Occurrence Of Tardive Dyskinesia Research Articles

Analysis of schizophrenia-associated genetic markers in the HLA region as risk factors for tardive dyskinesia.

The pathology of Tardive Dyskinesia (TD) has yet to be fully understood, but there have been proposed hypotheses for the cause of this condition. Our team previously reported a possible association of TD with the Complement Component C4 gene in the HLA region. In this study, we explored the HLA region further by examining two previously identified schizophrenia-associated HLA-region single-nucleotide polymorphisms (SNPs), namely rs13194504 and rs210133. The SNPs rs13194504 and rs210133 were tested for association with the occurrence and severity of TD in a sample of 172 schizophrenia patients who were recruited for four studies from three different clinical sites in Canada and USA. The rs13194504 AA genotype was associated with decreased severity for TD as measured by Abnormal Involuntary Movement Scale (AIMS) scores (p=0.047) but not for TD occurrence. SNP rs210133 was not significantly associated with either TD occurrence or AIMS scores. Our findings suggest that the rs13194504 AA genotype may play a role in TD severity, while SNP rs210133 may not have a major role in the risk or severity of TD.

Associations between Catechol-O-methyltransferase (COMT) polymorphisms and cognitive impairments, psychiatric symptoms and tardive dyskinesia in schizophrenia

IntroductionCatechol-O-methyltransferase (COMT) is a crucial enzyme involved in dopamine metabolism and has been implicated in the etiology of tardive dyskinesia (TD). We aimed to investigate the associations between COMT gene polymorphisms and the occurrence and severity of TD in a Chinese population, as well as the impact on the psychiatric symptoms and cognitive impairments observed in TD patients. MethodsA total of 216 chronic schizophrenia patients, including 59 TD patients and 157 NTD patients, were recruited for this study. Three SNPs of the COMT gene (rs4680, rs165599 and rs4818) were selected and genotyped using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS). TD severity, psychopathology and cognitive functioning were assessed using the Abnormal Involuntary Movement Scale (AIMS), the Positive and Negative Syndrome Scale (PANSS) and the Repeated Battery for Assessment of Neuropsychological Status (RBANS), respectively. ResultsIn TD patients, total AIMs scores were higher in carriers of the rs4680 AA genotype than in carriers of the AG and GG genotypes (p = 0.01, 0.006), carriers of the rs4818 GC and CC genotypes had higher orofacial scores than in GG genotypes (p = 0.032, 0.002). In male TD patients, carriers of the rs165599 GA genotype scored lower in the extremities and trunk scores than AA genotype carriers (p = 0.015). Moreover, in male TD patients, COMT rs4818 was associated with cognition, since the C allele carriers had significantly higher immediate memory (p = 0.043) and verbal function (p = 0.040) scores than the G allele carriers. In addition, rs165599 genotype interacted with TD diagnosis on depressed factor (p = 0.031). ConclusionWithin the Chinese population, COMT gene polymorphisms could potentially serve as biomarkers for the symptoms and prognosis of TD patients.

Genetic Susceptibility to Tardive Dyskinesia and Cognitive Impairments in Chinese Han Schizophrenia: Role of Oxidative Stress-Related and Adenosine Receptor Genes.

Tardive dyskinesia (TD) is a severe rhythmic movement disorder caused by long-term antipsychotic medication in chronic patients with schizophrenia (SCZ). We aimed to investigate the association between polymorphisms in oxidative stress-related genes (GSTM1, SOD2, NOS1, and NOS3) and adenosine receptor gene (ADORA2A), as well as their interactions, with the occurrence and severity of TD, and cognitive impairments in a Chinese Han population of SCZ patients. Two hundred and sixteen SCZ patients were recruited and divided into TD group (n=157) and non-TD group (n=59). DNA extraction was performed by a high-salt method, followed by SNP genotyping using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS). The severity of TD, psychopathology and cognitive functioning were assessed using the Abnormal Involuntary Movement Scale (AIMS), the Positive and Negative Syndrome Scale (PANSS) and the Repeated Battery for Assessment of Neuropsychological Status (RBANS), respectively. The combination of GSTM1-rs738491, NOS1-rs738409 and ADORA2A-rs229883 was identified as the best three-point model to predict TD occurrence (p=0.01). Additionally, GSTM-rs738491 CC or NOS3-rs1800779 AG genotypes may be protective factors for psychiatric symptoms in TD patients. TD patients carrying the NOS1-rs738409 AG or ADORA2A-rs229883 TT genotypes exhibited poorer cognitive performance. Our findings suggest that the interaction of oxidative stress-related genes and adenosine receptor gene may play a role in the susceptibility and severity of TD in Chinese Han SCZ patient. Furthermore, these genes may also affect the psychiatric symptoms and cognitive function of TD patients.

