The inflammatory response system in treatment-resistant schizophrenia: increased serum interleukin-6.
ABSTRACT There is some evidence that the pathophysiology of schizophrenia is related to activation of the inflammatory response system (IRS), as indicated by increased serum concentrations of interleukin-6 (IL-6), IL-6 receptor (IL-6R), IL-1R antagonist (IL-1RA) and IL-2R and lower serum concentrations of CC16, an endogenous anti-inflammatory protein with immunosuppressive and anti-inflammatory effects. The aims of the present study were to examine serum CC16 in relation to IL-6, IL-6R and gp130, the IL-6 transducing signal protein, in schizophrenia and in treatment-resistant schizophrenia (TRS). Serum IL-6 and sIL-6R were significantly higher in medicated schizophrenic patients than in normal controls. Serum IL-6 was significantly higher in TRS than in normal volunteers, whereas schizophrenic patients without TRS showed intermediate values. Serum CC16 was significantly lower in schizophrenic patients with a positive family history for psychoses than in normal volunteers and patients without a positive family history. There was a significant inverse relationship between serum CC16 and serum IL-6 or sIL-6R in schizophrenic patients, but not in normal volunteers. The results suggest that the inflammatory response in schizophrenia, as indicated by increased serum IL-6 and sIL-6R, may be causally related to lower serum CC16 and that the latter might be a trait marker for schizophrenia.
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ABSTRACT: OBJECTIVE: We recently reported that the type-2 cytokine response is increased in schizophrenia. The aim of this study was to analyse the effects of antipsychotic drugs on the serum levels of type-1 (TNF-α, IFN-γ), type-2 (IL-4, IL-10), type-17 (IL-17) and regulatory cytokines (TGF-β, IL-27 and IL-6). METHODS: Cytokine measurements in the patients were performed on day 0 and day 30 of the treatment using standard ELISA assays. Three groups of subjects were studied: patients that were unmedicated with First Episode Psychosis (FEP; n=88), patients that were treated with antipsychotics with Schizophrenia in relapse (SC in relapse; n=45) and healthy controls (n=36). RESULTS: TGF-β levels were increased in both patient groups and were further enhanced after treatment in the FEP group (p=0.014) but not in the SC relapse group. Antipsychotic treatment was correlated with lower levels of IL-4, IL-6 and IL-27 (p<0.005) in the FEP group. Finally, the serum levels of IL-17 were not significantly altered between the two measurements but were significantly lower in the FEP group (p<0.001) when compared with healthy controls. After therapy, patients with SC who were in relapse had decreased serum levels of IL-4 (p=0.006) and IL-6 (p=0.007). We also observed a weak negative correlation between the IFN-γ/TGF-β ratio and the total PANSS score and between the IL-17/TGF-β ratio and the negative and general psychopathology subscales. CONCLUSION: The increased type-2 cytokine serum levels in schizophrenia appear to be downregulated by antipsychotic treatment.Schizophrenia Research 04/2013; DOI:10.1016/j.schres.2013.03.027 · 4.43 Impact Factor
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ABSTRACT: Background: The variations in proinflamatory cytokine levels have been associated with schizophrenia (SCH), duration of illness, psychopathology and treatment. The aim of the study was to investigate serum levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in schizophrenic patients during exacerbation and remission, and its association with course of illness and therapy. Subjects and methods: We measured serum levels of IL-6 and TNF-α in 43 schizophrenic patients in exacerbation and remission and compared them to 29 healthy controls, matched by sex, age, body mass index (BMI) and smoking habits. The severity of psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS). Results: There was no difference in levels of IL-6 and TNF-α in exacerbation compared to remission in schizophrenic patients. IL-6 was higher and TNF-α was lower in schizophrenic patients in both exacerbation and remission in comparison with healthy controls. TNF-α in exacerbation was in negative correlation with IL-6 in remission. No statistical significance was found between levels of cytokines and sex, age, BMI, smoking habits, antipsychotic medication, duration of treatment and duration of illness. IL-6 levels were in positive correlation with the age of onset and the duration of untreated psychosis. In schizophrenic patients on adjunctive treatment with mood stabilizers, TNF-α levels increased in remission. Conclusion: Our results suggest that the connection between schizophrenia, cytokines and medication is multifaceted, and not necessarily linear. Adjunct mood stabilizers not only ameliorate psychopathology, but might convey immunomodulatory effects as well. Further longitudinal studies could elucidate potential beneficial effect of combined therapy in treatment of SCH.
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ABSTRACT: Schizophrenia is associated with increased oxidative stress, although the source of this redox disequilibrium requires further study. Altered tryptophan metabolism has been described in schizophrenia, possibly linked to inflammation and glutamate-directed excitotoxicity. Social isolation rearing (SIR) in rats induces various behavioural manifestations akin to schizophrenia, as well as altered frontal cortical glutamate N-methyl-d-aspartate (NMDA) receptor binding and increased oxidative stress, all reversed by antipsychotic treatment. Tryptophan is catabolized via the kynurenine pathway to kynurenine, 3-hydroxykynurenine, quinolinic acid (QA), kynurenic acid (KYNA), anthranilic acid and 3-hydroxyanthranilic acid (3-OHAA), ultimately contributing to neuronal integrity and redox balance in the brain. We studied tryptophan metabolism and neuroprotective-neurodegenerative balance in post-natal SIR rats, and its response to clozapine treatment. Male Sprague-Dawley (SD) rats (10 rats/group) were exposed to SIR or social rearing for 8 weeks, whereupon they received either sub-chronic vehicle or clozapine (5 mg/kg i.p) treatment. Plasma tryptophan metabolites were analysed by liquid-chromatography electrospray ionization tandem mass spectrometry. Plasma tryptophan, kynurenine, anthranilic acid, 3-OHAA and QA were significantly elevated in SIR vs. socially housed rats. KYNA and the neuroprotective ratio were significantly decreased. The latter implies a decrease in KYNA (neuroprotective) but an increase in QA (neurodegenerative) directed components of the pathway. Clozapine significantly reversed all the above alterations in SIR animals. Concluding, SIR in rats significantly disrupts tryptophan metabolism via the kynurenine pathway with increased risk for neurodegenerative changes in the brain. These changes are reversed by clozapine, emphasising the importance of these findings for the neurobiology and treatment of schizophrenia.Neuropharmacology 03/2012; 62(8):2499-506. DOI:10.1016/j.neuropharm.2012.02.021 · 4.82 Impact Factor