Oxidative stress and tardive dyskinesia: Pharmacogenetic evidence

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Abstract

Tardive dyskinesia (TD) is a serious adverse effect of long-term antipsychotic use. Because of genetic susceptibility for developing TD and because it is difficult to predict and prevent its development prior to or during the early stages of medication, pharmacogenetic research of TD is important. Additionally, these studies enhance our knowledge of the genetic mechanisms underlying abnormal dyskinetic movements, such as Parkinson's disease. However, the pathophysiology of TD remains unclear. The oxidative stress hypothesis of TD is one of the possible pathophysiologic models for TD. Preclinical and clinical studies of the oxidative stress hypothesis of TD indicate that neurotoxic free radical production is likely a consequence of antipsychotic medication and is related to the occurrence of TD. Several studies on TD have focused on examining the genes involved in oxidative stress. Among them, manganese superoxide dismutase gene Ala–9Val polymorphisms show a relatively consistent association with TD susceptibility, although not all studies support this. Numerous pharmacogenetic studies have found a positive relationship between TD and oxidative stress based on genes involved in the antioxidant defense mechanism, dopamine turnover and metabolism, and other antioxidants such as estrogen and melatonin. However, many of the positive findings have not been replicated. We expect that more research will be needed to address these issues.

Highlights

► The oxidative stress hypothesis of TD is one of the pathophysiologic models for TD. ► Several studies on TD have focused on the genes involved in oxidative stress. ► Numerous oxidative stress based on genes are associated with TD. ► MnSOD Ala–9Val polymorphisms are relatively consistent associated with TD.

Introduction

Tardive dyskinesia (TD) is a serious adverse side effect of long-term antipsychotic use. Twenty to thirty percent of schizophrenic patients treated with typical antipsychotics develop TD (Jeste and Caligiuri, 1993, Kane et al., 1988, Yassa and Jeste, 1992). It is difficult to estimate the prevalence of TD and reported rates differ among studies. A meta-analysis of 39,187 subjects from 76 studies reported an overall prevalence of 24.2% (Yassa and Jeste, 1992). Because TD is a potentially irreversible side effect of antipsychotic use, it adversely affects the compliance of schizophrenia patients. Thus, it is very important to be able to predict and prevent TD. However, predicting and preventing its development prior to or during the early period of antipsychotic medication is challenging.

The typical sign of TD is involuntary orofacial dyskinesia, observed in approximately 80% of TD cases (Rapaport et al., 2000). However, other regions such as the trunk and extremities may also be affected. Most TD is generally caused by the use of first-generation antipsychotics (FGAs) (Janno et al., 2004), but they may also be caused by second-generation antipsychotics (SGAs) (Correll and Schenk, 2008). Although many SGAs have been introduced and prescribed widely in the treatment of schizophrenia, FGAs are still extensively prescribed due to reasons such as similar effectiveness between the two generations of antipsychotics (Lieberman, 2007), the adverse side effects of SGAs such as metabolic syndrome, and the lower cost of FGAs compared to SGAs.

Not all patients exposed to long-term antipsychotics develop TD; only a small proportion of patients develop TD. This suggests that there are individual variations in the development of TD. Genetic susceptibility may play a key role in this pattern (Van Tol et al., 1992). Several preclinical animal studies suggest that genetic factors contribute to individual variations in TD. Many studies have found that TD is related to genetic and familial causes (Muller et al., 2001, Tamminga et al., 1990, Weinhold et al., 1981, Yassa and Ananth, 1981). Several investigations about gene–gene interaction and gene–environment interaction suggest that theses interactions contribute to individual variations in TD. Gene–environment interaction study found an age-related association of two serotonergic genes, the 5-HT2C (HTR2C) and the 5-HT2A receptor (HTR2A) with susceptibility to TD (Segman and Lerer, 2002). Gene–gene interaction study found an additive effect of the two risk alleles, both the Gly9 allele of the DRD3 Ser9Gly polymorphism and the Ser23 allele of the 5-HT2C Cy23Ser polymorphism (Segman et al., 2000). Other interaction study showed that there was a significant excess of DRD3 Gly allele carriers among carriers of the cytochrome P450 (CYP) 17 C/C genotype with TD compared with those without TD (Segman et al., 2002). Patients who had the risk genotype both DRD3 (Gly9/Gly9) and CYP1A2 (C/C) showed more severe TD, than those who had only one risk genotype (Gly9/Gly9 or C/C) (Basile et al., 2001). There was a gene–gene interaction study between the Ala–9Val polymorphism of MnSOD and the Ser9Gly polymorphism of DRD3 with TD. The MnSOD–Val DRD3–Gly genotype combination was the most frequent among patients with TD (64%), whereas the MnSOD–Ala DRD3–Ser genotype (24%) was the least frequent. The Gly allele of DRD3 is known to increase susceptibility to TD, and the ala allele of MnSOD is known to have protective effect against TD (Lerer and Segman, 2006).

Several studies have found a positive association between TD and genetic polymorphisms, including polymorphisms of the dopamine D2 and D3 receptors (DRD2 and DRD3) (Chen et al., 1997, Chong et al., 2003, Steen et al., 1997), 5-HT2A receptor (Segman et al., 2001), and 5-HT2C receptor genes (Segman et al., 2000). Various pharmacogenetic studies of TD have investigated candidate genes related to cytochrome P450 (CYP), diverse neurotransmitters, oxidative-stress-related genes, neurotrophic factors, opioid receptors, estrogen receptors, the γ-aminobutyric acid (GABA) pathway, and the glutaminergic pathway.

