The tryptophan catabolite or kynurenine pathway in schizophrenia: meta-analysis reveals dissociations between central, serum and plasma compartments.

The tryptophan catabolite (TRYCAT) pathway is implicated in the pathophysiology of schizophrenia (SCZ) since the rate-limiting enzyme indoleamine-dioxygenase (IDO) may be induced by inflammatory and oxidative stress mediators. This systematic review searched PubMed, Web of Science, and Google Scholar for papers published from inception until August 2021 and meta-analyzed the association between SCZ and TRYCATs in the central nervous system (CNS) and peripheral blood. We included 61 studies comprising 2813 patients and 2948 healthy controls. In the CNS we found a significant (p<0.001) increase in the kynurenine/tryptophan (KYN/TRP) (standardized mean difference, SMD=0.769, 95% confidence interval, CI: 0.456; 1.082) and kynurenic acid (KA)/KYN+TRP (SMD=0.697, CI:0.478-0.917) ratios, KA (SMD=0.646, CI: 0.422; 0.909) and KYN (SMD=1.238; CI: 0.590; 1.886), while the 3OH-kynurenine (3HK) + KYN-3-monooxygenase (KMO)/KYN ratio was significantly reduced (SMD=-1.089, CI: -1.682; -0.496). There were significant differences between KYN/TRP, (KYN+KA)/TRP, (3HK+KMO)/KYN, KA, and KYN levels among the CNS and peripheral blood, and among serum and plasma KYN. The only useful peripheral marker of CNS TRYCATs findings was the increased KYN/TRP ratio in serum (SMD=0.211, CI: 0.056; 0.366, p=0.007), but not in plasma. There was no significant increase in a neurotoxic composite score based on KYN, 3HK, and picolinic, xanthurenic, and quinolinic acid. SCZ is accompanied by increased IDO activity in the CNS and serum, and reduced KMO activity and a shift towards KA production in the CNS. This CNS TRYCATs profile indicates neuroprotective, negative immunoregulatory and anti-inflammatory effects. Peripheral blood levels of TRYCATs are dissociated from CNS findings except for a modest increase in serum IDO activity.

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The kynurenine pathway in bipolar disorder: a meta-analysis on the peripheral blood levels of tryptophan and related metabolites

Molecular Psychiatry ◽

10.1038/s41380-020-00913-1 ◽

2020 ◽

Author(s):

Francesco Bartoli ◽

Błażej Misiak ◽

Tommaso Callovini ◽

Daniele Cavaleri ◽

Riccardo M. Cioni ◽

...

Keyword(s):

Bipolar Disorder ◽

Peripheral Blood ◽

Meta Analysis ◽

Kynurenine Pathway ◽

Blood Levels

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Association between peripheral blood levels of C-reactive protein and Autism Spectrum Disorder in children: A systematic review and meta-analysis

Brain Behavior and Immunity ◽

10.1016/j.bbi.2020.04.008 ◽

2020 ◽

Vol 88 ◽

pp. 432-441

Author(s):

Fangna Yin ◽

Hongbing Wang ◽

Zeya Liu ◽

Junwei Gao

Keyword(s):

Systematic Review ◽

Autism Spectrum Disorder ◽

Peripheral Blood ◽

Meta Analysis ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Blood Levels ◽

C Reactive Protein ◽

Reactive Protein

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Association of Peripheral Blood Levels of Cytokines With Autism Spectrum Disorder: A Meta-Analysis

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.670200 ◽

2021 ◽

Vol 12 ◽

Author(s):

Huaying Zhao ◽

Hongqi Zhang ◽

Shijie Liu ◽

Wulin Luo ◽

Yongfeng Jiang ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Peripheral Blood ◽

