Classification of neuroleptics: implications for tardive dyskinesia

The dopamine (DA) receptor blocking effect of neuroleptics is believed to be responsible for their antipsychotic effect. This blockade can be demonstrated in experimental animals by the ability of neuroleptics to antagonize stereotypies induced by DA agonists. Biochemically DA receptor-blocking properties of neuroleptics are illustrated by direct binding to DA receptors or by measuring inhibition of DA-stimulated adenylate cyclase activity. Most pharmacological and biochemical experiments with neuroleptics have concentrated on dopaminergic effects of the compounds both after acute and long-term treatment. After long-term treatment with neuroleptics an increase in DA receptor number and an increase in stereotyped behavior are seen. DA supersensitivity have been implied in the development of tardive dyskinesia (TD) in patients on long-term neuroleptic medication. In search for neuroleptics which would be less prone to induce TD and more effective in treating dyskinesia we have looked at the profile of a series of neuroleptics in in vitro experiments and in acute and long-term in vivo experiments. Since neuroleptics also influence other transmitter systems than the dopaminergic we have investigated interactions with drugs affecting these transmitter systems. According to their differential effects on DA receptors (D1 and D2) and their ability to develop tolerance and supersensitivity, the neuroleptics can be classified into different groups, some of which might be expected to induce less TD and be preferred for treating dyskinesia.     

Effect of different neuroleptics in tardive dyskinesia and parkinsonism

Participating centers: ¹Sct. Hans Hospital, Dept. 2, Roskilde, Denmark; ²Vordingborg Amtshospital, Denmark; ³Nickby Sjukhus, Finland; ⁴Hesperia Sjukhus, Finland; ⁵Ek»sen Sjukhus, Finland; ⁶Dikemark Sykehus, Norway; ⁷Lillhagen Sjukhus, Gothenborg, Sweden Participating clinicians: J. Gerlach¹, U.G. Ahlfors⁴, K.F. Amthor⁶, S.J. Dencker⁷, A. Gravem⁶, B. Gunby⁶, U. Hagert³, S. Korsgaard¹, L. Lunding⁷, U. Noring¹, K. Ojannen⁵, T. Pitkonen⁴, U.J. Polvsen¹, T. Rossel⁷, E. Tolvanen³, J. Wæhrens² Participating tape raters: J. Gerlach¹, S. Korsgaard¹, U.J. Povlsen¹ Coordination and data collection: K. Elgen, L. Lang-Jensen, H. Lundbeck A/S, Copenhagen, Denmark Statistical analyses: O. Aaskoven, H. Lundbeck A/S, Copenhagen, Denmark Secretary: L. Gustavsen¹ Offprint requests to: J. Gerlach, Sct. Hans Hospital, Dept. 2, DK-4000 Roskilde, DenmarkThirty-three chronic psychiatric patients with tardive dyskinesia (TD) were included in a video-controlled multicenter study of the effect of chlorprothixene, perphenazine, haloperidol and haloperidol + biperiden in TD and parkinsonism. The drugs were given in a cross-over design in randomized order in dosages equipotent to the earlier neuroleptic treatment and administered for periods of 6 months with 6-week placebo periods before and after. A total of 55 treatment periods were completed; only seven patients were able to go through all three treatment phases (=96 weeks). Perphenazine (20.5 mg/day), haloperidol (5.5 mg/day), and haloperidol (11 mg/day) + biperiden (7 mg/day) induced a moderate suppression of TD and at the same time produced a corresponding aggravation in parkinsonism. Chlorprothixene (142 mg/day) had only a slight TD reducing effect and did not change parkinsonism. Thus the TD suppressing effect was inversely related to the parkinsonian-inducing effect of the neuroleptics. Following withdrawal of the drugs, TD increased in some cases and decreased in others compared to the pretreatment level. No significant correlation was found between the intensity of the withdrawal TD and either drugs or preceding parkinsonism or TD suppression. Only in a subgroup of seven patients who consecutively received all three neuroleptics, perphenazine, but not haloperidol and chlorprothixene, produced a post-treatment aggravation which was correlated to the parkinsonsim and TD suppression during treatment. Independent of the neuroleptic given, the TD intensity increased significantly from the first to the third placebo period. This suggests that drug holidays are inappropriate to prevent TD induction/aggravation.The Nordic Dyskincsia Study Group consists of the following:     

A controlled trial of amantadine hydrochloride and neuroleptics in the treatment of tardive dyskinesia

An 18-week, double-blind, crossover study of amantadine and neuroleptics in the treatment of tardive dyskinesia (TD) is described. A fixed-dose regimen was used, and objective rating scales for TD, extrapyramidal symptoms, and mental state were employed. The results indicate that amantadine is significantly better than placebo in the management of TD and that there is little risk of exacerbating psychosis. Further investigation of this potentially useful medication is warranted.     

High incidence of tardive dyskinesia in older outpatients on low doses of neuroleptics.

