Risk factors and predictors of levodopa-induced dyskinesia among multiethnic Malaysians with Parkinson's disease.

UNLABELLED: Chronic pulsatile levodopa therapy for Parkinson's disease (PD) leads to the development of motor fluctuations and dyskinesia. We studied the prevalence and predictors of levodopa-induced dyskinesia among multiethnic Malaysian patients with PD. METHODS: This is a cross-sectional study involving 95 patients with PD on uninterrupted levodopa therapy for at least 6 months. The instrument used was the UPDRS questionnaires. The predictors of dyskinesia were determined using multivariate logistic regression analysis. RESULTS: The mean age was 65.6 ± 8.5 years. The mean onset age was 58.5 ± 9.8 years. The median disease duration was 6 (7) years. Dyskinesia was present in 44% (n = 42) with median levodopa therapy of 3 years. There were 64.3% Chinese, 31% Malays, and 3.7% Indians and other ethnic groups. Eighty-one percent of patients with dyskinesia had clinical fluctuations. Patients with dyskinesia had lower onset age ( p < 0.001), longer duration of levodopa therapy ( p < 0.001), longer disease duration ( p < 0.001), higher total daily levodopa dose ( p < 0.001), and higher total UPDRS scores ( p = 0.005) than patients without dyskinesia. The three significant predictors of dyskinesia were duration of levodopa therapy, onset age, and total daily levodopa dose. CONCLUSIONS: The prevalence of levodopa-induced dyskinesia in our patients was 44%. The most significant predictors were duration of levodopa therapy, total daily levodopa dose, and onset age.

The interaction of polymorphisms of IL10 and DBH was associated with general symptoms of PANSS with TD in Chinese Han schizophrenic patients.

OBJECTIVE: Tardive dyskinesia (TD) is a human hyperkinetic movement disorder as a result of potentially irreversible long-term chronic first-generation antipsychotic medications. Unfortunately, mechanisms involved in the development of TD have been poorly understood. Previous studies have indicated that some genetic polymorphisms of immune system and dopamine beta-hydroxylase (DBH) genes may be involved in the pathogenesis of TD. Rs1800872 and rs72393728 are located on the promoter of interleukin-10 (IL10) and DBH gene, respectively. The genetic association between the rs1800872 and TD is unclear. Previous studies have indicated that genetic variations of IL 10 and DBH are implicated in the positive and negative symptoms in schizophrenia. However, the interaction of two variations with severity of TD and symptoms of schizophrenic patients with TD has not been reported. The present study investigated whether these variations and their interaction were associated with clinical phenotypes of TD with schizophrenia in a genetically homogeneous northern Chinese Han population. METHODS: Rs1800872 and rs72393728 were genotyped in schizophrenic patients with TD (n = 372) and without TD (NTD; n = 412). The Abnormal Involuntary Movement Scale (AIMS) and Positive and Negative Syndrome Scale (PANSS) were applied to assess the severity of TD and psychopathology of schizophrenia, respectively. RESULTS: The allele and genotype frequencies of rs1800872 and rs72393728 did not significantly differ between TD and NTD patients (p>0.05). No significant difference was found in the AIMS total score among the genotypes of two loci (p>0.05). Interestingly, the interaction of rs1800872 and rs72393728 showed a significant association with the PANSS general score (p = 0.011), and a trend toward to the PANSS total score (p = 0.055). CONCLUSION: These findings suggest that the interaction of rs1800872 and rs72393728 variants may play a role in psychopathology of the general symptoms on PANSS in schizophrenic patients with TD in a northern Chinese Han population.

Do tardive dyskinesia and L-dopa induced dyskinesia share common genetic risk factors? An exploratory study.

