The role of parkinsonism and antiparkinsonian therapy in the subsequent development of tardive dyskinesia

Tardive dyskinesia (TD) is a side effect of prolonged neuroleptic treatment presenting as abnormal involuntary movements. This troublesome disorder occurs in only 15-30% of patients taking neuroleptics, suggesting that these individuals may be physiologically distinct so as to be predisposed. This study analyzed possible factors contributing to TD development. Fifty patients on depot neuroleptics for more than 7.1 years were prospectively examined for TD and drug-induced parkinsonism (DIP) using the Smith-Trims rating scale for an average of 5 years. The patients were assessed for the severity of the movement and if the movement increased or decreased with respect to neuroleptic dosage, anticholinergic dosage, parkinsonism, and other related factors. Both TD and DIP increased over time. In the patients whose dose of neuroleptic decreased, the increase in TD ratings was not significant. Using a forward stepwise regression DIP was found to increase as TD worsened but did not appear to predict subsequent TD development. Anticholinergic treatment showed a less significant correlation with the change in TD. These results have implications for the management of combined TD and DIP presentation.     

The changing effector pattern of tardive dyskinesia during the course of neuroleptic withdrawal.

Tardive dyskinesia (TD) is a movement disorder that can be expressed at various body effector points, including the face, neck, arms, fingers, legs, and torso. In this prospective longitudinal study researchers examined whether the effector pattern of TD changed during the course of neuroleptic medication withdrawal in adults with mental retardation. Results indicated that the effector pattern of TD changed over the course of neuroleptic withdrawal. Peak dyskinesia was associated with the involvement of more body areas relative to baseline. Although dyskinesia decreased at follow-up and fewer body areas showed signs of dyskinesia, there were still differences in the effector pattern of dyskinesia relative to baseline at periods of 1 to 2 years following neuroleptic withdrawal. These findings suggest that TD is a dynamic disorder associated with changes in both severity and effector pattern over time. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neuropsychological impairment in Tardive dyskinesia.

Tardive dyskinesia (TD) is a movement disorder secondary to neuroleptic treatment. Whether TD is associated with neurocognitive dysfunction is a controversial issue. We reviewed 31 published studies evaluating neuropsychological (NP) test results in schizophrenic patients with and without TD and found that TD was generally reported to be associated with cognitive impairment. Numerous methodological limitations, however, restrict the conclusions made about the relationship between cognition and dyskinesia. We therefore undertook a study in which 143 schizophrenic patients were evaluated on a comprehensive NP test battery. On both global and learning deficit scores, TD patients demonstrated greater impairment than did a matched comparison group. Two aspects of TD (severity and topography) were related to severity of cognitive impairment. These findings suggest that dyskinesia and cognition may share some underlying mechanism in schizophrenia. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Tardive dyskinesia in a developmentally disabled population: Manifestation during the initial stage of a minimal effective dose program.

Forty individuals who were withdrawn from neuroleptic medication after the initiation of a minimal effective dose program at a residential facility for individuals with developmental disabilities were evaluated. Tardive dyskinesia (TD) was assessed using the Dyskinesia Identification System Condensed User Scale (DISCUS). Half of the participants being treated with neuroleptic medication (N) were also being treated with anticonvulsant medication (AC), so 2 withdrawal groups were formed. The N only group manifested an increase in DISCUS scores after the withdrawal of neuroleptic medication, but the N?+?AC group did not. On the basis of this intriguing new finding, it was speculated that treatment with anticonvulsant medication might prevent the development or suppress the expression of TD. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Adverse neurobiological effects of long-term use of neuroleptics: human and animal studies

Neuroleptics have revolutionized the treatment of schizophrenia and other psychoses since the early 1950s. Several adverse neurobiological effects are, however, associated with the long-term use of these agents. This article will review human and animal studies of these adverse effects, and also present some new data. Tardive dyskinesia (TD) is the most widely studied potentially persistent movement disorder resulting from long-term neuroleptic treatment, and several risk factors for TD development have been identified. Although drug-induced parkinsonism (DIP) usually disappears after the offending agent is withdrawn, a small portion of patients may have persistent parkinsonism. It is however, unclear if this is an aging-related effect. Persistent cognitive impairment associated with long-term use of typical neuroleptics has not been well documented. Atypical antipsychotics may produce improvement in cognitive performance in patients with chronic schizophrenia. MRI changes that are secondary to neuroleptics are possible, but have not yet been studied adequately. There is one unconfirmed report of neurofibrillary tangles associated with long-term neuroleptic use. A number of investigators have reported vacuous chewing movements, and neuropathologic changes following prolonged administration of neuroleptics in animals. We discuss the implications of the various reported adverse effects of long-term use of neuroleptics.     

