Towards precision medicine:What are the stratification hypotheses to identify homogeneous inflammatory subgroups

Diverse lines of research testify a link, presumably causal, between immune dysregulation and the development, course and clinical outcome of psychiatric disorders. However, there is a large heterogeneity among the patients? individual immune profile and this heterogeneity prevents the development of precise diagnostic tools and the identification of therapeutic targets. The aim of this review was to delineate possible subgroups of patients on the basis of clinical dimensions, investigating whether they could lead to particular immune signatures and tailored treatments. We discuss six clinical entry points; genetic liability to immune dysregula-tion, childhood maltreatment, metabolic syndrome, cognitive dysfunction, negative symptoms and treatment resistance. We describe the associated immune signature and outline the effects of anti-inflammatory drugs so far. Finally, we discuss advantages of this approach, challenges and future research directions. (c) 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/

Immuno-metabolic profile of patients with psychotic disorders and metabolic syndrome. Results from the FACE-SZ cohort

Background: Metabolic syndrome (MetS) is a highly prevalent and harmful medical disorder often comorbid with psychosis where it can contribute to cardiovascular complications. As immune dysfunction is a key shared component of both MetS and schizophrenia (SZ), this study investigated the relationship between immune alterations and MetS in patients with SZ, whilst controlling the impact of confounding clinical characteristics including psychiatric symptoms and comorbidities, history of childhood maltreatment and psychotropic treatments. Method: A total of 310 patients meeting DSM-IV criteria for SZ or schizoaffective disorders (SZA), with or without MetS, were systematically assessed and included in the FondaMental Advanced Centers of Expertise for Schizophrenia (FACE-SZ) cohort. Detailed clinical characteristics of patients, including psychotic symptomatology, psychiatric comorbidities and history of childhood maltreatment were recorded and the serum levels of 18 cytokines were measured. A penalized regression method was performed to analyze associations between inflammation and MetS, whilst controlling for confounding factors. Results: Of the total sample, 25% of patients had MetS. Eight cytokines were above the lower limit of detection (LLOD) in more than 90% of the samples and retained in downstream analysis. Using a conservative Variable Inclusion Probability (VIP) of 75%, we found that elevated levels of interleukin (IL)-6, IL-7, IL-12/23 p40 and IL-16 and lower levels of tumor necrosis factor (TNF)-α were associated with MetS. As for clinical variables, age, sex, body mass index (BMI), diagnosis of SZ (not SZA), age at the first episode of psychosis (FEP), alcohol abuse, current tobacco smoking, and treatment with antidepressants and anxiolytics were all associated with MetS. Conclusion: We have identified five cytokines associated with MetS in SZ suggesting that patients with psychotic disorders and MetS are characterized by a specific “immuno-metabolic” profile. This may help to design tailored treatments for this subgroup of patients with both psychotic disorders and MetS, taking one more step towards precision medicine in psychiatry. © 2022 The AuthorsImmuno-Génétique, Inflammation, retro-Virus, Environnement : de l'étiopathogénie des troubles psychotiques aux modèles animauxRéseau d'Innovation sur les Voies de Signalisation en Sciences de la Vi

T-cell subset phenotypes in patients with bipolar disorder or schizophrenia with history of childhood maltreatment

Introduction: History of Childhood Maltreatment (CM) has repeatedly been associated with an increased risk of developing bipolar disorders (BD) or schizophrenia (SZ). The impact of severe stress induced by CM is thought to be mediated by increased inflammation reflected by deregulated levels of circulating pro- and anti-inflammatory cytokines. However, little is known about the potential impact of exposition to CM on lymphocyte subpopulations or the role of pre-existing infections on the impact of CM. We thus explored the role of CM and the impact of past exposure to infections on lymphocyte subpopulation.as these could be important avenues to better understand the impact of severe stress in major mood and psychotic disorders. Patients and Methods: 118 adult patients with SZ and 152 with BD were included in the analysis. History of CM was assessed using the Childhood Trauma Questionnaire (CTQ), current and past psychiatric symptomatology were evaluated. Circulating lymphocytes subsets were analyzed using flow cytometry-based analysis. Past exposure to common infectious stigma including toxoplasma, Cytomegalovirus (CMV) and Ebstein-Barr Virus (EBV) were measured by solid phase-enzyme microplate and ELISA immunoassays. Relationship between CM, biological phenotypes and clinical phenotypes were analyzed using univariate and multivariate analyses. Results: We found that patients with BD and CM, as compared to those without, had higher levels of CD3+CD8+ cytotoxic T cells and CMV antibodies along decreased levels of CD45RA+CCR7+CD8+ naïve CD8 T cells, and a more severe clinical profile. We also observed that levels of CMV antibodies were inversely associated with the CD3+CD8+ lymphocyte subset level.Patients with SZ and CM have decreased levels of CD14+ monocytes. Accumulation of types of maltreatment is associated with increased Body Mass Index and CMV autoantibodies as well as decreased levels of CD14+ monocytes. Conclusion: We observed that adult patients with BD or SZ having been exposed to CM exhibit specific immune cell subset profiles, clinical features and stigma of past infections. Altogether, our findings, especially in the context of BD, allows us to suggest a possible interplay between CM and CMV infectious events possibly inducing premature aging and cellular senescence, two events already known to be associated with psychiatric conditions. Longitudinal studies of patients exposed to maltreatment are warranted to replicate, predict and anticipate the specific needs of these patients

