Safety and cardiovascular effects of multiple-dose administration of aripiprazole and olanzapine in a randomised clinical trial

Objective To assess adverse events (AEs) and safety of aripiprazole (ARI) and olanzapine (OLA) treatment. Methods Twenty-four healthy volunteers receiving five daily oral doses of 10 mg ARI and 5 mg OLA in a crossover clinical trial were genotyped for 46 polymorphisms in 14 genes by qPCR. Drug plasma concentrations were measured by high-performance liquid chromatography tandem mass spectrometry. Blood pressure (BP) and 12-lead electrocardiogram were measured in supine position. AEs were also recorded. Results ARI decreased diastolic BP on the first day and decreased QTc on the third and fifth day. OLA had a systolic and diastolic BP, heart rate and QTc lowering effect on the first day. Polymorphisms inADRA2A,COMT,DRD3andHTR2Agenes were significantly associated to these changes. The most frequent adverse drug reactions (ADRs) to ARI were somnolence, headache, insomnia, dizziness, restlessness, palpitations, akathisia and nausea while were somnolence, dizziness, asthenia, constipation, dry mouth, headache and nausea to OLA. Additionally,HTR2A,HTR2C,DRD2,DRD3,OPRM1,UGT1A1andCYP1A2polymorphisms had a role in the development of ADRs. Conclusions OLA induced more cardiovascular changes; however, more ADRs were registered to ARI. In addition, some polymorphisms may explain the difference in the incidence of these effects among subjects.