Dopamine blocking neuroleptics are now standard pharmacotherapy of Tourette disorder (TS) in children. This approach is based on an hypothesis of dopaminergic hyperfunctioning in TS. The investigator's prior study directly compared haloperidol and pimozide to determine relative efficacy and side effect profiles in children. The significant findings were: 1) superior relative efficacy of pimozide, based on a four fold higher incidence of treatment limiting side effects and clear extrapyramidal symptoms associated with haloperidol treatment while pimozide remained indistinguishable from placebo; 2) establishment of treatment dosing regimens for both neuroleptics at doses far lower than previously reported; 3) equivalent efficacy in tic and behavioral control between the two neuroleptics; 4) lack of cognitive or school performance deficits associated with treatment. This application seeks to enhance the treatment of TS by assessing a dopamine agonist strategy with pergolide which may be superior to dopamine blockade. In an open-label pilot study in 32 children (17 previously treated with neuroleptics), tic ratings dropped equal to or greater than 50 percent in 75 percent (24/32) after 6 weeks of pergolide treatment. Previously neuroleptic treated patients (11/17) responded positively to pergolide and preferred it to neuroleptic therapy.
Specific Aim I is to determine the safety and efficacy of pergolide in children 7-17 years with TS through: 1a) a dose-ranging and safety study to simultaneously obtain pharmacokinetic and dynamic data; 1b) To determine efficacy of pergolide for tic control in a double-blind placebo controlled, parallel, 10 week study. Dopamine agonists may have their greatest utility in the treatment of children with comorbid attention-deficit hyperactivity disorder (TS plus ADHD). For TS plus ADHD, first line treatment of ADHD with stimulants may induce tics, although mixed agonists such as methylphenidate (MPH) have improved tics in some patients. Pimozide, because of stimulant- like action (e.g., blocks dopamine reuptake as potent as buproprion), may have efficacy in TS plus ADHD for both domains.
Specific Aim II will determine the risk-benefit ratio of pimozide for ADHD symptoms in children 7-14 years with TS plus ADHD: 2a) by comparison with placebo in a balanced two arm crossover flexible dose design, 2b) in comparison with standard methylphenidate treatment of ADHD using a balanced 3 arm crossover, relative efficacy study. If pimozide is shown efficacious in TS plus ADHD, then the investigator will examine systematically any advantage of combined treatment.
Specific Aim 2 c) is to evaluated pimozide plus MPH combined treatment versus pimozide monotherapy for TS plus ADHD, in patients who require treatment for both disorders. This is a 12 week, double-blind, balanced repeated treatments, (pimozide, placebo, pimozide plus stimulant), crossover study.
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| Gilbert, D L; Sethuraman, G; Sine, L et al. (2000) Tourette's syndrome improvement with pergolide in a randomized, double-blind, crossover trial. Neurology 54:1310-5 |
| George, M S; Nahas, Z; Kozel, F A et al. (1999) Improvement of depression following transcranial magnetic stimulation. Curr Psychiatry Rep 1:114-24 |
| Sallee, F R; Sethuraman, G; Rock, C M (1994) Effects of pimozide on cognition in children with Tourette syndrome: interaction with comorbid attention deficit hyperactivity disorder. Acta Psychiatr Scand 90:4-9 |
