Search

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.

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.

BackgroundCannabis 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.MethodsWe 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)-1β, IL-6, IL-4, IL-10, tumour necrosis factor-α (TNF-α), interferon-γ (IFN-γ), transforming growth factor-β (TGF-β); 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.ResultsMediation: Cannabis consumption was not associated with increased inflammation, thus not supporting a mediating effect of inflammation. Moderation: Daily use and age of onset ConclusionsImmune 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.

IntroductionEvidence 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 analysisA 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-6Ethics and disseminationThe 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 numberISRCTN23256704.

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.

Background: Exposure to stressful aversive situations induces physiological and behavioral changes. Serotonin has been suggested to mediate such changes, as well as adaptation to stressful events. Serotoninergic projections arising from the median raphe nucleus to the dorsal hippocampus have been suggested to promote adaptation to chronic aversive stimuli. Such pathway may involve serotonin type 1a receptor-mediated neurotransmission. However, the serotonin 7 receptor can also be found in the median raphe nucleus and may be involved in mechanisms underlying response to stress. Aims: In this work we sought to investigate if activation of serotonin type 7 receptors would attenuate stress-induced deficits in different animal models of depression. Methods: Male Wistar rats with a guide-cannula aimed to the median raphe nucleus were submitted to restraint or forced swim stress and were tested in an elevated plus maze or forced swim test, respectively, 24 h later. SB 258741 (serotonin type 7 receptor antagonist) and/or LP 44 (serotonin type 7 receptor agonist) were administered intra-median raphe nucleus immediately before or after exposure to stress or before test. Control groups received intra-median raphe nucleus treatment 24 h or immediately before test in the elevated plus maze or forced swim test. Results: LP 44 attenuated restraint-induced exploratory deficits independently of the moment it was administered. Similar results were observed in the forced swim test, with the exception on post-stress condition. These effects on adaptation to stress induced by serotonin type 7 receptor activation were prevented by previous treatment with SB 258741. Conclusions: Our data support the idea that activation of median raphe nucleus serotonin 7 receptor is important to the development of adaptation to stress.

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 neuroimmune 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., Highlights • Tregs are cornerstone immune cells controlling the innate and adaptive immune balance. • Tregs regulate astrocytic-microglial neuroimmune interactions. • Clinical and experimental research suggest that Tregs are hypofunctional in psychosis, which may explain inflammation and glial dysfunction in psychosis . • Investment in Treg research will help to uncover novel mechanisms in psychosis. • Treg-enhancing therapies may guide personalised treatments in psychosis.

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.

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.

© 2020 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.

NMDA autoantibody encephalitis presenting as schizophrenia suggests the possible role of adaptive cell-mediated immunity in idiopathic schizophrenia. However, to our knowledge there have been no trials of the immune-suppressant methotrexate in schizophrenia. We tested if low-dose methotrexate as used in the treatment of systemic autoimmune disorders would be tolerable and effective in people with schizophrenia in a feasibility study. Ninety-two participants within 5 years of schizophrenia diagnosis were recruited from inpatient and outpatient facilities in Karachi, Pakistan. They were randomised to receive once weekly 10-mg oral methotrexate (n = 45) or matching placebo (n = 47) both with daily 5-mg folic acid, in addition to treatment as usual for 12 weeks. There were eight dropouts per group. Side effects were non-significantly more common in those on methotrexate and were not severe. One person developed leukopenia. Positive symptom scores improved more in those receiving methotrexate than placebo (β = −2.5; [95% CI −4.7 to −0.4]), whereas negative symptoms were unaffected by treatment (β = −0.39; [95% CI −2.01 to 1.23]). There were no immune biomarkers but methotrexate did not affect group mean leucocyte counts or C-reactive protein. We conclude that further studies are feasible but should be focussed on subgroups identified by advances in neuroimmune profiling. Methotrexate is thought to work in autoimmune disorders by resetting systemic regulatory T-cell control of immune signalling; we show that a similar action in the CNS would account for otherwise puzzling features of the immuno-pathogenesis of schizophrenia.

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.