Tardive Dyskinesia Development, Superoxide Dismutase Levels, and Relevant Genetic Polymorphisms.

Tardive dyskinesia (TD) is a prevalent movement disorder that significantly impacts patients with schizophrenia (SCZ) due to extended exposure to antipsychotics (AP). Several genetic polymorphisms, including superoxide dismutase (SOD) and DRD3 9ser, have been suggested as explanations why some patients suffer from TD. Methods. A PubMed search was used to search relevant articles using the following keywords: "Tardive Dyskinesia and Superoxide Dismutase". Fifty-eight articles were retrieved. Among them, 16 were included in this review. Results. Overall, 58 studies were retrieved from PubMed. Most studies investigated the association between TD and the SOD-related polymorphisms. In addition, previous studies reported an association between TD occurrence and other genetic polymorphisms. Conclusion. This study found that the risk of TD is associated with altered SOD levels and several genetic polymorphisms, including VAL 66 Met and DRD3 9ser.

Genetic Factors Associated With Tardive Dyskinesia: From Pre-clinical Models to Clinical Studies.

Tardive dyskinesia is a severe motor adverse event of antipsychotic medication, characterized by involuntary athetoid movements of the trunk, limbs, and/or orofacial areas. It affects two to ten patients under long-term administration of antipsychotics that do not subside for years even after the drug is stopped. Dopamine, serotonin, cannabinoid receptors, oxidative stress, plasticity factors, signaling cascades, as well as CYP isoenzymes and transporters have been associated with tardive dyskinesia (TD) occurrence in terms of genetic variability and metabolic capacity. Besides the factors related to the drug and the dose and patients’ clinical characteristics, a very crucial variable of TD development is individual susceptibility and genetic predisposition. This review summarizes the studies in experimental animal models and clinical studies focusing on the impact of genetic variations on TD occurrence. We identified eight genes emerging from preclinical findings that also reached statistical significance in at least one clinical study. The results of clinical studies are often conflicting and non-conclusive enough to support implementation in clinical practice.

Liver enzyme CYP2D6 gene and tardive dyskinesia.

Background: Tardive dyskinesia (TD) is an iatrogenic involuntary movement disorder occurring after extended antipsychotic use with unclear pathogenesis. CYP2D6 is a liver enzyme involved in antipsychotic metabolism and a well-studied gene candidate for TD. Materials & methods: We tested predicted CYP2D6 metabolizer phenotype with TD occurrence and severity in our two samples of European chronic schizophrenia patients (total n =198, of which 82 had TD). Results: TD occurrence were associated with extreme metabolizer phenotype, controlling for age and sex (p = 0.012). In other words, individuals with either increased and no CYP2D6 activity were at higher risk of having TD. Conclusion: Unlike most previous findings, TD occurrence may be associated with both extremes of CYP2D6 metabolic activity rather than solely for poor metabolizers.

Schizophrenia-associated gene dysbindin-1 and tardive dyskinesia.

Tardive dyskinesia (TD) is a potentially irreversible movement disorder observed following long-term antipsychotic exposure. Its cause is unknown; however, a genetic component has been supported by studies of affected families. Dysbindin-1, encoded by the dystrobrevin-binding protein 1 DTNBP1 gene, has been associated with schizophrenia and is potentially involved in dopamine neurotransmission through its regulation of dopamine release and dopamine D2 receptor recycling, making it a candidate for investigation in TD. We investigated common variants across the DTNBP1 gene in our schizophrenia/patients with schizoaffective disorder of European ancestry. We found a number of DTNBP1 three-marker haplotypes to be associated with TD occurrence and TD severity (p< 0.05). These preliminary findings, if replicated in larger independent samples, would suggest that drugs targeting dysbindin-1 may be an option in the prevention and treatment of TD.

Association Study of the Complement Component C4 Gene in Tardive Dyskinesia.

