Manganese superoxide dismutase gene Ala-9Val polymorphism might be related to the severity of abnormal involuntary movements in Korean schizophrenic patients

Objective

This study examined whether the manganese superoxide dismutase (MnSOD) gene Ala–9Val single-nucleotide polymorphism (SNP) is associated with neuroleptic-induced tardive dyskinesia (TD) and the severity of the abnormal involuntary movements in Korean schizophrenic patients.

Method

We investigated whether the MnSOD gene Ala–9Val SNP is associated with TD in Korean schizophrenic patients with (n = 83) and without (n = 126) TD who were matched for exposure to antipsychotics and other relevant variables.

Results

Logistic regression analysis revealed that being older (p = 0.026) was a risk factor for TD, but that there was no significant association between MnSOD gene and TD. Abnormal involuntary movements were more severe in carriers of the Ala allele than in noncarriers (p = 0.044).

Conclusion

These findings do not support that the MnSOD gene Ala–9Val SNP is associated with TD in Korean schizophrenic patients. However, this polymorphism might be related to the severity of abnormal involuntary movements in this population.     

Association of the manganese superoxide dismutase gene Ala–9Val polymorphism with clinical phenotypes and tardive dyskinesia in schizophrenic patients

Objective

Several recent studies that have investigated the genetic association between the manganese superoxide dismutase (MnSOD) gene Ala–9Val single-nucleotide polymorphism (SNP) and tardive dyskinesia (TD) have produced conflicting results. This study was to investigate whether this SNP was associated with clinical phenotypes and antipsychotic-induced tardive dyskinesia (TD) in schizophrenia in a genetically homogeneous Han Chinese inpatient population.

Methods

Genotyping was performed for the MnSOD gene Ala–9Val SNP in Chinese schizophrenia patients with (n = 176) and without TD (n = 346). The severity of TD was assessed using the abnormal involuntary movement scale (AIMS), and psychopathology using the Positive and Negative Syndrome Scale (PANSS).

Results

The frequencies of genotypes and alleles did not differ significantly between schizophrenic patients with and without TD (both p > 0.05). Also, there was no significant difference in the AIMS total score between the Val/Val and Ala allele carrier groups (p > 0.05). However, the PANSS negative symptom subscore was significantly higher in patients with Val/Val genotype (21.8 ± 7.3) than those with Ala alleles (20.1 ± 7.7) (t = 2.32, p = 0.03).

Conclusion

While the MnSOD gene Ala–9Val polymorphism did not play a major role in the susceptibility to TD in schizophrenic patients, it might be associated with negative symptoms of schizophrenia.     

The increased activity of plasma manganese superoxide dismutase in tardive dyskinesia is unrelated to the Ala-9Val polymorphism

That tardive dyskinesia (TD) may have its origins in free-radical toxicity has stimulated investigations into one enzyme important in the control of oxidative free radicals: superoxide dismutase (SOD). The manganese-containing form of this enzyme (MnSOD) is the major superoxide scavenger in mitochondria; a weak association between a functional genetic polymorphism (Ala-9Val) in the mitochondrial targeting sequence (MTS) of this enzyme and TD has been reported in a Japanese population. We have undertaken to determine both the plasma activity of MnSOD and the association of the Ala-9Val polymorphism in a well-matched series of male Chinese schizophrenic patients with (n=42) and without (n=59) TD, and normal male controls (n=50). MnSOD activity was elevated in the TD subjects over those without TD (P<0.05) and normal controls (P<0.05), an effect that was independent of age, age at first antipsychotic treatment, drug dosage and duration of illness. A significant positive correlation between total AIMS score and MnSOD activity was also observed (P<0.0001). No significant reduction in the frequency of the Ala allele was observed in the TD group (0.14) below non-TD (0.18) or control subjects (0.17); nor was there any relationship between MnSOD activity and the polymorphism. There was no difference between the mean AIMS scores for the two genotypes (V/V and A/V) in the TD group. We conclude that while we have further evidence of a disturbance in the mechanisms regulating oxidative free radicals in TD, this effect is not under the control of the genetic polymorphism investigated here.     

