Electrophysiological and pharmacological analysis of L-dopa-induced dyskinesia and tardive dyskinesia (author's transl)

Electrophysiological and pharmacological analysis of L-Dopa-induced dyskinesia and tardive dyskinesia (L.DD) due to neuroleptics was performed on 12 patients with Parkinson's disease and on 12 others with psychotic diseases. This analysis included the examination of spinal reflexes, monosynaptic H reflex, polysynaptic cutaneous reflex of the lower limb, muscular responses to passive movement [stretch reflex and shortening reaction (SR)] and the study of the motor response to a dopaminergic stimulus (I.V. injection of Piribedil (PBD), a dopamine agonist). There was no difference in EMG activity between L.DD and TD. Three EMG patterns can be distinguished: anarchic discharge pattern (ADA), tonic grouping discharge pattern (AST) and rhythmic burst pattern (ABR). PBD effects indicate a possible relationship between the EMG patterns and the sensitivity level of the motor dopamine receptors. During L-Dopa dyskinesia and tardive dyskinesia, the same changes in spinal reflexes were observed. Muscle tone tested by muscular responses to passive movement (shortening and myotatic reaction) was normal. Monosynaptic excitability explored by H/M ratio was within the normal range. In contrast, the polysynaptic nociceptive reflex was increased in every case. In Parkinsonian patients with L-Dopa dyskinesia, this pattern of the spinal reflexes was significantly different in comparison to the rigid phase. Intravenous infusion of PBD suppressed tremor and provoked the occurrence of dyskinetic activity in Parkinsonian patients with L-Dopa dyskinesia during the rigid phase. During the dyskinetic phase, as in tardive dyskinesia, PBD increases these phenomena and changes EMG activity in rhythmic pattern. It is suggested that L-Dopa dyskinesia and tardive dyskinesia can be determined by testing EMG activity, spinal reflexes and dopaminergic reactivity. There is evidence to suggest that the various types of involuntary abnormal movement represent a single entity, and that dopamine receptor supersensitivity may be involved.     

精制蝮蛇抗栓酶治疗迟发性运动障碍

目的：验证精制蝮蛇抗栓酶对迟发性运动障碍的疗效。方法对８例符合ＳｃｈｏｏｌｅｒＴＤ诊断标准的精神分裂症病人,在原抗精神病药物治疗不变的基础上加用蝮蛇抗栓酶,治疗３个疗后（１５天为１个疗程,每疗程间歇期３－７天）用ＴＤＲＳ、ＡＩＭＳ、ＢＰＲＳ和ＴＥＳＳ在应用抗栓酶前后及各疗程末进行评定,并进行自身配对比较分析,结果加用精制蝮蛇抗栓酶治疗３个疗程后ＴＤＲＳ、ＡＭＩＳ、ＢＰＲＳ总分明显降低（Ｐ〈０．０１     

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.     

Long-stay psychiatric patients: a prospective study revealing persistent antipsychotic-induced movement disorder

Objective

The purpose of this study was to assess the frequency of persistent drug-induced movement disorders namely, tardive dyskinesia (TD), parkinsonism, akathisia and tardive dystonia in a representative sample of long-stay patients with chronic severe mental illness.

Method

Naturalistic study of 209, mainly white, antipsychotic-treated patients, mostly diagnosed with psychotic disorder. Of this group, the same rater examined 194 patients at least two times over a 4-year period, with a mean follow-up time of 1.1 years, with validated scales for TD, parkinsonism, akathisia, and tardive dystonia.

Results

The frequencies of persistent movement disorders in the sample were 28.4% for TD, 56.2% for parkinsonism, 4.6% for akathisia and 5.7% for tardive dystonia. Two-thirds of the participants displayed at least one type of persistent movement disorder.

Conclusions

Persistent movement disorder continues to be the norm for long-stay patients with chronic mental illness and long-term antipsychotic treatment. Measures are required to remedy this situation.     

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.     

Sulphasalazine for rheumatoid arthritis: toxicity in 774 patients monitored for one to 11 years.

