Neutrophil-to-lymphocyte ratio in schizophrenia: A systematic review and meta-analysis

Karageorgiou, Vasilios; Milas, Gerasimos Panagiotis; Michopoulos, Ioannis

doi:10.1016/j.schres.2018.12.017

Cited by 100 publications

(96 citation statements)

References 54 publications

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“…Of note, because we can only derive proportion of cell types from whole blood DNA methylation data, and not actual counts, an increase in one or more cell types must be balanced by a decrease in one or more other cell types and an apparrent change in the proportion of one specific cell type does not mean that the actual abundance of that cell type is altered. Despite this, the results from DNA methylation-derived cell proportions are consistent with previous studies based on empirical cell abundance measures which have reported increased monocyte counts 67,68 , increased neutrophil counts 69,70 , increased monocyte to lymphocyte ratio 71,72 and increased neutrophil to lymphocyte ratio 71,73 in both schizophrenia and FEP patients compared to controls. Studies have also shown that higher neutrophil counts in schizophrenia patients correlate with a greater burden of positive symptoms 69 suggesting that variations in the number of neutrophils is a potential marker of disease severity 72 .…”

Section: Discussionsupporting

confidence: 88%

Large-scale analysis of DNA methylation identifies cellular alterations in blood from psychosis patients and molecular biomarkers of treatment-resistant schizophrenia

Hannon

Dempster

Mansell

et al. 2020

Preprint

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Objective:Psychosis -a complex and heterogeneous neuropsychiatric condition characterized by hallucinations and delusions -is a common feature of schizophrenia. There is evidence for altered DNA methylation (DNAm) associated with schizophrenia in both brain and peripheral tissues. We aimed to undertake a systematic analysis of variable DNAm associated with psychosis, schizophrenia, and treatmentresistant schizophrenia, also exploring measures of biological ageing, smoking, and blood cell composition derived from DNAm data to identify molecular biomarkers of disease. Methods:We quantified DNAm across the genome in blood samples from 4,483 participants from seven casecontrol cohorts including patients with schizophrenia or first-episode psychosis. Measures of biological age, cellular composition and smoking status were derived from DNAm data using established algorithms. DNAm and derived measures were analyzed within each cohort and the results combined by meta-analysis. Results:Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNAm data, with the largest differences seen in treatment-resistant schizophrenia patients. DNAm at 95 CpG sites was significantly different between psychosis cases and controls, with 1,048 differentially methylated positions (DMPs) identified between schizophrenia cases and controls. Schizophrenia-associated DMPs colocalize to regions identified in genetic association studies, with genes annotated to these sites enriched for pathways relevant to disease. Finally, a number of the schizophrenia associated differences were only present in the treatment-resistant schizophrenia subgroup. Conclusions:We show that DNAm data can be leveraged to derive measures of blood cell counts and smoking that are strongly associated with psychosis. Our DNAm meta-analysis identified multiple DMPs associated with both psychosis and a more refined diagnosis of schizophrenia, with evidence for differential methylation associated with treatment-resistant schizophrenia that potentially reflects exposure to clozapine.

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Section: Discussionsupporting

confidence: 88%

Large-scale analysis of DNA methylation identifies cellular alterations in blood from psychosis patients and molecular biomarkers of treatment-resistant schizophrenia

Hannon

Dempster

Mansell

et al. 2020

Preprint

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“…This difference may indicate more active secretion and loading of EVs in psychotic patients. According to two recent meta-analyses, the neutrophil-to-lymphocyte ratio is increased in patients with non-affective psychosis and schizophrenia (Karageorgiou, Milas & Michopoulos, 2019;Mazza et al, 2019), and several studies have shown other types of inflammation and immune alterations in psychotic patients (Karageorgiou, Milas & Michopoulos, 2019;Kroken et al, 2018;Pillinger et al, 2018) in line with our GO analyses. Possible mechanisms could be promotion of inflammation and immune activation by EVs trough their regulatory role or inflammation stimulating EV secretion from immune cells and tissues (Slomka et al, 2018).…”

Section: Go Analysissupporting

confidence: 89%

Extracellular vesicles in patients in the acute phase of psychosis and after clinical improvement: an explorative study

