Remoxipride,a selective dopamine D2 receptor antagonist,in tardive dyskinesia

Remoxipride in a dose range of 150–600 mg/day was evaluated in a single-blind placebo controlled study in eight patients with persistent tardive dyskinesia (TD). Dyskinesia score was significantly reduced without an increase in parkinsonism. The maximum mean reduction in dyskinesia rating score was 44%. After withdrawal of remoxipride TD scores returned to baseline levels without rebound deterioration. A negative correlation between remoxipride concentrations and the dyskinesia scores were found. Adverse effects were few and mild and no clinically relevant changes were seen in clinical chemistry, haematology or cardiovascular assessments. It is concluded that remoxipride in the dose range used has anti-dyskinetic effects but does not induce parkinsonism. Offprint requests to: U. Andersson     

Predictors of neuroleptic-induced dyskinesia and parkinsonism: the influence of measurement methods and definitions

The accurate and objective measurement of abnormal, involuntary movements remains highly desirable, whether the movements are secondary to pharmacotherapy or an expression of the primary illness. In a previous study, we found that the prevalence of tardive dyskinesia in a sample of 100 subjects ranged from 28% when using the Abnormal Involuntary Movement Scale (AIMS) or the Dyskinesia Identification Scale, Condensed User Version (DISCUS) to 62% using an instrumental measurement (IM) of peripheral dyskinesia. The goal of this study was to examine the relationship between various risk factors for tardive dyskinesia as predictor variables, and the AIMS, DISCUS, and IMs of dyskinesia, tremor, and velocity of motor movement as dependent variables. The sample consisted of 100, mostly patients with schizophrenia. Poor performance on the Mini-Mental State Examination (MMSE) and increasing age were the most consistent predictors of dyskinetic and parkinsonian movements. Various predictors were associated with specific abnormal movements. Head injury was related to slower speed of motor movements and the total DISCUS score. A history of smoking was associated with less IM dyskinesia. For those with coexisting parkinsonism and dyskinesia, significant associations were found with head injury, diabetes mellitus, and an AIMS score of 2 or greater in 2 body areas. Various classes of psychotropic agents seemed to have little influence on the MMSE or the development of dyskinesia and parkinsonism. Increasing age and a lower score on the MMSE seem to be particularly helpful in gauging the risk for parkinsonian and dyskinetic movements.     

Dopamine transporter density in patients with tardive dyskinesia: a single photon emission computed tomography study

RATIONALE: Tardive dyskinesia occurs frequently in schizophrenic patients chronically treated with classical antipsychotic medication. It may be caused by loss of dopaminergic cells, due to free radicals as a product of high synaptic dopamine levels. OBJECTIVE: To evaluate dopamine transporter density in the striatum in patients with tardive dyskinesia. METHODS: Striatal [123I]FP-CIT binding was measured with SPECT in seven schizophrenic patients with tardive dyskinesia and eight healthy controls. RESULTS: No significant difference was found between striatal [123I]FP-CIT binding ratios in patients with tardive dyskinesia and controls. CONCLUSIONS: This preliminary study indicates no change in striatal dopamine transporter density in schizophrenic patients with tardive dyskinesia. This finding does not support the hypothesis that tardive dyskinesia is caused by dopaminergic cell loss.     

Relationship between tardive dyskinesia,l-Dopa-induced hyperkinesia and parkinsonism

In a study of 16 psychotic patients with neuroleptic-induced tardive dyskinesia and 16 patients with Parkinson's disease and l-Dopa-induced hyperkinesia kinesia it was found that (1) tardive dyskinesia, compared to l-Dopa hyperkinesia, was localized almost exclusively to the oral region (P<0.01), whereas the l-Dopa hyperkinesia was more pronounced in the neck (P<0.05) and the extremities (P<0.05); (2) l-Dopa hyperkinesia showed an increasing tendency to oral preponderance with age, irrespective of the severity of parkinsonism and extra-oral hyperkinesia, while tardive dyskinesia only itensified with age, without any change in distribution; and (3) extraoral l-Dopa hyperkinesia was related to the localization and severity of pretreatment parkinsonism, and more to bradykinesia than to rigidity and tremor. It is concluded that the irreversible neurotoxic effect of neuroleptic drugs may be associated with agerelated changes in the oral somatotopic region of the basal ganglia (to be given consideration in any future search for the pathogenetic process underlying irreversible tardive dyskinesia), and that the pathophysiology of involuntary hyperkinesia in neuroleptic-treated psychiatric patients and in l-Dopatreated Parkinson patients may consist of a primary dopamine deficiency (pharmacological or structural), and a secondary relative hyperactivity in the dopaminergic system (dopaminergic hypersensitivity) possibly corresponding to hypoactivity in the cholinergic system.     