Tiapride in the treatment of tardive dyskinesia

The effect of Tiapride on dyskinesia was evaluated in 12 patients with tardive dyskinesia in a double-blind controlled cross-over trial. The effect was measured by a Doppler-radar device and by counting the number of involuntary movements from video-recordings. Besides these methods, subjective assessments were made on analogue scales by family, nurses and attendant doctors. The subjective evaluation appeared to be useless because of many inconsistent answers. The quantitative methods revealed a significant diminution of the involuntary movements in the Tiapride therapy period (P less than 0.01). It appears that tiapride is an effective drug in the treatment of tardive dyskinesia. No clinically important side-effects have been observed. The drug appeared not to induce parkinsonism.     

Abnormal involuntary movements in patients on long-acting neuroleptics

1. 1. Two hundred and thirty eight patients (144 males, 94 females) on long-acting neuroleptics; mainly fluphenazine decanoate, were surveyed and evaluated for abnormal involuntary movements and associated risk factors.

2. 2. A highly significant correlation was found between the three scales used in the evaluation.

3. 3. The prevalence rate for the transient, acute extrapyramidal syndrome was 37.38%, while that of tardive dyskinesia was 57%. Half of the tardive dyskinesia cases were of minimal severity. Most of these were located in orofacial region.

4. 4. Tardive dyskinesia was more frequent in younger patients but more severe in older age groups. Other associated risk factors were tremors and rigidity, and use of antiparkinsonien drugs.

5. 5. Tardive dyskinesia is a common abnormal involuntary movement in patients on long-acting neuroleptic. Early recognition of TD in this population could help in planning for its prevention by the use of minimum effective dose of medication.

Interactive effect of cytochrome P450 17alpha-hydroxylase and dopamine D3 receptor gene polymorphisms on abnormal involuntary movements in chronic schizophrenia.

BACKGROUND: Tardive dyskinesia is a chronic adverse effect of anti psychotic drugs, where association with a polymorphic site in the dopamine D3 receptor gene has been previously reported. Cytochrome P 450 17alpha-hydroxylase activity has been implicated with modulation of central dopamine release as well as neuroprotection. We investigated the association of a T -->C variation in the cytochrome P 450 17alpha-hydroxylase gene with tardive dyskinesia in patients with chronic schizophrenia. METHODS: Cytochrome P 450 17 allele and genotype frequencies were compared between matched schizophrenia patients with (n = 55) or without tardive dyskinesia (n = 58). Interactive effects of cytochrome P 450 17alpha-hydroxylase with the dopamine D3 Ser9Gly polymorphism on abnormal involuntary movements were examined. RESULTS: There was no difference in cytochrome P 450 17alpha-hydroxylase genotype distribution between patients with and without tardive dyskinesia; however, patients carrying the cytochrome P 450 17alpha-hydroxylase A2-A2 genotype and the dopamine D3gly allele had the highest orofacial (p <.04), distal (p <.05), and incapacitation (p <.04) scores on the Abnormal Involuntary Movements Scale. CONCLUSIONS: Schizophrenia patients who carry the dopamine D3gly allele and the cytochrome P 450 17alpha-hydroxylase A2-A2 genotype may be more likely to develop abnormal orofoacial and distal involuntary movements and to be incapacitated by these movements when chronically exposed to classical antipsychotic drugs.     

Manganese superoxide dismutase (MnSOD: Ala-9Val) gene polymorphism may not be associated with schizophrenia and tardive dyskinesia

There has been increasing evidence that the alteration of antioxidant enzymes such as manganese superoxide dismutase (MnSOD) might be implicated in the development of schizophrenia and/or tardive dyskinesia (TD). This study investigated the association of a MnSOD gene (MnSOD) polymorphism (Ala-9Val) with schizophrenia as well as its involvement in TD. Patients with schizophrenia (n=262) and healthy controls (n=263) were enrolled in this study and genotyped by a polymerase chain reaction-based method. The distribution of the MnSOD genotypes and alleles was not significantly different between patients and controls. Logistic regression analysis also failed to reveal any association between MnSOD genotypes and TD. Taken together, these results suggest that the MnSOD polymorphism does not contribute to the development of schizophrenia and/or TD, at least in the Korean population.     

