Genetics of Tardive Dyskinesia

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Abstract

Tardive dyskinesia (TD) is one of the most serious adverse side effects of antipsychotic drugs and is an important topic of pharmacogenetic studies. Since there is a genetic susceptibility for developing this adverse reaction, and given that it is hard to predict its development prior to or during the early period of medication, the genetic study of TD is a promising research topic that has a direct clinical application. Moreover, such studies would improve our understanding of the genetic mechanism(s) underlying abnormal dyskinetic movement. A substantial number of case-control association studies of TD have been performed, with numbers of studies focusing on the genes involved in antipsychotic drug metabolism, such as those for cytochrome P450 (CYP) and oxidative stress related genes as well as various neurotransmitter related genes. These studies have produced relatively consistent though controversial findings for certain polymorphisms such as CYP2D6*10, DRD2 Taq1A, DRD3 Ser9Gly, HTR2A T102C, and MnSOD Ala9Val. Moreover, the application of the genome-wide association study (GWAS) to the susceptibility of TD has revealed certain associated genes that previously were never considered to be associated with TD, such as the rs7669317 on 4q24, GLI2 gene, GABA pathway genes, and HSPG2 gene. Although a substantial number of genetic studies have investigated TD, many of the positive findings have not been replicated or are inconsistent, which could be due to differences in study design, sample size, and/or subject ethnicity. We expect that more refined research will be performed in the future to resolve these issues, which will then enable the genetic prediction of TD and clinical application thereof.

Introduction

Tardive dyskinesia (TD) is a serious adverse side effect that is occasionally experienced by schizophrenic patients who are treated with antipsychotic drugs. Although the prevalence rates are difficult to estimate and have reportedly differed between studies, a meta-analysis including 39,187 subjects from 76 studies found an overall prevalence of 24.2% (Yassa and Jeste, 1992). The most typical sign of TD is involuntary orofacial dyskinesia, but the trunk and extremities may also be affected. TD is generally caused by antipsychotics, and particularly first-generation antipsychotics (FGAs), but sometimes also second-generation antipsychotics (SGAs). Although many SGAs have been developed and are increasingly used, FGAs are still extensively prescribed due to factors such as the lack of any significant differences in the efficacy of the two generations of antipsychotic (Lieberman, 2007), the side effects of SGAs (such as metabolic syndrome), and the lower acquisition costs of FGAs.

The causes of the TD are deemed multifactorial; many multiple demographic causes including the age, gender, dosage, ethnicity, and duration of exposure to antipsychotics have been proposed, and several pathophysiological causes have also been proposed, none of which has been considered conclusive. Several biological mechanisms underlying the pathophysiology of TD have been proposed, including dopamine receptor hypersensitivity (Tarsy and Baldessarini, 1977), serotonergic dysfunction (Meltzer, 1994), γ-aminobutyric acid (GABA) insufficiency (Casey et al., 1980), and disturbances of antioxidative protection (Andreassen and Jorgensen, 2000). However, the pathophysiology of TD remains poorly understood.

Many studies have provided evidence that TD involves genetic and familial causes. Specifically, it has been found that TD occurs only in some patients taking antipsychotics, and that such occurrences involve a familial tendency, thus indicating a biological or genetic factor (Tamminga et al., 1990, Yassa and Ananth, 1981). This background has prompted many genetic studies of TD, which mainly involve pharmacogenetic investigations of antipsychotics. Another reason why many studies have investigated TD pharmacogenetics is that TD is the type of side effect that is potentially irreversible and it is very hard to predict who it will affect. Furthermore, TD causes patients serious distress and leads to noncompliance with pharmacotherapy. Elucidating the details of the genetic susceptibility to this side effect would make prescription after genotyping and biomarker-guided prediction possible (Ozdemir et al., 2006). In the future, it may become possible to calculate the probability of developing TD by considering the presence of certain associated variables (i.e., genes and demographic parameters). Moreover, the pharmacogenetic study of TD will contribute to discovery of the genetic mechanism underlying abnormal dyskinetic movement and movement disorders.