Tardive dyskinesia (TD) in schizophrenia patients treated with antipsychotic medications and L-dopa induced dyskinesia (LID) among Parkinson's disease (PD) affected individuals share similar clinical features. Both conditions are induced by chronic exposure to drugs that target dopaminergic receptors (antagonists in TD and agonists in LID) and cause pulsatile and nonphysiological stimulation of these receptors. We hypothesized that the two motor adverse effects partially share genetic risk factors such that certain genetic variants exert a pleiotropic effect, influencing susceptibility to TD as well as to LID. In this pilot study, we focused on 21 TD-associated SNPs, previously reported in TD genome-wide association studies or in candidate gene studies. By applying logistic regression and controlling for relevant clinical risk factors, we studied the association of the SNPs with LID vulnerability in two independent pharmacogenetic samples. We included a Jewish Israeli sample of 203 PD patients treated with L-dopa for a minimum of 3 years and evaluated the existence or absence of LID (LID+ = 128; LID- = 75). An Italian sample was composed of early LID developers (within the first 3 years of treatment, N = 187) contrasted with non-early LID developers (after 7 years or more of treatment, N = 203). None of the studied SNPs were significantly associated with LID susceptibility in the two samples. Therefore, we were unable to obtain proof of concept for our initial hypothesis of an overlapping contribution of genetic risk factors to TD and LID. Further studies in larger samples are required to reach definitive conclusions.

Tardive dyskinesia in the treatment of schizophrenia: the findings of the Research on Asian Psychotropic Prescription Pattern (REAP) survey (2001 - 2009).

OBJECTIVE: The aim of the study was to survey the frequency of tardive dyskinesia (TD) in patients with schizophrenia and its demographic and clinical correlates in selected Asian countries. METHOD: A total of 6,761 hospitalized schizophrenia patients in nine Asian countries and territories were examined from 2001 to 2009. TD was evaluated as "present" or "absent" according to the clinical judgment of experienced psychiatrists. The patients' socio-demographic and clinical characteristics and the prescriptions of psychotropic drugs were recorded using a standardized protocol and data collection procedure. RESULTS: The frequency of TD in the whole sample was 5.0% with wide variations between countries (0 - 14.9%). Multiple logistic regression analysis showed that the following variables were independently associated with TD: study time, study site, older age, male gender, more severe negative and extrapyramidal symptoms and less anticholinergic drugs. CONCLUSIONS: A generally low frequency of TD in Asian schizophrenia patients with inter-ethnic variations was recorded. It is unclear whether the low prevalence of TD compared with Western data is real or the result of it being insufficiently recognized.

The coding-synonymous polymorphism rs1045280 (Ser280Ser) in beta-arrestin 2 (ARRB2) gene is associated with tardive dyskinesia in Chinese patients with schizophrenia.

BACKGROUND: Tardive dyskinesia (TD) is a severe and potentially irreversible adverse effect of long-term antipsychotic treatment. Typical antipsychotics are commonly binding to the dopamine receptor D2 (DRD2), but the occurrence of antipsychotic-induced TD is rather delayed; therefore, the development of TD may be associated with mediators or signalling complexes behind DRD2, such as beta-arrestin 2 (ARRB2), an important mediator between DRD2 and serine-threonine protein kinase (AKT) signal cascade. METHODS: A case-control study to evaluate the association between rs1045280 (Ser280Ser) and antipsychotic-induced TD was performed amongst 381 patients (TD/non-TD = 228/153). RESULTS: There was a significant difference in the genotype distribution between TD and non-TD groups (P = 0.025); furthermore, the allelic analysis indicated that patients with T allele had increased risk of TD occurrence (OR(T) = 1.58, 95% CI = 1.14-2.19, P = 0.007). CONCLUSIONS: To the best of our knowledge, this is the first study reporting a positive association between the SNP rs1045280 and TD in schizophrenic patients.

Acculturation is associated with the prevalence of tardive dyskinesia and akathisia in community-treated patients with schizophrenia.

OBJECTIVE: Ethnicity is a risk factor for tardive dyskinesia (TD) and other antipsychotic drug-induced movement disorders (ADIMD). It is unclear whether this association is mediated through genetic, environmental or cultural factors individually or in combination. This pilot study aimed to explore this interaction by determining if acculturation in migrant groups contributed to the prevalence of ADIMD. METHOD: Culturally diverse but relatively genetically homogeneous (white Caucasian) patients with schizophrenia (n = 40) treated at a single site were assessed for the presence of ADIMD and level of acculturation. RESULTS: Higher levels of acculturation correlated with an increased prevalence of TD and akathisia but not Parkinsonism. The level of acculturation significantly predicted TD. CONCLUSION: This study identifies for the first time that acculturation significantly contributes to the prevalence of TD and akathisia but not Parkinsonism in culturally diverse migrant populations and must be accounted for when explaining ethnic variation in rates of ADIMD.

