Clinical implications of pharmacogenomics for tardive dyskinesia

Müller, Daniel J.; Shinkai, Takahiro; Luca, Vincenzo De; Kennedy, James L.

doi:10.1038/sj.tpj.6500233

Cited by 51 publications

(29 citation statements)

References 85 publications

(73 reference statements)

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“…All groups (with and without TD) were in HWE, except for the patients in the study by Akyol et al 76 A meta-analysis of the four samples, yielding a total of 134 patients with TD and 546 without, was conducted. 47,73,74,76 Heterogeneity and bias Significant heterogeneity was apparent for the allelic analyses (w 2 Table 1). …”

Section: Mnsod Studies Includedmentioning

confidence: 99%

“…Since the introduction of antipsychotic medication in 1952, tardive dyskinesia (TD), characterized by hyperkinetic involuntary movements of the choreoathetoid type with a fluctuating intensity over time, 1,2 is still a major concern as a potentially irreversible side effect, which can be distressing for patients owing to motor performance difficulties, social stigmatization and poorer quality of life. 3 Studies on genetic factors related to TD are often inconsistent owing to genetic methodological problems, such as sample heterogeneity, small effects of multiple genes, (epi)genetic interactions, pleiotropy and small sample size.…”

Section: Introductionmentioning

confidence: 99%

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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

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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.

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Section: Mnsod Studies Includedmentioning

confidence: 99%

Section: Introductionmentioning

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

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“…Risk factors other than antipsychotic exposure may play a significant role in the development of TD. Epidemiologic studies have identified advanced age (in fact the strongest demographic risk factor), the presence of organic brain disease, and a family history of tardive dyskinesia as potential contributors [8,22]. Higher doses of, and prolonged exposure to, antipsychotics are the strongest environmental risk factors for TD [8,22] though no consistent pharmacokinetic relationship has been identified between antipsychotic dose, plasma drug level, and the risk of TD [24].…”

Section: Uncertaintymentioning

confidence: 99%

“…How much of the disease process of tardive dyskinesia is due to antipsychotic medications [21][22][23]? Spontaneous dyskinesias have been described in antipsychotic-naïve patients suffering from schizophrenia with a frequency of up to 5% [1,2].…”

Section: Uncertaintymentioning

confidence: 99%

Ethical and Policy Considerations in the Application of Pharmacogenomic Testing for Tardive Dyskinesia: Case Study of the Dopamine D3 Receptor

Shamy¹,

Zai²,

Basile³

et al. 2011

CPPM

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Tardive dyskinesia (TD) is a serious adverse effect often associated with the first generation antipsychotic medications used in the management of mental health disorders such as schizophrenia. Pharmacogenomics is the study of human genomic variation in relation to individual and population variability in medication response and side effects. Neuropsychiatry is one of the clinical domains in which pharmacogenomic approaches have been extensively studied. In the late 1990s, the Glycine9 (Gly9) allele of the Serine-9-Glycine (Ser9Gly) polymorphism in dopamine D3 receptor gene (DRD3) was found to be associated with both a liability to, and worsened severity of, TD in schizophrenic patients treated with typical antipsychotics. This initial discovery has been subsequently replicated and testing for the Ser9Gly polymorphism has now become commercially available. The question that currently presents itself is whether its use should be encouraged for patients who may be prescribed a typical or atypical antipsychotic medication. However, the translation of this new technology to clinical practice presents multiple social, ethical and policy challenges. Though pharmacogenomic testing holds much promise in this scenario, many important questions remain to be answered before its widespread use can be medically and ethically justified. This article highlights the key advances in our understanding of the role of human genetic variation in the D3 receptor in relation to TD. Then, issues of uncertainty, consent, confidentiality, and access are considered with respect to the use of DRD3 polymorphism testing in risk stratification for susceptibility to tardive dyskinesia. We propose three recommendations that may help bring this technology into the clinic: 1) prospective pharmacogenomic studies of DRD3 polymorphism and TD risk should be conducted; 2) the design of such studies should be influenced by scientists, ethicists and policy makers to protect potentially vulnerable patients; and 3) appropriate knowledge transfer to front-line health care workers must take place.

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“…Its development in a subset of patients (~20-25%), familial nature, and concordance amongst twins indicate a possible genetic basis (for review see Muller et al 2004). In addition to the classical dopaminergic pathway genes, oxidative stress mediated neurotoxic damage is also an important hypothesis proposed to explain the development of TD.…”

mentioning

confidence: 99%

Genetic susceptibility to Tardive Dyskinesia in chronic schizophrenia subjects: Role of oxidative stress pathway genes

Thelma

Tiwari

Deshpande³

et al. 2007

Schizophrenia Research

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Keywordsnorth India; Tardive Dyskinesia; oxidative stress; NOS3; NQO1; Single nucleotide polymorphisms; association Tardive Dyskinesia (TD) is a severe debilitating movement disorder with a potentially irreversible course developing in schizophrenia patients under long term treatment with classical neuroleptics. Its development in a subset of patients (~20-25%), familial nature, and concordance amongst twins indicate a possible genetic basis (for review see Muller et al. 2004). In addition to the classical dopaminergic pathway genes, oxidative stress mediated neurotoxic damage is also an important hypothesis proposed to explain the development of TD. Considerable support to OS hypothesis comes from the observations of increased lipid peroxidation in cerebrospinal fluid in patients with TD and antioxidants such as vitamin E alleviate TD symptoms (Adler et al. 1999; for review see Lohr, 2003). Recently a novel antioxidant AD4 has been reported to reduce haloperidol induced vacuous chewing moments in rats (Sadan et al. 2005).In this study, genes involved in the maintenance of cellular redox balance namely, superoxide dismutase 2 (SOD2; MnSOD; Ala9Val), Uncoupling protein 2 (UCP2; 45bp del/ins), neuronal nitric oxide synthase (nNOS; NOS1; His902His, rs2682826), endothelial NOS (eNOS; NOS3; 27bp ins/del), glutathione S transferase (GST; GSTMI, TI; Presence/Null; GSTPI, Ile105Val) and NADPH: quinone oxidoreductase 1 (NQO1, Pro187Ser) were analysed. Schizophrenia patients with TD (n=96) and without TD (n=239) were recruited for the study. SNPs were genotyped using PCR-RFLP and allelic, genotypic and haplotypic association was tested using χ 2 test. Further, to test whether severity of TD was influenced by genotype, mean AIMS score was compared across the genotypic categories for each of the polymorphism using Kruskal Wallis H test.

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Clinical implications of pharmacogenomics for tardive dyskinesia

Cited by 51 publications

References 85 publications

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

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

Ethical and Policy Considerations in the Application of Pharmacogenomic Testing for Tardive Dyskinesia: Case Study of the Dopamine D3 Receptor

Genetic susceptibility to Tardive Dyskinesia in chronic schizophrenia subjects: Role of oxidative stress pathway genes

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