Tardive dyskinesia (TD) is a movement disorder that may develop in schizophrenia patients being treated long-term with antipsychotic medication. TD interferes with voluntary movements and leads to stigma, and can be associated with treatment non-adherence. The etiology of TD is unclear, but it appears to have a genetic component. There is emerging evidence of immune dysregulation in TD. In the current study, we set out to investigate the complex schizophrenia-associated complement component 4 (C4) gene for possible association with TD occurrence and TD severity as assessed by the Abnormal Involuntary Movement Scale (AIMS) in a sample of 129 schizophrenia patients of European ancestry. We have genotyped the copy numbers of long and short forms of C4A and C4B gene variants in 129 European ancestry patients with schizophrenia or schizoaffective disorder. We did not find predicted C4A or C4B expression to be nominally associated with TD risk or severity. However, we found the number of copies of C4BL to be nominally associated with TD severity (p = 0.020).

Investigation of the HSPG2 Gene in Tardive Dyskinesia – New Data and Meta-Analysis

Tardive dyskinesia (TD) is a movement disorder that may occur after extended use of antipsychotic medications. The etiopathophysiology is unclear; however, genetic factors play an important role. The Perlecan (HSPG2) gene was found to be significantly associated with TD in Japanese schizophrenia patients, and this association was subsequently replicated by an independent research group. To add to the evidence for this gene in TD, we conducted a meta-analysis specific to the relationship of HSPG2 rs2445142 with TD occurrence, while also adding our unpublished genotype data. Overall, we found a significant association of the G allele with TD occurrence (p = 0.0001); however, much of the effect appeared to originate from the discovery dataset. Nonetheless, most study samples exhibit the same trend of association with TD for the G allele. Our findings encourage further genetic and molecular studies of HSPG2 in TD.

A Cross-Sectional Study on the Characteristics of Tardive Dyskinesia in Patients with Chronic Schizophrenia.

BackgroundTardive dyskinesia (TD) is an abnormal involuntary movement disorder caused by patients’ long-term use of antipsychotic medication. It diminishes the social functioning of patients with mental disorders, thereby affecting their compliance with antipsychotic medication. The cause and nosogenesis of TD remains unclear; furthermore, because the presentation differs greatly among individuals it often goes undiagnosed or can be easily misdiagnosed. The present study aims to evaluate the abnormal movement patterns in patients with TD, and analyze the differences among different TD patterns, in order to seek effective methods of preventing, diagnosing and treating TD.AimsTo describe the movement patterns of patients with chronic schizophrenia with TD, and analyze their clinical characteristics and risk factors.MethodsA cross-sectional study was carried out on a psychiatric unit of the Xuhui Mental Health Center with inpatients who had chronic schizophrenia as participants. Abnormal Involuntary Movement Scale (AIMS) was employed to screen for patients with schizophrenia who also had TD. These patients’ movement disorders were evaluated, and they were divided into groups based on their movement patterns. Positive and Negative Syndrome Scale (PANSS) was used to assess the psychotic symptoms of patients, collect clinical information, compare the differences between the two groups and analyze the clinical characteristics and risk factors of TD.Results(1) A total of 448 patients met the inclusion criteria for chronic schizophrenia with 46 in the TD group and 402 in the control group. After the TD group and the control group was compared, significant differences were seen between the two groups in gender, age, total duration of illness, age of onset, dosage of antipsychotic medication (daily chlorpromazine equivalent), factor scores of negative symptoms on PANSS and PANSS total scores. (2) It was possible that age, factor scores of negative symptoms in PANSS, the amount of antipsychotic medication used (daily chlorpromazine equivalent) and gender are correlated with the occurrence of TD. (3) There were significant differences among the number of TD patients with movement disorders in facial and oral areas (67.4%), limbs (58.7%) and torso (37%). The AIMS scores corresponding with movement disorders in different parts of the body were also significantly different. (4) Comparing TD patients with single affected area and those with multiple affected areas, we found that they had significant differences in gender, age of onset, AIMS total scores, severity scores of abnormal movements and loss of range due to abnormal movements.Conclusion(1) Compared to the control group, the TD group had more men, was older, had a longer duration of illness, later age of onset, generally took a higher dosage of antipsychotic medication and presented with more severe negative symptoms. It is possible that age, factor scores of negative symptoms on PANSS, dosage of antipsychotic medication (daily chlorpromazine equivalent) and gender are correlated with the occurrence of TD. (2) The occurrence of movement disorders in facial and oral areas for patients with chronic schizophrenia with TD was the most frequent, and the symptoms were the most severe. (3) Compared to TD patients with a single affected area, TD patients with multiple affected areas may have an earlier age of onset, more severe movement disorders, and more setbacks in their movement and functioning.