Incidence of tardive dyskinesia and tardive dystonia in African Caribbean patients on long-term antipsychotic treatment: the Curaçao extrapyramidal syndromes study V.

OBJECTIVE: Tardive dyskinesia (TD) and tardive dystonia (TDt) syndromes represent severe side effects of first-generation antipsychotics (FGAs). Although second-generation antipsychotics (SGAs) confer a lower risk for tardive syndromes, many patients continue to use FGAs alone or in combination with SGAs. Some patients remain free of TD or TDt even after many years of antipsychotic treatment with predominantly FGAs. Do these patients remain at risk for TD or TDt and, consequently, should a switch to SGAs be considered? A longitudinal cohort study in patients on long-term antipsychotic treatment may answer this question. METHOD: A 9-year cohort study (1992-2001) was conducted of the whole, mostly chronic, psychiatric inpatient population on the Caribbean island of Curaçao (N = 194). Almost all patients (95%) were of African Carribean origin. TD and TDt were assessed (1 baseline, 6 follow-ups) with the Abnormal Involuntary Movement Scale and the Fahn-Marsden rating scale, respectively. New cases of TD or TDt were diagnosed if they fulfilled the criteria at 2 successive follow-up visits. RESULTS: In patients with a mean antipsychotic use of approximately 18 years, the yearly incidence rates of TD and TDt were 10.2% (95% CI = 7.7 to 13.5) and 0.7% (95% CI = 0.4 to 1.5), respectively. The severity of TD was strongly associated with the severity of TDt (beta = 0.08, 95% CI = 0.03 to 0.14) and vice versa (beta = 0.10, 95% CI = 0.03 to 0.16). TD severity was positively associated with age and akathisia but negatively associated with parkinsonism. CONCLUSIONS: Patients who are free of TD after many years of antipsychotic treatment still have a considerable risk for TD. Switching to an SGA may be warranted. The risk for incident TDt in this group was very low.

Prevalence of and risk factors for tardive dyskinesia in a Xhosa population in the Eastern Cape of South Africa.

OBJECTIVE: Despite prolonged use of antipsychotic drug treatment, the prevalence of tardive dyskinesia (TD) in a Xhosa population has not been evaluated. This study was undertaken to assess the prevalence and identify possible factors, including antioxidant intake and smoking history, which may increase or reduce the risk of TD. METHOD: One hundred two subjects who had been exposed to typical antipsychotic drugs for at least 6 months and were currently on an antipsychotic were screened for abnormal movements using the Abnormal Involuntary Movement Scale (AIMS) rating scale. Data about current and past antipsychotic therapy, diagnoses, smoking history, and dietary factors were gathered from the patient and from chart view. RESULT: Twenty-eight and four-tenths percent of subjects met criteria for tardive dyskinesia. Years of treatment and total cumulative antipsychotic dose were significant predictors of TD. Subjects with higher total consumption of foods containing antioxidants had lower rates of TD, but only consumption of onions was significantly associated with reduced prevalence. TD was less prevalent in smokers, but this difference did not reach statistical significance. Age, sex, and psychiatric diagnosis did not predict presence of TD. CONCLUSION: The result of this study indicate that TD in this population is more prevalent than previously believed within this local clinical context. Prolonged treatment and total antipsychotic drug exposure are important risk factors for TD in this population. Further study of the role of concurrent medications and dietary factors is indicated.

Genetic susceptibility to tardive dyskinesia in chronic schizophrenia subjects: III. Lack of association of CYP3A4 and CYP2D6 gene polymorphisms.