Objective: We investigated: i) the reliability and validity of a Brazilian version of the Community Assessment of Psychic Experiences (CAPE), developed to detect and characterize psychotic experiences in the general population; and ii) the association between psychotic experiences, childhood adversity, and cannabis use in a population-based sample. Methods: We performed factorial analyses and generalized linear models with CAPE scores as the dependent variable in a sample composed of 217 first-episode psychosis patients, 104 unaffected biological siblings, and 319 non-psychotic population-based participants. Results: After removing seven items from its positive dimension and two items from its negative dimension, a 33-item Brazilian version of the CAPE showed acceptable adjustment indices (confirmatory fit index = 0.895; goodness of fit index = 0.822; parsimony goodness of fit index = 0.761; root mean square error of approximation [RMSEA] = 0.055, p [RMSEA p 0.05] = 0.04) and internal consistency in all its dimensions (4 0.70). Childhood adversity was associated with higher scores in all three dimensions, as well as with total score. Lifetime cannabis use was associated with higher scores only in the positive dimension. Conclusion: The proposed Brazilian version of the CAPE corroborates the tridimensional approach for assessing psychosis-proneness, and the frequency and severity of psychotic manifestations are distributed as a spectrum in the general population., This research received financial support from the Fundação de Amparo á Pesquisa do Estado de São Paulo (FAPESP; 2012/05178-0). TCCR received a grant from CNPq (process 162125/2014-3). RS (process 2013/11167- 3), FC-Z (process 2019/13229-2), and DLR (process 2018/07581-2) received grants from FAPESP. JS and JM are supported by Infraestrutura Nacional de Computação Distribuída (INCD), funded by Fundação para a Ciência e a Tecnologia (FCT) and Fundo Europeu de Desenvolvimento Regional (FEDER; project 22153-01/ SAICT/2016). PRM and CMD-B received productivity grants from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; 307492/2014-1 and 303815/2015-9, respectively).

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

A large body of literature suggests the role of the hypothalamic-pituitary-adrenal (HPA) axis in postpartum depression (PPD). Nonetheless, these studies present discrepant methodology and results; thus, this hypothesis deserves further exploration. Areas covered: This review included studies investigating the HPA axis in PPD or postpartum blues published until November 2016. In total, 48 studies met the inclusion criteria. The HPA axis was mostly investigated in the immediate postpartum period (62.5%), and the majority of studies collected samples in the morning (43.8%), with one measure in a single day (43.8%), and blood was the fluid more often collected (58.4%). Seven out of 21 studies evaluating postpartum blues, and 15 out of 28 studies evaluating PPD detected abnormalities in the HPA axis functioning. Expert commentary: We found a significant heterogeneity in the methodology adopted by studies and consequently, in the results. Despite that, the majority of studies reported HPA changes in women with PPD during the remote period. Notably, reactivity tests pointed to attenuated HPA axis response. Ideally, future investigations should use validated reactivity tests, include larger sample sizes, consider many measures of cortisol throughout the day, and more than one day of collection. We also recommend that studies continue to use validated scales for mood assessment.

Background Associations between cannabis use and psychotic outcomes are consistently reported. Increased innate immune markers have also been suggested as risk factors for psychosis; nevertheless, no study has ever tested whether augmented blood inflammation could be a possible biological mechanism underlying the association between cannabis use and psychosis. We investigated: i) which patterns of peripheral blood cytokines (innate and adaptive immune markers) would be associated with the strongest effect on odds of psychosis; and ii) whether the contribution of cannabis use (lifetime use: yes/no; frequency of use: non-users, less than daily use; daily use) on risk of psychosis would vary between subgroups with low- or high-inflammation. Methods The Schizophrenia and Other Psychoses Translational Research: Environment and Molecular Biology (STREAM) is an epidemiological and case-sibling-control study, conducted in Ribeirão Preto catchment area (São Paulo, Brazil) between April 2012 and March 2015, which integrates the international multicentre consortium EU-GEI. We recruited 153 first-episode psychosis patients and 256 community-based controls aged between 16–64 years. Participants answered the Cannabis Experience Questionnaire and plasma cytokines (IL-1β, IL-6, TNF-α, IFN-γ, IL-4, IL-10, TGF-β) were measured by Multiplex. We firstly investigated which patterns of peripheral blood innate and adaptive immune markers would contribute to the strongest effect on the odds of psychosis. To do that, the sample was divided into quartiles according to cytokine’s percentile distribution (reference group: minimum value – 25th percentile; lower group: 25th – 50th percentile; middle group: 50th – 75th percentile; and upper group: 75th percentile – maximum value). We next investigated whether the effects of the different patterns of cannabis use (lifetime and frequency of use) on the risk of psychosis would differ between subgroups classified as low- or high-inflammatory, using the median (50th percentile) of each cytokine as the cut-off value. All the binary logistic regression analyses were correct for the effects of confounders (gender, age, ethnicity, years of education, body mass index, tobacco smoking, and recreational drugs). Results More than 60% of the patients were classified as high-inflammatory, whereas in the control group, around the same percentage was classified as low-inflammatory. After adjusting for confounders, we observed a dose-response relationship between the percentile’s distribution of IL-10, IL-6, TNF-α, TGF-β and risk of psychosis, with participants classified in the upper percentile having the highest odds ratio when compared with the reference group. The adjusted odds ratio (adj ORs) and 95% CIs range for each cytokine were the following: IL-10 from 4.68 (2.02–10.85) to 11.86 (5.01–28.11), IL-6 from 3.74 (1.61–8.69) to 9.62 (4.15–22.31); TNF-α from 2.18 (1.01–4.73) to 6.88 (3.12–15.17); TGF-β from 2.17 (1.01–4.67) to 3.20 (1.50–6.80). Lifetime cannabis use only increased risk of psychosis in the high-inflammatory subgroup (adj ORs, 95% CIs: IL10: 4.66, 1.62–13.39; IL-6: 2.75, 1.05–7.21). Daily use increased the risk of psychosis even further, and only in the high-inflammatory but not in the low-inflammatory subgroup (adj OR, 95% CIs: IL-10: 14.09, 2.26–87.93; TNF-α: 6.16, 1.28–29.74; IL-6: 4.68, 1.08–20.36), with the exception of TGF-β, for which the effects were seen in the low-subgroup (adj OR, 95% CI: 5.23, 1.17–23.42). Discussion The existence of distinct inflammatory profiles indicates possible biological predisposition facilitating immune activation. This would translate into a higher vulnerability to the effects of cannabis use, especially daily use, on risk of psychosis.