No association between the brain-derived neurotrophic factor gene Val66Met polymorphism and tardive dyskinesia in schizophrenic patients

OBJECTIVE: This study investigated whether the brain-derived neurotrophic factor (BDNF) gene Val66Met single-nucleotide polymorphism (SNP) is associated with antipsychotic-induced tardive dyskinesia (TD) in schizophrenia. METHODS: Genotyping was performed for the BDNF gene Val66Met SNP in Korean schizophrenic patients with (n=83) and without TD (n=126) who were matched for antipsychotic drug exposure and other relevant variables. RESULTS: The frequencies of genotypes (chi2=2.37, p=0.306) and alleles (chi2=0.03, p=0.867) did not differ significantly between these two groups. CONCLUSION: These findings suggest that the BDNF polymorphism does not play a major role in the susceptibility to TD in schizophrenic patients.     

Clinical effectiveness of the Kampo medicine kamishoyosan for adjunctive treatment of tardive dyskinesia in patients with schizophrenia: a 16-week open trial

The purpose of the present study was to evaluate the clinical effectiveness of kamishoyosan for antipsychotic-induced tardive dyskinesia, and to investigate the relationship between tardive dyskinesia and serum brain-derived neurotrophic factor (BDNF) levels. Sixty-nine schizophrenia patients were enrolled; of these, 49 presented with tardive dyskinesia while the remaining 20 patients showed no tardive dyskinesia. The tardive dyskinesia group was treated for 16 weeks with kamishoyosan and assessed using the abnormal involuntary movement scale. The abnormal involuntary movement scale scores in the tardive dyskinesia group were evaluated at baseline and after 4, 8, and 16 weeks of treatment. The BDNF levels of all subjects were measured at baseline in order to compare differences in serum BDNF levels between the tardive dyskinesia group and the non-tardive dyskinesia group, and to correlate the severity of tardive dyskinesia and serum BDNF in the tardive dyskinesia group. A meaningful reduction in total abnormal involuntary movement scale scores was observed in the tardive dyskinesia group treated with kamishoyosan at 4, 8, and 16 weeks of treatment (P < 0.01). No significant differences in serum BDNF levels were detected between the tardive dyskinesia group and the non-tardive dyskinesia group at baseline. Furthermore, no significant correlation was seen between the severity of tardive dyskinesia and serum BDNF levels. The present study suggests that kamishoyosan might be a promising adjunctive treatment for antipsychotic-induced tardive dyskinesia.     

Smoking and tardive dyskinesia in male patients with chronic schizophrenia

Interactions between smoking and movement disorders include the contrasting associations of more cigarette smoking with reductions in Parkinson's disease and increases in tardive dyskinesia (TD) symptoms. Here we examine the relationship between smoking and TD in a large sample of inpatients with schizophrenia. We used cross-sectional naturalistic methods to analyze the prevalence and severity of neuroleptic-induced TD in relation to cigarette smoking among 764 male chronic and medicated inpatients meeting DSM-IV criteria for schizophrenia. We administered a detailed questionnaire including general information, medical and psychological conditions, and smoking behaviors. We evaluated TD severity using the abnormal involuntary movement scale (AIMS) and psychopathology using the Positive and Negative Syndrome Scale (PANSS). The main statistical analyses used cross-tabulations for the prevalence of TD by smoking and multivariate regression analyses for continuous measures (AIMS and PANSS). We found that the prevalence of TD did not significantly differ between smokers (41% = 237/578) and non-smokers (37% = 69/186). Secondary outcomes showed a significant association between the AIMS total score and age, duration of illness and hospitalization times. Thus, smoking was not associated with TD in male Chinese schizophrenics, but consistent with previous reports, older patients with a longer duration of illness and more hospitalizations showed greater severity of TD.     

Negative association between Catechol-O-methyltransferase (COMT) gene Val158Met polymorphism and persistent tardive dyskinesia in schizophrenia

Summary. Chronic administration of typical antipsychotic agents, which mainly act on the dopamine receptors, implicates a role of dopamine system on the susceptibility of tardive dyskinesia (TD). In the present study, the association between a functional Val158Met polymorphism of Catechol-O-methyltransferase (COMT) gene and TD occurrence and TD severity was investigated in 299 Chinese schizophrenic patients with long-term antipsychotic treatment (TD: 166, non-TD: 133). After adjusting the effects of confounding factors, there was no significant association between COMT genotype and TD occurrence (p=0.367). Among TD patients, we found no significant correlation between COMT genotypes and the total scores of abnormal involuntary movement scale (AIMS) (p=0.629). We concluded that this COMT polymorphism might not play a major role in the susceptibility of TD nor on the severity of TD.     

