Pharmacogenetics of Tardive Dyskinesia Combined Analysis of 780 Patients Supports Association with Dopamine D3 Receptor Gene Ser9Gly Polymorphism

Lerer, Bernard; Segman, Ronnen H.; Fangerau, Heiner; Daly, Ann K.; Basile, Vincenzo S.; Cavallaro, Roberto; Aschauer, Harald; McCreadie, Robin G.; Ohlraun, Stephanie; Ferrier, Nicol; Masellis, Mario; Verga, M.; Scharfetter, Joachim; Rietschel, Marcella; Løvlie, Roger; Levy, Uriel Heresco; Meltzer, Herbert Y.; Kennedy, James L.; Steen, Vidar M.; Macciardi, Fabìo

doi:10.1016/s0893-133x(02)00293-2

Cited by 226 publications

(146 citation statements)

References 74 publications

(80 reference statements)

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“…The severity of TD has also been observed to increase with age in conformity with other reports. 4,11,22 However, severity of TD was higher among males compared to females in our study, which is in contrast to other reports. 23,24 This may be due to sampling variation or may reflect a variation unique to Indian population.…”

Section: Discussioncontrasting

confidence: 99%

“…Results from these studies have been inconsistent or untested in additional samples (for review see Basile et al 10 ) with the possible exception of the DRD3 ser9gly polymorphism, which has been supported by a pooled and meta-analysis. 11 Thus, pathophysiological mechanisms underlying TD remain poorly understood. A second large group of genes extensively investigated for association with TD are the cytochrome P450 (CYP450) family of genes.…”

Section: Introductionmentioning

confidence: 99%

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Genetic susceptibility to Tardive Dyskinesia in chronic schizophrenia subjects: I. Association of CYP1A2 gene polymorphism

et al. 2004

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Understanding the pharmacogenetic basis of developing iatrogenic disorders such as Tardive Dyskinesia (TD) has significant clinical implications. CYP1A2, an inducible gene of the cytochrome P450 family of genes, has been suggested to contribute to the metabolism of typical antipsychotics in subjects with schizophrenia on long-term treatment, and has been considered as a potential candidate gene for development of TD. In this study, we have investigated the significance of CYP1A2 gene polymorphisms in TD susceptibility among chronic schizophrenia sufferers (n ¼ 335) from north India. TD was diagnosed in B29% (96/335) of these subjects. Of the 96 TD positives, 28 had been treated with typical antipsychotics alone, 23 with atypical antipsychotics alone and 45 patients had received both classes of drugs during the course of their illness. Out of the six SNPs tested, CYP1A2*2, *4, *5, *6 were found to be monomorphic in our population. CYP1A2*1C and CYP1A2*1F were polymorphic and were analyzed in the study sample. Since these two allelic variants lead to lesser inducibility among smokers, the smoking status of TD patients was also considered for all subsequent analysis. We observed increased severity of TD among TD-Y smokers, who were carriers of CYP1A2*1C (G4A) variant allele and had received only typical antipsychotic drugs (F(1,8) ¼ 9.203, P ¼ 0.016). No significant association of CYP1A2*1F with TD was observed irrespective of the class of drug they received or their smoking status. However, we found a significant association of CYP1A2*1F with schizophrenia (w 2 ¼ 6.572, df ¼ 2, P ¼ 0.037).

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genetic susceptibility to Tardive Dyskinesia in chronic schizophrenia subjects: I. Association of CYP1A2 gene polymorphism

et al. 2004

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“…87,176,289 Polymorphisms in D3 receptors were first reported to contribute to drug-induced TD by Steen et al 230 and by Segman et al 231 In both studies, individuals with one or two copies of the Gly allele of a D 3 Ser9Gly polymorphism were more likely to develop TD with antipsychotic treatment. Several subsequent studies failed to replicate this finding, 204,232-234 but a combined study of 780 patients of different ethnic background, 235 and further reports of association in the United States, Chinese and Korean patients 221,236,237 confirm the validity and strength of this finding. The Gly variant is reportedly associated with significantly higher dopamine activity, which in turn could explain the association with movement disorders.…”

Section: Prediction Of Side Effectsmentioning

confidence: 92%

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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“…Based on these hypotheses, several genes from dopaminergic, serotonergic and oxidative stress pathways have been investigated for their possible contribution to susceptibility to TD (for review, see Basile et al 8 ). With the possible exception of the DRD3 ser9gly polymorphism, which has been supported by both pooled and metaanalyses, 9 no other polymorphism has been consistently implicated in the genesis of TD. As the basic mechanism proposed for TD development is chronic blockade of the receptors owing to high affinity of typical antipsychotics for dopamine receptors, any variation in the receptor affinity to the particular drugs owing to polymorphisms (e.g.…”

Section: Introductionmentioning

confidence: 94%

Genetic susceptibility to Tardive Dyskinesia in chronic schizophrenia subjects: V. Association of CYP1A2 1545 C>T polymorphism

Tiwari

Deshpande²,

Lerer

et al. 2006

Pharmacogenomics J

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Tardive dyskinesia (TD) is an iatrogenic disorder observed in B20-30% of schizophrenia patients on long-term treatment with typical antipsychotic drugs. CYP1A2 is involved in the metabolism of atypical antipsychotic drugs such as clozapine and olanzapine. It is not directly involved in the metabolism of typical antipsychotic drugs, but gains importance when the schizophrenia patients are under long-term chronic treatment, acting as a low-affinity high-capacity metabolizing enzyme. In this study, we have completely sequenced the coding region to ascertain the presence of common coding polymorphisms and their role if any in susceptibility to TD and schizophrenia. Four previously reported polymorphisms, CYP1A2*1F (intron A), rs2472304 & rs3743484 (intron D) and rs2470890 (CYP1A2 1545 C4T) in exon 7 were identified. We further investigated whether the CYP1A2 1545 C4T polymorphism has any role to play in susceptibility to TD and in schizophrenia per se. Association of this single nucleotide polymorphism with TD (P ¼ 0.03) and schizophrenia (P ¼ 0.04) was observed, but was rendered insignificant after corrections for multiple comparisons.

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Pharmacogenetics of Tardive Dyskinesia Combined Analysis of 780 Patients Supports Association with Dopamine D3 Receptor Gene Ser9Gly Polymorphism

Abstract: Variability among individuals in their therapeutic

Cited by 226 publications

References 74 publications

Genetic susceptibility to Tardive Dyskinesia in chronic schizophrenia subjects: I. Association of CYP1A2 gene polymorphism

Genetic susceptibility to Tardive Dyskinesia in chronic schizophrenia subjects: I. Association of CYP1A2 gene polymorphism

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

Genetic susceptibility to Tardive Dyskinesia in chronic schizophrenia subjects: V. Association of CYP1A2 1545 C>T polymorphism

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