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Association between HTR2C and HTR2A polymorphisms and metabolic abnormalities in patients treated with olanzapine and clozapine
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Pharmacogenetics)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Pharmacogenetics)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Pharmacogenetics)
2009 (English)In: Journal of Clinical Psychopharmacology, ISSN 0271-0749, E-ISSN 1533-712X, Vol. 29, no 1, 65-68 p.Article in journal (Refereed) Published
Abstract [en]

Serotonin 2C and 2A receptor (5-HT2C and 5-HT2A) antagonisms are hypothesized to play a role in the metabolic adverse effects induced by olanzapine and clozapine. Associations between polymorphisms in 5-HT2C and 5-HT2A receptor coding genes, HTR2C and HTR2A, with antipsychotic-induced weight gain have been reported. The impact of HTR2C and HTR2A polymorphisms on body mass index (BMI), glucose-insulin homeostasis, and blood lipid levels was evaluated in 46 patients with schizophrenia or schizoaffective disorder and treated with olanzapine (n = 28) or clozapine (n = 18) for at least 6 months. Olanzapine-treated patients with HTR2C haplotype C (-759C, -697C, and 23Ser) had higher BMI (P = 0.029) and C peptide levels (P = 0.029) compared with patients with haplotype B (-759T, -697C, and 23Cys). The frequency of patients homozygous for the HTR2C haplotype A (-759C, -697G, and 23Cys) was significantly higher among clozapine-treated patients with obesity (BMI >/= 30 kg/m) compared with nonobese patients (P = 0.015; odds ratio, 28; 95% confidence interval, 2-380). Patients carrying the HTR2A haplotype 2 (-1438A, 102T, and 452His) had significantly higher C peptide levels compared with haplotype 3 (-1438A, 102T, and 452Tyr) carriers in the olanzapine group (P = 0.034) and in the overall study population (P = 0.019). None of the haplotypes were associated with serum levels of insulin, triglycerides, and cholesterol or with homeostasis model assessment index for insulin resistance. In conclusion, both HTR2C and HTR2A gene polymorphisms seem to be associated with the occurrence of metabolic abnormalities in patients treated with olanzapine or clozapine.

Place, publisher, year, edition, pages
2009. Vol. 29, no 1, 65-68 p.
Keyword [en]
olanzapine, clozapine, weight gain, serotonin, receptor, polymorphism
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-97083DOI: 10.1097/JCP.0b013e31819302c3ISI: 000262558200014PubMedID: 19142110OAI: oai:DiVA.org:uu-97083DiVA: diva2:171870
Available from: 2008-04-17 Created: 2008-04-17 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Pharmacogenetics and Antipsychotic Treatment in Schizophrenia with Special Focus on Adverse Drug Reactions
Open this publication in new window or tab >>Pharmacogenetics and Antipsychotic Treatment in Schizophrenia with Special Focus on Adverse Drug Reactions
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Genetically determined differences in drug metabolism and disposition and drug targets play a pivotal role in the interindividual variability in the clinical outcome of antipsychotic treatment. The aim of this thesis was to study the impact of polymorphisms in genes involved in the pharmacokinetics and pharmacodynamics of antipsychotics, with special focus on their extrapyramidal and metabolic adverse effects.

Polymorphisms in serotonin 2A and 2C receptor coding genes (HTR2A and HTR2C) were found to be associated with the risk to develop extrapyramidal side effects (EPS) in patients on short term perphenazine treatment. A further study in a larger group of patients on long term treatment with various classical antipsychotics confirmed the association between occurrence of EPS and HTR2C polymorphisms. In another study, dose corrected steady state serum clozapine and N-desmethylclozapine concentrations (C/D) and insulin elevation during clozapine therapy were found to correlate with CYP1A2 but not with CYP2D6 polymorphisms. Furthermore, HTR2C and HTR2A polymorphisms were found to have significant influences on BMI and C-peptide levels in patients treated with olanzapine and clozapine. Evaluation of the impact of polymorphisms in genes encoding CYP3A4, CYP3A5 and P-glycoprotein (ABCB1) in addition to CYP2D6 on the steady state plasma levels of risperidone, 9-hydroxyrisperidone and their active moiety revealed a significant influence of ABCB1 genotype on 9-hydroxyrisperidone and active moiety C/Ds, while CYP2D6 genotype associated with risperidone C/Ds but not with 9-hydroxyrisperidone or active moiety C/D.

We have shown that polymorphisms in genes involved in the pharmacokinetics and the pharmacodynamics of antipsychotic drugs play a role in the occurrence of adverse effects, both EPS and metabolic disturbances, induced by antipsychotic treatment. Genotyping for HTR2A, HTR2C, CYP1A2, CYP2D6 and ABCB1 polymorphisms may therefore potentially provide useful information to identify patients at higher risk to develop EPS or metabolic adverse during schizophrenia treatment with antipsychotic drugs.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 57 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 335
Keyword
Medicine, Pharmacogenetics, schizophrenia, antipsychotic treatment, adverse effects, clinical outcome, Medicin
Identifiers
urn:nbn:se:uu:diva-8656 (URN)978-91-554-7170-5 (ISBN)
Public defence
2008-05-08, Enghoffsalen, Ingång 50, Akademiska Sjukhuset, Uppsala, 09:15
Opponent
Supervisors
Available from: 2008-04-17 Created: 2008-04-17Bibliographically approved

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