Towards precision medicine: What are the stratification hypotheses to identify homogeneous inflammatory subgroups

Diverse lines of research testify a link, presumably causal, between immune dysregulation and the development, course and clinical outcome of psychiatric disorders. However, there is a large heterogeneity among the patients? individual immune profile and this heterogeneity prevents the development of precise diagnostic tools and the identification of therapeutic targets. The aim of this review was to delineate possible subgroups of patients on the basis of clinical dimensions, investigating whether they could lead to particular immune signatures and tailored treatments. We discuss six clinical entry points; genetic liability to immune dysregula-tion, childhood maltreatment, metabolic syndrome, cognitive dysfunction, negative symptoms and treatment resistance. We describe the associated immune signature and outline the effects of anti-inflammatory drugs so far. Finally, we discuss advantages of this approach, challenges and future research directions. (c) 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/

Mental disorders and risk of COVID-19-related mortality, hospitalisation, and intensive care unit admission: a systematic review and meta-analysis

Background: Mental disorders might be a risk factor for severe COVID-19. We aimed to assess the specific risks of COVID-19-related mortality, hospitalisation, and intensive care unit (ICU) admission associated with any pre-existing mental disorder, and specific diagnostic categories of mental disorders, and exposure to psychopharmacological drug classes. Methods: In this systematic review and meta-analysis, we searched Web of Science, Cochrane, PubMed, and PsycINFO databases between Jan 1, 2020, and March 5, 2021, for original studies reporting data on COVID-19 outcomes in patients with psychiatric disorders compared with controls. We excluded studies with overlapping samples, studies that were not peer-reviewed, and studies written in languages other than English, Danish, Dutch, French, German, Italian, and Portuguese. We modelled random-effects meta-analyses to estimate crude odds ratios (OR) for mortality after SARS-CoV-2 infection as the primary outcome, and hospitalisation and ICU admission as secondary outcomes. We calculated adjusted ORs for available data. Heterogeneity was assessed using the I2 statistic, and publication bias was tested with Egger regression and visual inspection of funnel plots. We used the GRADE approach to assess the overall strength of the evidence and the Newcastle Ottawa Scale to assess study quality. We also did subgroup analyses and meta-regressions to assess the effects of baseline COVID-19 treatment setting, patient age, country, pandemic phase, quality assessment score, sample sizes, and adjustment for confounders. This study is registered with PROSPERO, CRD42021233984. Findings: 841 studies were identified by the systematic search, of which 33 studies were included in the systematic review and 23 studies in the meta-analysis, comprising 1 469 731 patients with COVID-19, of whom 43 938 had mental disorders. The sample included 130 807 females (8·9% of the whole sample) and 130 373 males (8·8%). Nine studies provided data on patient race and ethnicity, and 22 studies were rated as high quality. The presence of any mental disorder was associated with an increased risk of COVID-19 mortality (OR 2·00 [95% CI 1·58–2·54]; I2=92·66%). This association was also observed for psychotic disorders (2·05 [1·37–3·06]; I2=80·81%), mood disorders (1·99 [1·46–2·71]; I2=68·32%), substance use disorders (1·76 [1·27–2·44]; I2=47·90%), and intellectual disabilities and developmental disorders (1·73 [1·29–2·31]; I2=90·15%) but not for anxiety disorders (1·07 [0·73–1·56]; I2=11·05%). COVID-19 mortality was associated with exposure to antipsychotics (3·71 [1·74–7·91]; I2=90·31%), anxiolytics (2·58 [1·22–5·44]; I2=96·42%), and antidepressants (2·23 [1·06–4·71]; I2=95·45%). For psychotic disorders, mood disorders, antipsychotics, and anxiolytics, the association remained significant after adjustment for age, sex, and other confounders. Mental disorders were associated with increased risk of hospitalisation (2·24 [1·70–2·94]; I2=88·80%). No significant associations with mortality were identified for ICU admission. Subgroup analyses and meta-regressions showed significant associations of baseline COVID-19 treatment setting (p=0·013) and country (p<0·0001) with mortality. No significant associations with mortality were identified for other covariates. No evidence of publication bias was found. GRADE assessment indicated high certainty for crude mortality and hospitalisation, and moderate certainty for crude ICU admission. Interpretation: Pre-existing mental disorders, in particular psychotic and mood disorders, and exposure to antipsychotics and anxiolytics were associated with COVID-19 mortality in both crude and adjusted models. Although further research is required to determine the underlying mechanisms, our findings highlight the need for targeted approaches to manage and prevent COVID-19 in at-risk patient groups identified in this study. Funding: None. Translations: For the Italian, French and Portuguese translations of the abstract see Supplementary Materials section

Immuno-metabolic profile of patients with psychotic disorders and metabolic syndrome. Results from the FACE-SZ cohort

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