Double-Blind Placebo-Controlled Trial of Riluzole in Pediatric Bipolar Disorder
Condition: Bipolar Disorder; Anxiety Disorders; Bipolar Affective Disorder; Bipolar Depression
MeSH terms: Bipolar Disorder; Anxiety Disorders; Mood Disorders
Intervention: Riluzole
Intervention MeSH terms: Riluzole
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 6.0
Sex: All
Minimum age: 9 Years
Maximum age: 17 Years
Healthy volunteers: No
Keywords: Mania; Bipolar; Bipolar Disorder; Bipolar Manic-Depressive Illness; Bipolar Mood Disorder

Summary:

      Pediatric Bipolar Disorder (BD) is uncommon in children. Its symptoms include periods of
      manic behavior (being overly happy or giddy, feeling grandiose, feeling a decreased need for
      sleep, having too much energy, moving more than usual, talking fast, having speeded-up
      thoughts and other symptoms). Sometimes there also is depression (extreme feelings of sadness
      or irritability, not taking pleasure in things, even ones that used to be enjoyable, feeling
      worthless or guilty, sleeping too much or having trouble getting to or staying asleep,
      feeling slowed down or restless, having wishes to be dead or suicidal ideas, and other
      symptoms). Pediatric BD is often difficult to treat; children may respond only partially to
      the medications now available or have too many side effects to tolerate them.

      Riluzole is a medication that is thought to work on a brain chemical called glutamate that
      may be involved in symptoms of depression and BD. Previous research studies have shown that
      riluzole may help adults with BD who have depression and adults who have depression, anxiety
      disorders, or obsessive-compulsive disorders. Riluzole may also be helpful for children with
      obsessive-compulsive disorder. However, it has never been given to children with BD.

      This study will evaluate the effectiveness of riluzole in 80 patients between 9 and 17 years
      of age who have BD and symptoms of anxiety. Participants must have tried at least two other
      medications that have not been effective.

      The study will consist of four phases carried out over 4 to 5 months. Most children will be
      inpatients at the Pediatric Behavioral Health Unit for at least part of the study.

      In Phase 1, each patient will undergo blood and urine tests, and will gradually taper off his
      or her medication. The duration of this phase depends on the medication that the patient was
      receiving before starting the study.

      In Phase 2, the patient will remain off all medication for 1 week. Throughout this time,
      patients will be monitored carefully and medication will be restarted if needed.

      In Phase 3, which lasts 8 weeks, patients will be assigned randomly to receive only riluzole
      or only a placebo. Those who receive riluzole will have the dose adjusted as needed. Patients
      and families will be informed of which drug they were on at the end of this phase. Patients
      who improved on riluzole may continue to receive it from NIH for 1 month and will then be
      prepared for discharge from the study. Patients who received placebo and improved, and those
      who received riluzole but did not improve, will be treated with standard medications as
      appropriate and prepared for discharge from the study.

      Phase 4 is for patients who received placebo and did not improve. They will be given the
      chance to try riluzole for 8 weeks and, if it is effective, continue it for an additional 4
      weeks while they prepare to be discharged from the study.

      Patients will not be able to receive riluzole at the National Institutes of Health after the
      completion of the study. However, the child's doctor may be able to prescribe riluzole as an
      off-label use.

      Most patients will be admitted to the Pediatric Behavioral Health Unit at the National
      Institutes of Health Clinical Center during the medication withdrawal part of the study
      (Phases 1 and 2). From Phase 3 on, a patient may participate as an inpatient, outpatient, or
      in day treatment, depending on what is in his or her best interests.

      All participants in this study will be invited to also enroll in the National Institute of
      Mental Health protocol 00-M-0198, The Phenomenology and Neurophysiology of Affective
      Dysregulation In Children And Adolescents With Bipolar Disorder. Some research tests for that
      protocol will be done during the medication-free period of this protocol.

      ...
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

          -  Boys and girls

          -  Ages 9-17 years of age

          -  Meet DSM-IV criteria for bipolar disorder.

          -  The child must have a primary caregiver who can accompany him or her on trips to NIMH,
             provide reliable history and information, and complete rating scales.

          -  Patients must have a psychiatrist who provides clinical care for their BPD.

          -  All youth accepted into the study must be able to complete self-rating forms and to
             cooperate with other study procedures.

          -  Previous treatment failure as defined by:

               1. Failure to respond to an adequate trial (adequate dose for at least two weeks) of
                  a mood stabilizer (either lithium or divalproex) plus an adequate trial
                  (sufficient dose for an adequate duration) of an atypical antipsychotic (such as
                  risperidone, olanzapine, quetiapine, ziprasidone, or aripiprazole)

               2. Failure to respond to an adequate trial (sufficient dose for an adequate
                  duration) of two atypical antipsychotics (such as risperidone, olanzapine,
                  quetiapine, ziprasidone, or aripiprazole) or

               3. Evidence of intolerance (severe weight gain or other side effects) of a mood
                  stabilizer or atypical antipsychotic agent.

          -  The child is failing his/her current treatment as defined by (all 3 met):

               1. The child's current CGAS score must be less than 60.

               2. The child's current psychiatrist must agree that the child's response to his/her
                  current treatment is no more than minimal or there are drug side effects that are
                  proving problematic. According to this criterion, it would be clinically
                  appropriate to change the child's current treatment.

               3. On the basis of record review and interviews with child and parent, the research
                  team agrees that the child's response to his/her current treatment is no more
                  than minimal.

          -  Subject has a PARS score of greater than or equal to 10, derived from the total of the
             following individual items: 3 (overall severity of anxious feelings), 5 (overall
             avoidance), 6 (interference with family), and 7 (interference outside of the home). In
             addition, patients must score 3 or higher (i.e., in the clinical range) on at least
             one of the four items noted above.

        EXCLUSION CRITERIA:

          -  I.Q. less than 70

          -  Autistic disorder or severe pervasive developmental disorder; psychosis that
             interferes with the child's capacity to understand and comply with study procedures;

          -  Unstable medical illness (e.g. severe asthma) or contraindication to riluzole

          -  Medical illness that could cause the symptoms of bipolar illness (e.g. multiple
             sclerosis, thyroid disease);

          -  Pregnancy

          -  Renal or hepatic dysfunction that would interfere with excretion or metabolism of
             riluzole as evidenced by increase above upper limits of normal for BUN/creatinine, or
             two-fold elevation of serum transaminases (ALT/SGPT, AST/SGOT), gamma glutamate (GGT),
             or bilirubin.

          -  Documented history of hypersensitivity or intolerance to riluzole.

          -  Substance abuse within two months of study entry