The U.S. Food and Drug Administration (FDA) has approved the use of
risperidone (Risperdal) in children and adolescents to treat schizophrenia and
mania or mixed episodes of bipolar I disorder, making it the first atypical
antipsychotic drug approved for either disorder in young patients.
The FDA announced last month that risperidone is approved for the treatment
of schizophrenia in adolescents aged 13 to 17 and for the short-term treatment
of manic or mixed episodes of bipolar I disorder in children and adolescents
aged 10 to 17. Risperidone was approved in October 2006 for treating
irritability associated with autistic disorders in children and adolescents
aged 5 to 16 years.
The approval is based on clinical studies conducted by the manufacturer,
Janssen, a Johnson & Johnson subsidiary, at the request of the FDA under
the federal Best Pharmaceuticals for Children Act (BCPA). Previously, the FDA
had not approved an antipsychotic drug for treatment of schizophrenia in
younger patients, and only lithium had been approved for the treatment of
bipolar disorder in children as young as 12. The BCPA provides an incentive
for drug companies that are directly asked by the FDA to conduct much-needed
drug trials in children by extending drug patents or exclusivity period for
This approval is notable because antipsychotic drugs have been prescribed
in an off-label manner for children and adolescents for many years, with
little evidence-based guidance. Randomized, blinded, controlled studies of
these drugs in pediatric populations have been rare. Practitioners have to
rely primarily on the drugs' known effects in adult patients and anecdotal
information in children while using a trial-and-error approach.
Two studies lasting six and eight weeks were conducted on a total of 417
patients aged 13 to 17 with schizophrenia. Risperidone at a dosage ranging
from 0.15 mg/day to 6 mg/day resulted in significantly greater reduction in
total Positive and Negative Syndrome Scale (PPANSS) scores than did placebo.
Most notably, dosage higher than 3 mg/day did not lead to better efficacy, but
increased the number of adverse events.
A third study, this one lasting three weeks, was conducted in 169 children
with bipolar I disorder aged 10 to 17 who were experiencing a manic or mixed
episode. The two dose groups treated with risperidone had a significantly
greater reduction in Young Mania Rating Scale (YMRS) scores than the placebo
group. The dose group who received 3 to 6 mg/day of risperidone did no better
than the group who received 0.5 to 2.5 mg/day.
"Schizophrenia and bipolar disorders are severely disabling to
patients and devastating to their families," said APA President Carolyn
Robinowitz, M.D., in a press release in response to the FDA approval."
For many children with these disorders, the FDA's action today provides
additional information to guide treatment options in these special
populations. We anticipate that the approval of this medication will encourage
federal research agencies to accelerate urgently needed studies of mental
disorders in children."
The off-label use of psychoactive drugs in younger patients and the lack of
adequate clinical evidence in this population have been sources of
controversy. The varying degrees of suicide risk associated with
antidepressant use among pediatric and adolescent populations and adult age
groups is an example of the complex effects that require more clinical
studies. Misconceptions about mental illness have exacerbated public confusion
over medications to treat these disorders.
In recent years, atypical antipsychotics have been the subject of emerging
safety concerns, especially regarding glucose metabolism and significant
weight gain, which led the FDA to mandate a label warning for all atypical
antipsychotics (Psychiatric News, October 17, 2003).
These adverse effects in adult patients were similarly observed in
pediatric studies. Weight gain linked to risperidone was reported in 14
percent of 103 patients who participated in the long-term, open-label
extension of one of the schizophrenia studies assessed by the FDA. The average
weight increase was 9.0 kg (19.8 lb) after eight months. In the three-week
clinical trial of children with bipolar I disorder, a significantly higher
weight gain was seen in the risperidone group than in the placebo group.
Another notable adverse effect seen in pediatric as well as adult patients
taking atypical antipsychotics is elevated prolactin levels, which were as
frequent as 87 percent in these pediatric trials. Milk production and enlarged
breasts have also been reported.
The recommended risperidone dosage for adolescents with schizophrenia is
initially 0.5 mg daily, titrated upward by 0.5 to 1 mg daily depending on
tolerability, up to a maximum of 3 mg daily. For the treatment of bipolar
mania in pediatric patients, risperidone should be initiated at 0.5 mg once
daily and titrated upward by 0.5 to 1 mg daily as tolerated, to a target dose
of 2.5 mg daily.
Thomas Laughren, M.D., director of the FDA's Division of Psychiatry
Products, and Dianne Murphy, M.D., director of its office of Pediatric
Therapeutics, both emphasized at the press conference that the dose and
response data obtained from these studies provide important insight for
practitioners when they treat younger patients. A key finding "is that
there didn't seem to be any higher efficacy from the higher doses compared to
the lower doses," said Laughren. "We see this as a major benefit
coming out of the pediatric program, which is a better understanding of dose
Laughren acknowledged that the agency's requests for pediatric studies had
been issued for other antipsychotics and that studies of those drugs are
underway or under review.
The updated prescribing information for risperidone is posted at<www.risperdal.com/risperdal/shared/pi/risperdal.pdf>.▪