|
1
|
Elkjaer Greenwood Ormerod MB, Ueland T, Frogner Werner MC, Hjell G, Rødevand L, Sæther LS, Lunding SH, Johansen IT, Ueland T, Lagerberg TV, Melle I, Djurovic S, Andreassen OA, Steen NE. Composite immune marker scores associated with severe mental disorders and illness course. Brain Behav Immun Health 2022; 24:100483. [PMID: 35856063 PMCID: PMC9287150 DOI: 10.1016/j.bbih.2022.100483] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 06/28/2022] [Indexed: 12/29/2022] Open
Abstract
Background Low-grade inflammation has been implicated in the pathophysiology of severe mental disorders (SMDs) and a link between immune activation and clinical characteristics is suggested. However, few studies have investigated how patterns across immune markers are related to diagnosis and illness course. Methods A total of 948 participants with a diagnosis of schizophrenia (SCZ, N = 602) or bipolar (BD, N = 346) spectrum disorder, and 814 healthy controls (HC) were included. Twenty-five immune markers comprising cell adhesion molecules (CAMs), interleukin (IL)-18-system factors, defensins, chemokines and other markers, related to neuroinflammation, blood-brain barrier (BBB) function, inflammasome activation and immune cell orchestration were analyzed. Eight immune principal component (PC) scores were constructed by PC Analysis (PCA) and applied in general linear models with diagnosis and illness course characteristics. Results Three PC scores were significantly associated with a SCZ and/or BD diagnosis (HC reference), with largest, however small, effect sizes of scores based on CAMs, BBB markers and defensins (p < 0.001, partial η2 = 0.02-0.03). Number of psychotic episodes per year in SCZ was associated with a PC score based on IL-18 system markers and the potential neuroprotective cytokine A proliferation-inducing ligand (p = 0.006, partial η2 = 0.071). Conclusion Analyses of composite immune markers scores identified specific patterns suggesting CAMs-mediated BBB dysregulation pathways associated with SMDs and interrelated pro-inflammatory and neuronal integrity processes associated with severity of illness course. This suggests a complex pattern of immune pathways involved in SMDs and SCZ illness course.
Collapse
Affiliation(s)
| | - Thor Ueland
- NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- KG Jebsen Inflammatory Research Center, University of Oslo, Oslo, Norway
| | - Maren Caroline Frogner Werner
- NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Gabriela Hjell
- NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Psychiatry, Østfold Hospital, Graalum, Norway
| | - Linn Rødevand
- NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Linn Sofie Sæther
- NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
- Department of Psychology, University of Oslo, Oslo, Norway
| | - Synve Hoffart Lunding
- NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Ingrid Torp Johansen
- NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Torill Ueland
- NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Psychology, University of Oslo, Oslo, Norway
| | - Trine Vik Lagerberg
- NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
| | - Ingrid Melle
- NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Srdjan Djurovic
- Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway
- NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Ole Andreas Andreassen
- NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Nils Eiel Steen
- NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| |
Collapse
|
|
2
|
Haptoglobin in ultra-high risk of psychosis – Findings from the longitudinal youth at risk study (LYRIKS). Brain Behav Immun Health 2022; 23:100481. [PMID: 35757657 PMCID: PMC9214821 DOI: 10.1016/j.bbih.2022.100481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 05/24/2022] [Accepted: 06/04/2022] [Indexed: 11/21/2022] Open
|
|
3
|
Ziani PR, Feiten JG, Goularte JF, Colombo R, Antqueviezc B, Géa LP, Rosa AR. Potential Candidates for Biomarkers in Bipolar Disorder: A Proteomic Approach through Systems Biology. CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE 2022; 20:211-227. [PMID: 35466093 PMCID: PMC9048014 DOI: 10.9758/cpn.2022.20.2.211] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 07/02/2021] [Accepted: 07/03/2021] [Indexed: 11/18/2022]
Affiliation(s)
- Paola Rampelotto Ziani
- Laboratory of Molecular Psychiatry, Hospital Clinic of Porto Alegre, Porto Alegre, Brasil
- Postgraduate Program in Biological Sciences: Pharmacology and Therapeutics - Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Brasil
| | - Jacson Gabriel Feiten
- Laboratory of Molecular Psychiatry, Hospital Clinic of Porto Alegre, Porto Alegre, Brasil
- Postgraduate Program in Psychiatry and Behavioral Sciences, Faculty of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, Brasil
| | | | - Rafael Colombo
- Laboratory of Molecular Psychiatry, Hospital Clinic of Porto Alegre, Porto Alegre, Brasil
