Thursday, December 14, 2006

FDA Panel Urges Changes to Antidepressant Labeling

(HealthDay News) -- A U.S. Food and Drug Administration advisory panel recommended Wednesday that "black-box" warnings on widely used antidepressants be changed, but the exact wording on the warning is still up in the air.

The issue at hand was whether current warnings on an increased risk for suicidal thoughts and behaviors in children and adolescents should be extended to young adults, or even older patients.

All eight members on the panel advocated some kind of change in labeling after a day-long meeting, according to an FDA press briefing held late Wednesday. But in the end, six members voted to extend the current suicide warning beyond children, but no exact age cut-off was specified.

"The vote that we took was on two issues: No. 1 was, 'Is there a need to change the current labeling?' And there was a unanimous vote in favor. And issue No. 2 was, 'Should that change be made within the black box?' And once again we voted in favor," said panel member Dr. Daniel Pine, chief of child and adolescent research at the National Institute of Mental Health.

"There was a great deal of discussion -- but no presentation and no vote -- of the specific wording of what would go into this," he added.

That uncertainty included setting any age limit for the warning at this point in time. "The committee discussed the issue [of an age cut-off] but did not vote on it, Pine said. "Opinions were mixed."

Pine added that the FDA and the panel members agreed that "the level of detail in the data was such that it was not possible to give a precise age at which it was particularly concerning in terms of the association with suicidal thoughts or behavior, or not concerning."

Discussion on a more precise wording is set for the near future, the panelists said.

"The committee generally endorsed what we [FDA] had done and agreed with our interpretation of data," added Dr. Thomas Laughren, director of the division of psychiatry products at the FDA's Center for Drug Evaluation and Research. "The general agreement is that there does appear to be an age-related causal link to suicidality, but there was a lot of discussion about the need to do further research to find the basis for the apparent relationship.

There was also a good deal of concern on the effect black boxes may have had on discouraging appropriate prescribing."

Outside experts echoed that concern.

Although the recommendations were based on fears that taking antidepressants could increase the risk of suicide ideation, many psychiatrists worry that the "black-box warning" will backfire -- resulting in more suicides as patients shy away from depression treatment.

Expanding the warning "will increase the completed suicide rates," said Robert D. Gibbons, director of the Center for Health Statistics and a professor of biostatistics and psychiatry at the University of Illinois in Chicago. His research found an increase in completed suicides in children after the black-box warning was added.

Gibbons also pointed out that current black box warnings, although intended only for children and adolescents, have caused a decline in SSRI prescription rates for adults as well as in those for the younger age group.

Others agreed. "The existing black box warnings for children and adolescents has clearly steered people away from both prescribing these drugs, and from patients and families being willing to accept treatment," said Dr. Norman Sussman, a professor of psychiatry at New York University School of Medicine in New York City. "It'll probably happen in terms of a global effect with adults as well."

"The FDA's decision to implement black box warnings for all antidepressants in pediatrics has led to a precipitous decline in prescriptions," added Dr. David Fassler, a child and adolescent psychiatrist in Vermont and a trustee of the American Psychiatric Association. "I'm concerned that there are many young people with depression who are not currently receiving appropriate and effective treatment. My own hope is that the FDA exercises caution before deciding to extend this warning to the use of these medications with adults."

The FDA is not obligated to follow the recommendations of its advisory committees but usually does.

SSRIs, the class of antidepressants that includes Prozac (fluoxetine) and Paxil (paroxetine), have been the subject of intense controversy in recent years.

In October 2004, the FDA directed manufacturers of SSRIs to revise their labeling to include a black-box warning that alerts health-care providers to an increased risk of suicide and suicidal thoughts in children and teens.

In July 2005, the FDA issued a public health advisory that raised the possibility that the risk of suicidality also applied to adults taking SSRIs, after several studies pointed to that possibility.
More recently, however, a major new study found that SSRIs have actually saved thousands of lives by preventing suicides since they were introduced in 1988.

The FDA advisory panel considered an FDA-conducted meta-analysis of 372 studies involving more than 100,000 people taking antidepressants. That analysis found that the drugs might increase the short-term risk of suicidal thoughts and behavior among adults aged 18 to 24.

According to an Associated Press report, the FDA estimated the increased risk to be at as many as 14 additional cases of suicidal thoughts or behavior for every 1,000 children treated with antidepressants. For adults aged 18 to 24, there could be four additional cases per 1,000 people treated.

Some experts, including Gibbons, had questions about the integrity of the data in the review.
"The studies they're basing this on screened out people who were suicidal to begin," Sussman said. "You can't make any kind of inference on how many lives were saved because the depression was treated. They're saying the risk of committing suicide outweighs the benefit [from treatment], and that isn't necessarily accurate."

The panel meeting unleashed a veritable hailstorm of reactions and testimony from families of suicide victims, depressed patients, psychiatrists and activists, even before any recommendation was issued.

According to the AP, Ellen Hanson testified that her husband, Scott, hanged himself in 2004 shortly after starting on Paxil. The couple did not know there might be a suicide risk associated with the drug. "I know he didn't want to be dead," she told the panel. "Even two years later, I feel his death was an accident -- a medical accident."

But even suicidal thinking associated with the drugs is rare, Sussman said. "In reality, it's such a small percentage," he said. "It gets in the media and creates the false impression that these are dangerous drugs."

And one panel member worried that depressed individuals might back away from helpful medications. The solution may lie in close follow-up for all patients, said Dr. Robert Temple, director of the FDA's Office of Drug Evaluation, Center for Drug Evaluation and Research.

"We have a concern that people are not getting treated," Temple said at the Wednesday press briefing. "We think everybody at the time they are started on antidepressants ought to be observed closely because it's a dangerous time. This applies to everybody, even those over 65."
"We persist in believing that that's an important enough message that we don't want to discourage appropriate use," he added. "But we still think it needs an appropriate warning."

More information
There's more on the use of antidepressants in children and adults at the FDA.

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