Developing New Treatments for Tourette Syndrome: Therapeutic Trials With Modulators of Glutamatergic Neurotransmission

Study Design Overview: The goal of this study is to perform a short-term, proof of concept study to examine the safety, tolerability and efficacy of riluzole and D-serine in the treatment of tics. Each medication will be evaluated and compared to placebo as part of a randomized, double-blind, flexible dose, parallel, eight-week protocol, containing six weeks of active treatment (D-serine, riluzole, or placebo). A total of sixty patients (age 8-17 years) with Tourette syndrome or chronic motor tics (Tourette Syndrome Study Group criteria) having moderate to moderately-severe tics will participate; riluzole (n=24), D-serine (n=24), placebo (n=12).

This study contains six weeks of active treatment with D-serine, riluzole or placebo. The decision to implement a 6-week treatment protocol was based on the following: a) the ability to gradual increase doses of medication on a weekly basis over the first five weeks to dosages beneficial in other conditions; b) a treatment duration similar to that used in other glutamate modulatory treatment studies; and c) a time period necessary to identify a treatment effect in milder non-neuroleptic tic-suppressing medications such as clonidine. We emphasize that this is a short term, proof of concept study for riluzole and D-serine in the treatment of tics. Specific questions such as long term durability of beneficial effects, potential long-term side-effects, and comparisons to non-drug interventions are important, but not a focus of this pilot study.

The study will begin with a screening evaluation to ensure that each subject satisfies all eligibility criteria and to allow subjects to become familiar with our assessment procedures. Randomization of medications contained in look-alike capsules will occur at the baseline visit and is performed by a member of the Research Pharmacy staff. Patients will be evaluated at baseline, have direct formal scheduled evaluations at the end of treatment week's 2, 4, and 6 (+ 2 days), have telephone evaluations at the end of treatment week's 1, 3, and 5 (+ 2 days), and a final visit at 8 weeks. The primary outcome measure is effective tic suppression as determined by the difference in the Total Tic subscale (TTS) scores of the Yale Global Tic Severity Scale (YGTSS) at baseline and 6 weeks. Secondary outcome measures will include the change from baseline and 6 week scores for the YGTSS total score, the Clinical Global Impression -Improvement (CGI-I), and Patient Global Impression of Improvement (PGI-I). Secondary outcome for obsessive-compulsive behaviors will be measured by changes in the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS). Safety measures will include the use of an expanded Pittsburgh Side Effect Scale modified to include side effects of riluzole and D-serine, incidence of adverse events, measurement of vital signs (BP, pulse) and body weight, physical examination, laboratory studies (comprehensive metabolic panel (CMP), complete blood count (CBC), plasma amino acids, and urine analysis), the DuPaul ADHD Rating Scale, Child Depression Inventory-short version (CDI-S), and Multi-Dimensional Anxiety Scale for Children (MASC). A Drug Safety Monitoring Board containing three clinician-scientists with experience in pharmacological trials will meet quarterly to review this study.

1. Study Population:

a) Recruitment: Subjects with TS/CMT (ages 8-17 years) will be recruited from the Tourette Syndrome Clinic at the Johns Hopkins Hospital and child psychiatry practice.