olanzapine and Lipid-Metabolism-Disorders

Metabolic syndrome and elevated lipids, related to cardiovascular risk factors, are more prevalent in schizophrenia and there has been much debate about the extent to which specific antipsychotics contribute more to the increased risk of developing hyperlipidemia and metabolic syndrome. Most studies have concentrated on fasting levels in patients recently started on medication. Randomized prospective studies of metabolic effects of 2nd generation antipsychotics using both fasting measures and provocative tests may provide results that are more informative. We present results of a randomized prospective study of lipid metabolism and metabolic syndrome in chronic schizophrenic patients using both fasting and post-prandial lipid measures.. Hospitalized patients with chronic schizophrenia, most of whom had been treated with multiple antipsychotics in the past, were randomly assigned to treatment with a single antipsychotic, olanzapine or risperidone, for a period of 5 months. At baseline and every treatment month thereafter, fasting levels of lipids, free fatty acid (FFA) and leptin were assessed. At baseline and end of month 2 of treatment patients had a fatty meal test (FMT) in which postprandial lipids were measured at several time points before and after meal ingestion. Weight was assessed monthly and waist measures were taken at baseline and month 5. Data was analyzed on 23 patients randomized to risperidone and 23 patients randomized to olanzapine.. Overall, there were no differential drug effects on any fasting lipid measure and fasting triglycerides did not increase in olanzapine treated patients after 5 months of treatment. However, at 2 months of drug treatment the FMT revealed a significantly greater increase in triglycerides, and very low density (VLDL) cholesterol and triglycerides, in olanzapine compared to risperidone patients (Ps=.05-.01). There was no difference between treatments with olanzapine vs. risperidone on development of metabolic syndrome during the 5 month treatment period.. Chronic schizophrenic patients treated for years with first and second generation antipsychotics may have developed tolerance to the effects of olanzapine on increasing fasting triglycerides and other lipids, but some underlying metabolic abnormalities may be revealed in postprandial tests of lipid metabolism. These findings suggest that the development of standardized tests and criteria for measurement of postprandial triglycerides and related lipid levels, in addition to fasting levels, may be helpful in identifying metabolic effects of olanzapine and other second generation antipsychotics in chronically treated schizophrenics. In some reports postprandial increases in triglycerides have been identified as important risk factors for cardiovascular disease, but the actual differential consequences of these lipid metabolic differences for development of atherosclerosis and cardiovascular disease in patients treated with different antipsychotics need more objective outcome measures to determine and quantify cardiovascular risk outcomes.

Topics: Antipsychotic Agents; Benzodiazepines; Blood Pressure; Body Mass Index; Chronic Disease; Double-Blind Method; Female; Follow-Up Studies; Humans; Lipid Metabolism; Lipid Metabolism Disorders; Male; Models, Statistical; Multivariate Analysis; Olanzapine; Risperidone; Schizophrenia

Chronic treatment with second-generation antipsychotic drugs (SGAs) has been associated with an increased risk of metabolic syndrome. To evaluate the longitudinal changes in glucose-lipid homeostasis after SGA use, we studied the time-dependent effects of olanzapine (OLZ) (3 mg/kg, b.i.d.) or clozapine (CLZ) (20 mg/kg, b.i.d.) treatment on metabolic profiles for 9 weeks in rats. Although only OLZ significantly increased body weight in rats, both OLZ and CLZ elevated blood lipid levels. Chronic OLZ treatment induced significant weight gain leading to a higher fasting insulin level and impaired glucose tolerance, whereas CLZ lowered fasting insulin levels and impaired glucose tolerance independent of weight gain. Treatment with both drugs deranged AKT/GSK phosphorylation and up-regulated muscarinic M3 receptors in the rats' livers. Consistent with an elevation in lipid levels, both OLZ and CLZ significantly increased the protein levels of nuclear sterol regulatory element-binding proteins (SREBPs) in the liver, which was associated with improvement in hepatic histamine H1R. However, enhanced carbohydrate response element binding protein (ChREBP) signalling was observed in only CLZ-treated rats. These results suggest that SGA-induced glucose-lipid metabolic disturbances could be independent of weight gain, possibly through activation of SREBP/ChREBP in the liver.

Topics: Adipose Tissue, White; Animals; Antipsychotic Agents; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Blood Glucose; Clozapine; Disease Models, Animal; Glucose; Glucose Metabolism Disorders; Humans; Lipid Metabolism; Lipid Metabolism Disorders; Liver; Metabolic Networks and Pathways; Olanzapine; Rats; Sterol Regulatory Element Binding Proteins; Weight Gain