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800 Journal ofNeurology, Neurosurgery, and Psychiatry 1990;53:800-802 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.53.9.800 on 1 September 1990. Downloaded from SHORT REPORT

Sulpiride in

M Schwartz, L Moguillansky, G Lanyi, B Sharf

Abstract characteristics are listed in the table. All the The abnormal involuntary movements in patients had been treated over the past five tardive dyskinesia can be reduced by the years with neuroleptic drugs and there was no antagonist drugs, phenothia- change of drugs or their dose during the six zines and , but most months preceding or during the trial. cause an increase in Parkinsonian signs. The duration of the neuroleptic treatment , a derivative, and varied between 17 to 42 years (mean 28 3) and selective antagonist ofD2 receptors had a the tardive dyskinesia appeared at least several significantly beneficial effect on most of months before the start of the sulpiride treat- 15 patients (p < 0 01). In 12 patients the ment. All the patients were treated with anti- improvement was mkirked. The reduction cholinergic drugs. of abnormal movements was observed During the study sulpiride or placebo was even with low doses, and it was not neces- added to the daily treatment. A single blind sary to increase the dose of sulpiride crossover placebo controlled design was used, above 600 mg daily. There were no sig- with the patients receiving placebo or sulpiride nificant side effects during the trial nor in a randomised fashion. The initial dose of during an additional three months of sulpiride for all the patients was 100 mg/day treatment. orally (50 mg twice a day), and increased weekly by 100 mg/day until a marked clinical improvement, without side effects, was Tardive dyskinesia is an iatrogenic syndrome achieved ("optimal dose"). Two weeks after caused by long term use of neuroleptic drugs.' reaching the optimal dose in the sulpiride The movements are often irreversible.2 The group (average duration of active treatment neurophysiological mechanism of this with sulpiride was four weeks), the sulpiride syndrome remains unclear. Development of was stopped and switched to placebo. At that dopamine hypersensitivity in the time patients receiving placebo were switched striatum after prolonged neuroleptic treatment to sulpiride. Movement patterns and quantity might be the cause.34 Tardive dyskinesia can be were scored at baseline, at two weeks and two suppressed by postsynaptic weeks after termination of sulpiride treatment. receptor blockers, such as or After completion of this first phase of the

butyrophenones, but this blockade may induce study, sulpiride was reintroduced to all patients http://jnnp.bmj.com/ .' Otherwise, the treatment with at the optimal dose for three months and then neuroleptic drugs appears a trap: withdrawal, stopped. The patients were then reassessed or reducing the dose of these drugs exacerbates nine to 12 months after stopping. The scores the hyperkinetic movements and a patient were estimated according to a rating scale of Department of might thus remain on neuroleptic treatment for tardive dyskinesia and neurological side effects, Neurology, Bnai-Zion several years, despite improvement of the modified from Gerlach"2 (fig 1). Validation of Medical Center, Faculty of Medicine, psychiatric illness. Technion, Haifa Two different dopaminergic receptors have Table Patient data, diagnosis and duration of the on October 1, 2021 by guest. Protected copyright. M Schwartz been identified in the striatum: Dl and D2.67 neuroleptic treatment B Sharf Most neuroleptic drugs block both. Sulpiride, Fluegelman a benzamide derivative, is a selective antagonist Diagnosis, duration of Psychiatric Hospital neuroleptic treatment Treatment* (Mazra), Acre, of D2 receptors only. It does not block the DI No Sex Age years (last 5years)** L Moguillansky receptors, except in high concentrations. This G Lanyi 1 F 77 33 H, T selective action may provide an advantage in 2 F 80 Schizophrenia 40 Ch Correspondence to: tardive dyskinesia.271l1 3 F 75 Schizophrenia 42 T, Ch, H M Schwartz, Department of 4 M 63 Schizophrenia 18 H, Ch Neurology, Faculty of In this study we have therefore evaluated the 5 M 64 Schizophrenia 34 Ch, L, F Medicine, Bnai-Zion clinical efficacy of sulpiride in patients on 6 M 62 Schizophrenia 30 H, Ch, L Medical Center (Rotschild), 7 F 80 Schizophrenia 28 Ch, L 47 Golomb Street, PO Box long term neuroleptic treatment and tardive 8 F 62 Schizophrenia 18 T 4940, Haifa 31048, Israel. dyskinesia. 9 M 64 Schizophrenia 29 H, Ch, L Received 20 January 1989 10 M 66 Schizophrenia 42 Ch and in final revised form 11 M 37 Schizophrenia 15 H, L 13 December 1989. 12 F 70 Schizophrenia 34 H, Ch, L Accepted 9 January 1990 13 F 68 Schizophrenia 27 Ch, L, F Method 14 F 64 Schizophrenia, H, L *Presented in part at the 18 European Meeting on Fifteen psychiatric inpatients with tardive 15 M 77 Schizophrenia 17 H, T, L Clinical dyskinesia (eight female, seven male) were Neuropharmacology, *H= ; Ch = ; L = ; Brussels, Belgium, included in the study. Their ages ranged from T = ; F = . 13 May 1988. 37-80 years (mean 67 years). Individual patient **AJl patients were also treated with drugs. Sulpiride in tardive dyskinesia 801 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.53.9.800 on 1 September 1990. Downloaded from Figure 1 Rate scale of Passive Active tardive dyskinesia and Oral Amplitude Duration 30 neurological side effects tardive Score 0-6 Score 0-6 Score 0-3 (modifiedfrom Gerlach's dyskinesia Passive - active Passive - active Passive - active 25- rating scale'2). Jaw Tongue 20 Total = I I 15-

