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

Abstract

ObjectiveTo assess adverse events (AEs) and safety of aripiprazole (ARI) and olanzapine (OLA) treatment.MethodsTwenty‐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.ResultsARI 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 in ADRA2A, COMT, DRD3 and HTR2A genes 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, UGT1A1 and CYP1A2 polymorphisms had a role in the development of ADRs.ConclusionsOLA 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.

The pharmacogenetics of the new-generation antipsychotics – A scoping review focused on patients with severe psychiatric disorders

“…The incidence of akathisia was higher in DRD3 rs6280 Ser/Ser homozygotes vs. Gly allele carriers and asthenia appeared more often in DRD2 rs1799732 G/- subjects vs. G/G homozygotes ( 81 ).…”

“…Aripiprazole was associated with a higher diastolic blood pressure lowering effect in healthy volunteers participating in a phase I trial who presented a polymorphism in the serotonergic 5HT2A receptors (HTR2A rs6313C genotype) and one in the α2 adrenergic receptors gene (ADRA2A rs1800544 C/C vs. T/T or C/G) ( 81 ). This observation may be explained by the participation of alpha-2 receptors and 5HT2A receptors in vasodilatation and sympathetic cardiovascular regulation ( 81 ).…”

“…Another association was found between CYP1A2 NM/RM (normal metabolizers/rapid metabolizers) phenotype vs. UM (ultrarapid metabolizers) and reports of insomnia during aripiprazole administration ( 81 ). This observation is interesting because aripiprazole is not metabolized by CYP1A2 ( 81 ).…”

The Relationship between the Second-Generation Antipsychotics Efficacy and the Traditional Chinese Medicine Body Constitutions in Patients with Schizophrenia

“…Some studies proposed that possessing Stasis BC is significantly associated with hyperlipidaemia, atherosclerosis, coronary heart disease, or coronary artery disease [38][39][40]. Several studies demonstrated that olanzapine is a relatively unsafe drug, especially for patients who have coronary heart disease [41][42][43][44]. In addition, some research showed that antipsychotic drug use is associated with acute myocardial infarction and stroke [45][46][47][48].…”

PriME-PGx: La Princesa University Hospital Multidisciplinary Initiative for the Implementation of Pharmacogenetics

“…Thanks to the availability of these data (i.e., the outcomes of the clinical trials) and the informed consent of the healthy volunteers, a valuable source of information is available for pharmacogenetic research. In the last decade, our group contributed to the expansion of available pharmacogenetic knowledge with numerous publications [36,37,[41][42][43][44][45][46][47].…”