New strategies for old problems: tardive dyskinesia (TD). Review and report on severe TD cases treated with clozapine, with 12, 8 and 5 years of video follow-up

Tardive dyskinesia (TD) is the most feared and troublesome extrapyramidal side-effect of prolonged neuroleptic (NL) treatment. We present a review of TD. Its pathophysiology remains elusive, although extrapyramidal symptoms (EPS) increase the liability for TD. Nowadays, therefore, avoidance of all EPS remains the best preventive strategy, as it is not possible to predict which liable patients will develop TD, or of what type or severity. TD frequently includes dystonic features, and is more disabling when these dystonias are present. Clozapine (CLZ) has been reported to be effective in suppressing nearly 60% of TD syndromes, specially those with dystonic features. Based on the few reports in the literature on CLZ and TD by the early 1980s, we started to videotape the first severe TD patient treated with CLZ in 1984. We present the first three case reports of severe TD, with prominent disabling dystonic features, treated with CLZ and videotaped since pretreatment and then periodically for 12, 8 and 5 years of follow-up, respectively. The patients' current diagnosis, gender and age are: Case 1, DSM-IV Schizophrenia Residual Type, male, 39 years; Case 2, DSM-IV Polysubstance Related Disorder, Borderline Personality Disorder, female, 28 years; Case 3, DSM-IV Schizoaffective Disorder, male, 40 years. Two of them presented with a recurrence of TD because of CLZ interruption within the first 2 months of treatment, with no further breakthrough to date. The first two cases have complete remission of TD; the third case is still improving after 5 years of CLZ treatment, with only minor dystonic features persisting that constitute no impairment for work or daily routines at present. All patients, independent of their psychiatric primary diagnosis, have shown significant and progressive improvement in both motor and psychosocial aspects. None of them has been rehospitalized. Long-term treatment and follow-up is required to avoid TD recurrence and to assure full assessment of treatment effectiveness. Ideally, periodic video recording with standardized examination is advisable for long-term follow-up and outcome assessment. At present, CLZ could be regarded as the drug of choice for patients with TD, specially for those with disabling and or dystonic features and who require ongoing NL therapy. The use of novel antipsychotic agents for TD treatment and prevention, with their low EPS liability, is promising, but has yet to be tested.     

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OBJECTIVE: The assess the incidence of tardive dyskinesia (TD) in a sample of adolescents treated with neuroleptic medication and to identify the presence of any risk factors for TD within the affected group. METHOD: A retrospective chart review was conducted for 40 cases. The Abnormal Involuntary Movement Scale (AIMS) was used to measure side effects from medication at 6-month intervals over 2 years. Drug exposure was converted to chlorpromazine (CPZ) equivalent and the presence of risk factory for TD, such as a diagnosis of affective disorder, medication noncompliance, early age of illness onset, and concomitant antiparkinsonian medication, was also noted. RESULTS: Of the 40 cases reviewed, 2 patients (5%) met diagnostic criteria for TD, and another 5 patients (12.5%) showed symptoms of TD. CONCLUSIONS: TD is a serious risk at any age. Medication noncompliance, early age of illness onset, and concomitant use of antiparkinsonian medication may increase susceptibility to TD and should be carefully monitored.     

Risk factors for tardive dyskinesia in a large population of youths and adults.

