Combined analysis of 635 patients confirms an age-related association of the serotonin 2A receptor gene with tardive dyskinesia and specificity for the non-orofacial subtype

Lerer, Bernard; Segman, Ronnen H.; Tan, Ene Choo; Basile, Vincenzo S.; Cavallaro, Roberto; Aschauer, Harald; Strous, Rael D.; Chong, Siow Ann; Heresco-Levy, Uriel; Verga, M.; Scharfetter, Joachim; Meltzer, Herbert Y.; Kennedy, James L.; Macciardi, Fabìo

doi:10.1017/s1461145705005389

Cited by 111 publications

(75 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Initial reports on association between 5-HT 2A polymorphisms and TD 224,243,244 were not replicated in independent studies. 205,247,246 The association was later confirmed in a combined analyses controlling for patients' age, 245 an important factor in the development of TD. Serotonin 5-HT 2C promoter polymorphisms were reportedly associated with TD.…”

Section: Prediction Of Side Effectsmentioning

confidence: 81%

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

2007

View full text Add to dashboard Cite

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.

show abstract

Section: Prediction Of Side Effectsmentioning

confidence: 81%

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

2007

View full text Add to dashboard Cite

show abstract

“…Previously, other genes were included in meta-analyses such as (1) the gene encoding for 5-HT2A 82 (a) showing a small but significant association of the T102C genotype in several subgroups of TD and (b) the 5-HT2A His452Tyr polymorphism that showed a significant association with TD in a two-locus haplotype with T102C, (2) the joint comparison group of deficient alleles (*3, *4, *5) with TD 10 and (3) the gene encoding for DRD3 7,83 showed a significant excess of the Gly-allel and Gly-Gly homozygotes of the Ser9Gly polymorphism in patients with schizophrenia and TD. The meta-analysis of Bakker et al 7 showed a reduced or even opposite tendency in Asians compared to non-Asians.…”

Section: Resultsmentioning

confidence: 99%

Antipsychotic-induced tardive dyskinesia and polymorphic variations in COMT, DRD2, CYP1A2 and MnSOD genes: a meta-analysis of pharmacogenetic interactions

Bakker¹,

Harten²,

2008

Mol Psychiatry

138

118

View full text Add to dashboard Cite

Despite accumulating evidence pointing to a genetic basis for tardive dyskinesia, results to date have been inconsistent owing to limited statistical power and limitations in molecular genetic methodology. A Medline, EMBASE and PsychINFO search for literature published between 1976 and June 2007 was performed, yielding 20 studies from which data were extracted for calculation of pooled estimates using meta-analytic techniques. Evidence from pooled data for genetic association with tardive dyskinesia (TD) showed (1) in COMT val158met , using Val-Val homozygotes as reference category, a protective effect for Val-Met heterozygotes (OR = 0.63, 95% CI: 0.46-0.86, P = 0.004) and Met carriers (OR = 0.66, 95% CI: 0.49-0.88, P = 0.005); (2) in Taq1A in DRD2, using the A1 variant as reference category, a risk-increasing effect for the A2 variant (OR = 1.30, 95% CI: 1.03-1.65, P = 0.026), and A2-A2 homozygotes using A1-A1 as reference category (OR = 1.80, 95% CI: 1.03-3.15, P = 0.037); (3) in MnSOD Ala9Val, using Ala-Ala homozygotes as reference category, a protective effect for Ala-Val (OR = 0.37, 95% CI: 0.17-0.79, P = 0.009) and for Val carriers (OR = 0.49, 95% CI: 0.24-1.00, P = 0.047). These analyses suggest multiple genetic influences on TD, indicative of pharmacogenetic interactions. Although associations are small, the effects underlying them may be subject to interactions with other loci that, when identified, may have acceptable predictive power. Future genetic research will take advantage of new genomic knowledge.

show abstract

“…51 The CATIE TD sample was based on prospective design with multiple evaluations per patients, whereas the retrospective Israeli study employed a cross-sectional design and patients were assessed for TD only once. 21,22,32,33 Therefore, a further consideration is the use of the potentially highly valuable extreme phenotype approach in this cohort sample. Because of the fluctuating nature of TD, and the fact that TD may be suppressed by increasing antipsychotics doses, it is possible that for some patients the classification may not be accurate.…”

Section: Discussionmentioning

confidence: 99%

“…These include variants within COMT, DRD2, MnSOD, DRD3, HTR2A, CYP1A2 and CYP2D6. [21][22][23][24][25][26] Recently, two genomewide association studies (GWASs) and a large candidate gene study of TD were published, based on the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, using two different definitions for TD phenotype. [27][28][29] Although none of the top results reached genome-wide significance, the association of single-nucleotide polymorphism (SNP) rs3943552 in the GLI2 gene with TD was observed in the CATIE sample and independently supported in Jewish Israeli schizophrenia patients of Ashkenazi origin.…”

Section: Introductionmentioning

confidence: 99%

Support for association of HSPG2 with tardive dyskinesia in Caucasian populations

Greenbaum¹,

Alkelai²,

Zozulinsky³

et al. 2011

Pharmacogenomics J

View full text Add to dashboard Cite

Tardive dyskinesia (TD) is a severe adverse effect of chronic antipsychotic drug treatment. In addition to clinical risk factors, TD susceptibility is influenced by genetic predisposition. Recently, Syu et al. (2010) reported a genome-wide association screening of TD in Japanese schizophrenia patients. The best result was association of single-nucleotide polymorphism (SNP) rs2445142 in the HSPG2 (heparan sulfate proteoglycan 2) gene with TD. In the present study, we report a replication study of the five top Japanese TDassociated SNPs in two Caucasian TD samples. Applying logistic regression and controlling for relevant clinical risk factors, we were able to replicate the association of HSPG2 SNP rs2445142 with TD in a prospective study sample of 179 Americans of European origin by performing a secondary analysis of the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) genome-wide association study data set, and using a perfect proxy surrogate marker (rs878949; P ¼ 0.039). An association of the 'G' risk allele of HSPG2 SNP rs2445142 with TD was also shown in a sample of Jewish Israeli schizophrenia patients (retrospective, cross-sectional design; P ¼ 0.03). Although the associations were only nominally significant, the findings provide further support for the possible involvement of HSPG2 in susceptibility to TD.

show abstract

Combined analysis of 635 patients confirms an age-related association of the serotonin 2A receptor gene with tardive dyskinesia and specificity for the non-orofacial subtype

Cited by 111 publications

References 68 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

Antipsychotic-induced tardive dyskinesia and polymorphic variations in COMT, DRD2, CYP1A2 and MnSOD genes: a meta-analysis of pharmacogenetic interactions

Support for association of HSPG2 with tardive dyskinesia in Caucasian populations

Contact Info

Product

Resources

About