Serotonin precursor effects in tardive dyskinesia

In an attempt to determine the role of serotoninergic mechanisms in the pathophysiology of tardive dyskinesia, the serotonin precursor 5-hydroxytryptophan (5HTP) with carbidopa, a peripheral decarboxylase inhibitor, were given in a double-blind crossover design to seven patients with longstanding tardive dyskinesia. In the five patients who completed the study, there was no change in dyskinetic movements. Most of the patients had worsening of psychotic symptoms with 5HTP. The data suggest that serotonin precursors have no therapeutic effects in tardive dyskinesia. The implications for the role of serotonin in the pathophysiology of tardive dyskinesia are discussed.Supported by the Veterans Administration and the University of Iowa Clinical Research Center     

Ineffectiveness of deanol in tardive dyskinesia: A placebo controlled study

In a double-blind placebo-controlled study, deanol acetamidobenzoate, administered in doses up to 1.5 g q.d. for three weeks to chronic schizophrenic patients presenting moderate to severe tardive dyskinesia, failed to alleviate the dyskinetic movements. However, there was a tendency for a significant increase in the schizophrenic symptoms of the deanol-treated group relative to the control group. The ineffectiveness of deanol in alleviating tardive dyskinesia is consistent with its inability to enhance brain acetylcholine synthesis. The worsening of the schizophrenic symptoms may possibly result, from an interference by deanol with central cholinergic function.     

Effect of co-dergocrine mesylate on tardive dyskinesia a preliminary report

Twenty patients with signs of tardive dyskinesia secondary to antipsychotic medication participated in a double blind, controlled, parallel group study comparing codergocrine mesylate 4.5 mg once daily with a placebo. After 6 weeks medication a reduction in dyskinetic scores occurred in both groups, but at the end of a further 6-week period the patients on active treatment maintained their improvement while those on placebo did not. This may be due to a slow onset of action and a hangover of activity associated with the drug.     

Oxidative mechanisms and tardive dyskinesia

Tardive dyskinesia has been and continues to be a significant problem associated with long-term antipsychotic use, but its pathophysiology remains unclear. In the last 10 years, preclinical studies of the administration of antipsychotics to animals, as well as clinical studies of oxidative processes in patients given antipsychotic medications, with and without tardive dyskinesia, have continued to support the possibility that neurotoxic free radical production may be an important consequence of antipsychotic treatment, and that such production may relate to the development of dyskinetic phenomena. In line with this hypothesis, evidence has accumulated for the efficacy of antioxidants, primarily vitamin E (alpha-tocopherol), in the treatment and prevention of tardive dyskinesia. Early studies suggested a modest effect of vitamin E treatment on existing tardive dyskinesia, but later studies did not demonstrate a significant effect. Because evidence has continued to accumulate for increased oxidative damage from antipsychotic medications, but less so for the effectiveness of vitamin E, especially in cases of long-standing tardive dyskinesia, alternative antioxidant approaches to the condition may be warranted. These approaches may include the use of antioxidants as a preventive measure for tardive dyskinesia or the use of other antioxidants or neuroprotective drugs, such as melatonin, for established tardive dyskinesia.     

Clinical rating scales and instruments: how do they compare in assessing abnormal, involuntary movements?

