Maintenance treatment of severe tardive dyskinesia with clozapine: 5 years' follow-up

\Drug-induced tardive dyskinesia (TD) affects approximately 20% to 30% of schizophrenic patients. Although it is usually mild, from 1% to 8% of patients may develop severe TD. Second-generation antipsychotics have demonstrated a lower risk of inducing TD. However, despite the advances brought by second-generation antipsychotics, the treatment strategies for TD remain problematic, given both the lack of an established therapeutic choice and the need for long-term use of antipsychotics in the treatment of schizophrenia. Clozapine is an atypical antipsychotic with minimal risk of inducing TD. Furthermore, it has been suggested that clozapine might actually improve the symptoms of TD. Accordingly, we evaluated the effects of clozapine on severe TD over 5 years. Seven patients meeting Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition criteria for chronic exacerbated schizophrenia (mean age 28.5 +/- 10.2 years) and presenting severe TD, defined as Abnormal Involuntary Movements Scale score above 13, were treated with clozapine and followed up for 5 years. Extrapyramidal Symptoms Rating Scale assessment was performed in all patients at baseline, after 6 months and 3 and 5 years. Mean Extrapyramidal Symptoms Rating Scale scores decreased 83% after 3 years and 87.5% after 5 years. Mean dose for all patients was 428 +/- 269 mg/d after 5 years. Results from this open-label study suggest that clozapine may be a further option for the treatment of TD over long term.     

Treatment predictors of extrapyramidal side effects in patients with tardive dyskinesia: results from Veterans Affairs Cooperative Study 394

Predictors for the development of tardive dyskinesia (TD) have been studied extensively over the years, yet there are few studies of predictors of the course of TD after it has developed. Moreover, few studies have examined predictors of the course of other extrapyramidal side effects (EPS) in patients maintained on neuroleptics. The purpose of this study was to determine which modifiable variables are important in the prediction of EPS in patients with persistent TD over a period of as long as 2 years. One hundred fifty-eight patients enrolled in the Veterans Affairs Cooperative Study 394 were included in this study. A linear mixed-effects (LME) analysis to estimate the Abnormal Involuntary Movement Scale score (for TD severity), Simpson-Angus Scale (for parkinsonism severity), and Barnes Akathisia Scale at any given time after intake assessment was performed. The severity of each of the TD and EPS outcomes at any given visit was predicted by their respective baseline severity scores. Additional predictors of a favorable course of TD included lower doses of antipsychotic medications and use of anticholinergic medications. Other predictors of a favorable course of EPS included younger age and the use of atypical antipsychotic medication (for rigidity) and the use of anticholinergic medication (for tremor). These findings indicate that clinician-modifiable factors related to medication usage can influence the outcome of TD and EPS in patients with persistent TD.     

Tardive dyskinesia and antipsychotics: a 5-year longitudinal study of frequency, correlates and course

The present study comprised a naturalistic, multicentre, 5-year study of course and correlates of tardive dyskinesia (TD). One hundred and sixty-six patients treated with risperidone were included during 1995/96 and followed once a year for 5 years. Mean age at inclusion was 38 years, and mean illness duration was 12 years. Tardive dyskinesia was assessed by the Abnormal Involuntary Movement Scale, and each patient's cognitive function was tested with a comprehensive computerised test battery. At study entry, 14% had TD according to a criterion index. Fifty percent were aware of it, but few reported distress. Age and sex did not correlate with TD, but schizophrenia and bipolar diagnoses did. The presence and intensity of TD correlated with all Positive and Negative Syndrome Scale for Schizophrenia symptom dimensions except the affective factor, but not with type of medication or chlorpromazine-equivalent levels. Tardive dyskinesia patients were cognitively impaired in tests reflecting mental speed, but not in other cognitive modalities. Over the 453 patient years of exposure, five patients developed TD and 14 became free of it. Our findings support the view that TD: (i) is a dynamic phenomenon; (ii) is only partly drug-induced; (iii) has a mild course during treatment with modern neuroleptics; and (iv) appears to have some correlation with mental slowness.     

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.     

Clozapine versus typical antipsychotics a retro- and prospective study of extrapyramidal side effects

Schizophrenic patients in long-term neuroleptic monotherapy with clozapine (n=100) and perphenazine, flupenthixol or zuclopentixol (controls,n=100) were evaluated for extrapyramidal side effects (EPS) (blind) as well as other side effects and mental condition (non-blind). In both groups the patients had received neuroleptic treatment for a total of 14 years (median) and the present antipsychotic (clozapine or control drug) for 5 years. Thus the clozapine-treated patients had previously received traditional neuroleptics for 9 years (median). The study was both retrospective (0.3–19 years for clozapine, 0.3–24 years for control drug, by means of chart information) and prospective (1 year, with video-controlled evaluation of EPS). There was a significantly lower prevalence of tardive dyskinesia (TD) in clozapine treated patients than control patients, although prior to this treatment there were more TD patients in the clozapine group (P<0.05). This lower level of TD in the clozapine group was related to a lower induction of new cases (P<0.001) and a tendency towards greater disappearance of TD in the clozapine than in the control group (P=0.07). Clozapine treated patients without TD had started clozapine and ceased traditional neuroleptics at an earlier age than those with TD. Parkinsonian signs were seen in 33% of the clozapine patients versus 61% of the control patients, mainly as hypokinesia; tremor in 3% versus 11% and rigidity in 0 versus 19%. Psychic akathisia was found in 14% versus 40% and motor akathisia in 7% versus 29% of the patients, all differences significantly in favor of clozapine. Clozapine treated patients also had less neuroleptic-induced emotional indifference and depression, but more autonomic side effects than controls.     

