Influence of CYP2D6 and DRD2 polymorphisms on clinical outcomes of patients with schizophrenia
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Date
2009-03
Authors
Zahari, Zalina
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Abstract
CYP2D6 is a polymorphic enzyme involved in the metabolism of many centrally
acting drugs as well as cardiovascular drugs. Dopamine D2 receptor gene (DRD2) is a
candidate gene implicated in the efficacy of antipsychotic drugs. CYP2D6 and DRD2
polymorphisms have been associated with antipsychotic drug response in patients with
schizophrenia. The objectives of this study were to develop PCR methods for detection
of DRD2 polymorphisms and to investigate the association of the CYP2D6 and DRD2
polymorphisms with treatment outcomes in patients with schizophrenia. The protocol for
the study was approved by the Research and Ethical Committee, Universiti Sains
Malaysia (USM), Kelantan, Malaysia. The subjects were patients with schizophrenia
(DSM-IV) on antipsychotic treatment or had been treated with antipsychotic in the past.
Patients with co-morbid diagnoses of substance abuse or mental retardation were
excluded from the study. Written informed consent was obtained from the subjects after
full explanation of the study procedure. The selected patient was then called for
interview and further assessment. The psychopathological severity was evaluated using
the Positive and Negative Symptoms Scale (PANSS). The extrapyramidal side-effects
and akathisia were assessed with the Simpson Angus Scale (SAS) and the Barnes
Akathisia Rating Scale (BARS), respectively. DNA was extracted from blood taken
from the patients using salting out procedures and subjected to PCR-genotyping.
Specific primers were designed to develop PCR methods for detection of
polymorphisms. The PCR methods were specific and sensitive to detect CYP 2D6 and
DRD2 genotypes. These methods were used for genotyping analysis of 156 subjects
enrolled in this study for CYP 2D6 and DRD2 polymorphisms. The frequencies for
CYP2D6*1, *4, *5, *10 and CYP2D6 duplication were 39.1, 1.3, 3.8, 46.8 and 3.2%,
respectively; while CYP2D6*3, *6, *9, *14 and *17 were absent. The frequencies for
DRD2 variants Ser310, Cys311, Taql Al, -141C Del and -241G were 0.3, 3.2, 42.3, 14.7
and 17.6%, respectively. There was no patient tested positive for Ala96, Leu14l(T) and
Ile154 variants. We found that CYP2D6 polymorphism was significantly associated with
subtotal negative P ANSS score. Patients with the Cys311 allele presented with
significantly higher PANSS scores than those without the Cys311 allele. We also found
that CYP2D6 and DRD2 polymorphisms were not related to the side-effects of
antipsychotic therapy, and the SAS and BARS scores. However, A-241G polymorphism
was associated with the experience of side-effects in the past two years. The results
suggested that CYP2D6 and DRD2 polymorphisms may have implications in the
treatment response and the occurrence of neuroleptic-induced side-effects. Therefore,
CYP2D6 and DRD2 polymorphisms may be a predictor for the treatment outcomes of
patients with schizophrenia.
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Keywords
CYP2D6 and DRD2 polymorphisms , Patients with schizophrenia