OBJECTIVE: Recent studies have shown that quantitative instrumental measurements are more sensitive than clinical rating scales to subclinical dyskinesia and parkinsonism. We therefore hypothesized that an instrumental assessment would be more sensitive to the presence of dyskinetic and parkinsonian movements than the Abnormal Involuntary Movement Scale (AIMS), the Dyskinesia Identification Scale, Condensed User Version (DISCUS), and the Simpson-Angus Scale (SAS). We also hypothesized that the DISCUS, by virtue of its more detailed protocol, would be more sensitive than the AIMS. METHOD: Using blinded raters, we compared the clinical rating scales with instrumental measurements in 100 patients referred to a movement disorders clinic. We collected demographic data, risk factors for tardive dyskinesia, current medication use, Axis I and III disorders, and an estimate of cognitive functioning using the Mini-Mental Status Examination. RESULTS: There was no significant difference between the AIM and the DISCUS in the identification of dyskinesia. However, an instrumental assessment revealed a significantly greater prevalence of dyskinesia. The Mini-Mental Status Examination was the most prominent predictor of both instrumental and clinical measurements of parkinsonian and dyskinetic movements. CONCLUSIONS: It appears that even trained raters, utilizing standard rating scales, may underestimate the prevalence of some motor abnormalities. Instrumental ratings may be helpful to both the clinician and investigator, particularly when abnormal movements are not clinically obvious. The relationship between cognitive impairment and motor abnormalities remains an important area for further research.     

A clinical trial of nifedipine in schizophrenia and tardive dyskinesia.

Effects of the dihydropyridine calcium channel inhibitor nifedipine on chronic schizophrenia and tardive dyskinesia were studied in an 8-week double-blind crossover trial. Four of the ten patients had tardive dyskinesia, and three of these were not receiving neuroleptics. No effects on symptoms of chronic schizophrenia were found using Psychiatric Symptom Assessment Scale ratings. In the four patients with tardive dyskinesia, an average improvement in total Abnormal Involuntary Movement Scale scores of 57% was observed. These data suggest that dihydropyridine calcium channel inhibitors may be effective in the treatment of tardive dyskinesia in schizophrenic patients.     

Naloxone prevents and blocks the emergence of neuroleptic-mediated oral stereotypic behaviors.

A commonly used animal model for tardive dyskinesia is the oral stereotypy that is expressed by a challenge dose of a dopamine agonist after daily administration of dopamine antagonists (neuroleptics). In the first of two experiments the expression of this dopamine agonist-induced oral stereotypy was prevented by the concomitant administration of the opiate antagonist naloxone. In a second experiment, if the stereotypy was allowed to be expressed, it could be blocked by the administration of naloxone. To the extent that the effects of chronic neuroleptic treatment in rats is a model for tardive dyskinesia, the results suggest that administration of naloxone can both prevent and block the dyskinetic syndrome associated with neuroleptic use.     

Dopaminergic supersensitivity after neuroleptics: Time-course and specificity

It is known that a single dose of a neuroleptic can elicit dopaminergic supersensitivity in animals. On the other hand, the clinical syndrome of tardive dyskinesia takes many months or years to develop. To resolve this apparent discrepancy, it is possible that subclinical or latent tardive dyskinesia is fully compensated in most patients taking neuroleptics. In others, where the tardive dyskinesia is full-blown and grossly apparent, the dopaminergic supersensitivity may be decompensated. Such compensatory and decompensatory phases have been proposed earlier by Hornykiewicz (1974), in the case of Parkinson's Disease.Dopaminergic supersensivity persists for a period proportional to the length of the neuroleptic treatment. It is not yet clear whether the relation between the length of treatment and the persistence of supersensitivity holds for very long treatments but in principle the relationship might account for the persistence of tardive dyskinesia after years of neuroleptic pretreatment.     

Risperidone for pre-existing severe tardive dyskinesia: a 48-week prospective follow-up study

Atypical antipsychotics can alleviate the severity of tardive dyskinesia, but few studies have monitored their long-term effects. The present study investigated the effect of risperidone on pre-existing severe tardive dyskinesia among 40 patients with chronic schizophrenia over 48 weeks. The total Abnormal Involuntary Movement Scale (AIMS) score decreased in 35 patients (87.5%) and increased in three patients (7.5%). At the end of the 48-week trial, the mean total AIMS score decreased significantly, from 15.7+/-4.7 (baseline) to 10.6+/-4.4 (P<0.001), with a mean risperidone dosage of 3.6+/-1.5 mg/day. Twenty-three patients (57.5%) were responders with an average total AIMS score decrease of 8.0+/-2.7. Multiple logistic regression analysis controlling for age, gender, duration of illness, index hospitalization duration, risperidone dose, anticholinergic concomitant use and dystonia score change revealed that a change in the parkinsonism score was the most significant factor related to responders (odds ratio 3.476, 95% confidence interval 1.173-10.298). A significant improvement observed in tardive dyskinesia was noted at week 8, and this improvement persisted until week 48. The results show that the effect of risperidone on pre-existing tardive dyskinesia may be beneficial.     