Relationship between Tardive Dyskinesia and psychopathology in a group of schizophrenic patients attending a rehabilitation centre

Twenty-five of 76 patients suffering from chronic schizophrenia, treated in a rehabilitation centre, were found to have tardive dyskinesia (TD) according to the Tardive Dyskinesia Research Diagnostic Criteria (Schooler and Kane, 1982). Patients suffering from TD achieved significantly higher total scores on two subscales (affective flattening and blunting and avolition-apathy, respectively) of the Scale for the Assessment of Negative Symptoms. On the other hand, positive symptoms assessed by the Brief Psychiatric Rating Scale did not distinguish the two groups. Our findings support the idea that patients suffering predominantly from negative symptoms of schizophrenia may have a higher vulnerability for the development of TD than schizophrenic patients showing mainly positive symptoms.     

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.     

Homozygosity for the Gly-9 variant of the dopamine D3 receptor and risk for tardive dyskinesia in schizophrenic patients

This study was undertaken to re-examine whether homozygosity for the Gly-9 variant (allele 2) of the dopamine D3 receptor gene (DRD3) is associated with increased risk for tardive dyskinesia (TD) in schizophrenic patients. Seventy-one antipsychotic-treated subjects with schizophrenia from Newcastle upon Tyne, UK, were genotyped for the presence of allele 1 (Ser-9) and allele 2 (Gly-9) of the dopamine D3 receptor (DRD3) Ser-9-Gly polymorphism. Among 32 patients with TD, 7 subjects (22 %) were homozygous for the Gly-9 variant (2-2 genotype), whereas 4 out of 39 patients (10 %) without TD had this genotype. The non-significant tendency in this sample towards an over-representation of allele 2 and the 2-2 genotype among schizophrenic patients with TD is in line with our initial report as well as recent studies by others, indicating that the Gly-9 allele of DRD3 may be a susceptibility factor for the development of TD in neuroleptic-treated individuals with schizophrenia. There are, however, some recent non-supportive reports, and since the trend in our present study failed to reach statistical significance, further studies on larger samples and future meta-analysis may be necessary to establish the role of the DRD3 in the pathogenesis of TD.     

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.     

Evidence that lithium protects against tardive dyskinesia: the Cura?ao Extrapyramidal syndromes study VI.

Lithium may have neuroprotective properties and therefore could affect the occurrence of tardive dyskinesia (TD). We conducted a nine-year follow-up study with one baseline and six follow-up assessments including all psychiatric inpatients in Cura?ao (N=194). TD was measured with the Abnormal Involuntary Movement Rating Scale (AIMS). There were 758 follow-up observations in the 166 patients (mean age 54.4 yrs, SD 16.0) with at least one follow-up assessment. Most patients (74%) had schizophrenia. The mean baseline score of the AIMS was 4.1 (SD 4.7). Sixteen patients (9.6%) used lithium at baseline and eight patients started lithium during follow-up. Prevalent and incident lithium significantly reduced the severity of existing TD with respectively 2.3 and 2.9 point reduction on the AIMS (AIMS score range: 0-23) and a standardised effect size of 0.5 for prevalent TD and 0.6 for incident TD. In the restricted sample of those with a baseline score of zero on the AIMS, prevalent lithium significantly lowered the risk of new abnormal movements (standardised effect size of 0.7). In conclusion, the use of lithium was significantly negatively associated with both persistence and onset of TD. These results suggest a beneficial effect on TD of lithium in some patients using long-term antipsychotics.     

Association of CYP2D6 and CYP1A2 gene polymorphism with tardive dyskinesia in Chinese schizophrenic patients

