Orofacial Tardive Dyskinesia Research Articles

Genes of the Glutamatergic System and Tardive Dyskinesia in Patients with Schizophrenia.

Background: Tardive dyskinesia (TD) is an extrapyramidal side effect of the long-term use of antipsychotics. In the present study, the role of glutamatergic system genes in the pathogenesis of total TD, as well as two phenotypic forms, orofacial TD and limb-truncal TD, was studied. Methods: A set of 46 SNPs of the glutamatergic system genes (GRIN2A, GRIN2B, GRIK4, GRM3, GRM7, GRM8, SLC1A2, SLC1A3, SLC17A7) was studied in a population of 704 Caucasian patients with schizophrenia. Genotyping was performed using the MassARRAY Analyzer 4 (Agena Bioscience™). Logistic regression analysis was performed to test for the association of TD with the SNPs while adjusting for confounders. Results: No statistically significant associations between the SNPs and TD were found after adjusting for multiple testing. Since three SNPs of the SLC1A2 gene demonstrated nominally significant associations, we carried out a haplotype analysis for these SNPs. This analysis identified a risk haplotype for TD comprising CAT alleles of the SLC1A2 gene SNPs rs1042113, rs10768121, and rs12361171. Nominally significant associations were identified for SLC1A3 rs2229894 and orofacial TD, as well as for GRIN2A rs7192557 and limb-truncal TD. Conclusions: Genes encoding for mGlu3, EAAT2, and EAAT1 may be involved in the development of TD in schizophrenia patients.

Cytochrome P450 1A2 co-determines neuroleptic load and may diminish tardive dyskinesia by increased inducibility

Objectives. The aim of this study was to investigate a possible association between tardive dyskinesia (TD) and CYP1A2 (*1F, -163C>А, rs762551) polymorphism in Russian psychiatric inpatients. Methods. TD was assessed cross-sectionally using the Abnormal Involuntary Movement Scale (AIMS). Orofacial and limb-truncal dyskinesia were assessed with AIMS 1–4 and 5–7, respectively. Standard protocols were applied for genotyping. Analysis of covariance (ANCOVA) was used to compare the mean AIMS scores for each of the genotypic classes. Results. A total of 319 Caucasian patients from West Siberia with schizophrenia and 117 healthy volunteers were investigated. No significant differences between the patients and the controls in genotype frequencies were found. Analysis of covariance (ANCOVA) with age, sex, duration of disease, chlorpromazine equivalent (CPZEQ) incorporated as covariates showed that limb-truncal, but not orofacial TD, is associated with CYP1A2 (−163C>, rs762551) polymorphism (F = 3.27, P = 0.039). Patients with the C/C genotype had a higher mean AIMS 5–7 score than those with the A/C or the A/A genotype. Conclusions. Our results support the hypothesis that not only with clozapine, but also with other classical and atypical antipsychotics, smoking may decrease plasma levels; this is most extensively expressed in carriers of the CYP1A2*1F (-163C> A) polymorphism.

Mn-superoxide dismutase activity is associated with orofacial involuntary movements in schizophrenia patients with tardive dyskinesia.

Oxidative stress-induced damage may be involved in tardive dyskinesia (TD) development. Superoxide dismutase (SOD), the key antioxidant enzyme, was found abnormal in TD. We examined the role of oxidative stress in relation to TD and TD subtypes in schizophrenia using manganese SOD (MnSOD) as the biomarker. We recruited 152 male chronic patients with (n = 76) and without TD (n = 76) meeting Diagnostic and Statistical Manual of Mental Disorders-IV criteria for schizophrenia and 75 male control subjects. We examined the MnSOD activity for all subjects. Positive and Negative Syndrome Scale and the Abnormal Involuntary Movement Scale (AIMS) were assessed in the patients. Manganese SOD activity was lower in patients with TD than non-TD (p < 0.05). In the patients with TD, orofacial and total scores of AIMS were positively associated with MnSOD levels (both p < 0.05). Multiple regression analysis further confirmed that MnSOD was an independent contributor to both the orofacial and the total scores of AIMS (both p < 0.05). Oxidative stress reflected by compromised oxidative defense may play a role in the development and severity of TD. There may be an etiologic relationship between increased SOD level and dyskinetic movements associated with TD. In particular, MnSOD activity may have a specific role in orofacial TD.

