Manganese superoxide dismutase gene polymorphism and schizophrenia: relation to tardive dyskinesia.

There has been increasing evidence that deranged superoxide dismutase (SOD) activities might be a risk factor for schizophrenia and/or tardive dyskinesia (TD). In the present study, we investigated the genetic association between a functional polymorphism (Ala-9Val) in the human manganese (Mn) SOD gene and schizophrenia or TD (192 schizophrenics: 39 with TD and 153 without TD; 141 controls). No significant differences in the allelic or genotypic distribution between schizophrenics and controls were observed. However, we did find a significant difference in genotypic distribution between schizophrenics with and those without TD (p =. 03). Moreover, decreased -9Ala (mutant) allele was found among patients with TD (p =.02; odds ratio = 0.29; 95% confidence interval = 0.10-0.83). In conjunction with previous findings of increased free radicals and decreased SOD activities in TD subjects, these results suggest that the -9Ala (high activity) MnSOD allele may play a role in protecting against susceptibility to TD in schizophrenics.     

Relationship of symptomatology of schizophrenia and tardive dyskinesia.

The role of drug factors and patient factors in the development of tardive dyskinesia (TD) was examined in 31 TD patients and 31 non-TD patients matched by age and sex. TD patients achieved significantly lower total scores on the anxiety-depression factor of Brief Psychiatric Rating Scale (BPRS) (5.2 +/- 1.4 vs. 6.5 +/- 2.2; less than P) and significantly higher total scores on the activation factor (6.4 +/- 2.2 vs. 5.3 +/- 2.5; less than P). The finding that TD patients were less depressed may be explained by a hypermonoaminergic state developing in TD. Based on the findings of this study it is suggested that catatonic schizophrenic patients are more vulnerable to the development of TD.     

Association study of tardive dyskinesia and twelve DRD2 polymorphisms in schizophrenia patients

Tardive dyskinesia (TD) is a side-effect of chronic antipsychotic medication. Abnormalities in dopaminergic activity in the nigrostriatal system have been most often suggested to be involved because the agents which cause TD share in common potent antagonism of dopamine D2 receptors (DRD2), that notably is not balanced by effects such as more potent serotonin (5-HT)2A antagonism. Thus, a number of studies have focused on the association of dopamine system gene polymorphisms and TD. The most consistent findings have been found with the Ser9Gly polymorphism of the DRD3 gene. Although DRD2 has long been hypothesized to be the main target for antipsychotics, only a few polymorphisms in DRD2 have been investigated for their potential involvement in the aetiology of TD. In the present study, we investigated 12 polymorphisms spanning the DRD2 gene and their association with TD in our European Caucasian (n=202) and African-American (n=30) samples. Genotype frequencies for a functional polymorphism, C957T (Duan et al., 2003; Hirvonen et al., 2004), and the adjacent C939T polymorphism were found to be significantly associated with TD (p=0.013 and p=0.022 respectively). DRD2 genotypes were not significantly associated with TD severity as measured by AIMS (Abnormal Involuntary Movement Scale) with the exception of a trend for C939T (p=0.071). Both TD and total AIMS scores were found to be significantly associated with two-marker haplotypes containing C939T and C957T (p=0.021 and p=0.0087 respectively). Preliminary results indicated that C957T was also associated with TD in our African-American sample (p=0.047). Taken together, the present study suggests that DRD2 may be involved in TD in the Caucasian population, although further studies are warranted.     

CYP2D6 polymorphisms and the risk of tardive dyskinesia in schizophrenia: a meta-analysis

The present study aimed to evaluate whether there is any association between CYP2D6 alleles and susceptibility to tardive dyskinesia in patients with schizophrenia under treatment. A meta-analysis considered case-control studies determining the distribution of genotypes for any CYP2D6 polymorphism in unrelated tardive dyskinesia cases and controls without tardive dyskinesia among patients with schizophrenia who were treated with antipsychotic agents. Loss of function alleles were grouped together in a single comparison, whereas other alleles (2 and 10) were examined separately. Data were available for eight (n=569 patients), three (n=325 patients) and four (n=556) studies evaluating the effect of the loss of function alleles, the 2 allele and the 10 allele, respectively. Summary odds ratios (ORs) suggested that loss of function alleles increased the risk of tardive dyskinesia significantly [OR=1.43, 95% confidence interval (CI) 1.06-1.93, P=0.021], whereas there was no effect for 2 and inconclusive evidence for 10 (OR=0.82, 95% CI 0.50-1.32, P=0.41 and OR=1.19, 95% CI, 0.89-1.60, P=0.24, respectively). Patients who were homozygotes for loss of function alleles (poor metabolizers) had 1.64-fold greater odds of suffering tardive dyskinesia compared to other patients with schizophrenia, but the effect was not formally significant (95% CI 0.79-3.43). For the risk conferred by loss of function alleles, large studies provided more conservative estimates of a genetic effect than smaller studies (P=0.003). CYP2D6 loss of function alleles may predispose to tardive dyskinesia in patients with schizophrenia under treatment, but bias cannot be excluded.     

