Placebo Controlled Trial of Valproate and Risperidone in Young Children With Bipolar Disorders
Condition: Bipolar Disorder
MeSH terms: Bipolar Disorder
Study type: Interventional
Phase: Phase 3

Summary: 
      The primary aim of this proposal is to conduct a preliminary controlled trial of valproate
      and risperidone in children ages 3-7 yr. with bipolar disorders. A secondary aim is to
      carefully characterize these subjects using clinical rating scales and develop pilot data on
      a very young cohort of children with bipolar disorders that can be used to support an
      application to NIMH for a prospective, longitudinal study that will provide important
      information about the course, medication response, neurobiology and outcome of these
      patients.
    

Detailed description: 
      It is now recognized that pediatric bipolar disorders are highly prevalent and that they
      seriously disrupt the lives of children and adolescents, with studies showing poorer academic
      performance, disturbed interpersonal relationships, increased rates of substance abuse, legal
      difficulties, multiple hospitalizations, and increased rates of both suicide attempts and
      completions (Akiskal, Downs et al. 1985; Lewinsohn, Klein et al. 1995; Strober,
      Schmidt-Lackner et al. 1995). We are seeing an increasing number of very young children, ages
      3-7 years, with either frank symptoms of BP I disorder. Over 50% of these young patients have
      a first-degree relative with a bipolar disorder and all of these patient's families are
      significantly impacted by their BP symptoms. Many of these young BP patients have been
      treated with stimulants or antidepressants and few have been treated with mood stabilizing
      agents. Therefore, it is necessary to provide controlled studies of psychotropics in this
      younger bipolar population to provide clinical practice with an appropriate evidence-base.

      Several major questions exist about these very young bipolar patients:

        -  What is the response of these very young bipolar patients to mood stabilizers and or
           atypical antipsychotics?

        -  Will non-responders to mono-therapy with either valproate or risperidone respond to
           treatment with both agents?

        -  How can we best characterize these patients clinically?

        -  What is the long-term outcome of these patients?

        -  Will earlier treatment lead to better outcomes?

      The clinical use of mood stabilizers and atypical antipsychotic agents in children and
      adolescents with bipolar disorders has increased significantly over the past few years,
      despite the fact that only limited research has suggested that these agents are effective in
      this population. Common clinical practice is to have patients continue on medications for
      some time following remission, although the length of continuation treatment varies and
      available guidelines are based on consensus, not controlled trials. The increased number of
      medications prescribed has led to concern about over prescribing of psychotropics in children
      and adolescents (Zito, Safer et al. 2000; Zito, Safer et al. 2003). Therefore, it is
      necessary to provide additional controlled studies of mood stabilizing agents in this younger
      bipolar population to guide clinical practice.

      There is an overwhelming need for controlled trials of the various mood stabilizers and
      atypical antipsychotics that are now available and being used in the community with these
      young bipolar patients. Currently, we have the most experience with valproate and risperidone
      in bipolar children, ages 8 - 17 yr. and based on clinical experience, believe that these two
      agents are the safest and most likely to be efficacious in children ages 3-7 years. These
      agents are widely used in the community and controlled data are desperately needed regarding
      the effectiveness of these agents in bipolar children, ages 3-7 years. There are no specific
      behavioral treatments or psychotherapies that have been shown to be efficacious for these
      patients.

      Power Analysis (Provided by Dr. Judy Bean)

      Since this is a preliminary study prior to a larger controlled trial, the percent of
      responders receiving one of the drugs will be compared to the percent of responders in the
      placebo arm. The children will be randomized to achieve 24 total children in each drug arm
      and 12 in the placebo arm. This 2:2:1 randomization scheme was selected because the
      expectation is that the percent of responders, in each of the drug arms, will be greater than
      the percent in the placebo arm. The expectation is that 60% of the children receiving
      risperidone will respond (Frazier, Meyer et al. 1999), as compared to only 8% in the placebo
      group (Geller, Cooper et al. 1998). Power was calculated for a one-sided test since if
      placebo does better no application will be made to NIH. Using nQuery®, version 5.0, a
      chi-square test, with a 0.05 significance level, will have 96% power to detect the
      difference. For valproate, the percent of responders is expected to be 55%(Kowatch, Suppes et
      al. 2000), as compared to the 8% in the placebo arm. Again, using a chi-square test with a
      .05 significance level, the power will be 86 with 24 in the valproate arm and 12 in the
      placebo arm. This pilot study does not power to determine if the two drug arms are
      equivalent.
    

Intervention name(s): Risperidone oral solution; Valproate Oral Solution; Placebo
Intervention type(s): Drug; Drug; Other
Intervention description(s): liquid, BID dosing.; liquid, BID dosing.; liquid, BID dosing.
Other intervention name(s): Risperdal; VPA
Intervention MeSH terms: Valproic Acid; Risperidone; Pharmaceutical Solutions
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: child; adolescent; bipolar disorder