Cytokines And Olanzapine-induced Metabolic Adverse Effects In Schizophrenia

Objectives Olanzapine is first line medication among all the second generation antipsychotics for schizophrenia due to its superior efficacy.But it will lead to metabolic adverse effects so as to increase cardiovascular risk as well as reduce compliance of patients,which severely limits its clinical use.Cytokines are small proteins widely present in the organism function as signal transduction factors.They not only involved in inflammatory response,but are also closely associated with metabolic disorders.In recent years,cytokines and the second generation antipsychotics-induced metabolic adverse effects have drawn more and more attention.But the current studies mostly focused on one or a few cytokines,and the drug is mostly mixed rather than a single medication.In our study,we examined the effects of multiple cytokines(IFN-?,IL-1ra,IL-1?,IL-8,TNF-?,MCP-1,Leptin,VEGF)before and after olanzapine treatment once at a time,and explore their relationship with metabolic parameter changes.OBJECTIVE: To investigate whether cytokines are associated with olanzapine-induced metabolic adverse effects and whether cytokines can predict adverse effects of olanzapine treatment.Methods Using liquid suspension array technique,we measured 8 cytokines in serum before and after 4 weeks and 8 weeks' treatment in schizophrenia patients.The severity of the symptoms were assessed with the Positive and Negative Symptom Scale.According to the results of one-sample Kolmogorov-Smirnov test,two independent samples t-test was used to compare the age and BMI between SZ patients and health control group.The metabolic parameter levels and total score of the PANSS before and after treatment were analyzed by repeated-measured analysis of variance(RM-ANOVA).We used the Mann-Whitney U test to compare the levels of IL-1?,IL-8,IFN-?,and VEGF in the health control group and the patients before treatment.The levels of IFN-?,IL-8 and leptin were measured before and after treatment were analyzed by Friedman two-way analysis,and the levels of other cytokines were compared before and after treatment with RM-ANOVA.Depending on the circumstances,the correlation between the changes in metabolic parameters(post-treatment level minuses pre-treatment difference)with cytokine changes or baseline levels of cytokines was screened by Spearman or Pearson correlation analysis.The multiple linear regression analysis(MLR)method was used to explore the relationship between the changes of cytokines or baseline cytokine levels and metabolic parameter changes.Results 1.The levels of IL-1ra(P = 0.0001),MCP-1(P = 0.003)and VEGF(P = 0.014)were significantly increased in schizophrenia patients before treatment compared with health controls.There was no significant difference between SZ and HC in other cytokine levels.After 8 weeks of olanzapine treatment,there was no significant change in cytokine levels except Leptin(P <0.0001).2.The levels of BMI,fasting insulin,cholesterol,triglyceride,LDL,Apo B and leptin were significantly increased in patients with schizophrenia after 8 weeks of olanzapine treatment.The levels of IL-1ra before treatment were significantly correlated with the levels of cholesterol,LDL,Apo B and leptin changes(r = 0.576,p = 0.004;r = 0.567,p = 0.005;r = 0.490,p = 0.048;r = 0.524,P = 0.010).The independent predictive effect of IL-1ra was determined by multiple linear regression analysis with the patient's gender,age,and baseline BMI included as independent parameters: IL-1ra levels prior to treatment with cholesterol(adjusted R2 = 0.300,? = 0.576,P = 0.004),LDL(Adjusted R2 = 0.203,? = 0.490,P = 0.018),Apo B(adjusted R2 = 0.203,? = 0.490,P = 0.018)and leptin(adjusted R2 = 0.550,? = 0.540,P = 0.0012).There was no correlation between the level of the remaining cytokine before treatment and the amount of metabolic changes.There was no significant correlation between changes in cytokines and elevated metabolic index(BMI,fasting insulin,cholesterol,triglyceride,LDL,Apo B and leptin).In addition,the increase in leptin has a gender difference(adjusted R2 = 0.254,? = 0.562,P = 0.008)Conclusions 1.IL-1ra,MCP-1 and VEGF may be involved in the pathogenesis of schizophrenia.IL-1ra,MCP-1 and VEGF may be used as markers of schizophrenia and even as a potential for antipsychotic drugs target of action.2.There was a significant positive correlation between the level of IL-1ra prior to treatment and the increase in cholesterol,LDL,Apo B and leptin after 8 weeks of olanzapine treatment.The results suggest that IL-1ra may predict olanzapine-induced lipids and leptin metabolism abnormalities and may be potential biomarkers for cardiovascular risk assessment prior to olanzapine administration.