Dopamine blocking neuroleptics are standard therapy for Tourette disorder (GTS) in children. Standard therapy is associated with considerable morbidity as 42% of patients experience extrapyramidal symptoms (EPS). Our focus has been to develop therapies which have a superior benefit/risk ratio compared to standard treatment. Based on the hypothesis of dopaminergic (DA) hyperfunctioning in GTS, we have evaluated therapies which reduce DA transmission. Novel strategies evaluated in this proposal include: l) DA agonist, pergolide, through selective action at the DA autoreceptor, 2) combined DA and serotonergic (5-HT) antagonism via """"""""atypical"""""""" neuroleptic ziprasidone, 3) pilot evaluation of somatic therapy with repeated transcranial magnetic stimulation (rTMS).
Specific aim 1 a) to evaluate the safety and mechanism of action of pergolide in GTS; 1b) to determine efficacy of pergolide for tic control in children 7-17 years with GTS in a double-blind, placebo controlled, 16 week crossover study. Preliminary data gathered from open-label studies and a pilot double-blind trial (N=12), suggest that pergolide is safe, that it exhibits a potent and long-lasting effect on DA transmission, and that pergolide would prove superior to placebo in a larger controlled trial.
Specific aim 2) to evaluate the safety, pharmacodynamics, and feasibility of ziprasidone in children and adolescents with GTS. Pilot data from twelve patients in a pharmacodynamic study at 5, 10, and 20 mg single dose argues that ziprasidone should be further investigated as a potential treatment for GTS in children.
Specific aim 3 a) pilot feasibility and safety evaluation of repeated transcranial magnetic stimulation (rTMS) to influence tics in adolescents with GTS, 3b) pilot efficacy study of rTMS in adolescents with GTS unresponsive to conventional therapies. Preliminary studies have demonstrated that 20 minutes of 1Hz stimulation over motor cortex can reduce tics by 40% compared to sham treatment in adults with GTS. Pilot data show that at safe levels of intensity and frequency, decreased neuronal activity is evident at the stimulation site as well as a mirror site in the opposite hemisphere.
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