FDA Panel OKs 3 Antipsychotic Drugs for Pediatric Use, Cautions Against Overuse

Despite safety concerns, a US Food and Drug Administration (FDA) advisory panel recommended in June that the agency approve 3 atypical antipsychotic drugs for the treatment of children and adolescents with bipolar disorder or schizophrenia. The drugs are associated with substantial weight gain and metabolic problems.

Two atypical antipsychotic drugs, risperidone and aripiprazole, are currently approved for the treatment of these conditions in pediatric patients. But the FDA asked its advisors to consider whether there is sufficient evidence to support approval of 3 similar drugs for use in younger patients. These drugs—quetiapine, ziprasidone, and olanzapine—are currently approved for treating schizophrenia or bipolar disorder in adults and are used widely off label in children.

In its briefing materials, the FDA noted that quetiapine, ziprasidone, and olanzapine are associated with such adverse events as somnolence, weight gain, increases in blood lipids and glucose, and certain movement disorders. The agency said these risks “are of particular concern in pediatric patients” because of possible effects on growth and development and because the lifelong nature of these disorders means that these individuals may be exposed to the medications for many decades (http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PsychopharmacologicDrugsAdvisoryCommittee/UCM164423.pdf).

Ultimately, the panel voted in favor of approval for all 3 drugs, with certain caveats, according to interviews with members of the panel and records provided by the FDA. The panel recommended approving quetiapine for acute use in patients aged 13 to 17 years with schizophrenia, and patients aged 10 to 17 years with bipolar mania; ziprasidone for use as a second-line therapy for acute treatment of patients aged 10 to 17 years with manic or mixed episodes associated with bipolar disorder; and olanzapine for use as a second-line therapy for acute treatment of young patients with schizophrenia or manic or mixed episodes associated with bipolar I disorder.

But panel members were divided over ziprasidone's safety: 8 panel members voted that the drug is acceptably safe, 1 member voted that it was not, and 9 abstained from voting. In particular, there were some concerns about the cardiovascular risks of this drug because the drug increases the Q-T interval and can lead to such adverse effects as sudden death, explained panel member Benedetto Vitiello, MD, chief of the National Institute of Mental Health's (NIMH’s) Child and Adolescent Treatment and Preventative Intervention Research Branch, in an interview.

Panel members also disagreed about olanzapine's safety: voting 11-5 (with 2 abstentions) that the drug is acceptably safe for patients aged 13 to 17 years with schizophrenia, and 11-4 (with 3 abstentions) that it is acceptably safe for patients aged 13 to 17 years with bipolar disorder. Vitiello noted that olanzapine is associated with greater weight gain and metabolic disturbances than the other 2 drugs under consideration by the panel.

“Not all the patients respond to the [currently approved] medications,” Vitiello said. “It's good for clinicians to have a choice of drugs to improve treatment for patients.”

Many panel members also expressed concern that the antipsychotic drugs approved for bipolar disorder might be given to patients who do not meet the criteria for the disorder as outlined in the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (DSM-IV), said Wayne K. Goodman, MD, a panel member and director of the NIMH Division of Adult Translational Research and Treatment Development, in an interview. Goodman explained that there is a debate among psychiatrists about whether children with bipolar disorder present differently than adults, and some physicians are using looser criteria for diagnosis. If these looser criteria were used widely, many more children would be exposed to these drugs and their potentially serious risks, he noted. For example, some children with mood disorders, emotional dysregulation, attentional problems, or conduct disorder may be diagnosed with bipolar disorder under this wider definition and might receive antipsychotic drugs that may not be the best choice for them, he said.

Based on this concern, the committee asked the FDA to ensure that the label narrowly defines bipolar disorder based on the DSM-IV's criteria, and the FDA agreed to do so, Goodman said.

The FDA itself will ultimately decide whether to approve the drugs for these indications, but the agency usually follows an advisory committee’s advice.

While the agency weighs the panel's recommendations, Vitiello recommended that physicians become familiar with the potential risks and benefits of medications used to treat schizophrenia and bipolar disorder in children. He suggested that understanding the distinct safety profile of each of these drugs should help physicians match patients with the most appropriate medication. For example, he said, physicians may wish to avoid using a drug that is known to cause substantial weight gain or metabolic problems in a patient who is already overweight or who has diabetes.