We are conducting a prospective study of tardive dyskinesia (TD) in psychiatric patients over age 45, a large proportion of whom have had less than 1 month of total lifetime neuroleptic exposure. Patients are treated with the lowest effective dose of either haloperidol (usually 1-3 mg daily) or thioridazine (usually 25-75 mg daily). Patients are reexamined 1 month and 3 months after initial assessment and then at 3-month intervals. To date, a total of 68 patients (mean age 69.5 years) have been evaluated. Survival analysis showed a 27 percent cumulative incidence of TD (the 95% confidence interval being 14% to 40%) with 6 months of neuroleptic treatment in the study. The TD and non-TD patients did not differ on demographic and baseline clinical measures. Instrumental assessment showed that a greater proportion of TD patients had subclinical evidence of dyskinesia prior to the institution of neuroleptics, compared with non-TD patients.     

Atypical antipsychotic drugs and tardive dyskinesia: relevance of D2 receptor affinity

Evidence suggests atypical antipsychotic treatment is associated with a lower incidence of tardive dyskinesia (TD) than typical antipsychotic drugs, and is a potential antidyskinetic treatment. We present the case of a middle-aged woman never previously exposed to antipsychotic treatment who developed TD after 6 months of olanzapine monotherapy. Substitution of quetiapine for olanzapine alleviated her TD symptoms. The case demonstrates that atypical antipsychotic drugs have different effects in relation to TD. Potential psychopharmacological mechanisms explaining these differences are discussed, highlighting the importance of D2 receptor occupancy by atypical antipsychotic drugs for TD.     

Amoxapine-induced tardive dyskinesia

A case report of amoxapine-induced tardive dyskinesia following discontinuation of amoxapine therapy is reported. During 68 weeks of therapy, the patient received a maximum of amoxapine 400 mg/d. Six months after amoxapine discontinuation, the patient continued to have symptoms of tardive dyskinesia. These symptoms correlate with the dopamine receptor-blocking property of amoxapine and its metabolites. We propose that amoxapine therapy be monitored for the long-term as well as the short-term adverse effects of dopamine receptor-blockade.     

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.     

Clozapine in tardive dyskinesia

Clozapine, which has had limited clinical testing in the U.S.A., was evaluated in 12 chronic schizophrenic patients with tardive dyskinesia. Its antipsychotic activity was again demonstrated and it suppressed the symptoms of tardive dyskinesia with a marked rebound occurring in these symptoms when it was withdrawn; there was no rigidity or other Parkinsonian symptoms. However, out of a total of 12 patients, neutropenia (800 and 1120) occurred in two patients, convulsions in one patient, marked withdrawal effects in three patients, and a hypotensive collapse with atrial fibrillation in one patient. If these adverse effects are confirmed in a larger sample size, then despite the novel desirable effects of clozapine it would seem unlikely that it will gain widespread or routine use¹.     

Diazepam in tardive dyskinesia

Tardive dyskinesia, a syndrome of involuntary motor movements, can be a permanent consequence of the long-term use of antipsychotic drugs. While there is no well-established drug treatment, case reports and the results of a few clinical studies suggest that drugs that facilitate the GABA-ergic system may decrease the abnormal movements. One such class of drugs is the benzodiazepines. We administered diazepam to 13 subjects in a 24-week, crossover design study. Tardive dyskinesia and psychopathology were assessed by blind raters using the Abnormal Involuntary Movement Scale and the Brief Psychiatric Rating Scale (BPRS). The means of all movement measurements improved from the baseline, with orofacial, subtotal, symptom severity, and total reaching significance. However, we were unable to demonstrate a drug effect; the patients improved to a similar degree whether or not they received diazepam. Their psychiatric disorders did not worsen with diazepam administration and, in fact, improved slightly; the activation factor of the BPRS was significantly improved over baseline. Our results suggest that diazepam is not effective in managing the movements of tardive dyskinesia and that behavior modification strategies be investigated to help patients control symptoms.     

Serum neuroleptic concentrations and tardive dyskinesia

Using a liquid chromatographic assay, we measured serum neuroleptic concentrations in eight middle-aged or elderly female inpatients with tardive dyskinesia (TD) and eight controls. All 16 patients were receiving either thioridazine or mesoridazine at stable doses. TD patients were found to have a significantly higher ratio of serum concentration to daily dose of neuroleptics compared with controls. A 1-year follow-up revealed that this ratio did not change appreciably in those patients who continued to receive neuroleptics. Differences in serum neuroleptic levels were not related to peripheral inflammatory activity as indicated by serum -1-acid glycoprotein concentrations. Of the various thioridazine metabolites, sulforidazine (which is reportedly the most potent in terms of affinity for dopaminergic and -noradrenergic receptors) seemed to be significantly elevated in the serum of TD patients as compared with non-TD patients. Our data suggest a need for further pharmacokinetic investigations to study neuroleptic metabolism in patients with TD.     

迟发性运动障碍的诊疗进展

迟发性运动障碍(TD)典型表现为口舌舞蹈症,也可表现为痉挛性斜颈、其他形式的肌张力障碍、抽动和震颤,由长期服用多巴胺受体阻断剂引起,停用致病药物症状常不能完全消除,甚至有可能加重.本文综述TD的危险因素、临床特征、诊断、鉴别诊断以及治疗.     

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.