Fluperlapine in tardive dyskinesia and parkinsonism

Fluperlapine, a new clozapine-like neuroleptic drug with weak affinity for dopamine receptors, was evaluated in a blind, placebo controlled trial in 11 patients with stable hyperkinesia (ten with tardive dyskinesia (TD) and one with spontaneous dyskinesia). Drug effects during active treatment (200–600 mg/day) and during pre- and post-treatment placebo periods were determined by scoring randomly sequenced videotapes of TD and parkinsonian symptoms recorded weekly during standardized examinations. TD score was unchanged, while parkinsonism slightly decreased (P<0.05) and eye-blinking rates increased (P<0.05). Psychiatric symptoms showed no significant changes, although positive psychotic symptoms diminished in four patients. Side effects included dizziness, sedation and constipation. The effects in movement disorders found in this study may imply that fluperlapine is less liable than traditional neuroleptics to induce acute extrapyramidal side effects and tardive dyskinesia and is particularly beneficial in the treatment of patients vulnerable to neurological side-effects.     

A monitoring test for the liability of neuroleptic drugs to induce tardive dyskinesia

Two Cebus apella monkeys with haloperidol-induced tardive dyskinesia have been studied. Substitution of chlorpromazine, thioridazine, clozapine, melperone, or fluphenazine for the daily haloperidol administration temporarily reduced the signs of tardive dyskinesia. In a monkey with low-grade symptoms, persisting for more than 100 days after with-drawal of haloperidol, neuroleptic drugs induced a typical sequence of events: first the dyskinetic movements were abolished, but 1–3 days after administration of a single dose of a neuroleptic drug there was a rebound worsening of symptoms. It was noticed that this aggravation of symptoms corresponded in magnitude and duration to the approximate liability of each compound to induce tardive dyskinesia in man. It is therefore suggested that this animal model could be used to monitor neurological side effects in neuroleptic drugs.     

Haloperidol-induced tardive dyskinesia in monkeys

In three cebus monkeys the chronic daily administration of haloperidol (0.5 mg/kg/day orally) created sedation and parkinsonism during the first 5–7 weeks. Later the animals developed signs reminiscent of acute dystonia, as seen in the clinic during treatment with neuroleptics. These signs were dose-dependent and in extreme cases included widespread tonic and clonic seizures. After 3 and 12 months, respectively, two of the cebus monkeys developed buccolingual signs (grimacing and tongue protrusion), similar to tardive dyskinesia in the clinic.The tardive dyskinesia symptoms were reduced in a dose-dependent manner after each haloperidol administration, being most pronounced in the morning before haloperidol was given. Biperiden reduced acute dystonia but reinstated signs of tardive dyskinesia, which had been abolished by haloperidol. It is suggested that cebus monkeys may provide a useful animal model for the study of neurologic long-term complications from neuroleptic drugs.     

Abnormal movements and tardive dyskinesia in smokers and nonsmokers with schizophrenia genotyped for cytochrome P450 2D6

STUDY OBJECTIVE: To investigate the relationships between cytochrome P450 (CYP) 2D6 genotype, antipsychotic drug exposure, abnormal movements and tardive dyskinesia, and cigarette smoking. DESIGN: Prospective, longitudinal study. SETTING: University mental health research center. PATIENTS: Thirty-seven patients with schizophrenia. INTERVENTION: Patients were genotyped for CYP2D6*1, *3, and *4 alleles, and data were collected on their psychiatric symptoms, cigarette smoking status, and antipsychotic drug exposure. Abnormal movements were measured using the Abnormal Involuntary Movement Scale (AIMS). Presence of tardive dyskinesia was also evaluated. MEASUREMENTS AND MAIN RESULTS: A linear regression model used the AIMS scores as the dependent variable, and genotype, sex, smoking status, and antipsychotic drug exposure as independent variables. Antipsychotic drug exposure, genotype, and cigarette smoking interaction was significant (p<0.0212) for patients with the CYP2D6*1/*3, *4 genotype. Seventy-eight percent of smokers with the CYP2D6*1/*3, *4 genotype had tardive dyskinesia compared with 20-33% of patients in other groups. CONCLUSION: Patients with a CYP2D6*3 or *4 allele may shunt antipsychotic metabolism through other pathways that are induced by cigarette smoke. This induction may result in formation of neurotoxic metabolites, leading to increased AIMS scores and a higher frequency of tardive dyskinesia compared with patients without these alleles.     

