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:     

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.     

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.     

Combined treatment of tardive dyskinesia with clonidine and neuroleptics: A follow-up study of three cases for three years

Three cases of tardive dyskinesia with psychotic symptoms (one presenile psychosis; two schizophrenia) were successfully treated with both clonidine and neuroleptics for 3 years. The dyskinesia abolished or reduced by clonidine returned several months after discontinuation of clonidine. During the follow-up study, it was observed that combining neuroleptics with clonidine was superior to thioridazine, levomepromazine, or sulpiride for controlling the dyskinesia. These findings suggest that noradrenergic involvement is important in tardive dyskinesia and that other subtypes of dyskinesia might exist.     

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.     

A rating scale for tardive dyskinesia

A rating scale for tardive dyskinesia was developed, consisting of nearly all signs seen by two groups of investigators over a 5-year period. Thirty-four items were included in the scale with a possibility of writing in idiosyncratic signs. The scale was shown to have good reliability and validity in studies carried out by both the New York and Boston groups. It is recommended as a suitable instrument for describing the breadth of tardive dyskinesia syndrome and also for quantifying the disorder. A second scale, the abbreviated dyskinesia scale, contains 13 items which are more global than the items in the original scale. It also has been shown to be both reliable and valid. Its use is suited to situations requiring less extensively detailed assessments.     

Pharmacy-based screening program for tardive dyskinesia

An ongoing screening program using pharmacists to detect tardive dyskinesia (TD) was developed, and a pharmacy-based prevalence survey of TD in chronic hospitalized psychiatric patients was undertaken to determine the extent of abnormal involuntary movements. The results show that older patients and women in particular are at higher risk for developing abnormal movements. Higher doses of neuroleptics were used in non-TD patients, indicating a possible masking effect caused by these drugs. By using a standardized rating method such as the Abnormal Involuntary Movement Scale, pharmacists can and should be utilized in the surveillance of TD.     

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.     

Valbenazine for the treatment of tardive dyskinesia

Introduction: Tardive dyskinesia (TD) is a hyperkinetic movement disorder that may result from treatment with antipsychotics or other dopamine receptor blocking agents. Underlying pathophysiology is incompletely understood but since the 1970s dopamine depleting agents have been used to reduce involuntary movements. The search for safe, effective treatments for TD is ongoing. Valbenazine, a novel VMAT2 inhibitor, has recently been FDA approved for treatment of TD.

Areas covered: An overview of TD, unmet medical needs and current treatment guidelines are presented. The background, chemistry and clinical development of valbenazine to treat TD is detailed. A competitive market is developing as the treatment gap is identified and potential therapies are discussed in context of a broader market overview.

Expert opinion: Antipsychotic use is growing among adults and children in the U.S. Consequently, prevalence of TD is expected to rise. Cessation of antipsychotics is often not possible as the psychiatric condition may deteriorate. Increasing doses of an antipsychotic to suppress involuntary movements is not sustainable long term as underlying TD worsens and movements typically recur. There were no FDA approved treatments for TD. The approval of valbenazine to treat TD is a critical step in addressing this gap in neurologic care.     

Noncatecholaminergic treatments of tardive dyskinesia

We review the results of more than 120 studies of the treatment of tardive dyskinesia with noncatecholaminergic agents. The disorder is thought to arise from dopamine receptor supersensitivity brought on by long term neuroleptic-induced receptor blockade. Ironically, neuroleptics are the most consistently effective treatment of tardive dyskinesia. Nevertheless, it would be desirable to treat it with other compounds. The most intensively studied drugs are the cholinergics, including physostigmine, deanol, choline, and lecithin, but their efficacy has been equivocal. Anticholinergics, opiates, and tryptophan appear to worsen the syndrome or have no effect. Trials of gamma-aminobutyric acid agonists, lithium, and amantadine also produced mixed results. Effectiveness has been claimed for benzodiazepines, estrogens, and pyridoxine,, but the evidence is scant. A small number of preliminary reports on other treatments are also summarized. We discuss briefly the implications of these studies, but methodological problems limit interpretation.