Failure to down regulate NMDA receptors in the striatum and nucleus accumbens associated with neuroleptic-induced dyskinesia

The syndrome of vacuous chewing movements (VCMs) in rats is similar in many respects to tardive dyskinesia (TD) in humans. Both syndromes are characterized by delayed onset of persistent orofacial dyskinesias in a sub-group of subjects chronically treated with neuroleptics. Using the rat model, we examined the role of NMDA receptor-mediated corticostriatal neurotransmission in the expression of VCMs. Rats were treated for 36 weeks with haloperidol decanoate or vehicle and then withdrawn for an additional 28 weeks. Chronic persistent VCMs were induced in one subgroup of treated animals (+VCM), but not in another group (-VCM). Rats from +VCM, -VCM groups and vehicle-treated controls were selected for post mortem studies (n = 12 to 14 per group). NMDA receptor levels were assessed using [3H]-MK-801 binding in sections from the mid-striatum and nucleus accumbens. Chronic haloperidol treatment produced a marked reduction of NMDA receptor binding levels throughout the striatum and nucleus accumbens. Post hoc comparisons demonstrated that -VCM rats had lower NMDA receptor binding levels than +VCM and vehicle-treated controls. Ventromedial striatum and nucleus accumbens core were the most affected areas. These findings suggest that down-regulation of striatal NMDA receptor binding levels may protect against the expression of neuroleptic-induced dyskinesia.     

Effects of dopamine agonists in tardive dyskinesia

The authors used a combined behavioral and neuroendocrinological strategy to investigate the relevance of abnormalities in the brain dopaminergic systems to the pathophysiology of tardive dyskinesia by assessing the effects of apomorphine, a directly acting dopamine agonist, and d-amphetamine, an indirectly acting dopamine agonist, in patients with tardive dyskinesia. Administration of I.V. d-amphetamine increased dyskinetic movements in most patients with tardive dyskinesia, a finding consistent with the dopaminergic hypothesis. Contrary to predictions based on animal models, apomorphine did not increase dyskinetic movements in these patients but instead substantially reduced dyskinesia in some patients. Patients with tardive dyskinesia did not have a greater drop in serum prolactin or a greater rise in serum growth hormone after apomorphine than normal or chronic schizophrenic subjects without tardive dyskinesia.     

Factors for progression of periodontal diseases

Tardive dyskinesia is an involuntary movement disorder developing following treatment with neuroleptics. As many as 50% of chronic psychotic patients develop this disabling condition. No treatment has been found effective for tardive dyskinesia. This study was undertaken to meta-analyze the effects of vitamin E (alpha-tocopherol) reported in the last decade. All studies published since 1987, focusing on vitamin E and tardive dyskinesia are reviewed. Double-blind studies are analyzed using measures of effect and variance as described by secondary analysis of magnitude of effects in pooled data. A total of 223 patients received vitamin E treatment (400-1600 IU/day) for tardive dyskinesia, in 12 studies. A significant subgroup (28.3%) showed a modest improvement. Vitamin E was well tolerated, and only rarely did side effects occur-of no clinical significance. Vitamin E is a safe, well-tolerated compound that may provide some beneficial effects in patients suffering from neuroleptic-induced tardive dyskinesia.     

Assessment of accelerography with the TOF-GUARD: a comparison with electromyography

The effects of age were studied on a new animal model of tardive dyskinesia, i.e., the quantification of oral dyskinesia in rats repeatedly treated with reserpine. Adult and old rats received two injections of reserpine (0.5 or 1.0 mg/kg s.c.) or vehicle, separated by 48 h. One, 10, 25 and 40 days after the second injection of reserpine or vehicle, the animals were observed for quantification of the behavioral parameters of oral dyskinesia: tongue protrusion and vacuous chewing movement frequencies and duration of twitching of the facial musculature. Phenomenologically, control old rats and reserpine-treated adult animals showed very similar oral dyskinesia. When compared to control adult rats, the significant increase in tongue protrusion frequency induced by reserpine treatment was more persistent in the old rats than in the adult animals. Because it is well known that age increases the persistence of tardive dyskinesia, our data provide further support for the validation of reserpine-induced oral dyskinesia as an animal model of tardive dyskinesia. In addition, the possibility is raised that a common pathophysiological mechanism may underlie tardive dyskinesia and age- and reserpine-induced oral dyskinesia.     

