Effects And Mechanisms Of Different Atypical Antipsychotic Agents On Glucose And Lipid Metabolism In Schizophrenic Patients

OBJECTIVE:To compare the effects of clozapine, risperidone and olanzapine on the levels of body mass index (BMI), waist hip rate (WHR), fasting serum glucose (FBS), fasting insulin concentration (FINS), homeostasis model assessment of insulin resistance (HOMA-IR), triglycerides (TG), total cholesterol (TC), low- density lipoprotein cholesterol (LDL), high- density lipoprotein cholesterol (HDL), leptin, ghrelin and FGF21 in inpatients with schizophrenia; To investigate the relationship between BMI and the parameters involved in glucose and lipid metabolism in subjects; To prove that lipid metabolism disturbance is not the only cause that induces insulin resistance and glucose metabolism disturbance; To further explore the mechanism of atypical antipsychotic agents (APS) induced insulin resistance.METHODS:74 Chinese inpatients with schizophrenia, treated on monotherapy with clozapine (n=27), risperidone (n=19) and olanzapine (n=13) as monotherapy for at least one year or unmedicated (n=15), were recruited; Levels of BMI, WHR, FBS, FINS, HOMA-IR, TG, TC, LDL, HDL, leptin, ghrelin and FGF21 were measured; The relationship between BMI and these parameters were calculated by Spearman rank correlation; As a cell culture model of liver, the main insulin- sensitive target tissue, we analyzed glucose uptake, glycogen synthesis and several steps of the insulin- signaling cascade in adult mouse liver cells.RESULTS:(1) A significant difference in the mean levels of BMI and WHR was found between four groups. In post hoc test, it was seen that clozapine- treated group and olanzapine- treated group had higher levels of BMI and WHR than risperidone- treated group and control group; (2) In the comparison of the mean values of FBS, FINS and HOMA-IR levels between four groups, there was no statistically significant difference between groups. But, it could be seen that the clozapine- treated group had a highest level of FBS and the olanzapine-treated group had a highest level of FINS. We also found that there are some insulin resistance subjects with normal BMI; (3) There was no statistically significant difference between groups in the comparison of the mean levels of TC, TG and LDL. But a statistically significant difference between groups in the serum HDL level was found and there was a highest level of HDL in clozapine-treated group, compared to olanzapine-treated group, risperidone-treated group and control group; (4) There was a significant difference in the level of leptin, highest in clozapine-treated group; no significant increase of serum level was found between groups, but we also that there was a higher level of leptin in the drug-treated group, compared to control group; (5) There was no significant correlation between the values of FGF and BMI. But a positive correlation was found between WHR,FBS,FINs,HOMA-IR,TC,TG,LDL,ghrelin,leptin leves and BMI. A negative correlation was found between HDL and BMI; (6) Clozapine, risperidone and olanzapine inhibited glucose uptake and glycogen synthesis in a time-and dose-dependent manner with insulin stimulation; (7) Clozapine, risperidone and olanzapine did not affect the expression of IRS-1 mRNA with insulin stimulation.CONCLUSION:Treatment with SGAs is associated with abnormal glucose and lipid metabolism in inpatients with schizophrenia. In addition, abnormal lipid metabolism is not the only reason of inducing the glucose metabolism disturbance in schizophrenia patients with long-term monotherapy with SGAs. Clozapine, risperidone and olanzapine can induce the insulin resistance in mouse liver cells.