Sulphasalazine is being used increasingly to treat rheumatoid arthritis, though its long term safety profile has not been established in this condition. The incidence and nature of adverse effects occurring in 774 patients with rheumatoid arthritis treated with sulphasalazine for periods ranging from one to 11 years were therefore noted. Altogether 205 of the patients stopped treatment permanently due to an adverse effect. One hundred and fifty six (76%) of these events occurred within three months and few beyond the first year. Most events were trivial and were self limiting after withdrawal of the drug; of the potentially more serious adverse effects, 33 (66%) occurred within three months of treatment. None of the patients died or suffered lasting ill effects. It is concluded that adverse effects of treatment with sulphasalazine are generally seen within three months; though regular monitoring is desirable during that period, thereafter few worrying problems occur.     

Prevention of recurrent acute cystitis by methenamine hippurate: double blind controlled crossover long term study.

In a randomised, double blind, long term, crossover study 1 g twice daily of methenamine hippurate was compared with placebo for its preventive effect on recurrent attacks of acute cystitis. Methenamine hippurate and placebo were interchanged every six months for two years. During one of the years patients took 250 ml extra fluid every morning and evening. Out of 21 enrolled patients, 14 completed the first year and 13 both years of treatment, which permitted the evaluation of 27 patient years. There were 52 episodes of acute cystitis caused by reinfection: 41 occurred during placebo treatment and only 11 during the methenamine hippurate regimen (p less than 0.01). Extra fluid intake did not reduce the incidence of acute cystitis, nor did it reduce the effect of methenamine hippurate. Methenamine hippurate is an effective prophylactic agent against recurrent acute cystitis and has the advantage of not inducing cross resistance to conventional antibiotics.     

Trial of brief intermittent neuroleptic prophylaxis for selected schizophrenic outpatients: clinical outcome at one year.

A study was conducted to investigate a novel approach to the prophylaxis of schizophrenic relapse. The treatment strategy comprised brief intermittent courses of neuroleptic agents begun as soon as non-psychotic symptoms believed to be early signs of relapse appeared. Fifty four stable, remitted outpatients meeting the American Psychiatric Association''s DSM-III criteria for schizophrenia were randomised double blind to receive brief intermittent treatment with either active or placebo depot neuroleptic injections. Only three patients given placebo injections and two controls were admitted to hospital during one year of follow up. Eight (30%) of the patients given placebo injections and only 2 (7%) of the controls, however, had a recurrence of schizophrenic symptoms. Patients given placebo injections experienced fewer extrapyramidal side effects and showed a trend towards a reduction in tardive dyskinesia. Dysphoric and neurotic symptoms were identified before eight out of 11 relapses, and these symptoms were more frequent in patients given placebo depot injections. These results suggest a viable but not necessarily better alternative to continuous oral or depot treatment for less ill, chronic, stabilised schizophrenics based on the early treatment of putative prodromal symptoms of relapse.     

The effects of L-tryptophan on haloperidol-induced movement disorder in the rat

An animal model of haloperidol-induced tardive dyskinesia was studied in relation to the dietary manipulation of tryptophan and its effect on the movement disorder. This study showed a significant negative behavioral response to the neuroleptic drug, haloperidol. Increased dietary tryptophan (1.0 vs. 0.3%) significantly reduced the frequency of drug-induced head movements. Brain serotonin levels were elevated by the drug treatment. Brain serotonin levels correlated significantly with the behavioral response. Contrary to expectation, brain dopamine levels did not correlate with the behavioral response. These findings suggest a possible serotonergic involvement in neuroleptic-induced tardive dyskinesia and an amelioration of the disorder through tryptophan supplementation.     

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.     

