Risperidone Best for Initial Treatment of Childhood Mania

Pauline Anderson

January 05, 2012

January 5, 2012 — A new study shows that the antipsychotic drug risperidone is significantly superior to lithium and divalproex sodium for initial treatment of mania in children, and it is better tolerated, although this drug has potentially serious metabolic effects that raise concerns about its long-term use.

"The study is one of the largest and I think one of the most rigorous investigations of first-line treatment for childhood mania," said one of the study authors, Joan L. Luby, MD, professor of child psychiatry, Washington University, St. Louis, Missouri. "It provides information for clinicians about what is the best drug to try first."

The study, funded by the National Institute of Mental Health, was published online January 2 in Archives of General Psychiatry.

Three-Way Comparison

The 8-week Treatment of Early Age Mania (TEAM) study was a controlled, randomized, parallel comparison of risperidone (n = 89), lithium carbonate (n = 90), and divalproex sodium (n = 100) in antimanic medication-naive subjects carried out at 5 sites across the US.

The study included participants aged 6 to 15 years who had a DSM-IV diagnosis of bipolar I disorder, manic or mixed episode, for at least 4 consecutive weeks and whose Children’s Global Assessment Scale (CGAS) score was 60 or less. The CGAS provides a severity measure on the basis of a child's capacity to function at home, at school, and in social domains; a score of 60 or less signifies clinical impairment.

Randomization was stratified by age group (6 to 12 years and 13 to 15 years) and by the presence or absence of mixed mania, psychosis, and daily rapid cycling. On the basis of the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia (WASH-U-KSADS), for mania symptoms to be considered present, the level of severity had to be 4 or greater (moderate to extreme), consistent with clinically meaningful impairment. Mixed mania required meeting DSM-IV criteria for both mania and depressive disorders in overlapping time frames.

Subjects were given lithium (mean titrated level: 1.09 mEq/L), divalproex sodium (mean titrated level: 113.6 µg/mL), or risperidone (mean dose: 2.57 mg) in twice-daily dosing. The primary outcome measure was the Clinical Global Impression for Bipolar Illness Improvement – Mania scale (CGI-BP-IM) with ratings of 1 or 2, indicating very much or much improved, considered a response.

Treatment Discontinuance

Of the 279 subjects, 24.7% discontinued treatment. The discontinuance rate was significantly higher for those assigned to lithium than for those assigned to risperidone (32.2% vs 15.7%, P = .011) but did not differ between the risperidone and divalproex sodium groups (15.7% vs 26.0%, P = .09) or between the lithium and divalproex sodium groups (32.2% vs 26.0%, P = .35).

"Children don’t stay on those drugs (lithium and divalproex sodium) as long; for some reason they’re just less tolerant of those drugs so there was increased discontinuation with those drugs in this study," said Dr. Luby.

Subjects treated with risperidone had a significantly higher response rate than those treated with lithium (68.5% [n = 61] vs 35.6% [n = 32], P < .001) and those treated with divalproex sodium (68.5% [ n= 61] vs 24.0% [n = 24], P < .001). There was no significant difference in response rate in the lithium vs divalproex sodium comparison.

"The study showed that risperidone was significantly more effective than the other 2 older mood stabilizing agents," said Dr. Luby.

Outcomes were similar for both the younger and older age groups, for subjects with and without psychosis, and for those taking and not taking stimulants.

Weight Gain

Although risperidone showed a superior response, the mean weight gain for participants treated with this drug was significantly greater than for those treated with lithium (3.31 kg vs 1.42 kg, P < .001), as was the mean increase in body mass index (BMI) (1.37 vs 0.37, P < .001). The mean weight gain and increase in BMI was also significantly greater in the risperidone group than in the divalproex sodium group.

In addition, there was a significant difference in mean increased low-density cholesterol levels and mean decreased high-density cholesterol levels that favored the divalproex sodium group compared with the risperidone group.

"One of the drawbacks to risperidone was that children gained significantly more weight on it and they also had elevations of what we think of as 'bad' cholesterol," said Dr. Luby. "This drug also causes metabolic changes that we know are risk factors for developing diabetes."

But there were drawbacks to the other drugs as well. Both caused some weight gain, and lithium significantly raised thyrotropin levels.

The study had a relatively high rate of adverse events, but since there was no placebo group, it is impossible to determine whether these are true increases, said Dr. Luby. They could reflect the relatively rigorous assessment methods for adverse events used in the study.

A limitation of the study was that there is no valid diagnostic biological measure for childhood bipolar disorders. Although the study did use rigorous consensus diagnoses, the findings may not be generalized to studies that use other methods. Also, there were too few nonpsychotic participants for meaningful analyses of this subgroup.

The study gives doctors documented evidence of the superiority of risperidone, said Dr. Luby. In the past, clinicians may have used this drug more frequently in children with mania because it is relatively easy to use, "but we didn’t really have a large-scale empirical study that was a 3-way comparison until now," said Dr. Luby.

Cost and Benefit

Approached for a comment, Gabrielle A. Carlson, MD, professor of psychiatry and pediatrics and Director, Child and Adolescent Psychiatry, Stony Brook University School of Medicine, Stony Brook, New York, said the study reinforced what was already known.

"When it comes to aggressive, moody ADHD oppositional kids that some people call bipolar, the atypical antipsychotic risperidone has the most data behind it. It's certainly the more effective drug, but it comes with a cost."

In treating these children, consideration should be given both to these costs and to the potential benefits, said Dr. Carlson.

"If you're dealing with kids with trivial problems, it's obviously not worth the price." On the other hand, it may be worth it, she said, "if at the end of 8 weeks of good treatment, you're able to have the children back in school with a reasonable relationship with parents and peers, and their functioning is much improved."

Today, many specialists have jumped on "the bandwagon of hand-wringing and hair tearing" about the terrible metabolic and cardiovascular side effects of some antipsychotics, she added, when some of these affected kids "ought to be in the hospital; some are being thrown out of school."

The study was funded by the National Institute of Mental Health (NIMH). Dr. Luby reports the following for the work under consideration: grant from NIMH and provision of medicines from Abbott. She also reports the following from outside the submitted work: employment at Washington University School of Medicine in St. Louis; grants/grants pending from NIMH, National Alliance for Research on Schizophrenia and Depression, and CHADS; and royalties from Guildford Press. For conflict of interest information on the other authors, see original paper.

Arch Gen Psychiatry. Published online Jan 2, 2012. Abstract

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