Cytochrome P-450 2D6*10 C188T Polymorphism Is Associated with Antipsychotic-Induced Persistent Tardive Dyskinesia in Chinese Schizophrenic Patients

Liou, Ying‐Jay; Wang, Daqing; Bai, Ya‐Mei; Lin, Chao-Cheng; Yu, Shun-Chieh; Liao, Ding-Lieh; Lin, Ming‐Wei; Chen, Jen-Yeu; Lai, I-Ching

doi:10.1159/000077360

Cited by 45 publications

(21 citation statements)

References 24 publications

(41 reference statements)

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“…221 CYP2D6 PM variants have been found associated with TD, EPS, AIMS scores and parkinsonism in several studies including different ethnic groups. 211,213,215,220 In a study in German patients, CYP2D6 genotype was as good a predictor of adverse events as plasma haloperidol concentrations, 217 and adds to the clinical value of CYP genotyping. CYP1A2 variants constitute genetic risk factors for the development of drug-induced TD as suggested by positive association findings.…”

Section: Prediction Of Side Effectsmentioning

confidence: 99%

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

2007

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The last decade of research into the pharmacogenetics of antipsychotics has seen the development of genetic tests to determine the patients' metabolic status and the first attempts at personalization of antipsychotic treatment. The most significant results are the association between drug metabolic polymorphisms, mainly in cytochrome P450 genes, with variations in drug metabolic rates and side effects. Patients with genetically determined CYP2D6 poor metabolizer (PMs) status may require lower doses of antipsychotic. Alternatively, CYP2D6 ultrarapid matabolizers (UMs) will need increased drug dosage to obtain therapeutic response. Additionally, polymorphisms in dopamine and serotonin receptor genes are repeatedly found associated with response phenotypes, probably reflecting the strong affinities that most antipsychotics display for these receptors. In particular, there is important evidence suggesting association between dopamine 2 receptor (D2) polymorphisms (Taq I and À141-C Ins/Del) and a dopamine 3 receptor (D3) polymorphism (Ser9Gly) with antipsychotic response and drug-induced tardive dyskinesia. Additionally, there is accumulating evidence indicating the influence of a 5-HT2C polymorphism (À759ÀT/C) in antipsychotic-induced weight gain. Application of this knowledge to clinical practice is slowly gathering pace, with pretreatment determination of individual's drug metabolic rates, via CYP genotyping, leading the field. Genetic determination of patients' metabolic status is expected to bring clinical benefits by helping to adjust therapeutic doses and reduce adverse reactions. Genetic tests for the pretreatment prediction of antipsychotic response, although still in its infancy, have obvious implications for the selection and improvement of antipsychotic treatment. These developments can be considered as successes, but the objectives of bringing pharmacogenetic and pharmacogenomic research in psychiatric clinical practice are far from being realized. Further development of genetic tests is required before the concept of tailored treatment can be applied to psychopharmatherapy. This review aims to summarize the key findings from the last decade of research in the field. Current knowledge on genetic prediction of drug metabolic status, general response and drug-induced side effects will be reviewed and future pharmacogenomic and epigenetic research will be discussed.

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Section: Prediction Of Side Effectsmentioning

confidence: 99%

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

2007

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“…No study mentioned conducting specific tests for population stratification even though six 57,60,87,96,102,103 were known to include patients with different ethnic backgrounds. A minority (21/51) of studies [59][60][61][62]66,67,70,72,74,[76][77][78][79]81,82,[85][86][87][88]96,100 reported testing for Hardy-Weinberg equilibrium.…”

Section: Clinical Validitymentioning

confidence: 99%

“…Clinical validity CYP2D6 is arguably the most important CYP450 gene with regard to the metabolism of antipsychotics, with six typical 78 Cross-sectional 99 Japanese CYP2D6 Any typical antipsychotic Scordo et al 80 Cross-sectional 119 Caucasian CYP2D6 Any antipsychotic Culav-Sumic et al 62 Cross 67 Cross-sectional 214 Japanese CYP2D6 Any antipsychotic Lohmann et al 73 Cross-sectional 109 Caucasian (assumed) CYP2D6 Any antipsychotic Liou et al 72 Retrospective 216 Chinese CYP2D6 Any typical antipsychotic Kakihara et al 97 Prospective 41 Japanese (assumed) CYP2D6 Risperidone Tiwari et al 87 Cross antipsychotics (thioridazine, perphenazine, fluphenazine, zuclopenthixol, haloperidol and chlorpromazine) and two atypical antipsychotics (risperidone and, to some extent, olanzapine) metabolized by the enzyme encoded by it. 108 Thus, it is not surprising that most of the clinical validity studies also focused on CYP2D6 where some significant associations between TD and parkinsonism and PM genotype.…”