Association between TNF-α promoter -308A/G polymorphism and tardive dyskinesiain Chinese Han patients with schizophrenia

Objective

Previous studies have indicated that the immune may be involved in the pathogenesis of tardive dyskinesia (TD). Some genetic polymorphisms in the human leukocyte antigen (HLA) I and II regions have been associated with TD, and the tumor necrosis factor-α (TNF-α) gene is located in the HLA III region. TNF-α levels in the striatum significantly increased in haloperidol-induced TD in rats. The TNF-α gene −308A/G single nucleotide polymorphism (SNP) has been shown to directly influence TNF-α expression. The genetic association between the TNF-α gene −308A/G SNP and TD is unclear. The present study investigated whether this variation is associated with clinical phenotypes and TD in schizophrenia in a genetically homogeneous northern Chinese Han population.

Methods

We genotyped the TNF-α gene −308A/G SNP in patients with schizophrenia with TD (n = 350) and without TD (n = 410). The Abnormal Involuntary Movement Scale (AIMS) and Positive and Negative Syndrome Scale (PANSS) were used to assess the severity of TD and psychopathology of schizophrenia, respectively.

Results

The allele and genotype frequencies did not significantly differ between patients with schizophrenia with and without TD (p > 0.05). No significant difference was found in the total AIMS score between the genotypes (p > 0.05). However, the PANSS negative symptom subscore was associated with risk for TD (p = 0.004), and a significant difference was found in total AIMS score between the genotypes in TD patients (p = 0.013).

Conclusion

The TNF-α gene −308A/G polymorphism does not appear to play a major role in the susceptibility to TD in patients with schizophrenia in a northern Chinese Han population. However this polymorphism may play a role in the TD severity.     

NMDA receptor genotypes associated with the vulnerability to develop dyskinesia

Dyskinesias are involuntary muscle movements that occur spontaneously in Huntington''s disease (HD) and after long-term treatments for Parkinson''s disease (levodopa-induced dyskinesia; LID) or for schizophrenia (tardive dyskinesia, TD). Previous studies suggested that dyskinesias in these three conditions originate from different neuronal pathways that converge on overstimulation of the motor cortex. We hypothesized that the same variants of the N-methyl--aspartate receptor gene that were previously associated with the age of dyskinesia onset in HD were also associated with the vulnerability for TD and not LID. Genotyping patients with LID and TD revealed, however, that these two variants were dose-dependently associated with susceptibility to LID, but not TD. This suggested that LID, TD and HD might arise from the same neuronal pathways, but TD results from a different mechanism.     

Neurochemical Findings in the Cerebrospinal Fluid of Schizophrenic Patients with Tardive Dyskinesia and Neuroleptic-Induced Parkinsonism

Abstract: Monoamine and their acid metabolites were determined in the CSF of 18 drug-treated chronic schizophrenic patients with the symptoms of tardive dyskinesia and neuroleptic-induced Parkinsonism (Parkinsonism). Six healthy volunteers were used as the control group.
The norepinephrine (NE) levels were found to be significantly higher in the patients with tardive dyskinesia than in the controls. Furthermore, elevated CSF NE levels were also observed in the patients with Parkinsonism. Epinephrine (E) and Dopamine (DA) were not present in the CSF of the control group, whereas measurable levels of DA could be detected in 4 out of 9 and E was found in 8 out of 9 patients with tardive dyskinesia. The mean concentration of HVA was slightly but not significantly elevated in the patients with tardive dyskinesia and Parkinsonism. The mean values of CSF 5-HIAA were all within the normal range in both patient groups. From the above results, it was suggested that abnormal adrenergic activity rather than abnormal dopaminergic activity may play an important role as a mechanism in the etiopathogenesis of extrapyramidal disorders. Furthermore, in the patients with Parkinsonism, CSF neurochemical observations were similar to those of the patients with tardive dyskinesia in this study. It may help to explain the clinical coexistence of tardive dyskinesia and neuroleptic-induced Parkinsonism.     

