| 1 | Schizophr. Res. 2008 Jul 102: 352-5 |
|---|---|
| PMID | 18486454 |
| Title | Patients with schizophrenia show raised serum levels of the pro-inflammatory chemokine CCL2: association with the metabolic syndrome in patients? |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2008 Apr 32: 710-4 |
| PMID | 18096286 |
| Title | Increased serum levels of CCL11/eotaxin in schizophrenia. |
| Abstract | Inflammatory and immune alterations occur and may be relevant in patients with schizophrenia. Chemokines are a subgroup of cytokines that play a major role in the recruitment of determined subsets of leukocytes into tissues. To date no study has evaluated whether levels of chemokines are altered in patients with schizophrenia. To evaluate serum levels of CC and CXC chemokines of schizophrenic patients and age- and gender-matched controls. Forty male institutionalized schizophrenic patients (mean+/-SD age, 52.3+/-9.9) and 20 asymptomatic matched controls were recruited for this study. Severity of symptoms was assessed using BPRS, PANSS and AIMS. All patients were under typical antipsychotic treatment. Serum concentrations of chemokines were measured by ELISA. There was no statistical difference in serum levels of CCL2, CCL3, CCL24, CXCL9 and CXCL10 between controls and patients. Serum levels of CCL11 were increased in schizophrenic patients when compared to controls. Serum levels of chemokines were not correlated with the length of disease or hospitalization and the severity of involuntary movements, positive and/or negative symptoms. CCL11 is a ligand for CCR3, a receptor expressed preferentially on Th2 lymphocytes, mast cells and eosinophils. Higher serum levels of CCL11 in schizophrenia reinforce the view that this disease may be associated with a Th1/Th2 imbalance with a shift toward a Th2 immune response. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2008 Apr 32: 710-4 |
| PMID | 18096286 |
| Title | Increased serum levels of CCL11/eotaxin in schizophrenia. |
| Abstract | Inflammatory and immune alterations occur and may be relevant in patients with schizophrenia. Chemokines are a subgroup of cytokines that play a major role in the recruitment of determined subsets of leukocytes into tissues. To date no study has evaluated whether levels of chemokines are altered in patients with schizophrenia. To evaluate serum levels of CC and CXC chemokines of schizophrenic patients and age- and gender-matched controls. Forty male institutionalized schizophrenic patients (mean+/-SD age, 52.3+/-9.9) and 20 asymptomatic matched controls were recruited for this study. Severity of symptoms was assessed using BPRS, PANSS and AIMS. All patients were under typical antipsychotic treatment. Serum concentrations of chemokines were measured by ELISA. There was no statistical difference in serum levels of CCL2, CCL3, CCL24, CXCL9 and CXCL10 between controls and patients. Serum levels of CCL11 were increased in schizophrenic patients when compared to controls. Serum levels of chemokines were not correlated with the length of disease or hospitalization and the severity of involuntary movements, positive and/or negative symptoms. CCL11 is a ligand for CCR3, a receptor expressed preferentially on Th2 lymphocytes, mast cells and eosinophils. Higher serum levels of CCL11 in schizophrenia reinforce the view that this disease may be associated with a Th1/Th2 imbalance with a shift toward a Th2 immune response. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | J Affect Disord 2010 Oct 126: 312-6 |
| PMID | 20451256 |
| Title | A genome-wide association study of bipolar disorder in Norwegian individuals, followed by replication in Icelandic sample. |
| Abstract | In the present study we investigated genetic variants associated with bipolar disorder in a homogenous Norwegian sample, and potential genetic overlap with schizophrenia, using the Affymetrix 6.0 array. We carried out a genome-wide association study (GWAS) by genotyping 620 390 single-nucleotide polymorphisms (SNPs) in a case-control sample of Norwegian origin (the TOP study) including bipolar disorder (n=194), healthy controls (n=336) and schizophrenia (n=230), followed by replication and combined analysis in a genetically concordant Icelandic sample of bipolar disorder (n=435), and healthy controls (n=10,258). We selected 1000 markers with the lowest P values in the TOP discovery GWAS and tested these (or their surrogates) for association in the Icelandic replication sample. Polymorphisms on 35 loci were confirmed associated with bipolar disorder (nominal P value<0.05; not corrected for multiple testing) in the replication sample. The most significant markers were located in DLEU2, GUCY1B2, PKIA, CCL2, CNTNAP5, DPP10, and FBN1. The combined group of schizophrenia and bipolar disorder compared to controls did not provide additional significant findings. Relatively small number of samples. We detected weak but reproducible association with markers in several genes, in proximity to susceptibility loci found in previous GWAS studies of bipolar disorder. Further work is required to study their localization, expression, and regulation and international meta-analytic efforts will help to further elucidate their role. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | Psychoneuroendocrinology 2012 Dec 37: 1901-11 |
