Dopamine D3 receptor gene polymorphism and response to clozapine in schizophrenic Pakistani patients

Scharfetter, Joachim; Chaudhry, Haroon Rashid; Hornik, Kurt; Fuchs, Karoline; Sieghart, Werner; Kasper, Siegfried; Aschauer, Harald

doi:10.1016/s0924-977x(99)00044-9

Cited by 115 publications

(75 citation statements)

References 29 publications

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“…100,104 This same polymorphism has also been associated with general response to treatment with classical and atypical antipsychotics. 31,101,102 In vitro studies indicate that the Gly variants is associated with higher dopamine binding affinity. 161 However, the biological interpretation of this observation is difficult, as the Gly variants was mostly associated with good response in Caucasian patients 101,102,104 and with poor response in Chinese populations, suggesting that linkage disequilibrium (LD) status with another functional polymorphism may explain the different associations with response.…”

Section: Pharmacodynamic Factorsmentioning

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: Pharmacodynamic Factorsmentioning

confidence: 99%

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

2007

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“…One study observed a slight over-representation of the DRD3 Ser9Gly amino-acid exchange (allele *2) in patients with poor response to antipsychotics, particularly in the non-Ashkenazi, Israeli schizophrenics. Odds ratio or effect ratio Scharfetter, 1999 Malhotra, 1998…”

Section: Dopaminergic Systemmentioning

confidence: 99%

Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response

et al. 2004

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Genetic factors contribute to the phenotype of drug response. We systematically analyzed all available pharmacogenetic data from Medline databases on the impact that genetic polymorphisms have on positive and adverse reactions to antidepressants and antipsychotics. Additionally, dose adjustments that would compensate for genetically caused differences in blood concentrations were calculated. To study pharmacokinetic effects, data for 36 antidepressants were screened. We found that for 20 of those, data on polymorphic CYP2D6 or CYP2C19 were found and that in 14 drugs such genetic variation would require at least doubling of the dose in extensive metabolizers in comparison to poor metabolizers. Data for 38 antipsychotics were examined: for 13 of those CYP2D6 and CYP2C19 genotype was of relevance. To study the effects of genetic variability on pharmacodynamic pathways, we reviewed 80 clinical studies on polymorphisms in candidate genes, but those did not for the most part reveal significant associations between neurotransmitter receptor and transporter genotypes and therapy response or adverse drug reactions. In addition associations found in one study could not be replicated in other studies. For this reason, it is not yet possible to translate pharmacogenetic parameters fully into therapeutic recommendations. At present, antidepressant and antipsychotic drug responses can best be explained as the combinatorial outcome of complex systems that interact at multiple levels. In spite of these limitations, combinations of polymorphisms in pharmacokinetic and pharmacodynamic pathways of relevance might contribute to identify genotypes associated with best and worst responders and they may also identify susceptibility to adverse drug reactions.

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“…Although genetic factors that influence drug metabolism were studied in psychopharmacology long before current genomic technology was available (Poolsup et al 2000;Steimer et al 2001), work on pharmacodynamic aspects is still at an early stage. It has focused primarily on response to specific serotonin reuptake inhibitors (SSRIs) in major depression (Smeraldi et al 1998, Lerer and Macciardi in press) and to atypical antipsychotic drugs, primarily clozapine, in schizophrenia (Arranz et al 1998, Scharfetter et al 1999a.…”

Section: Variability Among Individuals In Their Therapeutic Response mentioning

confidence: 99%

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

Lerer

Segman

Fangerau

et al. 2002

Neuropsychopharmacology

225

132

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Dopamine D3 receptor gene polymorphism and response to clozapine in schizophrenic Pakistani patients

Cited by 115 publications

References 29 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

Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response

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

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