T43 - Genome-Wide Association Of Tardive Dyskinesia: Preliminary Findings

Background Tardive dyskinesia (TD) is a movement disorder manifested as involuntary movement of orofacial muscles or choreoathetoid movements of trunk and limbs. Commonly observed in schizophrenia, TD is potentially a persistent and irreversible condition associated with sustained antipsychotic treatment. While various theories have been put forth, the pathophysiology of TD is still unclear, with no well-accepted treatment. The occurrence of TD in only some patients appears to suggest possible individual genetic susceptibly. Recent genome-wide association studies (GWAS) have identified several candidate genes such as the GLI2 and HSPG2, however, none of these candidate genes were identical to those from candidate gene studies. Here, we performed a GWAS on TD schizophrenia patients of Chinese ethnicity. Methods The sample consisted of 842 schizophrenia patients of Chinese ethnicity, recruited from the Institute of Mental Health Singapore. Diagnosis of schizophrenia was ascertained on the Structured Clinical Interview for DSM-IV, and dyskinesia was rated on the Abnormal Involuntary Movement Scale (AIMS). Genotyping was performed using the Illumina 1M Duo Beadchip. Standard GWAS QC procedures were carried out. QC-ed markers were phased with SHAPEIT and imputed via Minimac3 (MACH) to the 1000 Genomes Project Phase 3 reference panel (GRch37). Subsequent association tests were conducted on PLINK2. Results None of the markers reached genome-wide significance. One-hundred top SNPs (top SNP: rs55823922, Rsq = 0.999, MAF = 0.241, Beta = 0.244, SE= 0.0485, p = 6.323x10-07) were identified. The genes in closest proximity to top SNPs are P2RY1 (purinergic receptor P2Y1), RAP2B (RAS protein 2B) and MBNL1 (Muscleblind like splicing regulator 1). Discussion None of the genes associated with TD were implicated in psychiatric conditions. The purinergic receptor 1 protein functions as a receptor for extracellular adenine nucleotides, and mediates adenosine diphosphate (ADP) induced intracellular calcium mobilisation in platelet binding; it is implicated in Alzheimer’s disease. The RAP2B is involved in cell growth, differentiation, and apoptosis, and is implicated in the Epidermal Growth Factor Receptor and Cholinergic Signalling pathways. MBNL1 is a member of the muscleblind protein family which has been implicated in myotonic dystrophy, a condition characterised by muscle abnormalities and muscle wasting. These susceptibility genes appear to be involved in neurodegenerative conditions, and are congruent with the neurodegenerative theory of TD. Further replication is warranted.

Association study between the neurexin-1 gene and tardive dyskinesia.

Tardive dyskinesia (TD) is a motor side effect that may develop after long-term antipsychotic treatment. Schizophrenia has recently been associated with the Neurexin-1 (NRXN1) gene that codes for a cell adhesion molecule in synaptic communication. This study examined five NRXN1 single-nucleotide polymorphisms (SNPs) for possible association with the occurrence and severity of TD in 178 schizophrenia patients of European ancestry. We did not find these SNPs to be significantly associated with TD. More research is needed with additional SNPs and in bigger samples before we can completely rule out the role of NRXN1 in TD.

T52 - The Potential Role of Low Frequency And Rare Variants In Tardive Dyskinesia Genetics

Background Tardive dyskinesia (TD) is a chronic, irreversible side effect of antipsychotic-treated schizophrenia patients TD occurrence is influenced by both clinical and demographic variables, as well as genetic factors. Contribution of common variants to TD susceptibility has been investigated in recent years, including by the genome-wide association study approach, but results are inconsistent. In order to discover the involvement of low frequency and rare variants in this phenotype, we implemented whole exome sequencing (WES) method. Methods We whole exome sequenced 20 Ashkenazi Jewish schizophrenia patients with severe TD, and 18 patients without any manifestation of TD (total AIMS score of zero) despite more than 10 years of exposure to antipsychotics. For prioritization, we concentrated on Loss of Function (LoF) rare variants. Results We were able to identify several interesting rare (1%-5%) and extremely rare ( Discussion WES may be implemented in pharmacogenetics studies of antipsychotics. Our preliminary results point to the role of low frequency and rare LoF variants in TD.