BackgroundInflammation is a possible biological mechanism underlying the association between childhood maltreatment and psychosis. Previous investigations on this regard were mainly conducted on chronic schizophrenia and lacked control for confounders. We aim to investigate the role of familial liability, childhood maltreatment and recent stress in determining cytokine abnormalities at the onset of psychosis.MethodsWe recruited 114 first-episode psychosis (FEP) patients, 57 unaffected biological siblings of FEP patients, and 251 community-based controls. Plasma cytokines (IL-1β, IL-6, TNF-α, IFN-γ, IL-4, IL-10 and TGF-β) were measured and differences across the groups analysed after adjusting for potential confounders.ResultsFEP had a higher pro- and anti-inflammatory cytokine profile (IL-1β, IL-6, TNF-α, IL-10 and TGF-β), which was not observed in unaffected siblings. Siblings presented decreased IL-1β when compared with patients and controls. Childhood maltreatment was associated with higher levels of TGF-β in both patients and siblings when compared with controls. Physical childhood abuse was associated with increased levels of TGF-β in FEP patients but with decreased levels in controls. Other childhood maltreatment subtypes or recent stressors did not affect cytokine levels in any of the groups.ConclusionsNormal or reduced cytokines in siblings represent possibly a protective factor and suggest that the identified inflammatory profile in FEP can be a real pathophysiological component of psychosis. Experience of childhood maltreatment may contribute as long-term immune priming for the TGF-β pathway, and increased levels of this cytokine in both patients and siblings exposed to childhood maltreatment point to a possible biological candidate of familial risk for psychosis.

Aim: We investigated GRIN1 and GRIN2B promoter methylation in first-episode schizophrenia patients compared with siblings and controls, testing for correlations between DNA methylation, cognitive performance and clinical variables. Materials & methods: Blood-derived DNA from all groups underwent bisulfite conversion and pyrosequencing to determine methylation at CpG sites within the GRIN1 and GRIN2B promoters and results were compared with the measure of global methylation LINE-1.Results: We found hypomethylation among all CpGs analyzed within GRIN2B promoter in patients and greater LINE-1 methylation in patients and siblings. CpG4 was correlated to a measure of intellectual function. Conclusion: Changes in GRIN2B promoter methylation may represent an environmental influence contributing to glutamatergic dysfunction in psychosis and relate to lower cognitive performance in subjects with first-episode schizophrenia.