| PMID | 22541717 |
| Title | Increased level of serum cytokines, chemokines and adipokines in patients with schizophrenia is associated with disease and metabolic syndrome. |
| Abstract | At present there are strong indications of a shared vulnerability factor for schizophrenia (SZ), diabetes and the metabolic syndrome (metS). In this study we focus on an aberrantly activated monocyte/macrophage system as the shared factor. We measured in SZ patients (n=144), the serum levels of monocyte/macrophage cytokines/chemokines/adipokines CCL2, CCL4, IL-1?, TNF-?, IL-6, PTX3, leptin, adiponectin, PAI-1, OPG and ICAM-1 and compared these levels to healthy controls (HC) (n=138). Using multivariate analysis, we studied the effect of the presence of the disease SZ, the components of the metS including BMI, the levels of lipids (HDL cholesterol and triglycerides (TG)), diabetes (hyperglycemia) and the use of antipsychotic medication, on the serum levels of these immune compounds. We found all measured immune compounds with the exception of PAI-1 and OPG to be elevated in the SZ patient population. Multivariate analysis showed that elevations were linked to gender (ICAM-1, leptin, TNF-? and adiponectin), an increased BMI (leptin, adiponectin), hyperglycemia/diabetes (CCL4, and OPG), reduced HDL-cholesterol or increased levels of TG (adiponectin and PTX3) or the metS (CCL2, leptin and adiponectin). IL-1? and IL-6 were the only immune compounds raised in the serum of patients not affected by any of the included factors. Although many of the immune compounds were found linked to (components of) the metS, the most dominant linkage was found with the disease schizophrenia, confirming earlier reports on increased monocyte/macrophage activation as a key component for understanding the pathogenesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 6 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2014 Jun 51: 153-8 |
| PMID | 24495780 |
| Title | A pharmacogenetic study of risperidone on chemokine (C-C motif) ligand 2 (CCL2) in Chinese Han schizophrenia patients. |
| Abstract | Previous observations of the pathophysiological distribution and pharmacological profile of the chemokine (C-C motif) ligand 2 (CCL2) have indicated its potential role in antipsychotic drug actions. More information on the pharmacogenetics of CCL2 may therefore be useful in developing individualized therapy. However, to our knowledge, rare studies have been reported in this area. This investigation was attempted to clarify whether CCL2 polymorphism could affect risperidone efficacy. We genotyped four SNPs (rs4795893, rs1024611, rs4586 and rs2857657) distributed throughout the CCL2 gene and examined them for association using the Positive and Negative Syndrome Scale (PANSS) score in two independent cohorts of Chinese schizophrenic patients (n = 208) from two different geographic areas, following an 8-week period of risperidone monotherapy. We found that all genotyped SNPs were significantly associated with risperidone treatment (rs4795893: p = 1.66E-04, rs4586: p = 0.001, rs2857657: p = 0.004, at week 4, in ANOVA). Our results indicate that there may be some effect of variations in the CCL2 gene on therapeutic efficacy of risperidone, and the associated polymorphisms may be a potential genetic marker for predicting the therapeutic effect of risperidone. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 7 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2014 Jun 51: 153-8 |
| PMID | 24495780 |
| Title | A pharmacogenetic study of risperidone on chemokine (C-C motif) ligand 2 (CCL2) in Chinese Han schizophrenia patients. |
| Abstract | Previous observations of the pathophysiological distribution and pharmacological profile of the chemokine (C-C motif) ligand 2 (CCL2) have indicated its potential role in antipsychotic drug actions. More information on the pharmacogenetics of CCL2 may therefore be useful in developing individualized therapy. However, to our knowledge, rare studies have been reported in this area. This investigation was attempted to clarify whether CCL2 polymorphism could affect risperidone efficacy. We genotyped four SNPs (rs4795893, rs1024611, rs4586 and rs2857657) distributed throughout the CCL2 gene and examined them for association using the Positive and Negative Syndrome Scale (PANSS) score in two independent cohorts of Chinese schizophrenic patients (n = 208) from two different geographic areas, following an 8-week period of risperidone monotherapy. We found that all genotyped SNPs were significantly associated with risperidone treatment (rs4795893: p = 1.66E-04, rs4586: p = 0.001, rs2857657: p = 0.004, at week 4, in ANOVA). Our results indicate that there may be some effect of variations in the CCL2 gene on therapeutic efficacy of risperidone, and the associated polymorphisms may be a potential genetic marker for predicting the therapeutic effect of risperidone. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 8 | Transl Psychiatry 2014 -1 4: e406 |
