Metabolic Effects of Aripiprazole and Olanzapine Multiple-Dose Treatment in a Randomised Crossover Clinical Trial in Healthy Volunteers: Association with Pharmacogenetics

Abstract

Introduction Aripiprazole and olanzapine are atypical antipsychotics. Both drugs can induce metabolic changes; however, the metabolic side effects produced by aripiprazole are more benign. The aim of the study was to evaluate if aripiprazole and olanzapine alter prolactin levels, lipid and glucose metabolism and hepatic, haematological, thyroid and renal function. Methods Twenty-four healthy volunteers received a daily oral dose of 10 mg aripiprazole and 5 mg olanzapine tablets for 5 days in a crossover randomised clinical trial and were genotyped for 51 polymorphisms in 18 genes by qPCR. Drug plasma concentrations were measured by LC–MS. The biochemical and haematological analyses were performed by enzymatic methods. Results Olanzapine induced hyperprolactinaemia but aripiprazole did not. Dopamine D3 receptor ( DRD3 ) Ser/Gly and ATP binding cassette subfamily B member 1 ( ABCB1 ) rs10280101, rs12720067 and rs11983225 polymorphisms and cytochrome P450 3A (CYP3A) phenotype had an impact on plasma prolactin levels. C-peptide concentrations were higher after aripiprazole administration and were influenced by catechol- O -methyltransferase ( COMT ) rs4680 and rs13306278 polymorphisms. Olanzapine and the UDP glucuronosyltransferase family 1 member A1 ( UGT1A1 ) rs887829 polymorphism were associated with elevated glucose levels. CYP3A poor metabolizers had increased insulin levels. Volunteers’ weight decreased significantly during aripiprazole treatment and a tendency for weight gain was observed during olanzapine treatment. Triglyceride concentrations decreased as a result of olanzapine and aripiprazole treatment, and varied on the basis of CYP3A phenotypes and the apolipoprotein C-III ( APOC3 ) rs4520 genotype. Cholesterol levels were also decreased and depended on 5-hydroxytryptamine receptor 2A ( 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. Conclusions Short-term treatment with aripiprazole and olanzapine had a significant influence on the metabolic parameters. However, it seems that aripiprazole provokes less severe metabolic changes. Trial Registration Clinical trial registration number (EUDRA-CT): 2018-000744-26 Graphical Abstract Electronic Supplementary Material The online version of this article (10.1007/s12325-020-01566-w) contains supplementary material, which is available to authorized users.

Genetic Polymorphisms Associated With the Pharmacokinetics, Pharmacodynamics and Adverse Effects of Olanzapine, Aripiprazole and Risperidone

“…It is hypothesized that additional drug-mediated mechanisms are partially responsible for antipsychotic-induced weight gain ( Himmerich et al, 2015 ). Olanzapine-induced weight gain was observed even after only 5 days acute treatment in healthy volunteers ( Koller et al, 2021 ). Other studies observed a 0.9 kg per month weight gain in schizophrenic patients treated with olanzapine ( Lieberman et al, 2005 ) or a weight gain of 13.9 kg in patients after 1 year of olanzapine treatment ( Kahn et al, 2008 ).…”

“…Olanzapine is also known to increase the risk of developing type II diabetes ( Lambert et al, 2006 ; Koller et al, 2021 ). Its M3 receptor antagonism causes an alteration in glucose control and insulin response, and the blockade of the H1 receptor favors the development of insulin resistance.…”

“…Risperidone can cause hypotension ( Wilson et al, 2017 ), while olanzapine and aripiprazole usually do not affect blood pressure ( Woo et al, 2009 ; Seven et al, 2017 ). Some studies observed a lower systolic and diastolic blood pressure, heart rate and QTc lowering effect on the first day of olanzapine treatment, however these effects progressively diminished on the following days probably due to developing tolerance ( Bever and Perry, 1998 ; Koller et al, 2021 ).…”

“…Several studies showed that the HTR2C −759C > T (rs3813929) T allele has a protective effect against olanzapine-produced weight gain ( Templeman et al, 2005 ). The C allele of the rs1414334 intronic polymorphism is associated with an increased risk for developing metabolic syndrome and a higher weight gain after olanzapine treatment ( Ma et al, 2014 ; Koller et al, 2021 ). This SNP is in complete linkage disequilibrium with the rs6318 ( p .Cys23Ser) polymorphism, where the Ser allele is constitutively more active ( Ma et al, 2014 ).…”

“…The presence of Gly in DRD3 rs6280 ( p .Ser9Gly) is associated with a better response to olanzapine ( Brennan, 2014 ). Moreover, the Gly allele was related to a higher increase in prolactin levels compared to Ser allele ( Koller et al, 2021 ) ( Table 2 ).…”