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

Grant Type
Clinical
Grant Year
2007-2008
Institution Location
MD
Institution Organization Name
Johns Hopkins University
Investigators Name
Singer, Harvey, MD

A critical need exists for the identification of new pharmacotherapies for the treatment of tics in patients with Tourette Syndrome (TS). Medications that block dopamine receptors, i.e. dopaminergic antagonists, have long been considered the primary pharmacotherapy for tic suppression. These agents, however, are not always effective and for some can cause significant side effects. While the dopaminergic system may play an important role in causing tics, other neurotransmitter systems may also be essential factors, either via their ability to alter dopaminergic activity or as a primary abnormality. One such agent that interacts extensively with the dopaminergic system is the excitatory neurotransmitter glutamate. Glutamate is the primary neurotransmitter in the mammalian brain, with approximately 60% of brain neurons using this substance to transmit messages between brain cells. The use of glutamate neurotransmitter modulators as potential therapeutic agents in TS is based upon several lines of evidence including: the neurotransmitter’s essential role in corticostriatal- thalamo-cortical (CSTC) circuits, i.e., pathways involved in tic symptoms; a wellestablished extensive interaction between the glutamatergic and dopaminergic neurotransmitter systems; and suggestive evidence implicating a dysfunction of the glutamatergic system in TS. Since current neurochemical data on TS support either a hypo- or hyper-glutamatergic condition, we have designed this treatment study to use both a medication that enhances glutamate activity (i.e., agonist, D-serine) and one that blocks glutamate activity (i.e., antagonist, riluzole). Both of these medications are being used in treatment trials for neuropsychiatric conditions commonly associated with Tourette Syndrome, such as obsessive-compulsive disorder. Riluzole and D-serine will be studied in the same study participant as part of a randomized, double-blind, 17-week (run in, three phase), cross-over study, in which the patient receives 4 weeks each of treatment with Riluzole, D-serine, and an inactive substance (placebo), interspersed with two-week wash-out periods between each treatment. Twenty children and adolescents with moderate to moderately severe TS or chronic motor tics will be enrolled in this study. The primary outcome measure will be effective tic suppression as determined by the difference in the Yale Global Tic Severity Scale’s (YGTSS) Total Tic scores between treatment arms. Secondary outcome measures will include the YGTSS Impairment Score, the Total YGTSS score, a Clinical Global Impression-Improvement Scale, and measures of Obsessive-Compulsive Behavior, ADHD, depression, and anxiety. An expanded Pittsburgh Side Effect Scale will be used to assess side effects of Riluzole and D-serine. Patients will be followed by phone at weekly intervals throughout the study and will be formally evaluated at the beginning and end of each treatment phase. Results from this pilot investigation may provide important new information on potential therapies for Tourette Syndrome. Data are expected to result in larger followup, multi-center trials in collaboration with the TSAs’ Clinical Trials Consortium. Harvey S. Singer, M.D., Kendra Harris, M.Sc. Johns Hopkins University School of Medicines Baltimore, MD Award: $75,000 This Award is funded by Randi Zemsky and Shirley and Sam Zemsky. Tourette Association of America Inc. – Research Grant Award 2007-2008