Down-regulation of haloperidol-induced striatal dopamine receptor supersensitivity by active analogues of L-prolyl-L-leucyl-glycinamide (PLG)

Tardive dyskinesia, a clinical syndrome, is one of the major side effects of protracted treatment with neuroleptics in schizophrenic patients. Functional supersensitivity of striatal dopamine receptors is believed to contribute to the pathogenesis of schizophrenia and tardive dyskinesia. In a rodent model of neuroleptic-induced dopamine receptor supersensitivity, we investigated the efficacy of structurally modified analogues of PLG to down-regulate the striatal dopamine receptor supersensitivity as determined by alterations in [³H]spiroperidol binding to striatal membranes in vitro. The PLG analogue, L-prolyl-L-leucyl-(+)-thiazolidine-2-carboxamide-HCl, when given at the dose of 10 mg/kg IP for 5 days prior to haloperidol (3 mg/kg IP 21 days) significantly prevented the up-regulation of striatal dopamine receptor supersensitivity, thus demonstrating a prophylactic effect. Two other analogues, L-prolyl-L-leucyl-5-aminomethyltetrazole and L-prolyl-L-leucyl-glycine-dimethylamide at a dose of 10 mg/kg IP when given concurrently with haloperidol for 21 days, suppressed the development of dopamine receptor supersensitivity. None of the analogues tested in the post-haloperidol session reversed the haloperidol-induced increase in the density of striatal dopamine receptors. Active PLG analogues hold promise as potential therapeutic agents for the amelioration of tardive dyskinesia.     

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.     

Prolonged conservative care versus early surgery in patients with sciatica caused by lumbar disc herniation: two year results of a randomised controlled trial

Objectives To evaluate the effects of early lumbar disc surgery compared with prolonged conservative care for patients with sciatica over two years of follow-up.Design Randomised controlled trial.Setting Nine Dutch hospitals.Participants 283 patients with 6-12 weeks of sciatica.Interventions Early surgery or an intended six months of continued conservative treatment, with delayed surgery if needed.Main outcome measures Scores from Roland disability questionnaire for sciatica, visual analogue scale for leg pain, and Likert self rating scale of global perceived recovery.Results Of the 141 patients assigned to undergo early surgery, 125 (89%) underwent microdiscectomy. Of the 142 patients assigned to conservative treatment, 62 (44%) eventually required surgery, seven doing so in the second year of follow-up. There was no significant overall difference between treatment arms in disability scores during the first two years (P=0.25). Improvement in leg pain was faster for patients randomised to early surgery, with a significant difference between “areas under the curves” over two years (P=0.05). This short term benefit of early surgery was no longer significant by six months and continued to narrow between six months and 24 months. Patient satisfaction decreased slightly between one and two years for both groups. At two years 20% of all patients reported an unsatisfactory outcome.Conclusions Early surgery achieved more rapid relief of sciatica than conservative care, but outcomes were similar by one year and these did not change during the second year.Trial Registry ISRCT No 26872154.     

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.     

Provocation of a paradoxical growth hormone response to corticotropin-releasing hormone by pretreatment with metoclopramide in patients with acromegaly and normal subjects

Two of 7 patients with acromegaly and one of 7 normal subjects exhibited a paradoxical rise in growth hormone (GH) to human corticotropin-releasing hormone (CRH) when pretreated with metoclopramide, although CRH alone did not induce an increase in GH. In one of these two patients with acromegaly, the GH increase to metoclopramide alone also reached the criteria of a paradoxical response. These two acromegalic patients showed a GH increase to metoclopramide pretreatment before and up to two months after surgery. In another acromegalic patient, whose GH level remained high 5 months after surgery, metoclopramide induced an increase in GH level, while in a patient who had an above-normal GH level 18 months after surgery, the resumption of physiological GH secretion after surgery was evidenced by a postoperative absence of a GH response to metoclopramide. It is suggested from these results that the GH response to metoclopramide and the metoclopramide-provoked GH response to CRH in patients with acromegaly result from the secretion of GH from nonadenomatous cells of the pituitary.     

Tardive dyskinesia.