This study was designed to identify predisposing factors for tardive dyskinesia (TD) in youths and adults within a large, predominantly developmentally disabled and mentally ill population. The findings support previously reported risk factors for TD, including increasing age, use of anticholinergic medication for those over 40 years old, and long duration of neuroleptic exposure for those over 18 years of age. Higher cumulative levels of "typical" neuroleptic dosage decreased the risk for TD for those over 18. Novel findings included the benefit of personality disorder in individuals 18 to 40 years old and the strong risk factor of profound mental retardation in all age groups. These findings reveal further complex interactions to the risk factors for TD. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Carbamazepine reduces dopamine-mediated behavior in chronic neuroleptic-treated and untreated rats: Implications for treatment of tardive dyskinesia and hyperdopaminergic states.

Chronic treatment with neuroleptic drugs such as haloperidol (HAL) can result in a syndrome of abnormal involuntary movements known as tardive dyskinesia (TD). The authors have obtained evidence that TD in humans is reduced in patients also taking anticonvulsant drugs, primarily carbamazepine (CBZ). To test for a causal role of CBZ in this effect, the authors quantified abnormal movements elicited by dopamine (DA) receptor stimulation in rats (Rattus norvegicus) withdrawn from chronic treatment with HAL or CBZ alone or in combination. The expected increased behavioral responsiveness to combined D1/D2 stimulation in rats treated with HAL for 8 weeks was significantly attenuated by chronic CBZ, which also attenuated behavioral responsiveness in otherwise untreated rats. Striatal D2 DA receptor density was elevated in rats treated chronically with HAL but unaffected by CBZ. Striatal D1 DA receptor density was elevated by chronic CBZ but unaffected by HAL. These findings suggest that by reducing DA supersensitivity, CBZ may be useful in treating TD and other hyperdopaminergic states. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Low superoxide dismutase activity in schizophrenic patients with tardive dyskinesia

BACKGROUND: Tardive dyskinesia (TD) is a therapy-resistant adverse effect of neuroleptics. Although the exact pathophysiology of TD is unknown, oxygen radicals have been speculated to play a role in TD based on several lines of evidence. Superoxide dismutase (SOD) is a key enzyme which scavenges oxygen radicals. The authors investigated the association between erythrocyte SOD activity and TD. METHODS: Erythrocyte SOD activities were measured, blinded as to the presence or absence of TD. In 30 patients with schizophrenia who had been on typical neuroleptics for more than 10 years. TD severity was independently assessed, using the abnormal involuntary movement scale (AIMS), by two raters. RESULTS: There was a significant decrease in erythrocyte SOD activity in the definite TD group (N = 10) as compared with the no TD (N = 8) and questionable TD (N = 12) groups. Erythrocyte Cu,Zn-SOD activities correlated with AIMS scores. CONCLUSIONS: Patients with TD had low SOD activities as compared to those without TD. As a causal link between SOD activity and TD was not established in this study, larger prospective studies are warranted to determine whether patients with low SOD activity are susceptible to neuroleptic-induced TD.     

Intermittent neuroleptic treatment and risk for tardive dyskinesia: Cura?ao Extrapyramidal Syndromes Study III

OBJECTIVE: The authors examined the association between three lifetime medication variables (cumulative amount of neuroleptics, number of interruptions in neuroleptic treatment, cumulative amount of anticholinergics) and the occurrence and severity of tardive dyskinesia. METHOD: The study was conducted in the only psychiatric hospital of a well-defined catchment area (the Netherlands Antilles). For all patients who had a history of taking neuroleptics for at least 3 months and were currently using neuroleptics (N = 133, mean age = 51.5 years), the presence and severity of tardive dyskinesia were measured with the Abnormal Involuntary Movement Scale. RESULTS: Of the three lifetime medication variables, only the number of neuroleptic interruptions was significantly related to tardive dyskinesia. The risk of tardive dyskinesia was three times as great for patients with more than two neuroleptic interruptions as for patients with two or fewer interruptions. CONCLUSIONS: This finding supports the schizophrenia protocol of long-term neuroleptic treatment rather than targeted or intermittent neuroleptic treatment.     

