Association of dopamine D3-receptor gene variants with neuroleptic induced akathisia in schizophrenic patients: A generalization of Steen's study onDRD3 and tardive dyskinesia

Eichhammer, Peter; Albus, Margot; Borrmann-Hassenbach, Margitta; Schoeler, A.; Putzhammer, Albert; Frick, Ulrich; Klein, Helmfried E.; Rohrmeier, Thomas

doi:10.1002/(sici)1096-8628(20000403)96:2<187::aid-ajmg13>3.0.co;2-8

Cited by 80 publications

(32 citation statements)

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“…A gene 120 bp duplication and the long allele of the D4 LPR were reported to decrease the risk of TD, 204,224 increasing the evidence supporting the involvement of dopamine receptors in susceptibility to TD. The D3 Ser9Gly polymorphism was also associated with neuroleptic induced akathisia, 239 a common side effect which is thought to be triggered by alterations in nucleus accumbeus D3 activity. Other investigated dopamine receptors were not found to contribute to these adverse effects.…”

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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“…7 Also, Jö nsson et al 8 in Swedish patients with schizophrenia suggested a linkage to a DNA marker in close proximity to the DRD3 gene on chromosome 3q. Recently, a genotypic association between the DRD3 receptor polymorphism and a susceptibility to neuroleptic-induced motor disturbances such as tardive dyskinesia and akathisia in schizophrenic patients was obtained in a number of studies [9][10][11][12] except for one. 13 Furthermore, the association between the DRD3 polymorphism and a schizoaffective variant of schizophrenia was reported.…”

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Dopamine D3 receptor (DRD3) gene polymorphism is associated with the intensity of eye movement disturbances in schizophrenic patients and healthy subjects

et al. 2001

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Altered dopamine neurotransmission and eye movement disturbances have been implicated in the pathogenic process of schizophrenia. So far, molecular genetic studies have shown little association between schizophrenia and polymorphism of any dopamine receptor or transporter genes except for some findings concerning D3 receptor (DRD3) gene. Eye movement disturbances occur in a majority of patients with schizophrenia and in a proportion of their first-degree relatives and they have been suggested as a phenotypic marker in genetic studies of this illness. Here we report an association between the Ser9Gly polymorphism of the DRD3 gene and the intensity of eye movement disturbances (fixation and smooth pursuit) observed in 119 schizophrenic patients and in 94 unrelated healthy control subjects. In schizophrenic patients, the mean intensity of both kinds of eye movement disturbances was highest in individuals with the Ser-Ser genotype, significantly lower in Ser-Gly and lowest in the Gly-Gly genotype. The Ser-Ser genotype was more prevalent in patients with a higher intensity of both fixation (58.1 vs 23.9% P Ͻ 0.001) and smooth pursuit disturbances (52.3 vs 25.8%, P Ͻ 0.02) and the Ser-Gly genotype frequency was lower in patients with higher fixation disturbances (37.0 vs 60.9%, P Ͻ 0.02). In control subjects, the genotype frequency Ser-Ser was higher in subjects with any degree of eye movement disturbances compared to subjects without such disturbances both for fixation and smooth pursuit performance (81.0 vs 50.7%, P Ͻ 0.05 and 79.2 vs 50.0%, P Ͻ 0.05, respectively). In control subjects the frequency of Ser-Gly was lower in the first group, for either fixation or smooth pursuit, compared to normal performers (9.5 vs 43.8%, P Ͻ 0.01 and 8.3 vs 45.7, P Ͻ 0.005, respectively). We suggest that the DRD3 Ser9Gly polymorphism may be a contributing factor to the performance of eye movements used as a phenotypic marker of schizophrenia. Molecular Psychiatry (2001) 6, 718-724.The hypothesis of altered dopamine neurotransmission in schizophrenia proposed on the basis of the mechanism of antipsychotic drugs action gained some support from recent neuroimaging data. 1 However, molecular genetic studies performed in recent decades did not show a strong association between schizophrenia and any gene coding either dopamine receptor or transporter except for dopamine receptor D3 (DRD3) gene polymorphism, where the relationship was found with some aspects of this illness. DRD3 is localized in limbic and cortical brain areas and probably affects locomotion as well as emotional and cognitive processes. 2 DRD3 knock-out mice show abnormalities in spontaneous level of locomotor activity. 3 The DRD3 gene was mapped to chromosome 3q13.3 and its polymorphic site in exon 1 with a serine to glycine substitution has been postulated as a useful investigating tool in psychiatric disorder. 4 Association studies of this polymorphism with schizophrenia have been mostly negative, including the most recent work of Joober et al. 5

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“…Например, P. Eichhammer и соавт. [76] сообщили об учащении раз-вития акатизии среди носителей аллеля Gly, однако два других исследования [77,78] дали в этом отношении от-рицательные результаты.…”

Section: дофаминергическая системаunclassified

Pharmacogenetic-based risk assessment of antipsychotic-induced extrapyramidal symptoms

Сосин

et al. 2015

Z. nevrol. psikhiatr. im. S.S. Korsakova

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Association of dopamine D3-receptor gene variants with neuroleptic induced akathisia in schizophrenic patients: A generalization of Steen's study onDRD3 and tardive dyskinesia

Cited by 80 publications

References 46 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

Dopamine D3 receptor (DRD3) gene polymorphism is associated with the intensity of eye movement disturbances in schizophrenic patients and healthy subjects

Pharmacogenetic-based risk assessment of antipsychotic-induced extrapyramidal symptoms

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