Antidepressant Black-Box Warnings Alter Pediatric Prescribing

SAN DIEGO, April 2 -- For better or worse, pediatric antidepressant prescriptions dropped 18.6% following an FDA hearing in 2004 that led to a black box warning a month later of increased suicidality risk, according to researchers here.

Although the downturn tapered off within about six months, lasting changes have been seen in practice patterns, reported Amir Kalali, M.D., of the drug development services company Quintiles, and colleagues, in the April issue of Archives of General Psychiatry.

In their analysis of a large prescription database, minors are now more likely to be treated for depression by psychiatrists than generalists.

The proportion of prescriptions doubled for bupropion (Wellbutrin) after the warnings but fell more than 15% for selective serotonin reuptake inhibitors (SSRIs), they found.

The researchers said they could not comment on whether the decrease in prescription volume was appropriate. However, "the epidemiology hasn't changed," said Dr. Kalali, who is also a psychiatry professor at the University of California in San Diego. "There are probably patients that need care that aren't getting care."

Previous studies on changes in prescriptions following the warnings had conflicting results. One presented at an FDA meeting suggested a continued increase whereas two others subsequently suggested a decrease.

To get a "more definitive look," the researchers examined the Verispan database linking retail pharmacy chains and some insurance companies. It covers 55% of all U.S. retail prescription claims, including private payers, Medicaid and cash transactions for a total of more than 1.4 billion prescriptions per year.

The FDA first issued a public health advisory on elevated risk of suicidal behavior and attempts in October 2003, which was followed by a hearing in February 2004.

The researchers found that the number of prescriptions to patients younger than 18 continued to increase until the February hearing (0.79% a month, 95% confidence interval 0.45% to 1.13%, P<0.001 for change from April 2002).

After the hearing and the subsequent black-box warning for SSRIs and newer antidepressants issued in March 2004, prescriptions decreased by 4.23% per month (95% CI ?8.44% to 0.18%, P=0.06).

The researchers attributed the wide confidence interval "to the seasonality of the data and a natural decrease in antidepressant prescription volume in the summer months."

The absolute change in the Verispan database was 18.6% from 851,000 prescriptions in February 2004 to 693,000 in August 2004.

Starting even before the FDA panel met again in September 2004 to discuss the full data, though, the pediatric antidepressant market stabilized with no significant changes in the number of prescriptions from July 2004 to March 2005 (95% CI ?1.16% to 1.48%, P=0.92).

Since then, the number of prescriptions has begun to rise again, said coauthor Elisa F. Cascade, M.B.A., of Quintiles in Research Triangle Park, N.C., based on unpublished data.

For older patients, only modest changes were seen in prescription volume. The findings were:

• An increase of 0.48% per month among 18- to 25-year-old patients before the black-box warnings (95% CI 0.27% to 0.70%; P<0.001),
• A decrease of 0.72% per month among patients age 18 to 25 after March 2004 (95% CI ?1.29% to ?0.14%, P=0.02), and
• No significant change among patients ages 26 or older (P=0.98).

These prescribing changes from generalists to psychiatrists may have an impact on access to care for children and teens, Dr. Kalali and colleagues noted.

"Although the number of depressed individuals younger than 18 years is small relative to the broader population," they wrote, "anecdotal evidence suggests overdemand for specialist services and, as a result, longer than historically observed waiting times for appointments."

Classes of antidepressants prescribed to the pediatric population also changed. Comparing the proportion of prescriptions in February 2004 versus February 2005, the researchers reported:

• A decrease in SSRI use (74.5% versus 57.9%).
• An increase in venlafaxine (Effexor) and duloxetine (Cymbalta) use (2.5% versus 5.8%).
• A doubling in use of bupropion, mirtazapine (Remeron), and trazodone (Desyrel) collectively (10.7% versus 20.8%),
• A decrease in use of tricyclic agents (2.8% versus 6.1%),
• Little change in use of stimulants (2.1% versus 2.3%), and
• A reduction in use of atypical antipsychotic agents (7.4% versus 3.0%).

These changes were not seen in the adult population.

"While bupropion and tricyclic agents have demonstrated efficacy in treating depression in adults, neither of these products (nor gabapentin [Neurontin]) is approved for use in depression in pediatric patients," they cautioned.

However, Dr. Kalali's findings are consistent with general clinical experience, said David Fassler, M.D., of the University of Vermont in Burlington. He was not involved in the study but has testified to the Senate on behalf of the American Academy of Child and Adolescent Psychiatry (AACAP) and American Psychiatric Association (APA) on the topic.

"The publicity and media coverage surrounding the FDA hearings and advisories clearly contributed to the significant reduction in = the use of SSRI antidepressants in the treatment of children and adolescents," he added.

The findings are of particular concern in the context of the "unexpected and disconcerting" 18.2% increase in the adolescent suicide rate from 2003 to 2004 reported by the CDC in the February 2007 issue of the journal Pediatrics, Dr. Fassler said.

"Based on the data currently available, it would be premature to conclude that there's a definitive causal relationship with the rate of prescriptions for SSRIs," he said.

While not all children with depression need to be treated with medication, he said, "the dramatic reduction in prescriptions clearly suggests that there are children and adolescents with depression who no longer have access to the full range of effective and appropriate treatment options."

"The current study underscores the importance monitoring the impact of regulatory decisions on practice patterns, access to care and public health outcomes, and of revisiting specific actions when and if warranted by subsequent data and research findings," he concluded.