Vitamin E in the treatment of tardive dyskinesia: a preliminary study over 7 months at different doses

Vitamin E has been suggested to be a promising new treatment for tardive dyskinesia. However, little is known about the optimum dose. Twenty patients with tardive dyskinesia whose medication had been unchanged for at least 1 month were selected and randomly divided into a treatment group with 11 patients and a control group with nine patients. The treatment group was started on 600 mg of vitamin E per day, and this dose was increased over the 7 months of the trial to 1600 mg per day. The medication for the control group was unchanged. Severity of tardive dyskinesia was rated on the Abnormal Involuntary Movement Scale. Patients in the treatment group initially showed a significant response to the lower dose of 600 mg per day. However, this improvement was not maintained and differences between the two groups reached significant levels only after the dose of vitamin E was increased to 1600 mg per day. At this dose, there was a significant and sustained reduction in the severity of tardive dyskinesia. The results suggest that vitamin E is of value in the treatment of tardive dyskinesia and that the optimum dose for treating tardive dyskinesia is 1600 mg per day. In addition, there may be a dose related therapeutic effect of Vitamin E in tardive dyskinesia.     

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.     

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.     

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.     

Effectiveness of vitamin E for treatment of long-term tardive dyskinesia

Eleven patients with tardive dyskinesia were treated in a double-blind study of vitamin E or placebo for 12 weeks. Abnormal Involuntary Movement Scale (AIMS) ratings were performed before and after treatment. Patients receiving vitamin E showed a significant reduction in their AIMS scale score, but patients receiving placebo showed no significant change. Vitamin E had a helpful effect even for patients whose tardive dyskinesia was mild and long-term.     

Tardive dyskinesia in dopa-responsive dystonia: a reappraisal of the dopamine hypothesis of tardive dyskinesia

Dopa-responsive dystonia, an autosomal-dominant disorder caused by mutations in the guanosine triphosphate (GTP)-cyclohydrolase I gene, is characterized by severe striatal dopamine depletion. Tardive dyskinesia, on the other hand, has often been associated with striatal dopamine overactivity. This article reports on a 44-year-old man with dopa-responsive dystonia who developed tardive dyskinesia on long-term haloperidol therapy. Nigrostriatal dopamine deficiency may be necessary for the development of tardive dyskinesia.     

Oral Dyskinesias and striatal lesions in rats after long-term co-treatment with haloperidol and 3-nitropropionic acid

The pathophysiologic basis of tardive dyskinesia remains unclear. It has been proposed that tardive dyskinesia may be a result of excitotoxic neurodegeneration in the striatum caused by a neuroleptic-induced increase in striatal glutamate release and impaired energy metabolism. To investigate this hypothesis, haloperidol decanoate (38 mg/kg/four weeks intramuscularly) and the succinate dehydrogenase inhibitor 3-nitropropionic acid (8 mg/kg/day via subcutaneous osmotic mini-pumps), were administered alone or together for 16 weeks to four-months-old rats. Control rats received sesame oil intramuscularly and had empty plastic tubes subcutaneously. Vacuous chewing movements, a putative analogue to human tardive dyskinesia, were recorded during and after drug treatment. Haloperidol alone, 3-nitropropionic acid alone, and 3-nitropropionic acid+haloperidol treatments induced an increase in vacuous chewing movements. However, vacuous chewing movements were more pronounced and appeared earlier in rats treated with 3-nitropropionic acid+haloperidol. After drug withdrawal, increases in vacuous chewing movements persisted for 16 weeks in the haloperidol alone and 3-nitropropionic acid+haloperidol group and for four weeks in the 3-nitropropionic acid alone group. Brains from each group were analysed for histopathological alterations. Bilateral striatal lesions were present only in rats with high levels of vacuous chewing movements in the 3-nitropropionic acid+haloperidol-treated rats. Nerve cell depletion and astrogliosis were prominent histopathologic features. There was selective neuronal sparing of both large- and medium-sized aspiny striatal neurons. These results suggest that mild mitochondrial impairment in combination with neuroleptics results in striatal excitotoxic neurodegeneration which may underlie the development of persistent vacuous chewing movements in rats and possibly irreversible tardive dyskinesia in humans.     

Neuroleptic-induced acute extrapyramidal syndromes and tardive dyskinesia

Neuroleptic drug-induced acute extrapyramidal symptoms and later-onset tardive dyskinesia are major limitations to these valuable drugs. Each of these disorders can be described by special risk factors that include patient characteristics, drug factors, and temporal considerations. The limitations that derive from these motor side effects have been one of the major reasons propelling the search for neuroleptic drugs that are free of these side effects. Strategies for managing the acute and late-onset extrapyramidal syndromes are presented. Significantly more research is needed, however, on all these disorders before a unified and cohesive explanation can account for these seemingly disparate syndromes. New medications, which effectively treat schizophrenia and are free of acute extrapyramidal syndromes and tardive dyskinesia, will be a giant step forward in patient care and our knowledge of the mechanisms controlling both mental function and motor control.     