- University of Caxias do Sul, Caxias do Sul, Brasil
| | - Bárbara Antqueviezc
- Laboratory of Molecular Psychiatry, Hospital Clinic of Porto Alegre, Porto Alegre, Brasil
| | - Luiza Paul Géa
- Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada
| | - Adriane Ribeiro Rosa
- Laboratory of Molecular Psychiatry, Hospital Clinic of Porto Alegre, Porto Alegre, Brasil
- Postgraduate Program in Biological Sciences: Pharmacology and Therapeutics - Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Brasil
- Postgraduate Program in Psychiatry and Behavioral Sciences, Faculty of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, Brasil
| |
Collapse
|
|
4
|
NKCC1 to KCC2 mRNA Ratio in Schizophrenia and Its Psychopathology: a Case-Control Study. J Mol Neurosci 2022; 72:1670-1681. [PMID: 35624355 DOI: 10.1007/s12031-021-01879-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 06/21/2021] [Indexed: 10/18/2022]
Abstract
Schizophrenia (SCZ) is a debilitating, destructive, and chronic mental disorder and affects approximately one percent of the human population. Diagnosis in psychiatry is based on the patient's descriptions of his/her symptoms, interviewer's observations, history of disorder over time, and response to treatment. All of these data measure phenotype-based functions. But it appears that accurate diagnosis of such a complex disorder must be based on valid and reliable factors. In the present study, gene selection was based on the possible role of γ-aminobutyric acid (GABA) in psychopathology of SCZ and expression in blood. We evaluated the association of Na+-K+-Cl- co-transporter 1 (NKCC1) and K+-Cl- co-transporter 2 (KCC2) genes' messenger ribonucleic acid (mRNA) levels, and also the NKCC1/KCC2 ratio with positive and negative syndrome scale (PANSS) and brief psychiatric rating scale (BPRS) scores in an SCZ group. By using real-time PCR (RT-PCR), the present study is the first attempt to explore levels of NKCC1 and KCC2 expression at mRNA level and their relative expression in human peripheral blood of patients with SCZ. Our results showed that the NKCC1 to KCC2 mRNA ratio is significantly increased (but based on the delta cycle of threshold [∆Ct] is significantly lower) in the total sample of cases rather than controls (p = 0.045) and also higher in male sample cases rather than male controls (p = 0.016). In female samples, we found a trend toward a significant effect between the case and control participants (p = 0.075). We also found statistically significant association between mRNA of NKCC1 and KCC2 genes and NKCC1/KCC2 mRNA ratio with the positive and negative syndrome scale (PANSS) and brief psychiatric rating scale (BPRS) scores.
Collapse
|
|
5
|
Yin XY, Cai Y, Zhu ZH, Zhai CP, Li J, Ji CF, Chen P, Wang J, Wu YM, Chan RCK, Jia QF, Hui L. Associations of decreased serum total protein, albumin, and globulin with depressive severity of schizophrenia. Front Psychiatry 2022; 13:957671. [PMID: 35958662 PMCID: PMC9357925 DOI: 10.3389/fpsyt.2022.957671] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 06/22/2022] [Indexed: 11/24/2022] Open
Abstract
OBJECTIVE Depression and schizophrenia (SCH) were accompanied by an acute phase response (APR) that was implicated in the alterations in total protein (TP), albumin, and globulin levels. The aims of this study are to examine serum TP, albumin, globulin levels, depressive symptoms, and their associations in patients with SCH. METHODS We recruited 34 patients with SCH and 136 healthy controls (HCs) according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Psychiatric symptoms and biomarkers were assessed using the Chinese version of the Positive and Negative Syndrome Scale (PANSS) as well as the bromocresol green and biuret methods. RESULTS Serum TP (F = 46.11, p < 0.001, η2 = 0.19), albumin (F = 31.69, p < 0.001, η2 = 0.14), and globulin (F = 12.48, p < 0.001, η2 = 0.06) levels were lower in patients than those in HCs after adjusting for covariates. Serum TP (r = -0.37, p = 0.03) and albumin (r = -0.37, p = 0.03) levels were negatively correlated with depressive score in patients. Stepwise multivariate regression analysis showed the negative associations of depressive score with serum TP (β = -0.13, t = -2.92, p = 0.007), albumin (β = -0.23, t = -2.36, p = 0.03), and globulin (β = -0.16, t = -2.40, p = 0.02) levels in patients. Serum TP, albumin, and globulin levels exhibited the accuracies of 87.1, 70.0, and 69.4% in discriminating between patients and HCs (area under the curve [AUC]: 0.78, 0.68, and 0.77; sensitivity/specificity: 52.9%/95.6%, 55.9%/73.5%, and 76.5%/67.6%). CONCLUSION Our data suggested that decreased serum TP, albumin, and globulin should be regarded as the SCH risk factors and were implicated in the depressive severity of SCH, which further provided the support for the hypothesis that SCH and depression were accompanied by the abnormal inflammatory cytokines with the APR.
