Plasma amino acids profile in first-episode psychosis, unaffected siblings and community-based controls.

Investigations of plasma amino acids in early psychosis and their unaffected siblings are rare. We measured plasma amino acids involved in the co-activation of dopaminergic, GABAergic, glutamatergic, and serotoninergic neurotransmitters in first-episode psychosis (FEP) patients (n = 166), unaffected siblings (n = 76), and community-based controls (n = 166) included in a cross-sectional study. Plasma levels of glutamic acid (GLU), glutamine, glycine, proline (PRO), tryptophan (TRP), tyrosine, serine and GABA were quantified by gas-chromatography-mass spectrometry. We used the generalized linear model adjusted by sex, age, and body mass index for group comparison and paired t-test for FEP-Sibling pairs. FEP had reduced GABA plasma levels compared to siblings and controls (p < 0.05 for both). Siblings had lower GLU, Glx and PRO (p < 0.05 for all) but increased TRP compared to patients and controls (p < 0.05 for both). FEP patients with longer duration of pharmacological treatment and medicated only with antipsychotics had increased GLU compared to FEP with shorter periods, or with those treated with a combination of medications (p < 0.05 for both). Finally, FEP patients treated only with antipsychotics presented higher Glx compared to those with mixed medications (p = 0.026). Our study suggests that FEP have low a GABA plasma profile. Unaffected siblings may be a possible risk group for metabolic abnormalities.

Epigenetic-mediated N-methyl-D-aspartate receptor changes in the brain of isolated reared rats.

Aim: We investigated: Grin1, Grin2a, Grin2b DNA methylation; NR1 and NR2 mRNA/protein in the prefrontal cortex (PFC); and hippocampus of male Wistar rats exposed to isolation rearing. Materials & methods: Animals were kept isolated or grouped (n = 10/group) from weaning for 10 weeks. Tissues were dissected for RNA/DNA extraction and N-methyl-D-aspartate receptor subunits were analyzed using quantitative reverse transcription (RT)-PCR, ELISA and pyrosequencing. Results: Isolated-reared animals had: decreased mRNA in PFC for all markers, increased NR1 protein in hippocampus and hypermethylation of Grin1 in PFC and Grin2b in hippocampus, compared with grouped rats. Associations between mRNA/protein and DNA methylation were found for both brain areas. Conclusion: This study indicates that epigenetic DNA methylation may underlie N-methyl-D-aspartate receptor mRNA/protein expression alterations caused by isolation rearing.