Atypical antipsychotics and gene expression in soft tissues

Background: Treatment of schizophrenia with atypical antipsychotics is frequently complicated by an increased incidence of weight gain, diabetes and an atherogenic lipid profile. Atypical antipsychotics such as olanzapine and ziprasidone have furthermore been shown to profoundly differ in their effects on weight and insulin sensitivity. So far, the precise mechanisms for these findings are not completely understood. Aims and Methods: To test, to which extent metabolic differences during treatment with atypical antipsychotics result from differences in gene expression. For this purpose, a genome-wide analysis of gene activity (expression profiling) will be performed. Gene expression profiles will be obtained from skeletal muscle and adipose tissue, both of which are known to be involved in glucose and lipid metabolism. Furthermore, adipokines and other metabolic mediators will be studied. The project will be performed as a single-centre, randomized, blinded, placebo-controlled study. Olanzapine (n=18), ziprasidone (n=18) or placebo (n=6) will be administered orally over 10 days to healthy male subjects. In vivo biopsies from skeletal muscle and subcutaneous fat will be taken pre- dose and after the first drug application on the first study day and once after the 10 days treatment period. Importance for clinical research and clinical practice: The results of this analysis will serve as the basis for future research in this field. New molecular targets could be identified, which could serve as early markers of metabolic disease or success of therapy applicable in a clinical setting. As psychiatric practice moves into an area of personalized medicine it might become increasingly more relevant to identify risk markers to screen patients at high risk for weight gain and metabolic changes. These results are relevant to primary and secondary prevention efforts that aim to address the multiple factors that contribute to increased prevalence of type 2 diabetes mellitus and cardiovascular disease in populations that are often treated with second-generation antipsychotic medications.

Treatment of schizophrenia with atypical antipsychotics is frequently complicated by an increased incidence of weight gain, diabetes and an atherogenic lipid profile. Atypical antipsychotics such as olanzapine and ziprasidone have furthermore been shown to profoundly differ in their effects on weight and insulin sensitivity. So far, the precise mechanisms for these findings are not completely understood. It was the aim of the present application to test, to which extent metabolic differences during treatment with atypical antipsychotics result from differences in gene expression. For this purpose, a genome-wide analysis of gene activity (expression profiling) was be performed. Gene expression profiles were obtained from skeletal muscle and adipose tissue, both of which are known to be involved in glucose and lipid metabolism. Furthermore, the role of adipokines was studied. The project was performed as a single-centre, randomized, blinded, placebo- controlled study. Olanzapine (n=6), ziprasidone (n=6) or placebo (n=4) was administered orally over 10 days to healthy male subjects. In vivo biopsies from skeletal muscle and subcutaneous fat were taken pre-dose and after the first drug application on the first study day and once after the 10 days treatment period. Due to methodological problems with the isolation of RNA from the obtained fat tissue samples, only data from skeletal muscle tissue are available. Study procedures and study drugs were well tolerated by the study participants. There was no effect of antipsychotics on weight or plasma adipokine concentrations compared with placebo or between antipsychotics. Genomewide analysis indicated changes in gene expression in genes involved in metabolism, although the results need to be confirmed in a larger study not only in healthy subjects but preferably also in patients with antipsychotic weight gain. The present analysis serves as the basis for future research in this field. Genome wide analysis has the potential to identify new molecular targets, which could serve as early markers of metabolic disease or success of therapy applicable in a clinical setting.