Collapse
Affiliation(s)
- Xu Yuan Yin
- Research Center of Biological Psychiatry, Suzhou Guangji Hospital, Suzhou Medical College of Soochow University, Suzhou, China
| | - Yuan Cai
- Research Center of Biological Psychiatry, Suzhou Guangji Hospital, Suzhou Medical College of Soochow University, Suzhou, China
| | - Zhen Hua Zhu
- Research Center of Biological Psychiatry, Suzhou Guangji Hospital, Suzhou Medical College of Soochow University, Suzhou, China
| | - Chang Ping Zhai
- Bengbu Mental Health Center, Anhui Veterans Hospital, Anmin Hospital Affiliated to Bengbu Medical College, Bengbu, China
| | - Jian Li
- Changshu No. 2 People's Hospital, The Affiliated Changshu Hospital of Xuzhou Medical University, Changshu, China
| | - Cai Fang Ji
- Research Center of Biological Psychiatry, Suzhou Guangji Hospital, Suzhou Medical College of Soochow University, Suzhou, China
| | - Peng Chen
- Research Center of Biological Psychiatry, Suzhou Guangji Hospital, Suzhou Medical College of Soochow University, Suzhou, China
| | - Jing Wang
- Research Center of Biological Psychiatry, Suzhou Guangji Hospital, Suzhou Medical College of Soochow University, Suzhou, China
| | - Yi Ming Wu
- Shanghai Yangpu Mental Health Center, Shanghai, China
| | - Raymond C K Chan
- CAS Key Laboratory of Mental Health, Institute of Psychology, Beijing, China
| | - Qiu Fang Jia
- Research Center of Biological Psychiatry, Suzhou Guangji Hospital, Suzhou Medical College of Soochow University, Suzhou, China
| | - Li Hui
- Research Center of Biological Psychiatry, Suzhou Guangji Hospital, Suzhou Medical College of Soochow University, Suzhou, China
| |
Collapse
|
|
6
|
Abstract
Neuropsychiatric diseases have traditionally been studied from brain, and mind-centric perspectives. However, mounting epidemiological and clinical evidence shows a strong correlation of neuropsychiatric manifestations with immune system activation, suggesting a likely mechanistic interaction between the immune and nervous systems in mediating neuropsychiatric disease. Indeed, immune mediators such as cytokines, antibodies, and complement proteins have been shown to affect various cellular members of the central nervous system in multitudinous ways, such as by modulating neuronal firing rates, inducing cellular apoptosis, or triggering synaptic pruning. These observations have in turn led to the exciting development of clinical therapies aiming to harness this neuro-immune interaction for the treatment of neuropsychiatric disease and symptoms. Besides the clinic, important theoretical fundamentals can be drawn from the immune system and applied to our understanding of the brain and neuropsychiatric disease. These new frameworks could lead to novel insights in the field and further potentiate the development of future therapies to treat neuropsychiatric disease.
