FDA Tries to Bridge Data Divide With New Antidepressant Warnings

March 3, 2007
Stephen Barlas

Volume 24, Issue 2

The FDA finds itself straddling a data divide as it decides how to rewrite the black box warnings on the labels of SSRI antidepressants. The agency will almost certainly mandate that the existing black box warning, which addresses suicidality in children and adolescents, be expanded to include young adults up to age 25 or 30. But in what might be a pioneering move for the FDA, the agency will probably also include new verbiage in the warning related to the benefits of antidepressants to people over the age of 30 years.

The FDA finds itself straddling a data divide as it decides how to rewrite the black box warnings on the labels of SSRI antidepressants. The agency will almost certainly mandate that the existing black box warning, which addresses suicidality in children and adolescents, be expanded to include young adults up to age 25 or 30. But in what might be a pioneering move for the FDA, the agency will probably also include new verbiage in the warning related to the benefits of antidepressants to people over the age of 30 years, according to Thomas P. Laughren, MD, director, division of psychiatry products at the agency.

Laughren talked with Psychiatric Times a week after the FDA's Psychopharmacologic Drugs Advisory Committee (PDAC) recommended changes to the black box warning that was added to antidepressants in January 2005. The PDAC meeting on December 13, 2006, featured 2 internal FDA studies on antidepressants and potential suicidality in the adult population. The studies showed that there was an increased risk among young adults aged 18 to 24 years and a decreased risk for an older group. There were also references to recent publications of data showing suicides in children trending upward and lower suicide rates in areas that had higher
SSRI use.

In the interview, Laughren said, “What we heard from [the] advisory committee concerned the current language in the black box warning having an inhibiting effect on prescriptions of antidepressants, which was never our intent. We will take a careful look at how we can redo the language to give it more balance.”

The American Psychiatric Association (APA) continues to have doubts about the overall benefits of a black box warning for any population group. “While we remain concerned about the impact of any addition to the black box, we applaud the advisory committee's suggestion that, for the first time, the FDA place statements about both risks and benefits within the current black box label,” said Carolyn Robinowitz, MD, president-elect of the APA.

Jason Young, a spokesperson for the APA, added that the group believes that black box warnings should be “scientific,” a standard they currently fail to meet because they neglect to mention data on suicidal thinking in untreated patients. Young suggested that the APA would like to see any expanded black box warning display 2 numeric values next to one another: the chances of suicidal thoughts while taking antidepressants versus the chances among untreated
patients. “That would be very different from the current pediatric label,” he said.

At the end of the December 13 PDAC meeting, the 8 members of the advisory committee who attended the sometimes emotional all-day meeting voted twice. The first time, they agreed unanimously that the FDA should extend application of the current black box warning to a slightly older population, perhaps to age 25 or 30. That was based on the results of the two FDA studies presented and debated during the meeting, which showed the risk of suicidality-not actual suicides-to be 4 to 6 per 1000 patients in the 18 to 24 age group. That compares with a risk of 14 in 1000 patients under the age of 18 who are being treated with antidepressant drugs.

Wayne K. Goodman, MD, professor and chairman of the department of psychiatry, McKnight Brain Institute of the University of Florida, a member of the PDAC and its former chairman, said that “the magnitude of the incremental risk for patients in the 18 to 24 age group is modest.”

But Goodman voted to extend the black box warning for patients up to age 25. He and 5 others voted for that warning to be in the form of a black box. Two of the 8 members of the PDAC voted against that step. In the context of rewriting the current black box warning, Goodman suggested, and a majority agreed, that the FDA should be urged to accompany the warning with a reference to the fact that the risk of suicidality in untreated depression is higher than the risk observed in clinical trials among those given placebo.

The current black box warning, which was written before the new data on suicide became available, makes no mention of the benefits of antidepressants to untreated patients, or even the importance of getting treatment for depressive disorders. Its first 2 sentences read: Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of [Insert established name] or any other antidepressant in a child or adolescent must balance this risk with the clinical need.

The reference to the need to balance the risk of suicide with “the clinical need” is the only allusion in the warning, or in any of the other key sections of the labeling, to the fact that antidepressants can alleviate depression. The PDAC apparently wants to provide physicians with a much stronger recognition of that fact in whatever new labeling the agency asks antidepressant manufacturers to adopt.

That desire was based on information on suicides recently released by the CDC and a group of academics who published an article in the November 2006 issue of the American Journal of Psychiatry titled “The Relationship Between Antidepressant Prescription Rates and Rate of Early Adolescent Suicide.” The lead author was Robert D. Gibbons, director, Center for Health Statistics and professor of biostatistics and psychiatry, University of Illinois at Chicago.

Gibbons and coauthors found that suicide rates among children aged 5 to 14 years during the period 1996 to 1998 were lower in counties with higher SSRI prescriptions. The CDC data were more recent (its numbers were from 2004). Gibbons said that although the FDA asked companies to put black box warnings on antidepressants in 2005, the CDC statistics for 2004 are still valid because SSRI prescriptions were already nose-diving in 2003 and 2004 because of media attention to a possible link between that category and increased risk of suicide.

Goodman believes that it is critically important to alert families and patients that it is dangerous to accept the arguments of scientologists and other anti-psychiatry groups who argue that clinical trial data show that placebo groups do almost as well as treated groups-the implication being that antidepressants aren't worth much. Goodman argued that it is misguided to extrapolate results for patients treated with placebo inside clinical trials, where they benefit from a medical safety net and all sorts of care advantages, to the results that can be expected for untreated patients outside clinical trials, who of course are most of the people in the United States with major depressive disorder.