In vivo analysis of hydrogen peroxide and lipid radicals in the striatum of rats under long-term administration of a neuroleptic

It has been hypothesized that free radicals play a causative role in tardive dyskinesia, which is an inveterate movement disorder caused by chronic administration of neuroleptics. To verify this hypothesis, rats were reared while being regularly treated with water containing a neuroleptic, haloperidol (HPD), for 1 year (HPD group). The changes in the striatal hydrogen peroxide content of the rats in the HPD and control groups were measured by using a Pt-disk microelectrode while the animals were in a freely moving state following intraperitoneal administration of HPD (HPD challenge). We also performed electron spin resonance (ESR) detection of lipid radicals in the striatum before the HPD challenge. HPD challenge led to significant elevation of the intrastriatal hydrogen peroxide in all animals, but the elevation in the HPD group was smaller than that in the control group. However, in the HPD group, marked ESR signals of intrastriatal lipid radicals were observed. We think that these results support the hypothesis on the role of free radicals in tardive dyskinesia.     

Effects of monosialoganglioside on a new model of tardive dyskinesia

1- The effects of monosialoganglioside GM1 were studied on a new model of tardive dyskinesia, i.e., the frequency of spontaneous tongue protrusions in rats repeatedly treated with reserpine. 2- Rats were co-treated with vehicle (VEH) or reserpine (RES) (0.1 mg/kg, s.c., every other day) and saline (SAL) or GM1 (5 mg/kg, i.p., every day) for 30 days and observed for tongue protrusions on days 10, 20 and 30. 3- During each test day animals of the RES + SAL group exhibited an increase in tongue protrusions relative to rats of the VEH + SAL group. However, rats of the RES + GM1 group showed an increased frequency of tongue protrusions only on day 10, when compared to animals of the VEH + SAL group. There were no significant differences in tongue protrusion frequency between the VEH + GM1 and the VEH + SAL groups. 4- These results differ from previous studies which reported a facilitatory effect of GM1 co-administration on conventional behavioral animal models of tardive dyskinesia. The possibility is raised that GM1 attenuates the reserpine-induced increase in tongue protrusions through its protective effect on glutamate/oxidative stress neurotoxicity.     

Burns in a suicide attempt related to psychiatric side effects of interferon

Tardive dystonia is one of the most serious adverse events of typical neuroleptic treatments. They differ from tardive dyskinesia by their clinical and evolutive features. The occurrence of tardive dystonia due to new antipsychotics remained unknown. For the first time in the literature, we report a case of typical tardive dystonia occurring in a young male schizophrenic patient treated for 8 months with risperidone. No remission was observed despite several therapeutics including botulinic toxin.     

Vitamin E attenuates the development of haloperidol-induced dopaminergic hypersensitivity in rats: possible implications for tardive dyskinesia

Chronic haloperidol treatment in rats results in behavioural supersensitivity to dopamine agonists. This mechanism has been suggested as a possible animal model for tardive dyskinesia. In the present study the simultaneous administration of vitamin E to chronic haloperidol treatment in rats prevented the development of behavioural supersensitivity to apomorphine. This finding suggest that the concomitant administration of vitamin E to neuroleptics might prevent the development of tardive dyskinesia in humans.     

Lithium attenuates dopamine depleting effects of reserpine and tetrabenazine but not that of alpha methyl-p-tyrosine

Concurrent administration of lithium (Li) significantly attenuates the dopamine (DA) depleting effects of reserpine and tetrabenazine, but does not change alpha-methyl-p-tyrosine (AMPT) induced DA depletion in rat brain. This effect of Li is probably mediated, in part, by inhibiting the magnesium-dependent binding of both reserpine and tetrabenazine to their specific receptor sites. Such interaction between these drugs may attenuate the beneficial effects of tetrabenazine and reserpine on patients with tardive dyskinesia or tardive dystonia who are treated concurrently with lithium for their psychiatric disorder.     

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.     

The prevention of tardive dyskinesia

The publication of numerous articles on tardive dyskinesia has had little effect on the excessive use of neurolepic drugs in psychiatric populations. If current prescribing patterns are not drastically changed, larger numbers of patients will be afflicted by conspicuous, sometimes disabling neurological side effects. The risk of permanent neurological disorder can be minimized by monitoring side effects and systematically reducing drug doses in hospitals, outpatient centers, and private practice. However, one should not underestimate the difficulty in implementing such a program in facilities that rely heavily on chemotherapy.