Developing New Treatments for Tourette Syndrome: Therapeutic Trials With Modulators of Glutamatergic Neurotransmission
Condition: Tourette Syndrome
MeSH terms: Tourette Syndrome; Syndrome
Intervention: D-serine; Riluzole; Placebo
Intervention description: The dosage schedule will be flexible with a maximum dose for each subject being 30 mg/kg/day. In any individual subject, dose escalation may proceed more slowly, or the dose may be reduced if necessary. At the 4 week visit, if an additional dosage increase is prescribed by Dr Singer, the pharmacy will provide an additional vial of capsules labeled as study drug, but containing either 250 or 500 mg tablets of D-serine or placebo; capsule content to be determined by patient's weight. No changes in dosage will be made during the final week of treatment.; The starting dose of riluzole will be 50 mg for one week; administered as one capsule (50) every morning. Dosage schedules will be flexible. If needed for tic suppression, the dose will be increased weekly by 50 mg and given in BID doses. The maximum dose will be 200 mg/day (administered as 2 capsules BID). In any individual subject, dose escalation may proceed more slowly, or the dose may be reduced if necessary. At the 4 week visit, if an additional dosage increase is prescribed by Dr Singer, the pharmacy will provide an additional vial of 14 capsules labeled as study drug, but containing placebo capsules. No changes in dosage will be made during the final week of treatment.; Placebo tablets will be formulated in look-alike capsules. At the 4 week visit, if an additional dosage increase is prescribed by Dr Singer, the pharmacy will provide an additional vial of 14 capsules labeled as study drug, but containing additional placebo capsules.
Intervention MeSH terms: Riluzole
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 39.0
Sex: All
Minimum age: 8 Years
Maximum age: 17 Years
Healthy volunteers: No
Keywords: Tourette syndrome; glutamatergic therapy; D-serine; riluzole; glutamate; glutamate agonist; glutamate antagonist; Tourette syndrome treatment study; OCD; tics

Summary:

      A joint NIH -Tourette Syndrome Association Conference has emphasized the critical need for
      the testing and development of new pharmacotherapy for tic suppression in Tourette syndrome
      (TS). This submission is a safety, tolerability and efficacy pilot study using two
      medications that modulate glutamate neurotransmission, riluzole, a glutamate antagonist, and
      D-serine, a glutamate agonist. Glutamate is the primary excitatory neurotransmitter in the
      central nervous system, an essential component of pathways implicated in TS and an extensive
      modulator of dopamine, the major neurotransmitter associated with tics.

      This is a single site, short-term, proof of concept study of riluzole and D-serine for the
      treatment of tics. Each medication will be evaluated and compared to placebo as part of a
      double-blind, randomized, parallel, flexible dose, three-arm, 8-week, treatment protocol
      (D-serine, riluzole, or placebo). A total of sixty patients (age 8-17 years) with TS and
      moderate to moderately-severe tics will receive study medication according to a 2:1 (dopamine
      modulating drug: placebo), randomized schedule, i.e., riluzole (n=24), D-serine (n=24),
      placebo (n=12). The primary outcome measure is tic suppression as determined by changes in
      the Total Tic Subscore of the Yale Global Tic Severity Scale (YGTSS). Secondary tic outcome
      measures include changes in the YGTSS Total Score and two Global Impression Scales. Further,
      since both riluzole and D-serine have been proposed as treatments for obsessive-compulsive
      behaviors, a TS co-morbidity, these symptoms will be followed. Safety measures include serial
      physical examinations, vital signs, laboratory studies (comprehensive metabolic panel,
      complete blood count, plasma amino acids, and urine analyses), documentation of side effects
      and adverse events, and measurement of changes in ADHD, depression and anxiety.

      This pilot investigation will provide important proof-of-concept data on glutamate therapies
      for TS and, in turn, evidence for large-scale, multi-center clinical trials.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Tourette syndrome (criteria based on the TS Classification Study Group), which
             includes onset before 18 years, multiple involuntary motor tics, one or more vocal
             tics, a waxing and waning course, the gradual replacement of old symptoms with new
             ones, the presence of tics for more than one year, the absence of other medical
             explanations (effects of a substance (e.g., stimulants) or a general medical condition
             for tics, and observation of tics by a reliable examiner) or Chronic Motor Tic
             disorder (criteria similar to Tourette syndrome except for the absence of vocal tics)

          -  Age 8-17 years, either gender

          -  Observable tics, achieving a minimum score of > 22 on the Total Tic score of Yale
             Global Tic Severity Scale (YGTSS)

          -  Tic symptoms severe enough to warrant therapy (e.g., causing psycho-social or physical
             difficulty)

          -  Written informed consent provided by the patient's parent (or legal guardian) and
             assent provided by the patient consistent with Institutional Review Board requirements

          -  Ability and willingness to comply with study protocol requirements

          -  Women of childbearing potential must be using a medically acceptable contraceptive
             method. Acceptable methods of birth control are limited to: Intra-Uterine Device
             (IUD), oral, implantable, injectable contraceptives and estrogen patch, double barrier
             method (spermicide+diaphragm), or abstinence

          -  Baseline weight of at least 33 kilograms

          -  Tic-suppressing drug naive, or currently not on treatment for TS (off medications for
             at least three weeks), or if, in the judgment of the PI, they are not adequately
             managed using current therapy (prescribed for greater than one month) and are willing
             to maintain a constant dose throughout the protocol.

        Exclusion Criteria:

          -  Secondary tics

          -  Significant medical illness (metabolic, endocrine, cardiac, hematological,
             gastrointestinal, pulmonary, epilepsy)

          -  Current major depression

          -  generalized anxiety disorder

          -  separation anxiety disorder

          -  psychotic symptoms (based on clinical evaluation and the results of the CY-BOCS,
             CDI-S, and MASC evaluations)

          -  pervasive developmental disorder

          -  autism

          -  mental retardation (I.Q. less than 70)

          -  anorexia/bulimia, or substance abuse

          -  Any other conditions that in the opinion of the Investigators would interfere with the
             evaluation of the results or constitute a health hazard for the patient

          -  Pregnancy

          -  Hypersensitivity to D-serine or riluzole

          -  Abnormal laboratory values on screening laboratory testing if clinically significant
             at the Principal Investigator's discretion.

        Subjects with co-morbid ADHD, obsessive compulsive disorder (OCD), and conduct disorder
        will not be excluded as long as these diagnoses are not the subject's primary problem