Section: Analytic Validitymentioning

confidence: 99%

Cytochrome P450 testing for prescribing antipsychotics in adults with schizophrenia: systematic review and meta-analyses

et al. 2010

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There is wide variability in the response of individuals to standard doses of antipsychotic drugs. It has been suggested that this may be partly explained by differences in the cytochrome P450 (CYP450) enzyme system responsible for metabolizing the drugs. We conducted a systematic review and metaanalyses to consider whether testing for CYP450 single nucleotide polymorphisms in adults starting antipsychotic treatment for schizophrenia predicts and leads to improvements in clinical outcomes. High analytic validity in terms of sensitivity and specificity was seen in studies reporting P450 testing. However, there was limited evidence of the role of CYP2D6 polymorphisms in antipsychotic efficacy, although there was an association between CYP2D6 genotype and extrapyramidal adverse effects. No studies reported on the prospective use of CYP2D6 genotyping tests in clinical practice. In conclusion, evidence of clinical validity and utility of CYP2D6 testing in patients being prescribed antipsychotics is lacking, and thus, routine pharmacogenetic testing prior to antipsychotic prescription cannot be supported at present. Further research is required to improve the evidence base and to generate data on clinical validity and clinical utility.

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“…Weight gain and metabolic syndrome 0.49-0.7 [144,145] ADRA2A Weight gain and movement disorders 2.5-4.2 [146][147][148] BDNF Weight gain and movement disorders NA [181,182] COMT Tardive dyskinesia 0.24-0.63 [108,123] CYP1A2 Tardive dyskinesia 1.9 [155,156] CYP2D6 Weight gain and movement disorders 1.6-4.4 [158][159][160][161][162][163][164][165] …”

Section: Adra1amentioning

confidence: 99%

Toward understanding genetic risk for differential antipsychotic response in individuals with schizophrenia

Arranz

Munro²

2011

Expert Review of Clinical Pharmacology

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Antipsychotic treatment response is highly heterogeneous and unpredictable in terms of both efficacy and side effects. A combination of factors influences treatment outcome, including clinical, demographic, environmental and genetic factors. No comprehensive studies have quantified the relative contributions of these factors to date. Two decades of pharmacogenetic and pharmacogenomic studies have attempted to identify key gene variants associated with antipsychotic response, with a dual goal of better understanding the mechanisms underlying drug response and guiding prescribing decisions in clinical care. Pharmacogenetic studies have succeeded in identifying several genes that are associated with antipsychotic treatment efficacy or side effects. However, the strength of these associations is modest and they are of limited clinical value. Genome-wide association studies, moving beyond hypothesis-based discovery, have greater potential to identify novel gene associations, although only a few genome-wide association studies have been conducted and they have not revealed clearly significant findings. The first pharmacogenetic tests to guide the selection or dosing of antipsychotic drugs are now commercially available. Their uptake has been limited by the modest level of prediction they offer, compounded by the lack of data supporting their clinical or economic benefits. Advances in genomic analysis techniques, the better characterization of larger subject cohorts and an improved understanding of the role of environmental factors and gene-environment interactions are renewing hope that future research will identify genetic variants with stronger associations with treatment outcome. Tests incorporating such genetic data, with environmental and clinical variables, may offer the potential to personalize medicine and significantly improve the efficacy and tolerability of antipsychotic treatment.

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Cytochrome P-450 2D6*10 C188T Polymorphism Is Associated with Antipsychotic-Induced Persistent Tardive Dyskinesia in Chinese Schizophrenic Patients

Cited by 45 publications

References 24 publications

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

Cytochrome P450 testing for prescribing antipsychotics in adults with schizophrenia: systematic review and meta-analyses

Toward understanding genetic risk for differential antipsychotic response in individuals with schizophrenia

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