Tardive dyskinesia and deficit schizophrenia

Telfer S, Shivashankar S, Krishnadas R, McCreadie RG, Kirkpatrick B. Tardive dyskinesia and deficit schizophrenia. Objective: Despite comparable antipsychotic exposure, some patients experience involuntary movements yet others do not. Negative symptoms have been associated with tardive dyskinesia (TD), but it is not certain whether this is an association with primary negative symptoms or the effects of medications. The aim of the present study was to determine whether patients with deficit schizophrenia (who have primary negative symptoms) are more likely to experience TD than those with non‐deficit schizophrenia. Method: In 2006, all the people with a clinical diagnosis of schizophrenia in Nithsdale, Southwest Scotland, were identified using the ‘key informant’ method. These patients were categorized into those with and without the deficit syndrome and assessed for the presence of TD. Patients were also assessed for akathisia and extrapyramidal side effects. Results: Of the 131 people assessed, 31 were categorized as having deficit schizophrenia (23.7%) and 100 people (76.3%) as non‐deficit. There was no difference between the two groups with regard to age, antipsychotic exposure, and duration of illness. There was a significant association between deficit features and TD with an odds ratio = 2.97 [95% CI 1.128–6.88, P = 0.009]. Conclusion: Our findings support the proposal that the pathological process underlying deficit schizophrenia can predispose to the development of TD.     

伴发迟发性运动障碍的精神分裂症患者血清脑源性神经营养因子水平的对照研究

目的 探讨外周血清脑源性神经营养因子(brain derived neurotrophic factor,BDNF)浓度与精神分裂症伴发的迟发性运动障碍(tadrive dyskinesia,TD)的关系.方法 收集精神分裂症伴发TD患者61例、不伴发TD的患者78例,以及正常对照102名.用酶联免疫吸附法检测BDNF水平,采用不自主运动量表(abnormal involuntary movement scale,AIMS)评估TD的严重程度,阳性和阴性症状量表(positive and negative symptom scale,PANSS)评估患者精神症状.结果 TD组、非TD组和对照组的BDNF水平分别为(9.35±1.60)μg/L、(10.12±2.03)μg/L、(12.27±2.7)μg/L,3组的差异有统计学意义(F=37.8,P<0.01);两两比较显示,TD组和非TD组均低于对照组(P<0.01),而TD组又低于非TD组(P<0.05).使用典型和非典型抗精神病药物患者之间的BDNF水平差异无统计学意义(P>0.05).TD组BDNF水平与AIMS总分、年龄、总病程负相关(r分别为-0.24、-0.32、-0.22,P均小于0.05),而在非TD组BDNF水平与上述因素均无相关(P>0.05).结论 精神分裂症伴发TD患者外周BDNF浓度下降,且其水平与异常运动严重程度相关,提示BDNF可能在TD的病理生理中发挥作用.     

The study of BDNF Val66Met polymorphism in Chinese schizophrenic patients

Accumulating evidence showed that brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of schizophrenia. Recent studies have reported that the Val66Met polymorphism of the BDNF gene may be associated with susceptibility for schizophrenia and age of onset of this disease, with mix results. In the present study, the BDNF Val66Met gene polymorphism was examined in 387 inpatients (259 men and 128 women) meeting the DSM-IV criteria for schizophrenia and unrelated 365 healthy controls (255 men and 110 women). The schizophrenia symptomatology was assessed by the Positive and Negative Syndrome Scale (PANSS). Age of onset was defined as the age at which the psychotic symptoms first appeared. Our results showed that genotype frequency distributions and allelic frequencies did not differ between patients and controls. No interaction was found between sex and genotypes. Analysis of covariance (ANCOVA) showed a significance of the BDNF Val66Met genotypes on the age of onset (F = 3.76, p < 0.02), after adjusting sex, age and duration of illness. Furthermore, ANCOVA showed that the significance of the BDNFVal66Met genotypes on age of onset was increased comparing the Val66Met heterozygotes with the combination of Val66Val and Met66Met homozygotes (F = 5.85, p < 0.01). Our results suggest that the BDNF Val66Met polymorphism may not contribute directly to the susceptibility to schizophrenia, but to the onset of the disease. Furthermore, our results show the heterozygous effect of the BDNF Val66Met gene on the clinical variability of schizophrenia phenotype.     