Meta Analysis ◽

Autism Spectrum ◽

Spectrum Disorder ◽

The Other ◽

Sensitivity Analyses ◽

Systemic Review ◽

Blood Levels ◽

Random Effects Models

Background: Although increasing evidence suggests an association between alterations in peripheral cytokines and autism spectrum disorder (ASD), a consensus is lacking. To determine whether abnormal cytokine profiles in peripheral blood were associated with ASD, we performed this systemic review and meta-analysis.Methods: A systematic literature search was conducted through the Embase, PubMed, Web of Knowledge, PsycINFO, and Cochrane databases up to 4 June 2020. Clinical studies exploring the aberration of peripheral cytokines of autistic patients and controls were included in our meta-analysis. We pooled extracted data using fixed- or random-effects models based on heterogeneity tests with Comprehensive Meta-analysis software. We converted standardized mean differences to Hedges' g statistic to obtain the effect sizes adjusted for sample size. Subgroup analyses, sensitivity analyses, meta-regression, and publication bias tests were also carried out.Results: Sixty-one articles (326 studies) were included to assess the association between 76 cytokines and ASD. We conducted our meta-analysis based on 37 cytokines with 289 studies. Since there were fewer than three studies on any of the other 39 cytokines, we only provided basic information for them. The levels of peripheral IL-6, IL-1β, IL-12p70, macrophage migration inhibitory factor (MIF), eotaxin-1, monocyte chemotactic protein-1 (MCP-1), IL-8, IL-7, IL-2, IL-12, tumor necrosis factor-α (TNF-α), IL-17, and IL-4 were defined as abnormal cytokines in the peripheral blood of ASD patients compared with controls. The other 24 cytokines did not obviously change in ASD patients compared with the controls.Conclusions: The findings of our meta-analysis strengthen the evidence for an abnormal cytokine profile in ASD. These abnormal cytokines may be potential biomarkers for the diagnosis and treatment of ASD in the future.

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The kynurenine pathway in schizophrenia and other mental disorders: Insight from meta-analyses on the peripheral blood levels of tryptophan and related metabolites

Schizophrenia Research ◽

10.1016/j.schres.2021.04.008 ◽

2021 ◽

Vol 232 ◽

pp. 61-62

Author(s):

Francesco Bartoli ◽

Riccardo M. Cioni ◽

Tommaso Callovini ◽

Daniele Cavaleri ◽

Cristina Crocamo ◽

...

Keyword(s):

Mental Disorders ◽

Peripheral Blood ◽

Kynurenine Pathway ◽

Blood Levels ◽

Meta Analyses

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Potential drug targets in the kynurenine pathway to treat acute schizophrenia

BJPsych Open ◽

10.1192/bjo.2021.461 ◽

2021 ◽

Vol 7 (S1) ◽

pp. S167-S167

Author(s):

Ayush Malhotra ◽

Paul Manowitz

Keyword(s):

Drug Targets ◽

Kynurenic Acid ◽

Meta Analysis ◽

Kynurenine Pathway ◽

Supporting Evidence ◽

Biochemical Pathway ◽

Acute Schizophrenia ◽

Plasma Tryptophan ◽

Wide Range ◽

Dopamine Hypothesis

AimsSchizophrenia is a serious developmental psychiatric disorder with a neurodegenerative component that causes marked deterioration in social relationships and ability to work. Present treatments are not satisfactory. Meta-analysis of placebo-controlled studies in acute schizophrenia shows that only a minority of patients have a good response to current antipsychotic medications. Therefore, there is a need for more effective psychopharmacologic treatments for this disorder.MethodThe purpose of this paper is to provide new interpretations of existing data to provide a scaffolding for the development of novel drug targets for the treatment of schizophrenia. The causes of schizophrenia are most likely heterogeneous and involve both genetic and environmental factors. The authors examined a wide range of purported causes of schizophrenia to identify a common biochemical pathway that would contribute to this disorder. This review specifically did not consider pathways that supported the dopamine hypothesis of schizophrenia since historically drugs focused on dopaminergic mechanism, as noted in the aims, have not been successful for many patients with schizophrenia.ResultTwo prominent schizophrenia-associated factors that have been widely studied with significant supporting evidence are stress and inflammation. Stress and inflammation share a common biochemical pathway that converges on the kynurenine pathway of the metabolism of tryptophan, an essential amino acid. At one end of the pathway, recently hospitalized patients with schizophrenia have been found to have low plasma tryptophan levels, whereas chronic schizophrenics have not, suggesting stress- and/or inflammation-induced increased metabolism of tryptophan. At the other end of the pathway, there is increased level of cerebrospinal fluid kynurenic acid in patients with schizophrenia as compared with healthy controls. Salivary kynurenic acid is associated with stress intolerance in schizophrenia. Importantly, natural occurring compounds in this pathway have significant CNS effects that include neurotoxicity and altered neural transmitter behavior.ConclusionStress and inflammation, both associated as causes of schizophrenia, are linked by a common biochemical pathway involving kynurenine. Examination of specific elements of the kynurenine pathway may aid in the identification of drug targets for schizophrenia.