Genetic underpinnings of tardive dyskinesia: passing the baton to pharmacogenetics

Manifestation of tardive dyskinesia (TD) among schizophrenia subjects on long-term antipsychotic treatment with typical drugs has been a clinical concern. Despite its association with extrapyramidal symptoms, typical drugs are still routinely prescribed globally though marginally superior atypical drugs have long been available. The genetic component in the etiology of TD is well documented. Search for these determinants has led to a few consensus associations of CYP2D6 *10, CYP1A2*1F, DRD2 Taq1A (rs1800497), DRD3 Ser9Gly (rs6280) and MnSOD Ala9Val (rs4880) variants with TD. However, translation of these observations into the clinic has not been achieved so far. This review discusses the salient features of TD etiopathology, current status of TD genetics, interactions between genetic and nongenetic factors, some major drawbacks, challenges and expected focus in TD research over the next decade, with emphasis on pharmacogenetics.     

A clinical trial of nifedipine in schizophrenia and tardive dyskinesia.

Effects of the dihydropyridine calcium channel inhibitor nifedipine on chronic schizophrenia and tardive dyskinesia were studied in an 8-week double-blind crossover trial. Four of the ten patients had tardive dyskinesia, and three of these were not receiving neuroleptics. No effects on symptoms of chronic schizophrenia were found using Psychiatric Symptom Assessment Scale ratings. In the four patients with tardive dyskinesia, an average improvement in total Abnormal Involuntary Movement Scale scores of 57% was observed. These data suggest that dihydropyridine calcium channel inhibitors may be effective in the treatment of tardive dyskinesia in schizophrenic patients.     

Association of the MscI polymorphism of the dopamine D3 receptor gene with tardive dyskinesia in schizophrenia.

In 112 schizophrenic patients previously treated with typical neuroleptics, we investigated the putative role of the dopamine D3 receptor gene (DRD3) in tardive dyskinesia (TD). Patients were assessed for TD severity using the Abnormal Involuntary Movement Scale (AIMS) and were subsequently genotyped for the MscI polymorphism that identifies a serine to glycine substitution in DRD3. A modified analysis of covariance model, which incorporated several clinical risk factors for TD, was utilized to detect differences in TD severity among the various genotypic groups. The glycine allele of DRD3 was found to be associated with typical neuroleptic-induced TD (F[2,95] = 8.25, p < .0005). Higher mean AIMS scores were found in patients homozygous for the glycine variant of the DRD3 gene, as compared to both heterozygous and serine homozygous patients. Although replication is necessary, this finding supports a role for the dopamine D3 receptor in the pathogenesis of TD.     

Association between the serotonin 2C receptor gene and tardive dyskinesia in chronic schizophrenia: additive contribution of 5-HT2Cser and DRD3gly alleles to susceptibility

RATIONALE: Tardive dyskinesia (TD) is a longterm adverse effect of dopamine receptor blockers. The dopamine D3 receptor gene (DRD3) ser9gly polymorphism has been previously associated with susceptibility to TD. Serotonin receptor antagonism has been proposed as a common mechanism contributing to the low extra-pyramidal effects profile of atypical antipsychotic drugs. OBJECTIVES: To examine the association of a functional polymorphism in the 5-HT2C receptor gene (HT2CR) with TD and the joint contribution of HT2CR and DRD3 to susceptibility. METHODS: Case control association analysis of allele and genotype frequencies among schizophrenia patients with (n=55) and without TD (n=60), matched for antipsychotic drug exposure and other relevant variables, and normal control subjects (n=97). Parametric analyses of the contribution of 5-HT2Cser and DRD3gly alleles to dyskinesia scores. RESULTS: We found a significant excess of 5-HT2Cser alleles in schizophrenia patients with TD (27.2%) compared to patients without TD (14.6%) and normal controls (14.2%; chi2=6.4, df 2, P=0.03) which was due to the female patients (chi2=8.6, df 2, P=0.01). Among the female TD patients there was an excess of cys-ser and ser-ser genotypes (chi2= 11.9, df 4, P=0.02). Analysis of covariance (ANCOVA), controlling for age at first antipsychotic treatment, revealed a significant effect of 5-HT2C genotype on orofacial dyskinesia (OFD) scores (F=3.47, df 2, P=.03). In a stepwise multiple regression analysis, 5-HT2C and DRD3 genotype (5-HT2Cser and DRD3gly allele carriage) respectively contributed 4.2% and 4.7% to the variance in OFD scores. CONCLUSIONS: These findings support a small but significant contribution of the HT2CR and DRD3 to susceptibility to TD, which is additive in nature.     

