Association between the serotonin 2C receptor gene and tardive dyskinesia in chronic schizophrenia: additive contribution of 5-HT2C ser and DRD3 gly alleles to susceptibility

Segman, Ronnen H.; Heresco-Levy, Uriel; Finkel, Boris; Inbar, Roi; Neeman, Tal; Schlafman, M; A, Dorevitch; Yakir, A; Lerner, Ana Beatriz Coutinho; Goltser, T; Shelevoy, A; Lerer, Bernard

doi:10.1007/s002130000521

Cited by 128 publications

(83 citation statements)

References 23 publications

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“…Studies on 5-HT6 and 5-HTT polymorphisms failed to find any association. 205,251,252 Further studies investigating 5-HT 2C , 5-HT 2A and D 3 genotypes with age and disease phenotypes 249,250 provided significant associations confirming the involvement of dopamine and serotonin systems in susceptibility to TD.…”

Section: Prediction Of Side Effectsmentioning

confidence: 76%

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: 76%

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

2007

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“…61 By using stepwise multiple regression analyses, the inclusion of DRD3 genotypes revealed an additive contribution of the 5-HT2C Ser allele and the DRD3 Gly allele, respectively, of 4.2 and 4.7% to the variance of orofacial dyskinesia (OFD) scores in the overall sample. 61 Zhang et al 62 found a significant association (including only males) with the 5-HT2C promoter variant À697C allele, but not with the À759C/T variants or with haplotype analyses. No association has been reported between the 5-HT6 receptor, or the serotonin transporter 59,63 and TD.…”

Section: The Serotonergic Systemmentioning

confidence: 99%

“…Only recently have studies begun to investigate the additive or interactive effects among different risk alleles. 37,61,83 . In our sample, the risk alleles of the DRD3 and CYP1A2 genes were found to be highly associated with TD (P ¼ 0.00007) in an additive, co-recessive model of interaction which accounted for 450% of the variance in risk for TD.…”

Section: Outlook: Clinical Implicationsmentioning

confidence: 99%

Clinical implications of pharmacogenomics for tardive dyskinesia

et al. 2004

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“…An intriguing study reported that the nonsynonymous substitution of G by C at position 68 of the 5HT2C gene (leading to a cys23ser conversion) additively contributed to increase TD susceptibility in individuals carrying gly9 DRD3. 24 We analyzed the 5HT2C gene in C. apella and found that all monkeys were homozygous for the cys23 allele. This finding suggests that high TD susceptibility can be present in a species in the absence of the serine version of the 5HT2C receptor and without the possible additive contribution of gly9 DRD3 and ser23 5HT2C reported in humans.…”

Section: T Werge Et Almentioning

confidence: 99%

“…Also, we have examined the 5HT2C gene in C. apella and determined the sequence around position +68, which has been shown to be polymorphic and potentially associated with TD in humans. 24 …”

Section: Introductionmentioning

confidence: 99%

Cebus apella, a nonhuman primate highly susceptible to neuroleptic side effects, carries the GLY9 dopamine receptor D3 associated with tardive dyskinesia in humans

et al. 2003

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Tardive dyskinesia (TD) is a severe side effect of traditional neuroleptics affecting a considerable number of schizophrenic patients. Accumulating evidence suggests the existence of a genetic disposition to TD and other extra pyramidal symptoms (EPS) most strongly linked to a ser/gly polymorphism in position 9 of the D3 dopamine receptor gene (DRD3). The Cebus apella monkey is the favored animal model to study TD and other EPS because of its high susceptibility to side effects of neuroleptics. We therefore determined the sequence of the DRD3 gene in this species and compared it with that of humans. We found that the highly TD susceptible C. apella monkey (n ¼ 21) carries the gly9/gly9 DRD3 genotype that has been associated with TD in humans. Contrarily, C. apella did not carry the ser23 5HT2C allele that has been reported to increase TD susceptibility in humans.

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Association between the serotonin 2C receptor gene and tardive dyskinesia in chronic schizophrenia: additive contribution of 5-HT2C ser and DRD3 gly alleles to susceptibility

Abstract: These findings support a small but significant contribution of the HT2CR and DRD3 to susceptibility to TD, which is additive in nature.

Cited by 128 publications

References 23 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

Clinical implications of pharmacogenomics for tardive dyskinesia

Cebus apella, a nonhuman primate highly susceptible to neuroleptic side effects, carries the GLY9 dopamine receptor D3 associated with tardive dyskinesia in humans

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