Sao Paulo Research Foundation (FAPESP, Brazil)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2012/05178-0, 2019/13229-2]

Schizophrenia is one of the most debilitating mental disorders and is aggravated by the lack of efficacious treatment. Although its etiology is unclear, epidemiological studies indicate that infection and inflammation during development induces behavioral, morphological, neurochemical, and cognitive impairments, increasing the risk of developing schizophrenia. The inflammatory hypothesis of schizophrenia is also supported by clinical studies demonstrating systemic inflammation and microglia activation in schizophrenic patients. Although elucidating the mechanism that induces this inflammatory profile remains a challenge, mounting evidence suggests that neuroimmune interactions may provide therapeutic advantages to control inflammation and hence schizophrenia. Recent studies have indicated that vagus nerve stimulation controls both peripheral and central inflammation via alpha-7 nicotinic acetylcholine receptor (α7nAChR). Other findings have indicated that vagal stimulation and α7nAChR-agonists can provide therapeutic advantages for neuropsychiatric disorders, such as depression and epilepsy. This review analyzes the latest results regarding: (I) the immune-to-brain pathogenesis of schizophrenia; (II) the regulation of inflammation by the autonomic nervous system in psychiatric disorders; and (III) the role of the vagus nerve and α7nAChR in schizophrenia.

Background The inflammatory hypothesis of schizophrenia suggests that abnormalities in inflammatory factors may contribute to the onset of this disease early in adulthood. Nevertheless, no study has investigated possible effects of shared environment by looking at cytokine levels in healthy siblings of first-episode psychosis patients (FEP). The aim of this study was to investigate inflammatory cytokine (IL-6, IL-10, TNF-a) abnormalities in a sizeable epidemiological-based sample of FEP patients, their healthy siblings and population-based controls. Methods This study is part of the epidemiological investigation “Schizophrenia and Other Psychoses Translational Research: Environment and Molecular Biology” (STREAM), conducted in Ribeirão Preto (São Paulo, Brazil) and surrounding area, which is part of the international consortium “European Network of National Schizophrenia Networks Studying Gene-Environment Interactions” (EU-GEI). We recruited a total sample of 507 participants, composed by 166 FEP patients (64% males; mean age: 30.3 ± 12.2), 76 siblings (30.3% males; mean age: 31.5 ± 11.0) and 265 population-based controls (50.2% males; mean age: 31.7 ± 11.2). Plasma cytokines IL-6, TNF-a and IL-10 were analysed by Multiplex Bead Array (Luminex xMap technology). We performed the multivariate general linear model (GLM) analysis with age as covariate, cytokines as dependent variables and diagnostic group and sex as explanatory variables. Results We found significant differences between the three groups [F (6,994) = 10.864; p < 0.001] in the plasma concentration of all the three cytokines (p < 0.001), independent of the sex of the participants (p = 0.115; interaction diagnosis & sex p = 0.115). FEP patients had significantly higher levels of IL-6, TNF-a, and IL-10 when compared to controls (p < 0.001 for all). When compared to their siblings, patients had higher levels of both TNF-a and IL-10 (p < 0.05 for both), and a trend to IL-6 (p = 0.058), whereas siblings did not differ from controls for any of the three cytokines analysed (p > 0.05 for all). Discussion This is the first study conducted in the South hemisphere to demonstrate the low-grade inflammatory profile in FEP patients, compared to their siblings and community-based controls. The fact that IL-6, TNF-a and IL-10 are all higher in the FEP group than their healthy siblings and community-based controls suggests the synergism of individual vulnerability factors in the development of this inflammatory profile.

Staphylococcus aureus is a Gram-positive bacteria described as an important causative agent of sepsis. The contact between host leukocytes and bacteria activates the innate immune response. Nitric oxide, tumor necrosis factor (TNF)-α and interleukin (IL)-1β play a key role in increasing microbicidal activity and controlling cell influx into infectious focus. Contrarily, IL-10 acts as an anti-inflammatory cytokine and bacterial killing suppressor. Immunoregulatory properties have also been attributed to hormones, including cholecystokinin (CCK). CCK protects cardiovascular function and inhibits the inflammatory response induced by lipopolysaccharide, product derived from Gram-negative bacteria. Nevertheless, the role of CCK during Gram-positive infection remains a literature gap. Our aims were to investigate whether CCK protects rats against bacterial dissemination during sepsis induced by S. aureus. We determined whether CCK modulates local and systemic inflammatory response, as well as the cell migration into the infectious focus and the bactericidal capacity of leukocytes. Our results revealed that proglumide (nonselective CCK receptor antagonist) pretreated rats showed higher bacterial counts in blood and peritoneal lavage fluid (PLF) and reduced TNF-α and IL-10 levels in PLF. Moreover, the dissemination of S. aureus may be related to the failure of neutrophil and macrophage migration into the peritoneal cavity. Also, CCK improved the phagocytic and bactericidal ability of these inflammatory cells. Noteworthy is that the adoptive transfer of CCK-treated neutrophils and macrophages in septic rats improved immune defense, reducing bacterial number in blood and PLF. All together, our study clearly demonstrates an important protective role of CCK against sepsis induced by S. aureus.