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Large Controlled Trial of Widely Used Mood Stabilizers Demonstrates Efficacy in Pediatric Bipolar Disorder

Shows Treatment Significantly Effective at Eight Weeks

Sunday, October 28, 2007

CINCINNATI – In the largest pediatric study of its kind on mood stabilizers, scientists from Cincinnati Children's Hospital Medical Center and two other centers demonstrated that divalproex sodium (Depakote") has efficacy for significantly improving symptoms of bipolar I disorder in children and adolescents, according to results presented today at the annual meeting of the American Academy of Child and Adolescent Psychiatry in Boston.

Many psychiatric medications prescribed for children and adolescents have not been indicated by the FDA for pediatric use. Making sure these drugs are effective and safe has been an important goal of pediatric psychiatry researchers as well as gaining FDA indications for appropriate use in children.

"Divalproex and lithium are the most widely used mood stabilizers for children and adolescents diagnosed with bipolar disorder," said Robert A. Kowatch, MD, a child and adolescent psychiatrist specializing in bipolar and other mood disorders at Cincinnati Children's. "Our study now proves that these agents definitely work, which may give clinicians and families peace of mind."

Dr. Kowatch presented the eight-week, acute efficacy results from the Pediatric Bipolar Collaborative Mood Stabilizer Trial, which also included a second, 16-week phase. The investigation is the first controlled trial to test and compare lithium and divalproex versus placebo for six months, the largest trial of lithium and divalproex to date and first to demonstrate efficacy for divalproex in children aged 7 to 17 years, diagnosed with bipolar I disorder, mixed or manic, based on standardized criteria.

Specifically, at the end of an eight-week treatment phase, patients receiving divalproex significantly decreased their average scores (p <0.01 compared to placebo) on the study's primary outcome measure for manic symptom severity, the Young Mania Rating Scale (YMRS). Fifty-six percent of patients in the divalproex group, 41 percent of those in the lithium group and 30 percent of the placebo group experienced a more than 50 percent decrease in their YMRS scores (comparisons by treatment group were: p<0.05 for divalproex vs. placebo, p=0.36 for lithium vs. placebo and p=0.10 for divalproex vs. lithium).

Also, the response rates on the study's other primary outcome measure, the Clinical Global Impressions Ratings (CGI) - improvement score, indicated that 54 percent of the divalproex group, 42 percent of the lithium group and 29 percent of the placebo group improved their CGI scores by one or two points, (p<0.05 for divalproex vs. placebo, p=0.26 for lithium vs. placebo and p=0.27 for divalproex vs. lithium).

The National Institute of Mental Health supported the Pediatric Bipolar Collaborative Mood Stabilizer Trial via a five-year grant. In addition to Cincinnati Children's, other sites involved were Wisconsin Children's Hospital and Case Western Reserve University. In the study, investigators randomly assigned 153 children to receive a placebo, lithium or divalproex. Neither the investigators nor patients knew to which treatment group the patients were assigned at the end of the eight week treatment phase. Those patients who responded to treatment could continue in the double-blind testing for another 16 weeks.

The classic form of the bipolar illness, also know as bipolar I disorder, occurs in children 6 to 17 years. The estimated annual number of for U.S. youths aged 19 years and younger receiving a diagnosis of bipolar disorder is about 1 percent, based on a 2007 NIH-funded analysis finding bipolar diagnoses occurring during 1,003 physician office-based visits by this age group per 100,000 population. Symptoms include severe, explosive mood swings, euphoria, irritable mood, decreased need for sleep without daytime fatigue, pressured speech that is difficult to interrupt, racing thoughts, distractibility that varies with mood, increased goal-directed activity, hypersexuality and, in some cases, hallucinations. Children with the illness are at increased risk of attempting suicide. Bipolar disorder, like epilepsy, tends to be a lifelong medical condition that can be managed with medication, psychotherapy and lifestyle changes such as stress reduction, regular sleep, accommodations at school and avoidance of caffeine, alcohol and drugs of abuse.

Dr. Kowatch is an internationally known expert for his research in child and adolescent bipolar disorders. In 2005, he organized and published the now current national treatment guidelines for bipolar I disorder on behalf of the Child & Adolescent Bipolar Foundation. The guidelines appeared in the March 2005 Journal of the American Academy of Child and Adolescent Psychiatry. The recommendations are based on evidence from research studies done in children and adults, case reports published in medical journals, and consensus by a group of experts as to current clinical practices.

Cincinnati Children's Hospital Medical Center, one of the leading pediatric research institutions in the nation, is dedicated to changing the outcome for children throughout the world. Cincinnati Children's ranks second among all pediatric institutions in the United States in grants from the National Institutes of Health. It has an established tradition of research excellence, with discoveries including the Sabin oral polio vaccine, the surfactant preparation that saves the lives of thousands of premature infants each year, and a rotavirus vaccine that saves the lives of hundreds of thousands of infants around the world each year. Current strategic directions include the translation of basic laboratory research into the development of novel therapeutics for the treatment of disease, and furthering the development of personalized and predictive medicine.