迟发性运动障碍与血清尿酸的关系

目的：观察伴迟发性运动障碍（TD）的精神分裂症患者血清尿酸变化，探索尿酸与TD的关系。方法：采用尿酸酶法测定23例TD患者、相匹配的23例非TD患者及24例正常对照的血清尿酸水平，使用异常不自主运动量表（AIMS）评定TD的严重程度。结果：TD组血清尿酸水平显著低于非TD组及对照组（P均〈0．01），而非TD组与对照组之间血清尿酸水平无差异。TD组中AIMS评分与血清尿酸水平呈负相关（r=-0．435，P〈0．05）。结论：TD患者存在低血清尿酸水平并与TD的严重程度有关，尿酸可能参与了TD的病理生理过程。     

Genetic association of BDNF val66met and GSK-3β-50T/C polymorphisms with tardive dyskinesia

Aims:  Neurodegenerative processes may be involved in the pathogenesis of tardive dyskinesia (TD), and a growing body of evidence suggests that brain-derived neurotrophic factor (BDNF) plays a role in both the antipsychotic effects and the pathogenesis of TD. BDNF and glycogen synthase kinase (GSK)-3β are important in neuronal survival, and thus abnormal regulation of BDNF and GSK-3β may contribute to TD pathophysiology. This study investigated the relationship between two polymorphisms, val66met in the BDNF coding region and -50T/C in the GSK-3β promoter, and susceptibility to TD among a matched sample of patients having schizophrenia with TD ( n  = 83), patients with schizophrenia without TD ( n  = 78), and normal control subjects ( n  = 93).
Methods:  All subjects were Korean. The BDNF val66met and GSK-3β-50T/C genotypes were determined by polymerase chain reaction and restriction fragment length polymorphism analyses.
Results:  Polymerase chain reaction analysis revealed no significant difference in the occurrence of the polymorphisms among the TD, non-TD, and control subjects, but a significant interaction was observed among the groups possessing BDNF val allele in compound genotypes ( P  = 0.001). We found that the schizophrenic subjects with the C/C GSK-3β genotype, who carry the val allele of the BDNF gene, are expected to have a decreased risk of developing neuroleptic-induced tardive dyskinesia ( P  < 0.001).
Conclusions:  Our results demonstrate that the GSK-3β C/C genotype with the BDNF val allele is associated with patients having schizophrenia without TD. This study also suggests that the BDNF and GSK-3β gene polymorphisms work in combination, but not individually, in predisposing patients with schizophrenia to TD.     

Association of MB-COMT polymorphisms with schizophrenia-susceptibility and symptom severity in an African cohort

The catechol-O-methyltransferase (COMT) gene is an attractive schizophrenia candidate gene, encoding a catabolic dopamine enzyme. The enzyme exists as two distinct isoforms, with the membrane bound enzyme (i.e. MB-COMT) being predominantly expressed in the brain. Since African populations remain underrepresented in genetic/genomic research, we performed an association study to determine whether MB-COMT genetic variants are associated with schizophrenia-susceptibility and symptom severity in the South African Xhosa population. Fourteen candidate polymorphisms were selected by means of a literature search and in silico analyses and were subsequently genotyped in a cohort of 238 Xhosa schizophrenia patients and 240 healthy Xhosa controls. Genetic association was tested with schizophrenia-susceptibility as well as symptom severity within the patient group. Polymorphisms of interest were also analysed using functional assays. Two SNPs, rs2020917 (OR=0.54, 95% CI 0.37-0.79; P=0.0011) and rs737865 (OR=0.52, 95% CI 0.36-0.74; P=0.0002), in the P2 promoter region were significantly associated with schizophrenia as well as an increase (increase=11.2%, 95% CI 3.7%-19.2%; P=0.0031) in reporter gene expression. The minor alleles of these SNPs were underrepresented in the schizophrenia cohort, indicating a possible protective effect. The P2 region also formed part of a haplotype found to be associated with the severity of the negative symptoms of the disorder. The data generated by this study indicate that genetic variation of MB-COMT could be associated with schizophrenia and negative symptom severity in the Xhosa population and may therefore be one of the genomic loci contributing towards the disorder in the South African community. Future large-scale studies in other African schizophrenia populations are required to further elucidate the significance of these findings.