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

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

P.3.c.042 Tardive dyskinesia and cytochrome P450 1A2 gene polymorphism in Russian patients with schizophrenia

Tardive dyskinesia (TD) is a potentially irreversible involuntary movement disorder with prevalence of about 20-30% in psychiatric patients on long-term treatment with antipsychotics. The identification of genetic factors contributing to development of TD would be of considerable clinical interest for individualized drug treatment. TD can be dissected into two distinct subsyndromes; orofaciolingual (TDof, involves movements of mouth and face) and limb-truncal dyskinesias (TDlt, involves purposeless choreiform movements of trunk and/or limbs) which probably have different genetic liability [1]. Recent investigations suggest that CYP1A2 may contribute to the development of TD as another CYP which may influence typical antipsychotics metabolism acting as a low-affinity high-capacity metabolizing enzyme [2,3]. Objective: The aim of this study was to investigate the association between orofaciolingual (TDof) and limb-truncal dyskinesias (TDlt) and Cyp1a2∗1F (C-163A, rs762551) polymorphism in Russian psychiatric inpatients. Methods: TD was assessed cross-sectionally in patients with clinically-established schizophrenia from four psychiatric centres in West Siberia by the use of the Abnormal Involuntary Movement Scale (AIMS). TDof and TDlt were assessed with AIMS items 1-4 and 5-7, respectively. Standard protocols were applied for genotyping. Analysis of covariance (ANCOVA) was used to compare the mean AIMS scores for each of the genotypic classes, with age, sex, duration of disease, chlorpromazine equivalent (CPZEQ) incorporated as covariates. Results: In total 319 Russian Caucasians patients (196 males, 123 females) with an age of 43±15.8 years (sample mean±SD) met the inclusion criteria. All patients had clinically-established schizophrenia and were included from four different psychiatric departments in West Siberia. Mean of disease duration was 17±14 years. The genotype distribution of Cyp1a2∗1F (C-163A, rs762551) polymorphism were in agreement with Hardy-Weinberg Equilibrium (Χ2 = 1.09, p=0.7). 44.8% were homozygous for the A-allele, 44.2% were heterozygous, and 10% were homozygous for the C-allele. Analysis of covariance (ANCOVA) with age, sex, duration of disease, chlorpromazine equivalent (CPZEQ) incorporated as covariates showed that TDlt, but not TDof, is an association with Cyp1a2∗1F (C-163A, rs762551) polymorphism (F = 3.27, p = 0.039). Patients with the C/C genotype had a higher mean AIMS items 5-7 score [2 (0-3.5)] [median (25%-75% percentiles)] than those with the A/C [1 (0-3)] or the A/A [0 (0-2)] genotype. Discussion: The increased TDlt severity in patients with the (C/C) genotype for CYP1A2 observed in the current study is in agreement with the literature data [2]. It should be noted that smoking is an estadlished inducer of CYP1A2 enzyme activity. Additionally, the plasma concentration of most typical antipsychotics is significantly reduced by smoking. It can be assumed that decrease of plasma level of typical antipsychotics in smokers are caused by activation of CYP1A2. 79% schizophrenic patients are smokers in our study and thus may have an increased CYP1A2-dependent pathway of metabolism of typical antipsychotics. Conclusions: C/C homozygounisity of rs762551might be associated with limb-trunkal but not with orofacial TD. Futher studies are needed to support our findings.

Botulinum toxin in the treatment of orofacial tardive dyskinesia: A single blind study

Objective Orofacial tardive dyskinesia (OTD) is difficult to treat and Botulinium Toxin A (BTA) may be an option. Methods In a single blind (raters were blind) study ( N = 12, duration 33 weeks) OTD was treated with Botulinum Toxin A in three consecutive sessions with increasing dosages. The severity was measured with the Abnormal Involuntary Movement Scale (AIMS). Results Overall there was a non-significant reduction in the severity of OTD ( p = 0.15). However, in the patients with no change in their antipsychotic medication ( N = 8) the reduction was significant ( p = 0.035). After the study, 50% of the patients preferred to continue the Botulinum Toxin A treatment. Conclusion BTA was well tolerated and showed a non-significant improvement for OTD. A larger double blind study is warranted.

