What is the recommended maximum dose of pimozide in the treatment of Tourette´s syndrome and what a

Fråga: What is the recommended maximum dose of pimozide in the treatment of Tourette´s syndrome and what are the possible side-effects? Is the risk for tardive dyskinesia related to the dose of pimozide?

Background: A 13-year old boy with Tourette´s syndrome and very disturbing tics. Pimozide treatment has been started and the dose has been increased to 10 mg/day without satisfactory therapeutic benefit.

Sammanfattning: In Tourette´s syndrome, a maximum pimozide dose of 20 mg/day in adults or 0.2 mg/kg/day in children under 12 years has been recommended, the average dose ranging from 7 to 16 mg/day. Extrapyramidal, anticholinergic and cardiac side-effects may occur. Some reports support the assumption that the risk of tardive dyskinesia would increase with the cumulative dose or with the length of drug exposure.

Svar: Tourette´s syndrome is a chronic disorder characterized by multiple muscular and vocal tics, fluctuating clinical course and the onset usually before the age of 15 years. Haloperidol is generally regarded as the drug of choice but the treatment is often associated with significant side-effects (1,2).

Pimozide has been reported to have a therapeutic effect equal to that of haloperidol but with less side-effects, especially sedation (3,4,5). The limited experience with the drug to date however does not adequately support the advantage (1). Approximately 10-15 per cent of patients on pimozide get extrapyramidal side-effects (e.g. tremor, rigidity, salivation) which can be controlled by reducing the dose or with antiparkinsonian therapy (e.g. benzopine) (1,5). Tinnitus and anticholinergic effects (blurred vision, constipation, dry mouth) are also common. Sedation, depression, impaired motivation, phobia, weight gain, gynecomastia and decreased libido have been reported. Up to 20-25 per cent of patients develop prolongation of the QT interval and other ECG changes (cf 5). Sudden, unexpected death has been reported in two young schizophrenics being treated with pimozide doses in the range of one mg/kg/day (5). The cause of death has not been established.

The recommended initial dose of pimozide in the treatment of Tourette´s syndrome is 1-2 mg/day and the dose is increased by 1-2 mg every ten days until control of symptoms is achieved (1,5). The maximum dose of 20 mg/day in adults and 0.2 mg/kg/day in children under 12 years of age has been recommended (1,6). The average dose needed to control tics has in different studies ranged from 7 to 16 mg/day (3,4,5). Doses up to 30 mg/day have been used but are not recommended because of the possible cardiotoxicity of pimozide. Experience on pimozide treatment in children under the age of 12 years is limited.

Tardive dyskinesia is a possible adverse effect of pimozide although it has not been reported during treatment of Tourette´s syndrome (5). Kane and Smith (7) have reviewed 56 studies on the prevalence and risk factors of tardive dyskinesia. Prevalences between less than 5 per cent and more than 60 per cent have been reported in patients taking neuroleptics. The authors estimate the average rate at about 15 per cent. Advancing age and, to a lesser extent, female sex are most consistently associated with increased prevalence. Prolonged treatment and the cumulative dose of the neuroleptic are other possible risk factors. Of 18 studies exploring the relationship between the cumulative dose and tardive dyskinesia prevalence, 4 reported a significant positive relationship and 14 did not. Similarly, 6 studies have found increasing length of drug exposure as a risk factor whereas 15 studies found no relationship (reviewed in 7). In one study, a positive correlation between the development of tardive dyskinesia and serum neuroleptic concentrations has been found (8). However, in another study no significant difference in serum levels of thioridazine or its metabolites could be found between patients with and without tardive dyskinesia (9). 1 Colvin CL, Tankanow RM: Pimozide: use in Tourette´s syndrome. Drug Intell Clin Pharm 1985; 19: 421-424 2 Gilles DRN, Forsythe WI: Treatment of multiple tics and the Tourette syndrome. Dev Med Child Neurol 1984; 26: 830-833 3 Ross MS, Moldofsky H: A comparison of pimozide and haloperidol in the tratment of Gilles de la Tourette´s syndrome. Am J psychiatry 1978; 135: 585-587 4 Shapiro AK, Shapiro E: Controlled study of pimozide vs placebo in Tourette´s syndrome, J Am Acad Child Psychiatry 1984; 23: 161-173 5 Pimozide for Tourette´s disorder. Med Lett Drugs Ther 1985; 27: 3-4 6 Pimozide approved for Tourette´s syndrome. FDA Drug Bull 1984; 14: 24-25 7 Kane JM, Smith JM: Tardive dyskinesia. Prevalence and risk factors, 1959 to 1979. Arch Gen Psychiatry 1982; 39: 473-481 8 Jeste DV, Linnoila M, Wagner RL, Wyatt RJ: Serum neuroleptic concentrations and TD. Psychopharmacology 1982; 76: 377- 9 Widerlöv E, Häggström JE, Kilts CD, Andersson U, Breese GR, Mailman RB: Serum concentrations of thioridazine, its major metabolites and serum neuroleptic-like activities in schizophrenics with and without tardive dyskinesia. Acta Psychiat Scand 1982; 66: 294-305