Choline chloride in animal models of tardive dyskinesia

Rats treated chronically with haloperidol show evidence of supersensitive dopamine receptors by increased stereotypy when challenged with apomorphine. When such animals are treated acutely with choline chloride at the time of challenge, no changes in stereotypy were observed. Chronic treatment, either during or after induction of supersensitivity, mitigated stereotypy after challenge. This model of dopaminergic supersensitivity is pertinent to the development of tardive dyskinesia in man after treatment with neuroleptic drugs. Our results with choline chloride in the animal model are consistent with their therapeutic action in tardive dyskinesia.     

Choline in tardive dyskinesia and Huntington's disease.

Eight men, 4 with tardive dyskinesia and 4 with Huntington's disease, were treated with oral doses of choline chloride up to 20 g daily for three to eight weeks. Prior to treatment, 7 of the 8 patients were tested with a graded dose of 3 mg of physostigmine salicylate, a cholinesterase inhibitor. Six of these 7 patients had a favorable acute response to physostigmine. The same six patients had a favorable response to chronic treatment with choline chloride. Relapses following a switch from active treatment to placebo were delayed, but this could not be explained on the basis of the rate of choline disappearance from plasma. Re-treatment with choline chloride reversed relapse in most instances. Choline chloride may ameliorate these movement disorders by increasing central cholinergic activity, but other mechanisms are possible. Its practical importance as a treatment needs further elucidation.     

Reversal of haloperidol-induced orofacial dyskinesia and neuroinflammation by isoflavones

Molecular Biology Reports - Schizophrenia is a mental illness and its pharmacological treatment consists in the administration of antipsychotics like haloperidol. However, haloperidol often causes...     

Use of gamma-linolenic acid in the treatment of schizophrenia and tardive dyskinesia.

There is good background evidence to suggest that essential fatty acids and their eicosanoid derivatives may play a role in schizophrenia and in with tardive dyskinesia. Trials involving treatment with essential fatty acids, or eicosanoids or drugs which stimulate eicosanoid synthesis have shown modestly promising results. Particularly favourable outcomes in both schizophrenia and tardive dyskinesia were associated with combined treatment using essential fatty acids and nutritional supplements.     

Mitochondrial ultrastructure and density in a primate model of persistent tardive dyskinesia

The use of neuroleptic drugs to treat schizophrenia is almost invariably associated with extrapyramidal movement disorders. One of these disorders, tardive dyskinesia (TD), can persist long after neuroleptic withdrawal suggesting that permanent neurological damage is produced. However, there appears to be no convincing pathology of TD and its pathogenesis remains unknown. Findings that neuroleptics interfere with normal mitochondrial function and produce mitochondrial ultrastructural changes in the basal ganglia of patients and animals suggest that mitochondrial dysfunction plays a role in TD. We have established a model for persistent TD in baboons that appears to involve compromised mitochondrial function. In this study, we evaluated two animals treated for 41 weeks with a derivative of haloperidol and two treated with vehicle only. Treatment was then withdrawn and the animals observed for a further 17-18 weeks. Treated animals developed abnormal orofacial signs that were consistent with TD. These symptoms persisted during the drug-free period. The animals were euthanased, the brains perfused-fixed then post-fixed in 4% paraformaldehyde and the caudate and putamen prepared for electron microscopy. Regardless of whether mitochondria were located in neural soma, excitatory terminals, glia or in non-somal neuropil there was no consistent difference either in size or number between treated and control animals. Thus, even if mitochondria in striatal neurons undergo ultrastructural alterations during neuroleptic therapy, these changes do not persist after drug withdrawal.     

