October 2009

Divalproex for Mania in Children and Adolescents: A Negative Study
The first double-blind study of divalproex (Depakote) in pediatric patients with bipolar disorder found no greater efficacy than placebo.

Chamomile Calms
A double-blind study suggests efficacy for chamomile as an alternative treatment for anxiety.

Quetiapine for GAD and MDD
In a variety of studies, quetiapine (Seroquel) was found to be effective in treating generalized anxiety and major depressive disorders.

In Brief
Valproate Does Not Improve Agitation in Patients with Dementia; Three More Atypical Antipsychotics May Be Approved for Pediatric Patients

Child and Adolescent Topics
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Divalproex for Mania in Children and Adolescents: A Negative Study

October 2009

Bipolar disorder in children and adolescents is characterized by long episodes, high relapse rates, and a heightened risk for suicide.1 Three drugs have approval from the U.S. Food and Drug Administration (FDA) to treat bipolar disorder in adolescents: lithium, risperidone (Risperdal and others), and aripiprazole (Abilify). However, divalproex (Depakote) is commonly used to treat bipolar disorder in children and adolescents, a practice supported only by open studies. Wagner and associates report on the first multicenter, double-blind, randomized, placebo-controlled trial of divalproex extended-release (ER) in young patients.1

Investigators enrolled 150 patients, aged 10 to 17 years, in a 28-day study with an optional 6-month open-label extension. Subjects, who had to be in a manic or mixed episode, were randomly assigned to take medication once daily—either placebo or divalproex ER, titrated to clinical response or a serum valproate concentration between 80 and 125 µg/mL.

The disappointing result was that divalproex showed no greater efficacy than placebo. The incidence of adverse events was similar between the two groups, but patients treated with divalproex gained more weight: an average of 1.0 kg versus 0.3 kg in the placebo cohort (P < .01). There was also a larger mean increase in serum ammonia associated with divalproex. With a normal range of less than 48 µmols/L, serum ammonia exceeded 90 µmols/L in four divalproex versus two placebo patients. One divalproex-treated patient was hospitalized for adverse events of increased ammonia and disorientation, which responded to lactulose treatment. Two divalproex-treated subjects in the double-blind study and 5 of 66 treated in the open-label extension had platelet counts below normal. In children, divalproex has been associated with decreased platelet count and thrombocytopenia.

Another concern with divalproex is menstrual irregularities and polycystic ovaries—especially in young women. The occurrence of these adverse events could not be accurately addressed in the 4-week double-blind portion of this study and investigators did not capture data on these symptoms in the open-label extension study. The most common adverse events overall in the trial were headache and vomiting.

Wagner et al conclude that there is insufficient evidence at this time to support the use of divalproex ER in the treatment of youths with bipolar I disorder in a manic or mixed state. They do call for at least one more controlled trial to confirm or refute their findings.

At this time, divalproex should be used with caution in children and adolescents. Hyperammonemia, which may appear as disorientation and lethargy in a child, is uncommon but potentially serious. Other concerns with divalproex include menstrual irregularities and polycystic ovaries, thrombocytopenia, and excessive weight gain.

1Wagner KD, Redden L, Kowatch RA, Wilens TE, Segal S, Chang K, Wozniak P, Vigna NV, Abi-Saab W, Saltarelli M: A double-blind, randomized, placebo-controlled trial of divalproex extended-release in the treatment of bipolar disorder in children and adolescents. J Am Acad Child Adolesc Psychiatry 2009;48:519-532.