Orofacial Dyskinesia, Frontal Lobe Dysfunction, and Coping in Older People With Psychosis

To investigate whether orofacial tardive dyskinesia (OTD) is associated with frontal lobe dysfunction and whether either are related to the coping abilities independent of psychiatric symptoms in older people with psychotic disorders. A total of 52 patients, aged over 65 years or over, who satisfied International Classification of Diseases, Tenth Revision criteria for psychotic disorders (F20-F29) were recruited into the study. OTD was measured using the Abnormal Involuntary Movements Scale and Waddington et al.'s (1993) criteria. Neuropsychological measures were specifically selected to assess different aspects of frontal function and coping was measured using a semistructured interview. Psychiatric symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). Patients with OTD showed more severe global cognitive impairment compared to patients without OTD. Group differences on measures of frontal lobe dysfunction were not maintained following adjustment for global cognitive impairment. Patients with OTD did not differ from patients without OTD on coping measures. Scores on the general psychopathology subscale of the PANSS, which includes symptoms associated with depression and anxiety, consistently predicted patients' negative perceptions of stressors and appraisals of coping, but cognitive impairment did not predict coping independent of symptoms. The association between coping and general psychopathology in older patients with psychosis warrants further investigation as both variables may be amenable to psychological interventions.

Combined analysis of 635 patients confirms an age-related association of the serotonin 2A receptor gene with tardive dyskinesia and specificity for the non-orofacial subtype

Tardive dyskinesia (TD) is an important limiting factor in the use of typical antipsychotic drugs. Genetic variability in the serotonin 2A (5-HT(2A)) receptor may influence risk for TD but the results of prior studies are not confirmatory. The objective of this study was to determine association of T102C and His452Tyr polymorphisms in the 5-HT(2A) receptor gene (HTR(2A)) with TD in a large, multicentre patient sample. The design employed case-control analysis controlling for possible confounders using pooled, original data from published and available unpublished samples and employing logistic regression, analysis of variance and meta-analysis. The study sample consisted of 635 patients with schizophrenia or schizoaffective disorder (256 with TD and 379 without TD) drawn from five research centres, divided into six groups based on population origin. The main outcome measure was association of a categorical diagnosis of TD based on the Research Diagnostic Criteria for TD with HTR(2A) T102C and His452Tyr genotypes and haplotypes. The findings indicate significant association of TD with HTR(2A) T102C genotype (p=0.002) over and above the effect of population group, also when controlling for age and gender (p=0.0008), but not with His452Tyr genotype. The T102C genotype was significantly associated with TD in older (>median age 47 yr, p=0.002) but not younger patients and in patients with non-orofacial (limb-truncal) (p=0.001) but not orofacial TD. By meta-analysis the Mantel-Haenszel (M-H) pooled odds ratio (OR) across all the available data was 1.64. A T102C-His452Tyr haplotype was significantly associated with TD (p=0.0008). These findings confirm that genetic variability in HTR(2A) contributes a small but significant degree of risk for the expression of TD, particularly in older patients and specifically for the non-orofacial (limb-truncal) type. Together with other genetic variants associated with TD the findings could be used to assess risk in patients who are candidates for treatment with typical antipsychotic medications.

Tardive dyskinesia: pergolid, a possible therapeutic option

There's still no effective treatment established for Tardive Dyskinesia. Aim of the study was to analyse the effect of pergolide, a D1 and D2 receptor agonist with prevalence for presynaptic auto receptors, in oro-facial tardive dyskinesia by means of a double-blind, placebo controlled cross-over study. Low-dose pergolide should activate presynaptic auto receptors, decrease dopamintransmission and reduce tardive dyskinesia. Assessment of dyskinesia was performed with the computer-assisted technique Digital-Imaging-Processing in addition to the clinical scale AIMS (Abnormal-Involuntary-Movement-Scale). 10 patients with oro-facial dyskinesia were examined for alteration to dyskinesia, psychopathology, vital functions and laborchemical parameter. Dyskinesia decreased 25 % for relax and 17 % for task conditions under pergolide treatment. Low-dose pergolide showed no side effects or worsening of the psychopathological state. Results of the Digital-Imaging-Processing correlated significantly with the results of clinical AIMS scale, but the computer-assisted technique gives more detailed information about degree and type of the movement disorder. Results suggest a therapeutic effect of pergolide in tardive dyskinesia, this has to be verified with a larger study population and longer observation. Assessment of dyskinesia is rater independent and more significant with the computer-assisted technique.

SUCCESSFUL THERAPY OF TARDIVE DYSKINESIA IN A 71‐YEAR‐OLD WOMAN WITH A COMBINATION OF TETRABENAZINE, OLANZAPINE AND TIAPRIDE

SUMMARYThere is no generally accepted treatment for tardive dyskinesia following intake of neuroleptics. Many compounds with effects on serotonine, GABA, cholinergic or dopamine receptors have been clinically useful. We report on a 71‐year‐old female patient suffering from orofacial tardive dyskinesia after treatment with haloperidol, which did not respond to monotherapy with antidyskinetic drugs. The syndrome disappeared almost completely within two weeks after a multidrug approach consisting of tetrabenazine, olanzapine and tiapride. A combination of antidyskinetic drugs should be considered in patients with severe tardive dyskinesia.