Rice bran oil prevents neuroleptic-induced extrapyramidal symptoms in rats: Possible antioxidant mechanisms

Tardive dyskinesia (TD) is one of the serious side effects of long-term antipsychotic treatment. Chronic treatment with neuroleptic leads to the development of abnormal oral movements called vacuous chewing movements (VCMs). The oxidative stress hypothesis of TD is one of the possible pathophysiologic models for TD. Preclinical and clinical studies of this hypothesis indicate that neurotoxic free radical production is likely to be a consequence of antipsychotic medication and is related to occurrence of TD. Oxidative stress is implicated in the pathophysiology of TD. Rats chronically treated with haloperidol orally at a dose of 0.2 mg/kg/day for a period of 5 weeks developed VCMs, which increased in a time-dependent manner as the treatment continued for 5 weeks. Motor coordination impairment started after the 1st week and was maximally impaired after 3 weeks and gradually returned to the 1st week value. Motor activity in an open field or home cage (activity box) not altered. Administration of rice bran oil (antioxidant) by oral tubes at a dose of 0.4 mL/day prevented the induction of haloperidol-elicited VCMs as well impairment of motor coordination. The results are discussed in the context of a protective role of antioxidant of rice bran oil in the prevention of haloperidol-induced extrapyramidal symptoms.

Clinical significance of pharmacogenomic studies in tardive dyskinesia associated with patients with psychiatric disorders.

Pharmacogenomics is the study of the effects of genetic polymorphisms on medication pharmacokinetics and pharmacodynamics. It offers advantages in predicting drug efficacy and/or toxicity and has already changed clinical practice in many fields of medicine. Tardive dyskinesia (TD) is a movement disorder that rarely remits and poses significant social stigma and physical discomfort for the patient. Pharmacokinetic studies show an association between cytochrome P450 enzyme-determined poor metabolizer status and elevated serum antipsychotic and metabolite levels. However, few prospective studies have shown this to correlate with the occurrence of TD. Many retrospective, case-control and cross-sectional studies have examined the association of cytochrome P450 enzyme, dopamine (receptor, metabolizer and transporter), serotonin (receptor and transporter), and oxidative stress enzyme gene polymorphisms with the occurrence and severity of TD. These studies have produced conflicting and confusing results secondary to heterogeneous inclusion criteria and other patient characteristics that also act as confounding factors. This paper aims to review and summarize the pharmacogenetic findings in antipsychotic-associated TD and assess its clinical significance for psychiatry patients. In addition, we hope to provide insight into areas that need further research.

P.3.a.006 Tardive dyskinesia, dehydroepiandrosterone sulfate and cytochrome P450c17α gene polymorphism in psychiatric inpatients

Tardive dyskinesia (TD) is a potentially irreversible antipsychoticinduced movement disorder with a prevalence of about 20-30% in psychiatric patients chronically exposed to antipsychotics. A wellknown theory states that TD is related to oxidative stress induced neurotoxicity. Dehydroepiandrosterone (DHEA) is an endogenous antioxidant with neuroprotective activity. The biosynthesis of DHEA depends upon the activity of cytochrome P450c17a (CYP17). The gene that encodes for CYP17 has a (T34C) single nucleotide polymorphism which enhances CYP17 transcription and expression. Objective: To test the hypothesis that carriership of a more active CYP17 variant would result in higher DHEA(S) levels and protect against neurotoxicity which results in orofaciolingual TD (TDof), limb-truncal TD (TDlt) or both (TDsum). Methods: TD was assessed cross-sectionally by the use of the Abnormal Involuntary Movement Scale (AIMS) in in 146 Caucasian psychiatric inpatients from Siberia. TDof and TDlt were assessed with AIMS items 1-4 and 5-7, respectively. The DHEAs levels were tested with aid of the DHEA-S ELISA Kit, (DRG International Inc.). DNA extraction and fluorogenic 5′-exonuclease TaqMan genotyping assays were conducted according to standard protocols and blind to the clinical status of the subjects [1]. The statistical software 'R' was used for the calculations. For creating an overview of the clinical and demographic features of the study population, excel and the statistical SPSS software, release 17, for Windows were used. The deviation from the Hardy-Weinberg Equilibrium was tested by the chi-squared test for the Cyp17 polymorphisms. Results: In total 146 patient with clinical diagnosis of schizophrenia or schizotypal disorder (ICD-10: F20 and F21, respectively) were included of which 91 males and 55 females. Demographic and clinical details have been provided with elsewhere [1,2]. The genotype distribution in the total population and by gender shows that the female patients of this population are more often carrier of the Cyp17 CC genotype compared to male patients. The results of the logistic regression analysis of the influence of the Cyp17 T-allele and the level of DHEAS on the occurrence of TD, TDof and TDlt indicate that carriers of the Cyp17 genotype CC have a significant lower risk of developing TD compared to carriers of the Cyp17 genotypes TC or TT (p