The effect of clozapine on preexisting tardive dyskinesia

Since the 1950s, the main treatment for schizophrenia has been the use of neuroleptic therapy. However, these medications may produce tardive dyskinesia in those patients who require prolonged neuroleptic treatment. With the advent of clozapine, patients with preexisting tardive dyskinesia began therapy and their symptoms did not worsen--and, in many cases, their symptoms improved dramatically. In this study, the mean Abnormal Involuntary Movement Scale (AIMS) scores from baseline to 6 months are compared for 12 patients in a private partial hospitalization program for schizophrenia. The findings reveal a drastic decrease in AIMS scores after 1 month of clozapine therapy and a steady decrease in scores throughout the 6 months of analysis.     

Incidence of tardive dyskinesia in early stages of low-dose treatment with typical neuroleptics in older patients

OBJECTIVE: The authors studied the risk of tardive dyskinesia for older patients in the early stages of treatment with typical neuroleptics. METHOD: They examined the cumulative incidence of tardive dyskinesia 1, 3, 6, 9, and 12 months after the institution of neuroleptic therapy among 307 psychiatric outpatients over age 45. The patients' median dose was 68.4 mg/day of chlorpromazine equivalent. RESULTS: In the patients who had never received neuroleptics at baseline (N = 87), the mean cumulative incidence of tardive dyskinesia was 3.4% and 5.9% at 1 and 3 months, respectively. There was no significant difference in the 12-month cumulative incidence of tardive dyskinesia among patients who had been neuroleptic-naive at baseline (22.3%) and the 89 patients who had received neuroleptics before baseline for 1-30 days (24.6%); however, the 131 patients who had received neuroleptics before baseline for more than 30 days tended to have a greater cumulative 12-month incidence of tardive dyskinesia (36.9%). CONCLUSIONS: The risk of tardive dyskinesia in older outpatients is high, even with relatively short treatment with low doses of conventional neuroleptics.     

Spontaneous abnormal involuntary movements in first-episode schizophrenia and schizophreniform disorder: baseline rate in a group of patients from an Irish catchment area

OBJECTIVE: This study investigated the rate of spontaneous abnormal involuntary movements in a group of patients presenting with a first episode of schizophrenia or schizophreniform psychosis. METHOD: Seventy-nine patients with a first episode of schizophrenia or schizophreniform psychosis who presented to a catchment area psychiatric service over a 3-year period, and who were neuroleptic-naive or had been medicated for less than 1 month, were examined for the presence of involuntary movements with use of the Abnormal Involuntary Movement Scale. RESULTS: Six patients (7.6%) had spontaneous dyskinesia as defined by the criteria of Schooler and Kane, and nine other patients had mild orofacial involuntary movements. The patients with spontaneous dyskinesia had completed significantly fewer years of education than the patients without dyskinesia. Spontaneous involuntary movements were unrelated to age at presentation for treatment. CONCLUSIONS: Spontaneous abnormal involuntary movements were evident among a proportion of patients with first-episode schizophrenia or schizophreniform psychosis at baseline presentation and were associated with reduced educational attainment. This finding supports previous suggestions that abnormal involuntary movements in schizophrenia may be related to the pathophysiology of the illness and therefore cannot be attributed entirely to the adverse effects of neuroleptic medication.     

Calcium stores in cultured fibroblasts and their changes with Alzheimer''s disease

Digital movement analysis (DMA) is a new instrumental approach to assessing oral tardive dyskinesia (TD) by means of digital image processing of a video signal, tracking five paper dots placed around the patient's mouth. A total of 40 schizophrenic patients, 30 with and 10 without TD, were examined twice (with a 3-month interval) with this new device. The patients were further examined with two TD rating scales: the St. Hans Rating Scale for extrapyramidal syndromes (SHRS) and the Abnormal Involuntary Movement Scale (AIMS). The schizophrenic patients accepted the instrumental assessment without any anxiety or resistance. The internal reliability of the apparatus was high, with correlation coefficients of 0.80-0.99. The DMA TD values correlated with the SHRS and AIMS scores with correlation coefficients of 0.48-0.73 indicating an acceptable, although not strong, concurrent validity. Fluctuations occurred from the first to the second examination independent of medication. For these fluctuations no correlation was found between DMA values and rating scores. Finally, the DMA device was able to detect perioral tremor as a sign of parkinsonism. It has been concluded that DMA is a useful supplement to classical TD rating, although further validity evaluation is warranted.     