AIM: To investigate the possible association of the CYP2D6 gene C100T polymorphism and the CYP1A2 gene C163A polymorphism with tardive dyskinesia (TD) in Chinese patients with schizophrenia. METHODS: The recruited schizophrenic patients were assessed with the Abnormal Involuntary Movement Scale (AIMS), and divided into groups with TD (n=91) and without TD (n=91) according to the AIMS score. Polymorphisms of the CYP2D6 and CYP1A2 genes were determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP). RESULTS: No allele frequencies deviated from Hardy-Weinberg equilibrium. No significant differences in genotypes frequencies of the CYP2D6 C100T polymorphism were observed between patients with TD and without TD (Chi2=4.078, P>0.05), but patients with TD had a significant excess of the T allele compared with those without TD (Chi2=4.28, P<0.05). Moreover, the frequency of the CYP1A2 C allele in patients with TD was significantly higher than that in those without TD (Chi2=6.38, P<0.05). An association between TD and the CYP2D6 100T and CYP1A2 163C alleles was observed. Additionally, there were no differences in the mean AIMS scores among different genotypes in TD patients as a group or in smokers. The results of logistic regression analysis demonstrated that mean age and duration of illness were risk factors for TD, but not sex, cumulative exposure to neuroleptic drugs in years, CYP2D6 or CYP1A2 genotype. CONCLUSION: The C100T polymorphism of the CYP2D6 gene and the C163A polymorphism of the CYP1A2 gene may be associated with neuroleptic drug-induced tardive dyskinesia in Chinese patients with schizophrenia. However, genetic factors have a weaker association with susceptibility to TD compared with mean age and duration of illness.     

Pharmacy-based screening program for tardive dyskinesia

An ongoing screening program using pharmacists to detect tardive dyskinesia (TD) was developed, and a pharmacy-based prevalence survey of TD in chronic hospitalized psychiatric patients was undertaken to determine the extent of abnormal involuntary movements. The results show that older patients and women in particular are at higher risk for developing abnormal movements. Higher doses of neuroleptics were used in non-TD patients, indicating a possible masking effect caused by these drugs. By using a standardized rating method such as the Abnormal Involuntary Movement Scale, pharmacists can and should be utilized in the surveillance of TD.     

Effects of anticholinergic agents on patients with tardive dyskinesia and concomitant drug-induced parkinsonism

Twenty-five percent of 80 consecutive patients who met research criteria for persistent tardive dyskinesia (TD) were found to have an energy peak in the parkinsonian tremor band (3-6 Hz) of the frequency spectrum of their machine-measured resting hand movements in addition to the abnormalities consistent with TD (increased energy in the 0.5-3 Hz frequency spectrum). Twelve of these patients were studied again in double-blind fashion 2 hours after receiving a placebo and again 2 hours after a single 4 mg dose of trihexyphenidyl hydrochloride (HCl). Compared with the placebo condition, the trihexyphenidyl HCl markedly diminished the measured energy in the 4 Hz band and had no effect or slightly decreased the energy at all other points on the frequency spectrum. Simultaneous Abnormal Involuntary Movement Scale ratings revealed no change in the dyskinetic movements between the conditions; there was a significant subjective improvement reported by the patients following the trihexyphenidyl HCl administration. These observations indicate that electromechanical devices identify a subpopulation of TD patients who may acutely benefit from anticholinergic treatment.     

千金藤立定治疗迟发性运动障碍30例

在原有抗精神病药治疗情况下,合用-千金藤立定(SPD)治疗迟发性运动障碍(TD)30例。SPD剂量50mg tid,一个疗程8wk。结果显效率23％,总有效率56％;大多数4wk内生效,亦有8wk才生效。SPD无明显副作用,未增多或加重抗精神病药副作用,精神病症状也未恶化。初步认为SPD治疗TD安全有效。     

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.     

Reliability, validity, and a total score cutoff for the dyskinesia identification system: condensed user scale (DISCUS) with mentally ill and mentally retarded populations

The reliability and validity of the Dyskinesia Identification System: Condensed User Scale (DISCUS) are presented for mentally ill (n = 2,822) and mentally retarded (n = 4,649) populations, as are DISCUS item means and standard deviations. A total score cutoff was developed and tested against physician diagnosis and the Research Diagnoses for Tardive Dyskinesia (RD-TD) intensity criterion. DISCUS total score significantly increased as age increased and was significantly greater for 108 TD cases compared to 108 matched no-TD cases. The DISCUS total score of 5 or above was significantly associated with physician TD diagnosis, the RD-TD intensity criterion, and an increasing number of individuals meeting the cutoff score as age increased. Based upon the data, the DISCUS is a reliable and valid TD assessment instrument. It is concluded that the DISCUS cutoff score is as valid a measure of TD as the current operationally defined RD-TD intensity criterion.     

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.     

The acute effects of a loading dose of phenylalanine in unipolar depressed patients with and without tardive dyskinesia.

The effects of a loading dose of 100 mg/kg phenylalanine (PHE) were assessed in three groups of DSM-III-R diagnosed unipolar depressed patients: patients with tardive dyskinesia (TD) (n = 11); patients exposed to neuroleptics (NLs) but without TD (n = 10); and patients never exposed to NLs (n = 10). No significant differences were obtained in fasting and 2 hour postloading PHE plasma levels between the groups. A statistically significant correlation was found between Abnormal Involuntary Movements Scale total scores and postloading PHE plasma levels (p less than .05). Three TD patients showed unusually large increases in PHE plasma levels and PHE:large neutral amino acid ratios. Abnormalities in PHE metabolism may contribute to the development and severity of TD in some NL-treated unipolar depressed patients.