Tardive dyskinesia is a potentially irreversible syndrome of involuntary hyperkinetic movements that occur in predisposed persons receiving extended neuroleptic (antipsychotic) drug therapy. It is usually characterized by choreoathetoid dyskinesias in the orofacial, limb, and truncal regions, but subtypes of this syndrome may include tardive dystonia and tardive akathisia. Although the mechanisms underlying the pathogenesis and pathophysiology of this disorder are unproven, altered dopaminergic functions will likely play a role in any explanation of it. Tardive dyskinesia develops in 20% of neuroleptic-treated patients, but high-risk groups such as the elderly have substantially higher rates. Risk factors include age, female sex, affective disorders, and probably those without psychotic diagnoses, including patients receiving drugs with antidopaminergic activity for nausea or gastrointestinal dysfunction for extended periods. Total drug exposure is positively correlated with tardive dyskinesia risk. Management strategies include a careful evaluation of both the psychiatric and neurologic states, a broad differential diagnosis, and adjustment of neuroleptic agents to the lowest effective dose that controls psychosis and minimizes motor side effects. No drug therapy is uniformly safe and effective for treating this disorder. A favorable long-term outcome of improvement or resolution correlates with younger age, early detection, lower drug exposure, and duration of follow-up.     

Harpagophytum Procumbens Ethyl Acetate Fraction Reduces Fluphenazine-Induced Vacuous Chewing Movements and Oxidative Stress in Rat Brain

Neurochemical Research - Long-term treatment with fluphenazine is associated with manifestation of extrapyramidal side effects, such as tardive dyskinesia. The molecular mechanisms related to the...     

Trial of brief intermittent neuroleptic prophylaxis for selected schizophrenic outpatients: clinical and social outcome at two years.

OBJECTIVE--To evaluate a novel approach to the prophylaxis of schizophrenic relapse characterised by administration of brief courses of neuroleptic for the earliest non-psychotic signs of relapse (prodromal symptoms). DESIGN--Two year follow up of subjects randomised, double blind, to receive either active (control group) or placebo (intermittent group) depot neuroleptic medication. Both groups received brief courses of oral neuroleptic when prodromal symptoms or relapse occurred. SETTING--Psychiatric outpatient department, Charing Cross Hospital, London. SUBJECTS--54 Stable patients in remission who met the American Psychiatric Association''s DSM-III criteria for schizophrenia on the basis of case notes. MAIN OUTCOME MEASURES--Survival without relapse, survival without hospitalisation, point prevalence of extrapyramidal side effects and tardive dyskinesia, structured assessment of social functioning (social adjustment scale II), and frequency of prodromal symptoms. RESULTS--Of 19 relapses recorded over two years, 10 (53%) were preceded by non-psychotic prodromal signs. Survival rates for both relapse and hospitalisation were worse with intermittent treatment than continuous treatment over the two year follow up: 92% of controls and only 54% of patients given intermittent treatment survived the two year period without hospitalisation. Prolonged or frequent relapses as well as episodes of prodromal symptoms were more frequent with intermittent treatment. Lower scores for extrapyramidal side effects were recorded in the intermittent treatment group, but periodic assessments of social functioning failed to show any social advantages from this. CONCLUSION--The findings are at variance with a previous report of one year follow up in this cohort and attest to the superiority of continuous depot neuroleptic prophylaxis in preventing both psychotic and neurotic or dysphoric morbidity in schizophrenia.     

Enhanced striatal 3H-spiroperidol binding induced by chronic haloperidol treatment inhibited by peptides administered during the withdrawal phase

Chronic intragastric administration of haloperidol (1.5 mg/kg/day) for 21 days followed by a 3-day withdrawal period resulted in the development of enhanced locomotor activity response to apomorphine, and an increase in the number of binding sites for 3H-spiroperidol in the striatal membranes of the rat brain. Subcutaneous administration of Pro-Leu-Gly-NH2 or cyclo(Leu-Gly) in doses of 2 mg/kg/day given for 3-days after termination of haloperidol treatment inhibited the enhanced response to apomorphine, as well as the increases in the number of 3H-spiroperidol binding sites in the striatum. If indeed, the supersensitivity of striatal dopamine receptors is one of the mechanisms in the development of tardive dyskinesia symptoms, the present results suggest that the above peptides may be helpful in ameliorating some of the symptoms of tardive dyskinesia induced by neuroleptic drugs.