Prevalence, Severity and Characteristics of Tardive Dyskinesia Among Schizophrenia Patients in an Israeli Psychiatric Center

Tardive dyskinesia (TD) is a debilitating side-effect of antipsychotic treatment associated with reduced compliance and quality of life. TD prevalence is difficult to estimate accurately and is influenced by the increased use of antipsychotic drugs and the aging of the population. We assessed the prevalence, severity and characteristics of TD among schizophrenia patients at a university-affiliated psychiatric center in Israel. One hundred and twenty eight patients with schizophrenia were recruited and underwent demographic and clinical assessments. Subjects who met Schooler-Kane criteria for probable TD were compared to those without TD. Forty five subjects met probable TD criteria (prevalence: 35.2%; 95% CI 26.9% -44.1 %.). Subjects with TD were older and had a longer duration of treatment with antipsychotic medications. Diabetes mellitus, hypertension, head injuries and more severe psychiatric symptomatology did not predict TD. Patients in the TD-group had higher rates of extrapyramidal symptoms (EPS) and were more likely to receive an anticholinergic agent. The type of antipsychotic medication was not found to be associated with TD occurrence. Our findings confirm the established relationships between presence of TD and age, duration of antipsychotics treatment, anticholinergic treatment and the presence of EPS. Furthermore, our data support recent findings indicating that TD is still a prevalent disorder representing an unresolved public health issue. Keywords: Aging, anticholinergic agents, atypical and typical antipsychotics, extrapyramidal side-effects, schizophrenia, Tardive dyskinesia.

Tardive Dyskinesia Induced by a Switch From Haloperidol Depot to Paliperidone Palmitate

Tardive Dyskinesia Induced by a Switch From Haloperidol Depot to Paliperidone Palmitate

Association study of the vesicular monoamine transporter gene SLC18A2 with tardive dyskinesia

Tardive dyskinesia (TD) is an involuntary movement disorder that can occur in up to 25% of patients receiving long-term first-generation antipsychotic treatment. Its etiology is unclear, but family studies suggest that genetic factors play an important role in contributing to risk for TD. The vesicular monoamine transporter 2 (VMAT2) is an interesting candidate for genetic studies of TD because it regulates the release of neurotransmitters implicated in TD, including dopamine, serotonin, and GABA. VMAT2 is also a target of tetrabenazine, a drug used in the treatment of hyperkinetic movement disorders, including TD. We examined nine single-nucleotide polymorphisms (SNPs) in the SLC18A2 gene that encodes VMAT2 for association with TD in our sample of chronic schizophrenia patients (n = 217). We found a number of SNPs to be nominally associated with TD occurrence and the Abnormal Involuntary Movement Scale (AIMS), including the rs2015586 marker which was previously found associated with TD in the CATIE sample (Tsai et al., 2010), as well as the rs363224 marker, with the low-expression AA genotype appearing to be protective against TD (p = 0.005). We further found the rs363224 marker to interact with the putative functional D2 receptor rs6277 (C957T) polymorphism (p = 0.001), supporting the dopamine hypothesis of TD. Pending further replication, VMAT2 may be considered a therapeutic target for the treatment and/or prevention of TD.

Oxidative stress and tardive dyskinesia: Pharmacogenetic evidence

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.