Extrapyramidal syndromes in neuroleptic-treated patients: prevalence, risk factors, and association with tardive dyskinesia.

Prevalence and risk factors for extrapyramidal syndromes (EPS) were investigated in a sample of 1,559 patients. The overall prevalence of EPS was 29.4% (N = 458). Among the EPS-diagnosed patients, parkinsonism as assessed by the presence of core parkinsonian symptoms (rigidity, tremor, bradykinesia) was present in 65.9% of patients (N = 302), akathisia in 31.8% (N = 145), and acute dystonia in 2.1% (N = 10). Old age and long-term neuroleptic drug (NL) treatment were significantly associated with EPS in both the univariate and the multivariate analyses, whereas no relationship was observed with average NL daily doses and current NL treatment. EPS was diagnosed in 50.2% of 285 patients with persistent tardive dyskinesia (TD). Distribution of EPS in patients with TD showed that tremor and akathisia were more frequent in peripheral TD cases than in orofacial TD cases. Furthermore, there was a stronger association of NL-induced parkinsonism with peripheral TD than with orofacial TD. This study suggests that the association between EPS and TD may be limited to specific subtypes of TD. Peripheral TD showed a higher association with parkinsonism and with akathisia, suggesting that these symptoms may share a common pathophysiology.

Tardive dyskinesia in a chronically institutionalized population of elderly schizophrenic patients: prevalence and association with cognitive impairment.

Chronically hospitalized geriatric inpatients with schizophrenia are at particular risk for both tardive dyskinesia (TD) and cognitive impairment but have been insufficiently studied in this regard. Similarly, the relationship between TD and cognitive impairment has not be adequately addressed in this population. (1) To determine the prevalence of TD in a cohort of chronically institutionalized schizophrenic geriatric inpatients. (2) To examine the relationship between the manifestations of TD in various body regions and several potentially related variables including current pharmacological regimen, age, age at first hospitalization and cognitive status. TD was assessed by the Modified Simpson Dyskinesia Scale and cognitive status by the Mini-Mental State Examination (MMSE). The relationship between manifestations of TD and other variables was examined by t-tests, ANOVA, MANOVA and correlational analysis. The prevalence of TD was 60%. Prevalence increased with age but was not related to current antipsychotic or anticholinergic regimen. Mean MMSE score did not differ between groups of patients with and without TD as defined by the criteria of Schooler and Kane (1982); however, the mean MMSE score was significantly (p < 0.0004) lower in subjects with orofacial TD as defined by Waddington and Youssef (1996), and the difference was not entirely accounted for by the older age of the latter group. TD and cognitive impairment both increase with age. However, TD alone does not account for the severity of cognitive impairment in this population. The present study provides further support for the hypothesis that the correlation between TD and cognitive impairment holds primarily for the orofacial manifestations of TD.

Tardive dyskinesia in a chronically institutionalized population of elderly schizophrenic patients: prevalence and association with cognitive impairment

Background. Chronically hospitalized geriatric inpatients with schizophrenia are at particular risk for both tardive dyskinesia (TD) and cognitive impairment but have been insufficiently studied in this regard. Similarly, the relationship between TD and cognitive impairment has not been adequately addressed in this population. Objectives. (1) To determine the prevalence of TD in a cohort of chronically institutionalized schizophrenic geriatric inpatients. (2) To examine the relationship between the manifestations of TD in various body regions and several potentially related variables including current pharmacological regimen, age, age at first hospitalization and cognitive status. Method. TD was assessed by the Modified Simpson Dyskinesia Scale and cognitive status by the Mini-Mental State Examination (MMSE). The relationship between manifestations of TD and other variables was examined by t-tests, ANOVA, MANOVA and correlational analysis. Results. The prevalence of TD was 60%. Prevalence increased with age but was not related to current antipsychotic or anticholinergic regimen. Mean MMSE score did not differ between groups of patients with and without TD as defined by the criteria of Schooler and Kane (1982); however, the mean MMSE score was significantly (p<0·004) lower in subjects with orofacial TD as defined by Waddington and Youssef (1996), and the difference was not entirely accounted for by the older age of the latter group. Conclusions. TD and cognitive impairment both increase with age. However, TD alone does not account for the severity of cognitive impairment in this population. The present study provides further support for the hypothesis that the correlation between TD and cognitive impairment holds primarily for the orofacial manifestations of TD. © 1998 John Wiley & Sons, Ltd.