Prolactin as a biomarker for treatment response and tardive dyskinesia in schizophrenia subjects: old thoughts revisited from a genetic perspective

Previous studies investigated whether prolactin (PRL) serum level was a biomarker of antipsychotic response, schizophrenia symptomatology, and tardive dyskinesia. Most of the findings support that antipsychotic drugs modulate PRL levels but PRL is not a steady indicator. Recent results suggest a genetic effect of PRL and PRL receptor (PRLR) polymorphisms in PRL levels indicating that independently of antipsychotic therapy subjects could have altered PRL levels due to their genetic background.We evaluated whether PRL and PRLR variants were associated with treatment outcome and tardive dyskinesia. We observed no association of PRL/PRLR polymorphism with treatment response (best genotypic results include PRL rs849885 and PRLR rs4703509 permuted p=0.326). Regarding tardive dyskinesia, the major allele of PRL rs37364 was nominally associated with risk for tardive dyskinesia in the European ancestry sub-sample (permuted p=0.183). Although we reported no significant associations, it is definitely worthy of investigation to see if together (genetic variants in the PRL system and PRL serum measures) could be a reliable biomarker for antipsychotic response and TD prevalence. Our results suggest that more studies in this context are required to shed light in the molecular mechanisms underlying antipsychotic response and tardive dyskinesia occurrence.     

Quantitative instrumental measurement of tardive dyskinesia: a review.

In this paper we review currently available quantitative instrumental techniques for the assessment of tardive dyskinesia (TD). We discuss the advantages and disadvantages of the use of accelerometers, electromyography, force gauges, position transducers, and Doppler ultrasound from both a diagnostic and a utilitarian perspective. Data obtained using these techniques appear to correlate significantly with patient scores on clinical rating scales. In some cases, the use of these techniques has facilitated the detection of subclinical dyskinesia and helped to differentiate TD from other movement disorders. We believe that a review of these qualitative techniques will be of interest to the clinician, as well as to investigators involved in studying TD.     

Functional catechol-O-methyltransferase gene polymorphism and susceptibility to schizophrenia.

Genetic polymorphism of catechol-O-methyltransferase (COMT), involved in the degradation of catecholamine neurotransmitters, has been investigated as a candidate for modifier of susceptibility to development of schizophrenia. To address this issue further, we carried out a study in Korean schizophrenic patients and controls. The study population consisted of 103 Korean inpatients diagnosed as schizophrenic and their 103 age and sex matched controls. The patients were divided into two groups on the basis of history of aggressive behavior, family history of schizophrenia and related disorders, and age at onset of the disease. The COMT genotypes were determined by a PCR based method. No statistically significant overall associations between the COMT genotypes and risk of schizophrenia were observed. However, subjects with at least one low activity associated COMT-L allele showed a tendency of elevated risk for schizophrenia (OR=1.7, 95% CI=0.9-3.1) compared with those homozygous for the high activity associated COMT-H alleles. Moreover, when cases were stratified by family history of schizophrenia, a significant combined effect was seen: the cases with concurrent family history of schizophrenia and the COMT-L allele containing genotypes had an almost 4-fold (OR=3.9, 95% CI=1.1-14.3) higher risk of schizophrenia compared to controls with the COMT-HH genotypes. Future studies with larger sample sizes are, however, needed to confirm this novel finding.     