Collapse
|
|
7
|
Wagh VV, Vyas P, Agrawal S, Pachpor TA, Paralikar V, Khare SP. Peripheral Blood-Based Gene Expression Studies in Schizophrenia: A Systematic Review. Front Genet 2021; 12:736483. [PMID: 34721526 PMCID: PMC8548640 DOI: 10.3389/fgene.2021.736483] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 08/31/2021] [Indexed: 12/19/2022] Open
Abstract
Schizophrenia is a disorder that is characterized by delusions, hallucinations, disorganized speech or behavior, and socio-occupational impairment. The duration of observation and variability in symptoms can make the accurate diagnosis difficult. Identification of biomarkers for schizophrenia (SCZ) can help in early diagnosis, ascertaining the diagnosis, and development of effective treatment strategies. Here we review peripheral blood-based gene expression studies for identification of gene expression biomarkers for SCZ. A literature search was carried out in PubMed and Web of Science databases for blood-based gene expression studies in SCZ. A list of differentially expressed genes (DEGs) was compiled and analyzed for overlap with genetic markers, differences based on drug status of the participants, functional enrichment, and for effect of antipsychotics. This literature survey identified 61 gene expression studies. Seventeen out of these studies were based on expression microarrays. A comparative analysis of the DEGs (n = 227) from microarray studies revealed differences between drug-naive and drug-treated SCZ participants. We found that of the 227 DEGs, 11 genes (ACOT7, AGO2, DISC1, LDB1, RUNX3, SIGIRR, SLC18A1, NRG1, CHRNB2, PRKAB2, and ZNF74) also showed genetic and epigenetic changes associated with SCZ. Functional enrichment analysis of the DEGs revealed dysregulation of proline and 4-hydroxyproline metabolism. Also, arginine and proline metabolism was the most functionally enriched pathway for SCZ in our analysis. Follow-up studies identified effect of antipsychotic treatment on peripheral blood gene expression. Of the 27 genes compiled from the follow-up studies AKT1, DISC1, HP, and EIF2D had no effect on their expression status as a result of antipsychotic treatment. Despite the differences in the nature of the study, ethnicity of the population, and the gene expression analysis method used, we identified several coherent observations. An overlap, though limited, of genetic, epigenetic and gene expression changes supports interplay of genetic and environmental factors in SCZ. The studies validate the use of blood as a surrogate tissue for biomarker analysis. We conclude that well-designed cohort studies across diverse populations, use of high-throughput sequencing technology, and use of artificial intelligence (AI) based computational analysis will significantly improve our understanding and diagnostic capabilities for this complex disorder.
Collapse
Affiliation(s)
- Vipul Vilas Wagh
- Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune, India
| | - Parin Vyas
- Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune, India
| | - Suchita Agrawal
- The Psychiatry Unit, KEM Hospital and KEM Hospital Research Centre, Pune, India
| | | | - Vasudeo Paralikar
- The Psychiatry Unit, KEM Hospital and KEM Hospital Research Centre, Pune, India
| | - Satyajeet P Khare
- Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune, India
| |
Collapse
|
|
8
|
Ľupták M, Michaličková D, Fišar Z, Kitzlerová E, Hroudová J. Novel approaches in schizophrenia-from risk factors and hypotheses to novel drug targets. World J Psychiatry 2021; 11:277-296. [PMID: 34327122 PMCID: PMC8311514 DOI: 10.5498/wjp.v11.i7.277] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 04/06/2021] [Accepted: 06/18/2021] [Indexed: 02/06/2023] Open
Abstract
Schizophrenia is a severe psychiatric disorder characterized by emotional, behavioral and cognitive disturbances, and the treatment of schizophrenia is often complicated by noncompliance and pharmacoresistance. The search for the pathophysiological mechanisms underlying schizophrenia has resulted in the proposal of several hypotheses to explain the impacts of environmental, genetic, neurodevelopmental, immune and inflammatory factors on disease onset and progression. This review discusses the newest insights into the pathophysiology of and risk factors for schizophrenia and notes novel approaches in antipsychotic treatment and potential diagnostic and theranostic biomarkers. The current hypotheses focusing on neuromediators (dopamine, glutamate, and serotonin), neuroinflammation, the cannabinoid hypothesis, the gut-brain axis model, and oxidative stress are summarized. Key genetic features, including small nucleotide polymorphisms, copy number variations, microdeletions, mutations and epigenetic changes, are highlighted. Current pharmacotherapy of schizophrenia relies mostly on dopaminergic and serotonergic antagonists/partial agonists, but new findings in the pathophysiology of schizophrenia have allowed the expansion of novel approaches in pharmacotherapy and the establishment of more reliable biomarkers. Substances with promising results in preclinical and clinical studies include lumateperone, pimavanserin, xanomeline, roluperidone, agonists of trace amine-associated receptor 1, inhibitors of glycine transporters, AMPA allosteric modulators, mGLUR2-3 agonists, D-amino acid oxidase inhibitors and cannabidiol. The use of anti-inflammatory agents as an add-on therapy is mentioned.