Environmental ways forward in a postmodern (nursing) world

Anticholinergic treatment of neuroleptic extrapyramidal movement disorders (EPS) has been associated with induction of tardive dyskinesia. Also an increasing abuse of anticholinergics by schizophrenic patients is noted. Since as early as 1976, positive effects of amantadine (AMA) on neuroleptic EPS have been described, therefore a controlled study of these reports seemed worthwhile. Forty-two schizophrenic patients (of which 7 were dropouts) of three centers entered the study and were treated for EPS in a double-blind design: 18 (11 m, 7 f) with AMA and 17 (8 m, 9 f) with biperiden (BIP). Identical preparations of AMA 100 mg, tid) and BIP (2 mg, tid) were used in treatment of haloperidol-induced EPS (AMA, mean 22.4 mg haloperidol; BIP, mean 19.6 mg haloperidol). Effects of treatment and possible side effects were rated: EPS for the intensity of EPS, BPRS for quantification of psychotic symptoms, FSUCL for rating the side effects and KUSTA to document patients' mood. Ratings were recorded on days 0, 3, 7, 14, 28 and at discontinuation, respectively. All patients were treated with haloperidol and levomepromazine (for tranquilization/sleep induction) and the respective antiparkinsonian agent for 14 days. Patient characteristics did not differ significantly in either groups. In the AMA treatment group, 2 patients dropped out for noncompliance, in the BIP group, 5 (3 no effect, 1 noncompliance, 1 agitation). All results as recorded with the different rating instruments showed a significant (p < 0.01) overall improvement, whereas no significant differences between treatment groups could be determined, notably the treatment effect of both drugs on EPS was similar. Thus, the application of AMA in cases of neuroleptic EPS seems justified and is a useful alternative of anticholinergic drugs. Certain advantageous aspects of AMA treatment of EPS with regard to the glutamate hypothesis of schizophrenia and tardive dyskinesia are discussed.     

Akathisia in adults with mental retardation: development of the Akathisia Ratings of Movement Scale (ARMS)

We developed an akathisia rating scale for use with persons who have mental retardation and screened for the occurrence of akathisia in three samples: 66 adults receiving maintenance neuroleptic treatment, 20 adults not receiving neuroleptics, and 8 adults undergoing neuroleptic dose reduction. The scale had an acceptable level of interrater reliability and validly measured group differences related to neuroleptic treatment status. Using an empirically derived cut-off-score, we estimated the prevalence rate for akathisia to be 5% in neuroleptic-free subjects, 17% in neuroleptic-maintenance subjects, and 25% in neuroleptic-reduction subjects. Akathisia, dyskinesia, and stereotypy manifested as qualitatively different movement topograhies. The occurrence of dyskinesia stereotyped movement disorder was associated significantly with an increased occurrence of akathisia.     

Electrophoretic mobility of five polypeptides using nine different capillary chemistries over the pH range of 3.5-6.5

Clozapine has been shown to have superior effectiveness compared with classic neuroleptics in treating refractory schizophrenia in Caucasians, but its efficacy and safety in Chinese have not been adequately studied. Forty Chinese schizophrenic patients were recruited in a 12-week, double-blind, comparative trial. Twenty-one patients were randomly assigned to clozapine treatment and 19 to chlorpromazine treatment. The average dose was 543 +/- 157 and 1163 +/- 228 mg/day for clozapine and chlorpromazine, respectively. The results showed that six clozapine-treated patients (28.6%) had more than 20% improvement in Brief Psychiatric Rating Scale score and were classified as responders, whereas none of the chlorpromazine-treated patients was classified as a responder. The degree of improvement in positive symptoms, negative symptoms and Brief Psychiatric Rating Scale scores in the clozapine group was inversely correlated with the severity of negative symptoms at entry into the trial. Two clozapine-treated patients were withdrawn from the study, one because of leukopenia and nausea, and the other because of vomiting and hypotension. Chlorpromazine treatment was prematurely discontinued in two patients, because of jaundice and over sedation in one, and because of severe weight loss in the other (9 kg). The rate of moderate-to-severe sialorrhea was high in clozapine-treated patients (28.6%). Two clozapine-treated patients and two chlorpromazine-treated patients showed significant improvement in previously existing tardive dyskinesia and one chlorpromazine-treated patient exhibited aggravation of tardive dyskinesia. The results of this study indicate that clozapine treatment might have advantages over chlorpromazine for Chinese schizophrenic patients who are refractory to typical neuroleptic treatment.     