TD is a potentially irreversible side effect and it is very difficult to predict who will develop TD. Thus, it is very important and essential to study the pharmacogenetic evidence related to TD. In the future, it may be possible to predict the probability of developing TD by considering the presence of certain associated variables, especially genetic factors (Ozdemir et al., 2006). Furthermore, the pharmacogenetic study of TD will contribute to a better understanding of the genetic mechanisms underlying diverse dyskinetic movement disorders. For example, l-DOPA-induced dyskinesia (LID) of Parkinson's disease (PD) patient is maybe related to TD. l-DOPA is the most effective pharmacological treatment of PD, but the development of LID is problematic condition (Mercuri and Bernardi, 2005). Several studies indicate that this problematic condition is related to the sensitization developed by dopaminergic receptors, in response to the loss of dopamine associated with PD (Aubert et al., 2005, Fisone and Bezard, 2011). Dopamine receptor supersensitivity is one of the TD pathophysiology hypotheses (Tarsy and Baldessarini, 1977).

The pathophysiology of TD is not well established. The causes of TD are believed to be multifactorial. Several biological mechanisms underlying the pathophysiology of TD have been suggested, including dopamine receptor supersensitivity (Tarsy and Baldessarini, 1977), serotonergic dysfunction (Meltzer, 1994), GABA insufficiency (Casey et al., 1980), and the oxidative stress hypothesis (Andreassen and Jorgensen, 2000). Traditionally, the dopamine–receptor supersensitivity hypothesis has been considered the most influential hypothesis (Klawans and Rubovits, 1972). However, there have been problems in using the dopamine supersensitivity hypothesis because when the offending antipsychotic is withdrawn, supersensitivity declines and dopamine receptor numbers return to baseline. However, the majority of studies indicate that TD is irreversible (Sachdev, 2000). Thus, it is unlikely that dopamine supersensitivity fully contributes to TD. Several studies have suggested that there must be a neurotoxic process to explain the irreversibility of TD, also known as the ‘neuronal degeneration hypothesis’ (Elkashef and Wyatt, 1999, Sachdev et al., 1999). Oxidative damage may increase with age, a possible explanation of increased rates of TD as age increases (Hensley and Floyd, 2002, Wickens, 2001). Thus, the oxidative stress hypothesis is currently regarded as a possible explanation for TD and has been studied more recently. The oxidative stress hypothesis is based on two studies that have shown that free radical scavengers such as vitamin E improve TD symptoms and lipid peroxidation products increase in the cerebrospinal fluid of patients with TD (Adler et al., 1998, Lohr et al., 1990, Tsai et al., 1998). Free radicals are highly reactive chemical species with an unpaired electron. The brain is vulnerable to free radical damage (Southorn and Powis, 1988). The brain uses a large amount of energy, receiving about 20% of the cardiac output of oxygenated blood (Lohr et al., 2003). Additionally, the brain contains enormous amounts of polyunsaturated fatty acids, which are related to activity in lipid peroxidation cascades (Jenner, 1994, Lohr, 1991). Specific regions of the brain such as the basal ganglia are rich in transition metals (Weiner et al., 1977). Additionally, the brain contains large amounts of catecholamines, such as dopamine. A preclinical study has shown that neurotoxic free radical production may be an important consequence of antipsychotic treatment (Cadet and Lohr, 1989). Further, there is considerable evidence that increased oxidative stress plays a key role in the occurrence of TD (Cadet and Kahler, 1994, Elkashef and Wyatt, 1999). Thus, it is beneficial to study oxidative stress to better understand and prevent TD, especially with regard to pharmacogenetic evidence. In this article we will review pharmacogenetic studies of TD related to the oxidative stress hypothesis.

Section snippets

Impairment in the antioxidant defense mechanism

Oxygen radical formation is common because most of the energy for the body is supplied through the chemical reaction of oxygen occurring throughout the body (Tenback and van Harten, 2011). Ideally all of the oxygen should be reduced to water by a four-electron reduction reaction through cytochrome oxidase. However, a small percentage of oxygen may be reduced by only one, two or three electrons, resulting in superoxide anion (O2), hydrogen peroxide (H2O2) or the hydroxyl radical. The most

Genes related to the antioxidant defense mechanism

Among the oxidative-stress pathway-related enzymes, SOD is the first-line antioxidant defense enzyme that plays a critical role in preventing cell damage induced by free radicals. In particular, MnSOD is an intramitochondrial enzyme that scavenges the superoxide anions produced by mitochondrial energy metabolism through a process that converts O2 into hydrogen peroxide (H2O2; Fridovich, 1998, Robinson, 1998). The MnSOD gene is located in the long arm (6q25) of chromosome 6 in humans. Several

Conclusion

Among the polymorphism studies examining TD and its association with the oxidative stress hypothesis, only MnSOD Ala–9Val polymorphism studies have found a consistent relationship, although these studies remain controversial (Lee and Kang, 2011). There have been many polymorphism studies about TD based on dopamine receptor supersensitivity, serotonergic dysfunction, and GABA insufficiency. However, a relatively inadequate number of studies have investigated the relationship between TD and the

Acknowledgment

This work was supported by grant A111949 from the Korea Healthcare Technology R & D Project, Ministry of Health & Welfare.

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