The candidate genes that are thought to determine susceptibility to TD are cytochrome P450 (CYP), diverse neurotransmitter, and oxidative-stress-related genes. The medication response is very closely related to the drug metabolism, and CYP genes have been investigated extensively. In addition, the neurotransmitter-related genes, and especially those related to dopamine and serotonin, have been studied substantially because these neurotransmitters are deemed to be the targets of antipsychotics. Several recent studies of oxidative-stress-related genes have provided evidence of a relationship between TD and oxidative stress. Moreover, numerous pharmacogenetic studies have investigated genes related to neurotrophic factors, opioid receptors, estrogen receptors, the GABA pathway, and the glutaminergic pathway. Fig. 1 shows hypothetical genetic factors contributing to TD.

Section snippets

Genes Involved in Pharmacokinetics

The metabolism of antipsychotic drugs is a crucial determinant of their therapeutic and adverse effects. The contribution of pharmacokinetic factors is important to the clinical outcome of antipsychotic treatment. Antipsychotic drugs are metabolized and distributed by various enzymes. For example, since perphenazine is metabolized extensively by CYP2D6, variants of CYP2D6 may substantially influence the exposure of perphenazine to patients. It is hypothesized that reduced metabolism of

Genes Involved in Pharmacodynamics

Pharmacogenetic studies of pharmacodynamic factors have been conducted in order to validate therapeutic targets. Neurotransmitter systems in the brain are considered to be altered in patients with schizophrenia, and hence have been targets of antipsychotic therapy. Antipsychotics have diverse affinities for each neurotransmitter receptor, including dopamine, serotonin, adrenergic, glutamate, histamine, and muscarine receptors. Therefore, the pharmacodynamic properties of antipsychotics are

Oxidative-Stress-Related Genes

Neuronal degeneration by oxidative stress has been suggested as a mechanism for TD pathogenesis. Excessive reactive oxygen species (ROS) produced by an imbalance between free-radical metabolism and the antioxidant defense mechanism can interact with lipids, proteins, and nucleic acids, resulting in cellular dysfunction or cell death (Halliwell, 1997). Neuronal cells appear to be highly susceptible to oxidative damage, and several studies have found that elevated lipid peroxidation in the

Estrogen Receptor

It has been suggested that estrogen modulates dopamine receptors in the central nervous system and decreases the incidence and/or relieves the symptoms of TD. However, in a study of the relationship between estrogen receptor-α gene polymorphisms and TD in 118 schizophrenia and 128 matched non-TD schizophrenia patients, Lai et al. (2002) found only a marginal association.

Opioid Receptor

There are several lines of evidence that the opioid receptors are involved in the pathology of TD (Cadet and Rothman, 1986,

The Genome-Wide Association Approach

The genetic study method that is most widely used and provides an ample number of samples is the case-control association study. In practice, because TD is a side effect that only develops in patients with schizophrenia who are taking antipsychotics, it is difficult to conduct a linkage study involving family members with TD. For this reason, the hypothesis-based association study with the candidate gene approach is thought to be one of the best methods of TD research, providing substantial

Future Research: Copy-number Variations and Epigenetics

Other new genetic testing technologies have recently been developed. Some researchers have stressed that other types of genetic variation such as deletions or duplications—the so-called copy-number variations (CNVs)—may have been neglected (Redon et al., 2006). Moreover, other less common genetic variations such as microsatellite polymorphisms and translocations, inversions, and substitutions may be relevant to pharmacogenomics (Court, 2007). Unfortunately, many of the current platforms and

TD as a Phenotype

While many significant findings of genetic studies for TD have been reported, the results obtained in a considerable proportion of these studies have not been replicated. The more important causes for these discrepancies include study design, sample size, and ethnicity. Diagnosing TD is not simple, and the diagnostic criteria and/or inclusion criteria for TD have differed somewhat among TD studies. Most of the pharmacogenetic studies of TD have adopted the AIMS (Guy, 1976) and/or criteria for

Conclusion

Relatively consistent findings have been reported on certain polymorphisms such as CYP2D6*10, DRD2 Taq1A, DRD3 Ser9Gly, HTR2A T102C, SLC6A11, and MnSOD Ala9Val, although they remain controversial. Moreover, several GWASs on TD have found positive findings with rs7669317 on 4q24, GLI2, GABA pathway genes, and HSPG2. Although many genetic studies have been conducted on TD, the positive results of a considerable proportion of these studies have not been replicated or are inconsistent. These

Acknowledgment

This work was supported by the Korea Research Foundation Grant funded by the Korean Government (KRF-2008-313-E00333).

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