Genetic susceptibility to eating disorders: associated polymorphisms and pharmacogenetic suggestions

Anorexia nervosa (AN), bulimia nervosa (BN) and binge-eating disorder (BED) are characterized by abnormal eating behaviors often resulting in dramatic physical consequences for the patients. The etiology of eating disorders (EDs) is currently unknown; however, a strong genetic contribution is likely to be involved. To date, the majority of genetic studies have focused on candidate genes, and polymorphic variants of genes coding for substances likely to be involved in the etiopathogenesis of EDs have been assessed for association with AN, BN, BED and/or ED-related phenotypic traits. Results have been generally inconsistent and cannot be considered conclusive because of several methodological flaws and differences, such as small sample sizes, ethnic heterogeneity of studied populations, lack of statistical correction for multiple testing, adoption of different diagnostic criteria and population stratification. Although, at present, no convincing evidence for associations of candidate genes with EDs has been provided, the 5-HT(2A) receptor gene and the BDNF gene seem to be promising candidates for genetic influences on AN, since polymorphic variants of these genes have been found quite consistently, although not specifically, linked to AN restricting subtype in large sample studies. Moreover, pharmacogenetic investigations have suggested a possible role of some gene polymorphisms in predicting the response to treatment with selective serotonin reuptake inhibitors in BN, but results are still preliminary. The heterogeneity of ED phenotypes is believed to represent the most relevant variable responsible for contradictory and not conclusive results. Future studies should focus on more homogeneous subgroups, either relying on specific ED traits or identifying endophenotypes. This will be useful also for prevention and treatment of EDs.     

A case of relapsed tardive dyskinesia due to clozapine dose reduction.

There is no proven effective treatment for tardive dyskinesia (TD). However, clozapine has been reported to be effective in suppressing TD symptoms. In this article, we report a TD case who received clozapine. The patient recovered from TD symptoms with a dose of 450 mg/day clozapine. At the end of the first year, clozapine was decreased to a dose of 250 mg/day and TD symptoms re-emerged.     

Disclosure of tardive dyskinesia: effect of written policy on risk disclosure.

Over half of the states in the country have written statutory and/or regulatory policies that require psychiatrists treating inpatients within the state mental health system to disclose risks associated with treatment to voluntarily admitted patients. A severe side effect associated with the long-term use of neuroleptic medication is tardive dyskinesia (TD). A nationwide study was conducted to investigate the effect of written risk disclosure policy on psychiatrists' self-reported disclosure of the risks associated with neuroleptics to individuals diagnosed as having schizophrenia of a chronic nature. Participating in the study were 520 psychiatrists from 94 state/county mental hospitals located in 35 states. Fifty-four percent of those psychiatrists reported that they typically disclosed TD to the target patient population. The study results did not support the hypothesis that the presence of statutory and regulatory policy on disclosure of risk results in psychiatrists typically disclosing TD to patients.     

Targeted to medication-induced dyskinesia and tardive dyskinesia:A role of 5-HT_(1A) receptor

Objective To outline the recent progress in drug discovery for medication-induced dyskinesia(Parkinson disease,PD)and tardive diskinesia(schizophrenia)with emphasizing the role of 5-HT1A receptor.Methods Development of extrapyramidal syndrome(EPS)followed either chronic L-DOPA administration in PD(L-DOPA-induced dyskinesia,LID)or antipsychotic treatment in schizophrenia(Tardive dyskinesia,TD)remains a challenge in the clinical practice and drug discovery.In addition to the abnormal dopamine activity in the nigrostrial area that contributes to the LID or TD,recent information indicates that 5-HT1A receptor also plays an important role which is merging as promising target in treatment of LID or TD.Results l-Stepholidine(l-SPD),isolated from the Chinese herb Stephania,is known as a dual dopamine receptor agent(D1 receptor agonistic and D2 antagonistic activity).In addition,we further demonstrated that l-SPD binds to 5-HT1A receptor and exhibits a partial agonistic activity.In LID rat model,l-SPD not only attenuated the development of L-DOPA-induced dyskinesia(LID),but also relived the established LID.The effect of l-SPD on LID was completely blocked by pretreatment of 5-HT1A receptor antagonist,indicating the role of 5-HT1A receptor.Furthermore,we designed and synthesis a dual dopamine/5-HT1A receptor agonist MCL-135,which also exhibits a significant relief on LID while elicits its antiparkinsonian action.Conclusions 5-HT1A receptor plys an important role in the development of LID,targeted to dual dopamine/5-HT receptor may represent a promising strategy for drug design and discovery in LID and TD treatment.