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Serotonin and dopamine receptor gene polymorphisms and the risk of extrapyramidal side effects in perphenazine-treated schizophrenic patients
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology. (Pharmacogenetics)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology. (Pharmacogenetics)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology. (Pharmacogenetics)
2007 (English)In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 190, no 4, 479-484 p.Article in journal (Refereed) Published
Abstract [en]

Rationale: Perphenazine, a classical antipsychotic drug, has the potential to induce extrapyramidal side effects (EPS). Dopaminergic and serotonergic pathways are involved in the therapeutic and adverse effects of the drug. Objectives: To evaluate the impact of polymorphisms in the dopamine D 2 and D3 and serotonin 2A and 2C receptor genes (DRD2, DRD3, HTR2A, and HTR2C) on short-term effects of perphenazine monotherapy in schizophrenic patients. Materials and methods: Forty-seven Estonian inpatients were evaluated before and after 4-6 weeks of treatment by Simpson-Angus rating scale, Barnes scale, and Positive and Negative Symptom Scale. Genotyping was performed for common DRD2, DRD3, HTR2A, and HTR2C gene polymorphisms, previously reported to influence receptor expression and/or function. Results: Most of the patients (n = 37) responded to the treatment and no significant association was observed between the polymorphisms and antipsychotic response. The 102C allele of HTR2A and the -697C and 23Ser alleles of HTR2C were more frequent among patients with EPS (n = 25) compared to patients without EPS (n = 22) (p = 0.02, 0.01, and 0.02, respectively). The difference between patients with and without EPS in variant allele frequencies remained significant after multiple model analyses including age, gender, and duration of antipsychotic treatment as covariants. There was no significant association between EPS occurrence and polymorphisms in the DRD2 and DRD3 genes. Conclusions: An association was observed between polymorphisms in HTR2A and HTR2C genes and occurrence of acute EPS in schizophrenic patients treated with perphenazine monotherapy. Larger study populations are needed to confirm our findings.

Place, publisher, year, edition, pages
2007. Vol. 190, no 4, 479-484 p.
Keyword [en]
Perphenazine, Receptor gene polymorphisms, Extrapyramidal side effects, Schizophrenia
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-97080DOI: 10.1007/s00213-006-0622-xISI: 000243926900008PubMedID: 17102980OAI: oai:DiVA.org:uu-97080DiVA: diva2:171867
Available from: 2008-04-17 Created: 2008-04-17 Last updated: 2011-02-14Bibliographically 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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Gunes, ArzuDahl, Marja-Liisa

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