Collapse
Affiliation(s)
- Matej Ľupták
- Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague 12800, Czech Republic
| | - Danica Michaličková
- Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague 12800, Czech Republic
| | - Zdeněk Fišar
- Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague 12000, Czech Republic
| | - Eva Kitzlerová
- Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague 12000, Czech Republic
| | - Jana Hroudová
- Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague 12800, Czech Republic
- Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague 12000, Czech Republic
| |
Collapse
|
|
9
|
Zhang X, Yin L, Jia X, Zhang Y, Liu T, Zhang L. iTRAQ-based Quantitative Proteomic Analysis of Dural Tissues Reveals Upregulated Haptoglobin to be a Potential Biomarker of Moyamoya Disease. CURR PROTEOMICS 2021. [DOI: 10.2174/1570164617666191210103652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Background:
Moyamoya Disease (MMD) is a rare cerebrovascular disease with a high rate
of disability and mortality. Immune reactions have been implicated in the pathogenesis of MMD, however,
the underlying mechanism is still unclear.
Objective:
To identify proteins related to MMD specially involved in the immunogenesis, we performed
a proteomic study.
Methods:
In this work, dural tissues or plasma from 98 patients with MMD, 17 disease controls without
MMD, and 12 healthy donors were included. Proteomic profiles of dural tissues from 4 MMD and
4 disease controls were analyzed by an isobaric tag for relative and absolute quantitation (iTRAQ)-
based proteomics. The immune-related proteins were explored by bioinformatics and the key MMDrelated
proteins were verified by western blot, multiple reaction monitoring methods, enzyme-linked
immunosorbent assay, and tissue microarray.
Results:
1,120 proteins were identified, and 82 MMD-related proteins were found with more than 1.5
fold difference compared with those in the control samples. Gene Ontology analysis showed that 29
proteins were immune-related. In particular, Haptoglobin (HP) was up-regulated in dural tissue and
plasma of MMD samples compared to the controls, and its up-regulation was found to be sex- and
MMD Suzuki grade dependent. Through Receiver Operating Characteristic (ROC) analysis, HP can
well discriminate MMD and healthy donors with the Area Under the Curve (AUC) of 0.953.
Conclusion:
We identified the biggest protein database of the dura mater. 29 out of 82 differentially
expressed proteins in MMD are involved in the immune process. Of which, HP was up-regulated in
dural tissue and plasma of MMD, with sex- and MMD Suzuki grade-dependence. HP might be a potential
biomarker of MMD.
Collapse
Affiliation(s)
- Xiaojun Zhang
- The 85th Hospital of the Chinese People's Liberation Army, Shanghai 200052, China
| | - Lin Yin
- Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Xiaofang Jia
- Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Yujiao Zhang
- Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Tiefu Liu
- Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Lijun Zhang
- Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| |
Collapse
|
|
10
|
Roomruangwong C, Noto C, Kanchanatawan B, Anderson G, Kubera M, Carvalho AF, Maes M. The Role of Aberrations in the Immune-Inflammatory Response System (IRS) and the Compensatory Immune-Regulatory Reflex System (CIRS) in Different Phenotypes of Schizophrenia: the IRS-CIRS Theory of Schizophrenia. Mol Neurobiol 2019; 57:778-797. [PMID: 31473906 DOI: 10.1007/s12035-019-01737-z] [Citation(s) in RCA: 96] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Accepted: 08/16/2019] [Indexed: 12/20/2022]
Abstract
Several lines of evidence indicate that aberrations in immune-inflammatory pathways may contribute to the pathophysiology of schizophrenia spectrum disorders. Here, we propose a novel theoretical framework that was previously developed for major depression and bipolar disorder, namely, the compensatory immune-regulatory reflex system (CIRS), as applied to the neuro-immune pathophysiology of schizophrenia and its phenotypes, including first-episode psychosis (FEP), acute relapses, chronic and treatment-resistant schizophrenia (TRS), comorbid depression, and deficit schizophrenia. These schizophrenia phenotypes and manifestations are accompanied by increased production of positive acute-phase proteins, including haptoglobin and α2-macroglobulin, complement factors, and macrophagic M1 (IL-1β, IL-6, and TNF-α), T helper (Th)-1 (interferon-γ and IL-2R), Th-2 (IL-4, IL-5), Th-17 (IL-17), and T regulatory (Treg; IL-10 and transforming