Tunset

Haslene‐Hox

Bossche

et al. 2020

PeerJ

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Extracellular vesicles (EVs) are cell-derived structures that transport proteins, lipids and nucleic acids between cells, thereby affecting the phenotype of the recipient cell. As the content of EVs reflects the status of the originating cell, EVs can have potential as biomarkers. Identifying EVs, including their cells of origin and their cargo, may provide insights in the pathophysiology of psychosis. Here, we present an in-depth analysis and proteomics of EVs from peripheral blood in patients (n = 25) during and after the acute phase of psychosis. Concentration and protein content of EVs in psychotic patients were twofold higher than in 25 age- and sex-matched healthy controls (p < 0.001 for both concentration and protein content), and the diameter of EVs was larger in patients (p = 0.02). Properties of EVs did not differ significantly in blood sampled during and after the acute psychotic episode. Proteomic analyses on isolated EVs from individual patients revealed 1,853 proteins, whereof 45 were brain-elevated proteins. Of these, five proteins involved in regulation of plasticity of glutamatergic synapses were significantly different in psychotic patients compared to controls; neurogranin (NRGN), neuron-specific calcium-binding protein hippocalcin (HPCA), kalirin (KALRN), beta-adducin (ADD2) and ankyrin-2 (ANK2). To summarize, our results show that peripheral EVs in psychotic patients are different from those in healthy controls and point at alterations on the glutamatergic system. We suggest that EVs allow investigation of blood-borne brain-originating biological material and that their role as biomarkers in patients with psychotic disorders is worthy of further exploration.

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“…Neutrophil-tolymphocyte ratio (NLR) is a simple and inexpensive marker of systemic inflammation. The inflammation hypothesis of schizophrenia is supported by the significant increase of NLR both in FEP patients and in chronic cases (13). Immune dysregulation could represent a vulnerability factor for schizophrenia (14,15) and Th1 and Th2 imbalance is a reported immunological alteration in schizophrenia patients (16,17).…”

Section: Introductionmentioning

confidence: 99%

Elevated Osteopontin and Interferon Gamma Serum Levels and Increased Neutrophil-to-Lymphocyte Ratio Are Associated With the Severity of Symptoms in Schizophrenia

et al. 2020

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Inflammation and immune dysregulation could contribute to the pathogenesis of schizophrenia. Osteopontin (OPN) is a cytokine-like glycoprotein involved in inflammation and in modulating immune responses, and it can also directly modify the cytokine expression and survival of microglia. Furthermore, elevated gene expression of OPN in first episode psychosis has recently been described, but to date OPN level has not been investigated in schizophrenia. Imbalance of T-helper subtypes could also represent a vulnerability factor for schizophrenia. In this study, we analyzed the concentration of OPN, levels of cytokines associated with T-helper subtypes: interferon gamma (IFNy) for Th1, interleukin (IL)-10 for Th2, IL-8 for Th17, and neutrophil-to-lymphocyte ratio (NLR) in 22 patients with schizophrenia assessed for the intensity of their symptoms by the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression scale (CGI) scores. Serum OPN, IFNy, IL-10, and IL-8 concentrations were measured by ELISA kits and NLR was calculated from blood count. We found significant correlation between the level of OPN and PANSS-total and PANSS-general scores. IFNy level and NLR showed significant correlation with PANSS-total, PANSS-positive, PANSS-general, and CGI score. Among the measured markers antipsychotic therapy only had significant effects on NLR and OPN level, both of which were significantly reduced after long-term antipsychotic treatment. Our results indicate that elevated OPN and IFNy concentrations, and increased NLR are associated with severe symptoms in schizophrenia and suggest the importance of Th1 subtype in patients with high PANSS-positive and PANSS-general subscore. Significant correlation between NLR and PANSS scores strengthens the inflammation hypothesis of schizophrenia.

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Neutrophil-to-lymphocyte ratio in schizophrenia: A systematic review and meta-analysis

Cited by 100 publications

References 54 publications

Large-scale analysis of DNA methylation identifies cellular alterations in blood from psychosis patients and molecular biomarkers of treatment-resistant schizophrenia

Large-scale analysis of DNA methylation identifies cellular alterations in blood from psychosis patients and molecular biomarkers of treatment-resistant schizophrenia

Extracellular vesicles in patients in the acute phase of psychosis and after clinical improvement: an explorative study

Elevated Osteopontin and Interferon Gamma Serum Levels and Increased Neutrophil-to-Lymphocyte Ratio Are Associated With the Severity of Symptoms in Schizophrenia

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