Score 0-6 Parkinsonism Passive - active Score 0-3 10 Jaw Facial expr. Tongue Bradikinesia 5- Lips Tremor Face Posture 0. Head Arm swing Trunk Gait rigidity Upper extr. Salivation Placebo Sulpiride Placebo Sulpiride Lower extr. Total = Figure 3 Tardive dyskinesia scores: body movements. Total

the evaluation of the results was effected accor- two had not shown any Parkinsonian signs ding to the Wilcoxon's test. before the start of the trial. This side effect appeared mostly with doses of200 to 400 mg of sulpiride without significant difference to the Results sex of the patients. These Parkinsonian signs All the patients completed the trial. Individual did not interfere with overall functioning ofthe patient scores of treatment with sulpiride and patients. placebo are presented in fig 2 and 3. Patients Treatment with sulpiride was continued for treated with sulpiride showed significantly three additional months after the completion of lower tardive dyskinesia scores (p < 0.01) than the trial, without side effect after that: treat- during placebo treatment. In six patients (1, 2, ment with sulpiride was eventually stopped in 3, 8, 13 and 15-table), the improvement was all the patients. The involuntary movements marked; the movements diminished or stopped did not reappear except in four patients. In completely. In six other patients (6, 7, 9, 10, 11 these patients, the treatment with sulpiride was and 14) the improvement was less marked, with restarted on the optimal dose found during the movements of body and perioral regions trial. remaining. In two of those patients (9 and 10), doses of sulpiride were not increased due to a slight increase of pre-existing Parkinsonism Discussion and in one patient (14), an increase of sulpiride It appears from this study that sulpiride over 600 mg daily, aggravated pretreatment reduced abnormal movements ofmouth, trunk epileptic seizures. In three patients there was and limbs in patients with tardive dyskinesia. no real improvement. Ofthose, one patient (12) The improvement was observed even with low showed slight Parkinsonism on 300 mg daily of doses. Contrary to results in previous pub- sulpiride, and patients 4 and 5 did not benefit lications, it was not necessary to increase http://jnnp.bmj.com/ from doses of 300 to 600 mg sulpiride daily. the dose of sulpiride above 600 mg daily. Most Female patients generally responded better of the patients received 200-400 mg daily and than males. Five ofthe six patients with marked the side effects were insignificant. improvement were females. We found it surprising that in most of the Side effects were observed in six patients: patients, tardive dyskinesia disappeared after a one patient had convulsions as mentioned treatment period of three months and in some, above; five patients had slight Parkinsonism: the movements did not reappear after sulpiride was stopped. Such results have not been repor- on October 1, 2021 by guest. Protected copyright. ted before. The question arises, was it the result of loss of hypersensitivity in the dopamine Figure 2 Tardive Passive dyskinesia scores: oral 25. Active receptors of the striatum or that sulpiride dyskinesia. reinstated the normal function of the receptors in these patients? 20. The wide variation in clinical presentation of tardive dyskinesia is hard to explain by dener- 15- vation of dopamine receptors alone. Possibly other neurotransmitters like acetylcholine, gamma-amino- (GABA), nore- 10- pinephrine and serotonin are involved in this disorder. 12-14

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1 Faurbye A, Rasch PJ, Peterson PB, et al. Neurological 0- symptoms in pharmacotherapy of psychoses. Acta Psy- chiatrica Scand 1964;40:10-27. 2 Gerlach J, Casey DE. Sulpiride in tardive dyskinesia. Acta Placebo Sulpiride Placebo Sulpiride Psychiatrica Scand Suppl 1984;69:93-102. 802 Schwartz, Mogtdllansky, Lanyi, Sharf

3 Klawans HL. The pharmacology oftardive dyskinesia. Am J 9 Haggstrom JC. Sulpiride in tardive dyskinesia. Current J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.53.9.800 on 1 September 1990. Downloaded from Psychiatry 1973;130:82-6. Therap Res 1980;27:164-9. 4 Clow A, Theodorov A, Jenner P, et al. Cerebral dopamine 10 Jenner P, Marsden CD. Substituted benzamide drugs as function in rats following withdrawal from one year of selective neuroleptic agents. Neuropharmacol 1981; continuous neuroleptic administration. Eur JPharm 1980; 20:1285-93. 63:145-57. 11 Quinn N, Marsden CD. A double blind trial of sulpiride in 5 Kazamatsuri H, Chien CP, Cole JO. Therapeutic ap- Huntington's disease and tardive dyskinesia. J Neurol proaches to tardive dyskinesia. Arch Gen Psychiatry Neurosurg Psychiatry 1984;47:844-7. 1972;27:491-9. 12 Gerlach J. Tardive dyskinesia. Dan Med Bull 1979;36: 6 Kebabian JW, Calne DB. Multiple receptors for dopamine. 209-45. Nature 1979;277:93-6. 13 Simpson GM, Pi EH, Sramek JJ. Management of tardive 7 Schachter M, Bedard P, Debono AG, et al. The role of D, dyskinesia: current update. Drugs 1982;23:381-93. and D2 receptors. Nature 1980;286:157-9. 14 Casey DE, Gelach J, Magelund G, et al. R-Acetylenic 8 Casey DE, Gerlach J, Simmelsgaard H. Sulpiride in tardive GABA in tardive dyskinesia. Arch Gen Psychiatry 1980; dyskinesia. Psychopharmacol 1979;66:73-7. 37:1376-9. http://jnnp.bmj.com/ on October 1, 2021 by guest. Protected copyright.