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Glial and neuronal markers in bipolar disorder: A meta-analysis testing S100B and NSE peripheral blood levels

Progress in Neuro-Psychopharmacology and Biological Psychiatry ◽

10.1016/j.pnpbp.2020.109922 ◽

2020 ◽

Vol 101 ◽

pp. 109922

Author(s):

Francesco Bartoli ◽

Błażej Misiak ◽

Cristina Crocamo ◽

Giuseppe Carrà

Keyword(s):

Bipolar Disorder ◽

Peripheral Blood ◽

Meta Analysis ◽

Blood Levels ◽

Neuronal Markers

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Peripheral Blood S100B Levels in Autism Spectrum Disorder: A Systematic Review and Meta-Analysis

Journal of Autism and Developmental Disorders ◽

10.1007/s10803-020-04710-1 ◽

2020 ◽

Author(s):

Zhen Zheng ◽

Peng Zheng ◽

Xiaobing Zou

Keyword(s):

Systematic Review ◽

Peripheral Blood ◽

Calcium Binding ◽

Neuronal Damage ◽

Meta Analysis ◽

Autism Spectrum ◽

Healthy Controls ◽

S100 Calcium Binding Protein ◽

The Central Nervous System ◽

Standardized Mean Difference

Abstract The S100 calcium-binding protein beta subunit (S100B) protein, which mostly exists in the central nervous system, is commonly noted as a marker of neuronal damage. We conducted the first systematic review with meta-analysis to compare peripheral blood S100B levels in individuals with ASD with those in healthy controls. A systematic search was carried out for studies published before May 5, 2020. In total, this meta-analysis involved ten studies with 822 participants and 451 cases. The meta-analysis revealed that individuals with ASD had higher peripheral blood S100B levels than healthy controls [standardized mean difference (SMD) = 0.97, 95% confidence interval (95% CI) = 0.41–1.53; p < 0.001]. Peripheral blood S100B levels may have potential as a useful biomarker for ASD.

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CHAPTER 9: Immunology of TBEV-Infections

Tick-borne encephalitis - The Book ◽

10.33442/26613980_9-3 ◽

2020 ◽

Keyword(s):

Central Nervous System ◽

T Cells ◽

Cerebrospinal Fluid ◽

Nervous System ◽

Nk Cells ◽

Peripheral Blood ◽

Sample Collection ◽

Tick Borne Encephalitis ◽

Viral Infectious Disease ◽

The Central Nervous System

Tick-borne encephalitis (TBE) is a viral infectious disease of the central nervous system caused by the tick-borne encephalitis virus (TBEV). TBE is usually a biphasic disease and in humans the virus can only be detected during the first (unspecific) phase of the disease. Pathogenesis of TBE is not well understood, but both direct viral effects and immune-mediated tissue damage of the central nervous system may contribute to the natural course of TBE. The effect of TBEV on the innate immune system has mainly been studied in vitro and in mouse models. Characterization of human immune responses to TBEV is primarily conducted in peripheral blood and cerebrospinal fluid, due to the inaccessibility of brain tissue for sample collection. Natural killer (NK) cells and T cells are activated during the second (meningo-encephalitic) phase of TBE. The potential involvement of other cell types has not been examined to date. Immune cells from peripheral blood, in particular neutrophils, T cells, B cells and NK cells, infiltrate into the cerebrospinal fluid of TBE patients.

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