Mapping the effects of three dopamine agonists with different dyskinetogenic potential and receptor selectivity using pharmacological functional magnetic resonance imaging.

The mechanisms underlying dopamine agonist-induced dyskinesia in Parkinson's disease remain poorly understood. Similar to patients, rats with severe nigrostriatal degeneration induced by 6-hydroxydopamine are more likely to show dyskinesia during chronic treatment with unselective dopamine receptor agonists than with D2 agonists, suggesting that D1 receptor stimulation alone or in conjunction with D2 receptor stimulation increases the chances of experiencing dyskinesia. As a first step towards disclosing drug-induced brain activation in dyskinesia, we examined the effects of dopamine agonists on behavior and blood oxygenation level-dependent (BOLD) signal in the striatum and motor cortex of rats with unilateral nigrostriatal lesions. Rats were rendered dyskinetic before pharmacologic functional magnetic resonance imaging by means of a repeated treatment regime with dopamine agonists. The unselective agonist apomorphine and the selective D1/D5 agonist SKF-81297 induced strong forelimb dyskinesia (FD) and axial dystonia and increased BOLD signal in the denervated striatum. Besides, SKF-81297 produced a significant but smaller BOLD increase in the intact striatum and a symmetric bilateral increase in the motor cortex. The D2 family agonist quinpirole, which induced mild dyskinesia on chronic treatment, did not produce BOLD changes in the striatum or motor cortex. Further evidence to support an association between BOLD changes and dyskinesia comes from a direct correlation between scores of FD and magnitude of drug-induced BOLD increases in the denervated striatum and motor cortex. Our results suggest that striatal and cortical activation induced by stimulation of D1/D5 receptors has a primary role in the induction of peak dose dyskinesia in parkinsonism.     

Seroquel: behavioral effects in conventional and novel tests for atypical antipsychotic drug

Seroquel was compared to clozapine and several other antipsychotic agents in tests predictive of antipsychotic activity or extrapyramidal symptoms. In the conditioned avoidance test in squirrel monkeys as well as several paradigms using apomorphine or amphetamine-induced behavioral alterations, seroquel displayed the profile of a drug with potential antipsychotic activity. In these paradigms the potency of seroquel was somewhat less than clozapine in rodent tests, while the reverse was true in higher species, i.e. monkeys, cats. In tests designed to evaluate the propensity to induce EPS or tardive dyskinesia, for example, the production of dyskinetic reactions in haloperidol-sensitized cebus monkeys, seroquel displayed a profile similar to clozapine and disparate from typical antipsychotic drugs. In drug-naive cebus monkeys seroquel sensitized significantly fewer monkeys than haloperidol and the dyskinetic reactions were of significantly less intensity. It is anticipated that this novel antipsychotic agent will have a significantly reduced propensity to produce extrapyramidal symptoms and tardive dyskinesia than typical antipsychotics.     

Tardive dyskinesia and impaired glucose tolerance

The authors examined the role of impaired glucose metabolism in the pathophysiology of tardive dyskinesia in schizophrenic patients with and without persistent TD. Glucose tolerance and insulin levels were determined in 86 patients with persistent tardive dyskinesia and in 108 patients without tardive dyskinesia. Dyskinesias were assessed by the abnormal involuntary movement scale (AIMS) and extrapyramidal symptoms by the Simpson--Angus rating scale (SARS). Fasting blood glucose levels were significantly lower while the first and second hour glucose levels did not reveal any differences in patients with tardive dyskinesia compared with those without tardive dyskinesia. Insulin levels did not differ in these two groups. Our cross-sectional epidemiological study does not suggest hyperglycemia to be a risk factor for tardive dyskinesia. However, prospective long-term studies with multiple assessment points are needed to clarify the role of glucose metabolism in the development of tardive dyskinesia.