The effects of aripiprazole and olanzapine on pupillary light reflex and its relationship with pharmacogenetics in a randomized multiple‐dose trial

Koller, Dóra; Saiz‐Rodríguez, Miriam; Zubiaur, Pablo; Ochoa, Dolores; Almenara, Susana; Román, Manuel; Romero-Palacián, Daniel; Miguel-Cáceres, Alejandro de; Martín, Samuel; Navares‐Gómez, Marcos; Mejía, Gina; Wojnicz, Aneta; Abad‐Santos, Francisco

doi:10.1111/bcp.14300

Cited by 23 publications

(39 citation statements)

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“…Based on our results, T allele carriers may be under prolonged OLA exposure and therefore show higher glucose concentrations. This result is confirmed by our previous study as this polymorphism affected OLA pharmacokinetics 42 .…”

Section: Discussionsupporting

confidence: 90%

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

Koller

Almenara

Mejía

et al. 2020

Preprint

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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.

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Section: Discussionsupporting

confidence: 90%

“…The terminal rate constant (ke) used for the extrapolation was determined by regression analysis of the log-linear part of the concentration-time curve. The AUC and C max were adjusted for dose and weight (AUC/dW and C max /dW, respectively) and were logarithmically transformed for statistical analysis 18 .…”

Section: Pharmacokinetic Analysismentioning

confidence: 99%

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

Koller

Almenara

Mejía

et al. 2020

Preprint

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“…On the basis of our results, T allele carriers may be under prolonged OLA exposure and therefore show higher glucose concentrations. This result is confirmed by our previous study as this polymorphism affected OLA pharmacokinetics [20].…”

Section: Discussionsupporting

confidence: 90%

“…, leptin (LEP) rs7799039, leptin receptor (LEPR) rs1137101, opioid receptor mu 1 (OPRM1) rs1799971 and UGT1A1 rs887829 [20].…”

Section: Genotypingmentioning

confidence: 99%

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

et al. 2020

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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.

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“…All subjects were adequately informed about the study and, if agreeing to participate, signed an informed consent form before inclusion. The inclusion and exclusion criteria were reported in our previous publication (Koller et al, 2020).…”

Section: Methodsmentioning

confidence: 99%

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

Koller

Almenara

Mejía

et al. 2020

Human Psychopharmacology

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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.

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The effects of aripiprazole and olanzapine on pupillary light reflex and its relationship with pharmacogenetics in a randomized multiple‐dose trial

Cited by 23 publications

References 44 publications

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

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

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

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

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