Tardive dyskinesia is a severe debilitating movement disorder characterized by choreoathetotic movements developing in one-fifth of the patients with schizophrenia. In this study we have investigated the significance of CYP3A4*1B and CYP2D6*4 polymorphisms in TD susceptibility among chronic schizophrenia patients (n = 335) from north India. Tardive dyskinesia was diagnosed in approximately 29% (96/335) of these patients. No significant association of either of the two SNPs with TD (CYP3A4*1B chi2 = 0. 308, df = 1, p = 0.579; CYP2D6*4 chi2 = 0.006, df = 1, p = 0.935) was observed. However a trend towards increased severity of TD in patients heterozygous for the CYP2D6*4 mutation was observed.

Ethnicity and the course of tardive dyskinesia in outpatients presenting to the motor disorders clinic at the Maryland psychiatric research center.

BACKGROUND: Although newly emergent tardive dyskinesia (TD) is less of a concern, about one-fourth to one-third of patients on or previously on chronic first-generation antipsychotic agents have TD. The long-term course and outcome, as well as their predictors, are unknown. Earlier studies identify ethnicity as one of the risk factors for the development of TD, and case reports have noted a preponderance of African-American males in cohorts of patients with tardive dystonia. The current study examines the anatomic distribution and course of TD in a cohort of schizophrenia patients of European and African descent with TD who were referred to the Motor Disorders Clinic (MDC). METHODS: We evaluated data collected on 1149 TD patients who were given a focused neurologic examination for movement disorders. Movements were evaluated with the MPRC Scale for Involuntary Movements (IMS). All patients met RDC-TD criteria for diagnosis of persistent TD. One to 10-year follow-up data on 528 patients were evaluated to examine the course of TD following recommendations made to referring primary clinicians. Suggested interventions to referring primary clinicians included dose reduction of first-generation antipsychotic medication, or switching to a second-generation antipsychotic. RESULTS: Initial evaluation included 701 European American (EA) patients and 448 African-American (AA) patients. AA patients had a significantly higher proportion of males [chi(1) = 7.50, P < 0.05]. EA subjects had a higher mean age than AA patients 42.8 +/- 11.2 and 39.8 +/- 10.4, respectively [F(1,1147) = 22.27, P < 0.05]. Mean neuroleptic exposure (chlorpromazine equivalents) was similar in both groups after controlling for differences in age.Follow-up data analyzed in 528 patients (329 EA and 199AA) showed a significant ethnicity by TD interaction [F(1,504) = 4.26, P < 0.05]. Examination of body distribution of dyskinetic movements showed an effect of ethnicity. Subsequent analyses suggest EA patients experienced more improvement in TD over the course of follow up [F(1,319) = 22.39, P < 0.05] compared with AAs [F(1,189) = 1.58, P > 0.05]. These findings were unchanged when age, change in antipsychotic drug dose, and duration of follow-up were covaried. CONCLUSION: Reports from earlier studies note ethnicity (African descent) as a risk factor in the development of TD. Our study findings suggest ethnicity might be an important factor in predicting a poor course of TD.

The effect of vitamin E treatment on tardive dyskinesia and blood superoxide dismutase: a double-blind placebo-controlled trial.

Free radicals may be involved in the pathogenesis of tardive dyskinesia (TD). Vitamin E, a free radical scavenger, has been reported to improve symptoms of TD. The present study was designed to replicate this finding in a group of Chinese patients with TD, and to examine the effect of vitamin E treatment on blood superoxide dismutase (SOD), a critical enzyme in the detoxification of free radicals. Forty-one inpatients with TD completed a double-blind, placebo-controlled, parallel-group study of vitamin E. Twenty-two of the patients were randomly assigned to receive a fixed dose of 1200 IU/d vitamin E, and 19 were assigned to a placebo for 12 weeks. Patients were assessed primarily using the Abnormal Involuntary Movement Scale (AIMS) at baseline, weeks 6 and 12. Blood SOD levels were measured by radioimmunometric assay before and after treatment. The results showed that the reduction in AIMS score from baseline was significantly higher with vitamin E treatment compared with placebo (45.9% vs. 4.3%). Blood SOD levels were significantly increased after treatment with vitamin E (P = 0.001), but no change with placebo treatment (P < 0.05). These results support earlier findings of the efficacy of vitamin E in the treatment of TD. Moreover, the efficacy of vitamin E may be due to its ability to increase SOD level, which may reduce oxidative injure in tardive dyskinesia.