Risk factors for orofacial and limbtruncal tardive dyskinesia in older patients: a prospective longitudinal study.

Although there is a consensus that orofacial and limbtruncal subtypes of tardive dyskinesia (TD) exist and may represent distinct pathophysiologic entities, few studies have examined the incidence of and risk factors associated with the development of these TD subtypes. Two hundred and sixty-six middle-aged and elderly outpatients with a median duration of 21 days of total lifetime neuroleptic exposure at study entry were evaluated at 1- to 3-month intervals. Using "mild" dyskinesia in any part of the body for diagnosis of TD, the cumulative incidence of orofacial TD was 38.5 and 65.7% after 1 and 2 years, respectively, whereas that of limbtruncal TD was 18.6 and 32.6% after 1 and 2 years. Preclinical dyskinesia was predictive of both orofacial and limbtruncal TD. History of alcohol abuse or dependence was a significant predictor of orofacial TD only whereas tremor was a significant predictor of limbtruncal TD only. Findings support suggestions that orofacial and limbtruncal TD may represent specific subsyndromes with different risk factors.

Saccadic Distractibility in Schizophrenic Patients With Tardive Dyskinesia

To the Editor.— Abnormalities in smooth-pursuit eye movements (SPEMs) in schizophrenic patients and their unaffected family members are well recognized. 1 This SPEM abnormality is thought to be independent of age, sex, and concurrent neuroleptic treatment, but may be partially accounted for by the presence of moderate to severe orofacial tardive dyskinesia (TD). 1,2 The underlying mechanism of this SPEM abnormality is not clear. Recently, it has been suggested that the abnormality may not be of the pursuit system at all but secondary to the lack of normal inhibition of the saccadic system during smooth pursuit. In this model, saccadic intrusions are thought to superpose themselves on the SPEMs, thereby producing the abnormal tracking. 1 Saccadic intrusions can also be seen in schizophrenic patients during fixation on a steady target. 1 Moreover, in experimental paradigms evaluating the control of saccadic eye movements, we recently observed that compared with normal controls,

The significance of subtyping tardive dyskinesia: a study of prevalence and associated factors

The prevalence of tardive dyskinesia (TD) in 137 Nigerian psychiatric patients was 27%. There were no differences in the prevalence rate between patients with affective disorder and those with schizophrenia. There were also no significant differences between the sexes but a trend for the more severe forms of dyskinesia to be commoner in females was noticed. Demographic, clinical and treatment variables were investigated for association with TD and each of its two putative subsyndromes: orofacial and appendicular dyskinesias. Two cases of severe and persistent tardive dystonia, associated with orofacial TD, were seen in two young adults, one with relatively short exposure to neuroleptics. After initial univariate screening, multivariate statistical methods revealed that different factors were associated with each of the two subsyndromes. While length of hospitalization correlated significantly with orofacial dyskinesia, cumulative duration of exposure to high-potency neuroleptics and number of ECTs received were significantly associated with appendicular TD. Neither age nor sex correlated with either of the subsyndromes. The findings confirm and extend previous observations suggesting that these dyskinesias may involve different pathophysiological mechanisms.

Variation in oro-facial tardive dyskinesia during depot antipsychotic drug treatment.

Oro-facial (tardive) dyskinesia, occurring in patients on long-term antipsychotic (dopamine antagonist) medication, can be suppressed temporarily by increasing the drug dose. Lowering the dose can exacerbate the condition. In patients receiving regular fluphenazine decanoate (FPZ) and flupenthixol decanoate (FPT) injections, characteristic profiles of the fluctuations in plasma level concentrations, occurring during the injection interval, have been demonstrated. The possible effects of these relatively predictable plasma level changes on the severity of oro-facial dyskinesia, and parkinsonism, were investigated. Regular assessment of oro-facial dyskinesia throughout the injection interval was carried out in six patients receiving FPZ and two patients receiving FPT. In both groups, changes were observed in the severity of oro-facial dyskinesia consistent with the expected effects of drug level fluctuations. The main implication of this finding is that, in investigations of tardive dyskinesia in patients receiving depot medication, ratings should be carried out at a standard time relative to injections.