growth factor (TGF)-β1) cytokines, cytokine-induced activation of the tryptophan catabolite (TRYCAT) pathway, and chemokines, including CCL-11 (eotaxin), CCL-2, CCL-3, and CXCL-8. While the immune profiles in the different schizophrenia phenotypes indicate the activation of the immune-inflammatory response system (IRS), there are simultaneous signs of CIRS activation, including increased levels of the IL-1 receptor antagonist (sIL-1RA), sIL-2R and tumor necrosis factor-α receptors, Th-2 and Treg phenotypes with increased IL-4 and IL-10 production, and increased levels of TRYCATs and haptoglobin, α2-macroglobulin, and other acute-phase reactants, which have immune-regulatory and anti-inflammatory effects. Signs of activated IRS and CIRS pathways are also detected in TRS, chronic, and deficit schizophrenia, indicating that these conditions are accompanied by a new homeostatic setpoint between upregulated IRS and CIRS components. In FEP, increased baseline CIRS activity is a protective factor that may predict favorable clinical outcomes. Moreover, impairments in the CIRS are associated with deficit schizophrenia and greater impairments in semantic and episodic memory. It is concluded that CIRS plays a key role in the pathophysiology of schizophrenia by negatively regulating the primary IRS and contributing to recovery from the acute phase of illness. Therefore, components of the CIRS may offer promising therapeutic targets for schizophrenia.
Collapse
Affiliation(s)
- Chutima Roomruangwong
- Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Cristiano Noto
- Schizophrenia Program (PROESQ), Department of Psychiatry, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
- GAPi (Early Psychosis Group), Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
| | - Buranee Kanchanatawan
- Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | | | - Marta Kubera
- Department of Experimental Endocrinology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland
| | - Andre F Carvalho
- Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Centre for Addiction & Mental Health (CAMH), Toronto, ON, M6J 1H4, Canada
| | - Michael Maes
- Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
- Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria.
- IMPACT Strategic Research Centre, Deakin University, Geelong, Vic, Australia.
| |
Collapse
|
|
11
|
Silverman M, Frankovich J, Nguyen E, Leibold C, Yoon J, Mark Freeman G, Karpel H, Thienemann M. Psychotic symptoms in youth with Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) may reflect syndrome severity and heterogeneity. J Psychiatr Res 2019; 110:93-102. [PMID: 30605785 DOI: 10.1016/j.jpsychires.2018.11.013] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Revised: 11/04/2018] [Accepted: 11/13/2018] [Indexed: 12/27/2022]
Abstract
OBJECTIVE In the clinical syndrome Pediatric Acute-onset Neuropsychiatric Syndrome (PANS), obsessive compulsive disorder (OCD) and/or food refusal symptoms have an abrupt-onset (over 48 h) coupled with at least two other specified neuropsychiatric symptoms. We aimed to characterize in detail for the first time, psychotic symptoms experienced by children with PANS as well as the impact of psychotic symptoms on disease severity and course of illness. We inform about the diagnosis of the clinical description: PANS and hope to improve evaluation, treatment, diagnostic validity and future investigation. METHODS Retrospective review of 143 consecutive PANS clinic patient charts meeting inclusion criteria. The Caregiver Burden Inventory, Global Impairment Score, and Children's Global Assessment Scale were used to assess impairment. RESULTS Visual and auditory hallucinations were each experienced by 36%, of which most (83%) were transient and complex (non-threatening voices or figures). 6.3% and 5.5% of patients experienced delusions and thought disorganization respectively. Those with psychotic symptoms showed statistically significant differences in disease impairment and caregiver burden. There were no differences in time to treatment access or length of illness. CONCLUSIONS Over 1/3 of children with PANS experienced transient hallucinations. They were more impaired than those without psychotic symptoms, but showed no differences in disease progression. This difference may point toward heterogeneity in PANS. When evaluating children with acute psychotic symptoms, clinicians should screen for abrupt-onset of a symptom cluster including OCD and/or food refusal, with neuropsychiatric symptoms (enuresis, handwriting changes, tics, hyperactivity, sleep disorder) before initiating treatment.