| PMID | 24984193 |
| Title | Increased M1/decreased M2 signature and signs of Th1/Th2 shift in chronic patients with bipolar disorder, but not in those with schizophrenia. |
| Abstract | We here present data on immune gene expression of chemokines, chemokine receptors, cytokines and regulatory T-cell (T-reg) markers in chronic patients suffering from either schizophrenia (SCZ, N=20) or bipolar disorder (BD=20) compared with healthy controls (HCs, N=20). We extracted RNA from peripheral blood mononuclear cells and performed real-time (RT)-PCR to measure mRNA levels of chemokines, chemokine receptors, cytokines and T-reg markers. All the analyses were Bonferroni-corrected. The classical monocyte activation (M1) markers il6, ccl3 were significantly increased in BD as compared with both HC and SCZ patients (P=0.03 and P=0.002; P=0.024 and P=0.021, respectively), whereas markers of alternative (M2) monocyte activation ccl1, CCL22 and il10 were coherently decreased (controls: P=0.01, P=0.001 and P=0.09; SCZ subjects: P=0.02, P=0.05 and P=0.011, respectively). Concerning T-cell markers, BD patients had compared with HC downregulated ccr5 (P=0.02) and upregulated il4 (P=0.04) and compared with both healthy and SCZ individuals downregulated CCL2 (P=0.006 and P=0.003) and tgf? (P=0.004 and P=0.007, respectively). No significant associations were found between any immune gene expression and clinical variables (prior hospitalizations, Brief Psychiatric Rating Scale, medications' dosages and lifetime administration). Although some markers are expressed by different immune cell types, these findings suggest a coherent increased M1/decrease M2 signature in the peripheral blood of BD patients with potential Th1/Th2 shift. In contrast, all the explored immune marker levels were preserved in SCZ. Further larger studies are needed to investigate the relevance of inflammatory response in BD, trying to correlate it to psychopathology, treatment and outcome measures and, possibly, to brain connectivity. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 9 | J Neuroinflammation 2014 -1 11: 128 |
| PMID | 25069615 |
| Title | Cytokine pathway disruption in a mouse model of schizophrenia induced by Munc18-1a overexpression in the brain. |
| Abstract | An accumulating body of evidence points to the significance of neuroinflammation and immunogenetics in schizophrenia, and an imbalance of cytokines in the central nervous system (CNS) has been suggested to be associated with the disorder. Munc18-overexpressing mice (Munc18-OE) have provided a model for the study of the alterations that may underlie the symptoms of subjects with schizophrenia. The aim of the present study was to elucidate the involvement of neuroinflammation and cytokine imbalance in this model. Cytokines were evaluated in the cortex and the striatum of Munc18-OE and wild-type (WT) mice by enzyme-linked immunosorbent assay (ELISA). Protein levels of specific microglia and macrophage, astrocytic and neuroinflammation markers were quantified by western blot in the cortex and the striatum of Munc18-OE and WT mice. Each cytokine evaluated (Interferon-gamma (IFN-?), Tumor Necrosis Factor-alpha (TNF-?), Interleukin-2 (IL-2) and CCL2 chemokine) was present at higher levels in the striatum of Munc18-OE mice than WT. Cortical TNF-? and IL-2 levels were significantly lower in Munc18-OE mice than WT mice. The microglia and macrophage marker CD11b was lower in the cortexes of Munc18-OE mice than WT, but no differences were observed in the striatum. Glial Fibrillary Acidic Protein (GFAP) and Nuclear Factor-kappaB (NF-?B)p65 levels were not different between the groups. Interleukin-1beta (IL-1?) and IL-6 levels were beneath detection limits. The disrupted levels of cytokines detected in the brain of Munc18-OE mice was found to be similar to clinical reports and endorses study of this type for analysis of this aspect of the disorder. The lower CD11b expression in the cortex but not in the striatum of the Munc18-OE mice may reflect differences in physiological activity. The cytokine expression pattern observed in Munc18-OE mice is similar to a previously published model of schizophrenia caused by maternal immune activation. Together, these data suggest a possible role for an immune imbalance in this disorder. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 10 | Neurosci Biobehav Rev 2014 May 42: 93-115 |
| PMID | 24513303 |
| Title | Chemokines and chemokine receptors in mood disorders, schizophrenia, and cognitive impairment: a systematic review of biomarker studies. |