Peripheral-type benzodiazepine-binding sites in platelets of schizophrenics with and without tardive dyskinesia

The density of peripheral-type benzodiazepine (BZ)-binding sites was studied in platelets of 10 medicated chronic schizophrenics with tardive dyskinesia (TD), 10 medicated chronic schizophrenics without TD, 7 drug-free schizophrenics, and 10 normal controls. The age range of the study population was 36-60 years. Age and sex distribution were similar in all 4 groups. The unmedicated schizophrenics did not differ in their maximal binding capacity from the healthy controls. A significant decrease in the density of peripheral-type BZ-binding sites in platelets was observed in treated schizophrenics both with and without TD in comparison to controls and untreated schizophrenics. The reduction in [3H]PK 11195 binding was more pronounced in TD patients (31.3% of controls) than in patients without TD (21.1% of controls). However, this parameter failed to discriminate statistically between TD and non-TD medicated schizophrenics.     

Effect of Emblica officinalis tannoids on a rat model of tardive dyskinesia

Effect of active tannoid principles of E. officinalis, comprising of emblicanin A (37%), emblicanin B (33%), punigluconin (12%) and pedunculagin (14%), was investigated on a rat model of tardive dyskinesia (TD) induced by once daily administration of haloperidol (1.5 mg/kg, ip) for 28 days. Involuntary orofacial movements (chewing movements, buccal tremors and tongue protusion) were assessed as TD parameters. The tannoid principles of E. officinalis (EOT) were administered concomitantly with haloperidol in the doses of 10, 20 and 50 mg/kg, po, for 28 days. Sodium valproate (200 mg/kg, po), a Gaba-mimetic agent, and vitamin E (400 mg/kg, po), an antioxidant, were used as the standard drugs and administered for the same period. EOT induced a dose-related inhibition of all the three TD parameters assessed, as did vitamin E. The effect of sodium valproate remained statistically insignificant. The results suggest that EOT exerts a prophylactive effect against neuroleptic-induced TD which is likely to be due to its earlier reported antioxidant effects in rat brain areas, including striatum.     

A cerebellar-thalamocortical pathway drives behavioral context-dependent movement initiation

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Successful treatment of one case of tardive dyskinesia with electromyographic feedback from the masseter muscle

Evidence from one case with a 15-month follow-up is presented to support the conclusion that electromyographic (EMG) feedback from the masseter was effective in controlling tardive dyskinesia, while a combination of EMG feedback from the frontalis and verbal muscle relaxation training were not.     

Effect of Withania somnifera glycowithanolides on a rat model of tardive dyskinesia.

Withania somnifera glycowithanolides (WSG) were investigated for their preventive effect on the animal model of tardive dyskinesia (TD), induced by once daily administration of the neuroleptic, haloperidol (1.5 mg/kg, i.p.), for 28 days. Involuntary orofacial movements (chewing movements, tongue protusion and buccal tremors) were assessed as TD parameters. WSG (100 and 200 mg, p.o.), administered concomitantly with haloperidol for 28 days, inhibited the induction of the neuroleptic TD. Haloperidol-induced TD was also attenuated by the antioxidant, vitamin E (400 and 800 mg/kg, p.o.), but remained unaffected by the GABA-mimetic antiepileptic agent, sodium valproate (200 and 400 mg/kg, p.o.), both agents being administered for 28 days like WSG. The results indicate that the reported antioxidant effect of WSG, rather than its GABA-mimetic action, may be responsible for the prevention of haloperidol-induced TD.     

The effects of electromyographic feedback training on suppression of the oral-lingual movements associated with tardive dyskinesia