Tardive dyskinesia among Chinese and Malay patients with schizophrenia.

The prevalence of tardive dyskinesia (TD) was studied with the Abnormal Involuntary Movements Scale in Chinese and Malay patients with schizophrenia who were hospitalized in a Singapore state psychiatric institute. We also studied the relationship of neuroleptic-induced extrapyramidal side effects to TD. By using established criteria, the rates of TD were 40.6% for Chinese and 29.0% for Malays, higher than previously reported for Chinese subjects. Older age and lower current neuroleptic dose were significantly associated with TD. Multivariate analysis, after controlling for other salient risk variables, did not show a significant difference in TD prevalence rates between the two races. We conclude that suggested differences in interethnic rates of TD among Chinese, Malays, and Westerners are unlikely to exist and that any variation in prevalence is more likely to be determined by differences in duration of exposure and dose levels of neuroleptic drugs.

Awareness of tardive dyskinesia in Asian patients with schizophrenia.

While ethnocultural differences in risk of tardive dyskinesia (TD) have been suggested, no previous studies have examined whether this factor also plays a role in lack of awareness of TD. This study examined this question in an Asian population with schizophrenia. Six hundred seven patients in a state mental hospital in Singapore were assessed using the Abnormal Involuntary Movement Scale (AIMS) and the Simpson-Angus Rating Scale. Of the 607 patients, 242 (39.9%) met criteria for TD, and 163 (67.4%) patients were not aware of the presence of TD. No significant differences in terms of age, gender, and duration of illness were found between those aware of their TD and those not aware. Daily neuroleptic doses and scores for the AIMS and Simpson-Angus Rating Scale were significantly different, although after logistic regression, only the Simpson-Angus Rating Scale scores remained significant. The finding that a large proportion of our patients lacked awareness of their TD is consistent with other reports in the West and provides evidence that this feature is characteristic of the illness rather than of a specific ethnocultural group. We found an association between lack of awareness and greater severity of extrapyramidal symptoms (EPS), suggesting that there may be a subtype of TD in which lack of awareness and greater vulnerability of developing EPS are features.

An investigation of ethnic and gender differences in the pharmacodynamics of haloperidol.

The objective of this study was to examine neuroleptic effectiveness among Asians and Caucasians, and to investigate inter-ethnic pharmacodynamic differences. Asians and Caucasians suffering a first episode of psychosis were maintained on low oral doses of haloperidol (2 mg/day) for the first week of treatment. Doses were increased weekly until the optimal therapeutic dosage was achieved. This was defined as the point at which subjects: (a) experienced significant clinical improvement; or (b) developed extrapyramidal side effects. Plasma haloperidol and prolactin were measured at intake, at the end of first week of the treatment on haloperidol 2 mg/day, and at optimal therapeutic dosage. The average optimal dosage for Asians and Caucasians was equal. However, at the end of the first week of haloperidol at a fixed dose of 2 mg, Caucasian males had significantly lower plasma haloperidol levels than Asian males while no ethnic differences in haloperidol levels were found among females. There were no ethnicity or gender effects on plasma prolactin response after 1 week of treatment. Ethnicity and gender may affect haloperidol metabolism.

A transcultural study of psychopharmacotherapy for schizophrenia of neuroleptic treatment between Tokyo and Bali.

We made a comparison of drug treatment for the patients with schizophrenia between two psychiatric hospitals in Tokyo, Japan, and Bali, Indonesia. An initial preliminary, cross-sectional study revealed that the mean daily dose of neuroleptics was significantly higher in Tokyo than it was in Bali. A second, longitudinal, study showed that the mean neuroleptic dose for newly admitted patients in the acute phase was higher, and the number of patients receiving maintenance treatment after discharge larger in Tokyo, while the mean duration of hospitalization was shorter, and the re-admission rate 1 year after discharge lower in Bali. These findings suggest that the course of schizophrenia is more favorable in Bali. As a result of lower dose of neuroleptics, the prevalence of tardic dyskinesia was much lower in Bali than it was in Tokyo.