| Abstract | The search for immune biomarkers in psychiatric disorders has primarily focused on pro-inflammatory cytokines. Other immune proteins including chemokines have been relatively neglected in such studies. Recent evidence has implicated chemokines in many neurobiological processes potentially relevant to psychiatric disorders, beyond their classical chemotactic functions. These may include neuromodulator effects, neurotransmitter-like effects, and direct/indirect regulation of neurogenesis. This systematic review presents the existing early evidence which supports an association of many chemokines with the psychiatric disorders: depression, bipolar disorder, schizophrenia, mild cognitive impairment and Alzheimer's disease. The non-specific association of chemokines including CXCL8 (IL-8), CCL2 (MCP-1), CCL3 (MIP-1?) and CCL5 (RANTES) with these disorders across diagnostic categories implies a generalised involvement of many chemokine systemic with psychiatric disease. Additional chemokines with great mechanistic relevance including CXCL12 (SDF-1) and CX3CL1 (fractalkine) have been rarely reported in the existing human literature and should be included in future clinical studies. The potential utility of these proteins as pathologically relevant biomarkers or therapeutic targets should be considered by future clinical and translational research. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 11 | Front Cell Neurosci 2015 -1 9: 357 |
| PMID | 26441528 |
| Title | Systematic Review of the Neurobiological Relevance of Chemokines to Psychiatric Disorders. |
| Abstract | Psychiatric disorders are highly prevalent and disabling conditions of increasing public health relevance. Much recent research has focused on the role of cytokines in the pathophysiology of psychiatric disorders; however, the related family of immune proteins designated chemokines has been relatively neglected. Chemokines were originally identified as having chemotactic function on immune cells; however, recent evidence has begun to elucidate novel, brain-specific functions of these proteins of relevance to the mechanisms of psychiatric disorders. A systematic review of both human and animal literature in the PubMed and Google Scholar databases was undertaken. After application of all inclusion and exclusion criteria, 157 references were remained for the review. Some early mechanistic evidence does associate select chemokines with the neurobiological processes, including neurogenesis, modulation of the neuroinflammatory response, regulation of the hypothalamus-pituitary-adrenal axis, and modulation of neurotransmitter systems. This early evidence however does not clearly demonstrate any specificity for a certain psychiatric disorder, but is primarily relevant to mechanisms which are shared across disorders. Notable exceptions include CCL11 that has recently been shown to impair hippocampal function in aging?-?of distinct relevance to Alzheimer's disease and depression in the elderly, and pre-natal exposure to CXCL8 that may disrupt early neurodevelopmental periods predisposing to schizophrenia. Pro-inflammatory chemokines, such as CCL2, CCL7, CCL8, CCL12, and CCL13, have been shown to drive chemotaxis of pro-inflammatory cells to the inflamed or injured CNS. Likewise, CX3CL has been implicated in promoting glial cells activation, pro-inflammatory cytokines secretion, expression of ICAM-1, and recruitment of CD4+ T-cells into the CNS during neuroinflammatory processes. With further translational research, chemokines may present novel diagnostic and/or therapeutic targets in psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 12 | Mol Genet Genomic Med 2016 Jan 4: 18-27 |
| PMID | 26788534 |
| Title | Evaluation of genetic association of neurodevelopment and neuroimmunological genes with antipsychotic treatment response in schizophrenia in Indian populations. |
| Abstract | Neurodevelopmental and neuroimmunological genes critically regulate antipsychotic treatment outcome. We report genetic associations of antipsychotic response in 742 schizophrenia patients from Indian populations of Indo-European and Dravidian ancestry, segregated by disease severity. Meta-analysis comparing the two populations identified CCL2 [rs4795893: OR (95% CI) = 1.79 (1.27-2.52), P = 7.62 × 10(-4); rs4586: OR (95% CI) = 1.74 (1.24-2.43), P = 1.13 × 10(-3)] and GRIA4 [rs2513265: OR (95% CI) = 0.53 (0.36-0.78), P = 1.44 × 10(-3)] in low severity group; and, ADCY2 [rs1544938: OR (95% CI) = 0.36 (0.19-0.65), P = 7.68 × 10(-4)] and NRG1 [rs13250975, OR (95% CI) = 0.42 (0.23-0.79), P = 6.81 × 10(-3); rs17716295, OR (95% CI) = 1.78 (1.15-2.75), P = 8.71 × 10(-3)] in high severity group, with incomplete response toward antipsychotics. To our knowledge, this is the first study to identify genetic polymorphisms associated with the efficacy of antipsychotic treatment of schizophrenia patients from two major India populations. |
| SCZ Keywords | schizophrenia, schizophrenic |