Metabolic effects of aripiprazole and olanzapine multiple-dose treatment in healthy volunteers. Association with pharmacogenetics.

Abstract

BackgroundAripiprazole and olanzapine are atypical antipsychotics. Both drugs can induce metabolic changes, however, the metabolic side effects produced by aripiprazole are more benign. ObjectivesTo evaluate if aripiprazole and olanzapine alter prolactin levels, lipid and glucose metabolism and hepatic, hematological, thyroid and renal function. MethodsTwenty-four healthy volunteers received 5 daily oral doses of 10 mg aripiprazole and 5 mg olanzapine in a crossover randomized clinical trial and were genotyped for 51 polymorphisms in 17 genes by qPCR. Drug plasma concentrations were measured by LC-MS. The biochemical and hematological analyses were performed by enzymatic methods. ResultsOlanzapine induced hyperprolactinemia but not aripiprazole. DRD3 Ser/Gly and ABCB1 rs10280101, rs12720067 and rs11983225 polymorphisms and CYP3A phenotype had an impact on plasma prolactin levels. C-peptide concentrations were higher after aripiprazole administration and were influenced by COMT rs4680 and rs13306278 polymorphisms. Olanzapine and the UGT1A1 rs887829 polymorphism were associated with elevated glucose levels. CYP3A poor metabolizers had increased insulin levels. Triglyceride concentrations were decreased due to olanzapine and aripiprazole treatment and were variable based on CYP3A phenotypes and the APOC3 rs4520 genotype. Cholesterol levels were also decreased and depended on HTR2A rs6314 polymorphism. All hepatic enzymes, platelet and albumin levels and prothrombin time were altered during both treatments. Additionally, olanzapine reduced the leucocyte count, aripiprazole increased free T4 and both decreased uric acid concentrations. ConclusionsShort term treatment with aripiprazole and olanzapine had a significant influence on the metabolic parameters. However, it seems that aripiprazole provokes less severe metabolic changes.