Collapse
Affiliation(s)
- Melissa Silverman
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, United States; Stanford Pediatric Acute-onset Neuropsychiatric Sydrome Clinic and Research Program at Lucile Packard Children's Hospital, Stanford University, Stanford, CA, United States.
| | - Jennifer Frankovich
- Pediatric Division of Allergy, Immunology, and Rheumatology, Stanford University, Stanford, CA, United States; Stanford Pediatric Acute-onset Neuropsychiatric Sydrome Clinic and Research Program at Lucile Packard Children's Hospital, Stanford University, Stanford, CA, United States
| | - Emily Nguyen
- Stanford Pediatric Acute-onset Neuropsychiatric Sydrome Clinic and Research Program at Lucile Packard Children's Hospital, Stanford University, Stanford, CA, United States
| | - Collin Leibold
- Pediatric Division of Allergy, Immunology, and Rheumatology, Stanford University, Stanford, CA, United States; Stanford Pediatric Acute-onset Neuropsychiatric Sydrome Clinic and Research Program at Lucile Packard Children's Hospital, Stanford University, Stanford, CA, United States
| | - Jong Yoon
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, United States; VA Palo Alto Health Care System, 3801 Miranda Ave., Building 4, 2nd Floor, Palo Alto, CA, 94304, United States
| | - G Mark Freeman
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, United States
| | - Hannah Karpel
- Pediatric Division of Allergy, Immunology, and Rheumatology, Stanford University, Stanford, CA, United States; Stanford Pediatric Acute-onset Neuropsychiatric Sydrome Clinic and Research Program at Lucile Packard Children's Hospital, Stanford University, Stanford, CA, United States
| | - Margo Thienemann
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, United States; Stanford Pediatric Acute-onset Neuropsychiatric Sydrome Clinic and Research Program at Lucile Packard Children's Hospital, Stanford University, Stanford, CA, United States
| |
Collapse
|
|
12
|
Kroken RA, Sommer IE, Steen VM, Dieset I, Johnsen E. Constructing the Immune Signature of Schizophrenia for Clinical Use and Research; An Integrative Review Translating Descriptives Into Diagnostics. Front Psychiatry 2018; 9:753. [PMID: 30766494 PMCID: PMC6365449 DOI: 10.3389/fpsyt.2018.00753] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Accepted: 12/19/2018] [Indexed: 12/11/2022] Open
Abstract
Schizophrenia is considered a syndrome comprised by several disease phenotypes, covering a range of underlying pathologies. One of these disease mechanisms seems to involve immune dysregulation and neuroinflammation. While the current dopamine receptor-blocking antipsychotic drugs decrease psychotic symptoms and prevent relapse in the majority of patients with schizophrenia, there is a huge need to explore new treatment options that target other pathophysiological pathways. Such studies should aim at identifying robust biomarkers in order to diagnose and monitor the immune biophenotype in schizophrenia and develop better selection procedures for clinical trials with anti-inflammatory and immune-modulating drugs. In this focused review, we describe available methods to assess inflammatory status and immune disturbances in vivo. We also outline findings of immune disturbances and signs of inflammation at cellular, protein, and brain imaging levels in patients with schizophrenia. Furthermore, we summarize the results from studies with anti-inflammatory or other immune-modulating drugs, highlighting how such studies have dealt with participant selection. Finally, we propose a strategy to construct an immune signature that may be helpful in selecting and monitoring participants in studies with immune modulating drugs and also applicable in regular clinical work.
Collapse
Affiliation(s)
- Rune A Kroken
- Psychiatric Division, Haukeland University Hospital, Bergen, Norway.,Norwegian Centre for Mental Disorders Research, Haukeland University Hospital, Bergen, Norway.,Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Iris E Sommer
- Department of Neuroscience and Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.,Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway
| | - Vidar M Steen
- Department of Clinical Science, Norwegian Centre for Mental Disorders Research, KG Jebsen Centre for Psychosis Research, University of Bergen, Bergen, Norway.,Dr. E. Martens Research Group of Biological Psychiatry, Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway
| | - Ingrid Dieset
- Norwegian Centre for Mental Disorders Research, KG Jebsen Centre for Psychosis Research, Oslo University Hospital and University of Oslo, Oslo, Norway.,Division of Mental Health and Addiction, Acute Psychiatric Department, Oslo University Hospital, Oslo, Norway.,Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Erik Johnsen
- Psychiatric Division, Haukeland University Hospital, Bergen, Norway.,Norwegian Centre for Mental Disorders Research, Haukeland University Hospital, Bergen, Norway.,Department of Clinical Medicine, University of Bergen, Bergen, Norway
| |
Collapse
|