Blind, controlled, long-term study of the comparative incidence of treatment-emergent tardive dyskinesia with olanzapine or haloperidol

OBJECTIVE: Tardive dyskinesia is a serious and common complication of neuroleptic treatment. Olanzapine is a novel antipsychotic agent exhibiting regional mesolimbic dopaminergic selectivity and a broad-based pharmacology encompassing serotonin, dopamine, muscarinic, and adrenergic receptor binding affinities. The authors' goal was to compare the incidence of tardive dyskinesia among patients receiving olanzapine and those receiving the conventional dopamine 2 antagonist haloperidol. METHOD: Data were analyzed from three actively controlled and blind long-term responder studies of subjects meeting DSM-III-R criteria for schizophrenia, schizophreniform disorder, or schizoaffective disorder treated with olanzapine (N = 707, up to 20 mg/day, 237 median days of exposure) or haloperidol (N = 197, up to 20 mg/day, 203 median days of exposure) who did not have evidence of tardive dyskinesia at baseline. All of the subjects had a chronic disease course (mean greater than 10 years), and there were no significant between-treatment group differences in demographic or disease characteristics. The Abnormal Involuntary Movement Scale and research diagnostic criteria for tardive dyskinesia were used to define the comparative incidence rates of long-term treatment-emergent tardive dyskinesia. RESULTS: The incidence of newly emergent tardive dyskinesia at any visit after baseline, at the final visit, and at the final two clinical assessments was statistically significantly lower among olanzapine-treated patients than among haloperidol-treated patients. CONCLUSIONS: These findings support an atypical extrapyramidal symptom profile and the potential of a significantly lower risk of tardive dyskinesia with olanzapine than with haloperidol among patients requiring maintenance antipsychotic treatment.     

Levels of engagement in hospital and community-based homes for people with learning disabilities: can individual characteristics account for differences?

BACKGROUND: There is controversy over whether tardive dyskinesia (TD) is solely a consequence of antipsychotic drug treatment or in part may reflect an intrinsic aspect of the disease process. Pathophysiologic factors could, independently or in concert with drug effects, lead to the development of dyskinetic signs. METHODS: We studied prospectively 118 patients in their first episode of psychosis who were treatment-naive or had less than 12 weeks of antipsychotic drug exposure at study entry. Patients received standardized antipsychotic drug treatment and were evaluated for up to 8 1/2 years with regular assessments of psychopathologic signs and symptoms and side effects. RESULTS: The cumulative incidence of presumptive TD was 6.3% after 1 year of follow-up, 11.5% after 2 years, 13.7% after 3 years, and 17.5% after 4 years. Persistent TD had a cumulative incidence of 4.8% after 1 year, 7.2% after 2 years, and 15.6% after 4 years. Taken individually, both antipsychotic drug dose, entered as a time-dependent covariate, and poor response to treatment of the first psychotic episode were significant predicters of time to TD. When antipsychotic drug dose and treatment response were examined together, treatment responders had significantly lower hazards for presumptive TD than nonresponders (hazard ratio, 0.29; 95% confidence interval, 0.09 to 0.97). Dose was a trend-level predicter, with each 100-mg chlorpromazine equivalent unit increase in dose associated with a 5% increase in the hazard of presumptive TD (hazard ratio, 1.05; 95% confidence interval, 0.99 to 1.11). CONCLUSION: Poor response to the treatment of a first episode of psychosis and, to a lesser extent, antipsychotic drug dose are important factors in the development of TD. This suggests that there may be a disease-related vulnerability to TD manifest with antipsychotic drug exposure. Potential pathophysiologic factors might include neurodevelopmentally induced structural neuropathologic characteristics, sensitization of nigrostriatal dopamine neurons, and the induction of glutamatergically mediated neurotoxic effects.