Tardive dyskinesia and ethnicity: review of the literature.

Tardive dyskinesia (TD) is a side effect of long-term neuroleptic administration. The wide variation of 2 to 51% in its reported prevalence can be attributed to the varied definitions of TD, the use of different methods of assessment, and the lack of control of independent variables. Why only certain patients develop this side effect is an intriguing question. The occurrence of TD in family members and in those persons with a family history of Parkinson's disease (PD) is suggestive of genetic vulnerability. Further support for a genetic predisposition comes from the fact that only certain strains of monkeys, such as the Cebus apella strain, have a higher propensity to develop TD than others, such as the Macaca sepciosa strain. If genetic factors play a significant role in the development of TD, then, genetically diverse ethnic groups may have a different propensity for the development of TD. One method of evaluating such a possibility is to compare its prevalence in different countries. The current literature on ethnic differences in the prevalence rates of TD is reviewed. This area of study needs further rigorous investigation.

Ethnicity and movement disorders.

This article is a review of studies involving ethnicity and spontaneous as well as iatrogenic movement disorder. We have focused on Parkinson's disease and tardive dyskinesia. Some early studies reported that African Americans had lower rates of Parkinson's disease than Caucasians, whereas more recent surveys have not found such a difference. Several studies suggested that African Americans have a higher risk of developing tardive dyskinesia than Caucasians, even when differences in neuroleptic drug use are accounted for. Asians seem to have a lower or equal risk of developing tardive dyskinesis as compared with Caucasians. We discuss the possible contribution of ethnicity to the etiology of movement disorders and the implications thereof.

Abnormal movements in never-medicated Indian patients with schizophrenia.

BACKGROUND: Historical records suggest dyskinesia was observed in severely ill institutionalised patients with schizophrenia in the pre-neuroleptic era. More recent work has not found dyskinesia in never-medicated younger and middle aged patients. The present study complements this recent work and avoids the confounders of severity of illness and institutionalism by examining elderly patients in a wide variety of community settings. METHOD: Movement disorders were examined in 308 elderly individuals in Madras, India, using the Abnormal Involuntary Movements Scale, the Simpson and Angus Parkinsonism Scale and the Barnes Akathisia Scale. Patients' mental state was assessed by the Positive and Negative Syndrome Scale. RESULTS: Dyskinesia was found in 15% of normal subjects (n = 101, mean age 63 years), 15% of first degree blood relatives of younger schizophrenic patients (n = 103, mean age 63 years), 38% of never medicated patients (n = 21, mean age 65 years) and 41% of medicated patients (n = 83, mean age 57 years). The respective prevalences for Parkinsonism were 6%, 11%, 24% and 36%; and for akathisia 9%, 5%, 21% and 23%. Dyskinesia was associated with negative schizophrenic symptoms. CONCLUSIONS: Dyskinesia in elderly schizophrenic patients is an integral part of the illness and not associated with antipsychotic medication.

Oculogyric spasm in Asian psychiatric in-patients on maintenance medication.

BACKGROUND: The objective was to investigate the occurrence and characteristics of oculogyric spasm (OGS) in an Asian country. METHOD: All 2035 Asian (88% Chinese, 7% Malays and 5% Indonesians) psychiatric in-patients in the state psychiatric hospital in Singapore were surveyed for occurrence of oculogyric spasm (OGS) over a two-month period. RESULTS: Thirty-four patients (1.7%) developed OGS (53% male and 47% female). All the 34 patients had been on maintenance antipsychotic drugs for more than five months. Eighteen patients had recurrent attacks. The mean chlorpromazine equivalent daily dose for those patients with recurrent OGS was 511 mg. This was significantly higher (P < 0.05) than the 277 mg daily dose received by those without recurrent OGS. Most (68%) of the attacks occurred between 1400-2000 h suggesting that OGS may have a diurnal variation. CONCLUSIONS: OGS presenting as tardive dystonia may be due to a relative increase in cholinergic activity.