The efficacy of electromyographic feedback training in reducing the magnitude and frequency of the oral-lingual movements associated with tardive dyskinesia (TD) was investigated in a groups design. Twenty adult male inpatients diagnosed as having TD using the Abnormal Involuntary Movements Scale (AIMS) were randomly assigned to one of two treatment conditions. Following identification, all participants were initially reduced to the lowest effective dosage of neuroleptics, and then discontinued from anticholinergics. Following one month on this regimen, they were given a course of feedback training consisting of ten 14-minute sessions. Group one participants were provided with a tone contingent upon oral-lingual movements above a yoked threshold. Group two participants were given noncontingent feedback tones generated randomly. Weekly AIMS were administered as well as an initial baseline during each session to determine current level of oral-lingual activity. An analysis of session effects indicated significantly more suppression of oral-lingual activity in the contingent group versus the noncontingent feedback group. Jaw and forehead activity also measured showed reductions of similar magnitudes for both groups.This work was sponsored in part by a Research Advisory Grant from the Department of Veterans Affairs awarded to Joanne Intrator. We gratefully acknowledge the valuable contributions of K. Duvvi, S. Kemble, and L. Kolman.     

A comparison of the efficiency of melatonin treatments in advancing oestrus in ewes

Early oestrous cycles were induced in adult, maiden, 18-month-old Suffolk-cross ewes, maintained from birth in natural photoperiod by the following treatments applied from mid-June: subcutaneous implantation of melatonin (1 g) in Silastic packets, daily, oral, melatonin administration (3 mg/ewe) at 15:30 h, an artificial photoperiod of 8L:16D (lights on 07:30 h). Ovarian cycles began 5-10 weeks before those of control ewes maintained in a natural photoperiod. In contrast, the onset of ovarian cycles in ewes given s.c. implants of melatonin (1 g) in April, and a further group in May, was highly variable, and not significantly different from that of the control ewes. Plasma melatonin profiles in sheep with implants showed a night-time rise super-imposed on a constant level, which was itself within the physiological night-time range. Implant-derived melatonin declined with time but remained at or above physiological night-time levels for at least 3 1/2 months. These results indicate that melatonin implants in June, but not in April or May, advance onset of oestrus in the non-lactating, adult ewe. The effects of melatonin implants in June on onset of ovarian cycles were indistinguishable from those of melatonin feeding or artificial short photoperiod initiated at this time of year.     

The effects of electromyographic feedback training on suppression of the oral-lingual movements associated with tardive dyskinesia.

The efficacy of electromyographic feedback training in reducing the magnitude and frequency of the oral-lingual movements associated with tardive dyskinesia (TD) was investigated in a groups design. Twenty adult male inpatients diagnosed as having TD using the Abnormal Involuntary Movements Scale (AIMS) were randomly assigned to one of two treatment conditions. Following identification, all participants were initially reduced to the lowest effective dosage of neuroleptics, and then discontinued from anticholinergics. Following one month on this regimen, they were given a course of feedback training consisting of ten 14-minute sessions. Group one participants were provided with a tone contingent upon oral-lingual movements above a yoked threshold. Group two participants were given noncontingent feedback tones generated randomly. Weekly AIMS were administered as well as an initial baseline during each session to determine current level of oral-lingual activity. An analysis of session effects indicated significantly more suppression of oral-lingual activity in the contingent group versus the noncontingent feedback group. Jaw and forehead activity also measured showed reductions of similar magnitudes for both groups.     

Cost effectiveness of biofeedback and behavioral medicine treatments: A review of the literature

This paper reviews multicomponent behavioral medicine studies that contain cost-effectiveness andor cost-benefit data relevant to the field of biofeedback and relaxation training, primarily when assisted by biofeedback, with or without stress management, in the treatment of psychosomatic illness and pain. A model for evaluating biofeedback treatment is presented. Cost-effectiveness data concerning reduction in physician visits and/or medication use, decrease in medical care costs to patients, reduction in hospital stays and rehospitalization, reduction of mortality, and enhanced quality of life are reviewed. Evidence suggests that multicomponent behavioral medicine treatments are cost-effective on all dimensions reviewed. Cost/benefit ratios range between 1:2 and 1:5, with a median of 1:4. Evidence that could increase the cost effectiveness of biofeedback is reviewed.This work first appeared in a paper presented as the presidential address at the 18th annual meeting of the Biofeedback Society of America, Boston, March 15, 1987.