FDA Actions on Antidepressants and Suicidality: 10 Years Later
This is the first of a two-part series on the 2004 FDA hearings on antidepressants and suicidality in adolescents. Part two will focus on the effect of the antidepressant label warning on prescribing and adolescent health.
“Emotions ran very high,” said Matt Rudorfer, M.D., recalling hearings 10 years ago when a Food and Drug Administration (FDA) advisory board heard testimony about the risk of suicidality associated with antidepressant use in adolescents. Rudorfer, associate director for treatment research in the Division of Services and Intervention Research at the National Institute of Mental Health, was chair of the advisory committee at the first hearing in February 2004 and served as a consultant at a second hearing in September 2004.
“There was an unusually large number of public attendees including, most dramatically, a number of family members who had lost relatives, usually children, to suicide, and who were concerned that antidepressant medications their children had been taking were responsible,” Rudorfer told Psychiatric News. “It became apparent that many were quite angry and in some cases blamed either the FDA or the pharmaceutical companies. So there was an unusual kind of tension at the meeting—on the one hand it was a discussion about science and pharmacology and medical practice such as is usual at meetings like this, and on the other hand there was this very palpable sense of public concern and anger.”
He recalls an image from those meetings that now seems emblematic of how an extraordinarily complex topic—about suicide and suicidal thinking and their relationship to depression and/or the effects of antidepressants—would be clouded by emotion and media attention.
Text of Antidepressant Black-Box Warning
The boxed warning on antidepressants currently says, “Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of [drug name] or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber.”
An FDA spokesperson told Psychiatric News, “It is important to note that the FDA’s most recent changes to the prescribing information, or labeling, for antidepressants seeks to balance the suicidality warning language with a reminder that depression is a serious illness that itself is the major risk factor for suicidal thoughts and actions.”
“The picture that comes back to my mind was of a security guard on the sidelines,” he said. “That was not so remarkable—except for the presence of his sidearm. It seemed to announce that this was an unusual scenario and one with a potential for violence.”
The advisory panel voted 15-8 in September 2004 to approve the inclusion of a boxed warning on labeling for antidepressants about a potential risk for suicidality, cautioning clinicians to closely monitor their young patients taking antidepressants. Three years later, in May 2007, the boxed warning was updated, extending the warning to include young adults aged 18 to 24 (see box for wording of the FDA language and FDA commentary).
From the beginning, and in the decade since, APA has protested the warning, predicting that it would prevent parents from seeking care for their children—and clinicians from prescribing antidepressants—and insisting that by far the greater danger was untreated depression.
“We are concerned that the publicity surrounding this issue may frighten some parents and discourage them from seeking help for their children,” child psychiatrist David Fassler, M.D., told the 2004 panel. “The most important point that I can make is that the biggest risk for a child with depression is to be left untreated.”
But the atmosphere at the 2004 hearings, which also attracted the inflammatory presence and rhetoric of members of the Church of Scientology, was one that required a different approach for groups like APA hoping to have their voices heard. “We had an opponent [in Scientology] with a well-publicized antipsychiatry agenda,” said APA Chief Communications Officer Jason Young, who was involved in shaping APA’s response to the hearings. “We understood that we could not just select one person to testify and expect that person to carry the organization’s message. We worked with NAMI, Mental Health America, and scores of other groups to coordinate our response.”
One fruit of that collaboration was creation of an information website—ParentsMedGuide.org—sponsored by the American Psychiatric Association and the American Academy of Child and Adolescent Psychiatry, with information about a range of mental health topics and specific information about depression, antidepressants, and their benefits and side effects. “With ParentsMedGuide, we could communicate directly with parents and remove some of the hype and mystery by providing science-based information,” Young said.
When it came time for the advisory panel to render a decision at the end of the September hearing, Rudorfer recalled that the scene took on the aspects of theater. “It was quite surreal. When it was my turn [to vote], I leaned into the microphone and said ‘no’ [to the boxed warning]. I said I had two main concerns—I thought the quality of the data [the FDA had to work with] was not good, and I said that after hearing everything, I regarded the risk of untreated depression as greater than any risk we had heard about [antidepressant-related] suicide.” (To hear an audio recording of Rudorfer’s account of the hearings, click here.)
But Rudorfer was in the minority. In the clinical trials to which the FDA had access for registration of SSRIs, there were records for the drug and placebo groups showing a higher rate of suicidal ideation—however that ideation might have been expressed—in the drug-treated cohorts. (The hearings examined data on SSRIs and SNRIs, but the warning was applied to all antidepressants; the committee did not want to create the unintended consequence of causing clinicians to revert to using older antidepressants.)
Thomas Laughren, M.D., who at the time of the hearings was team leader of the Psychiatric Drug Group in the FDA Division of Neuropharmacological Drug Products, told Psychiatric News he believes the data were strong. “We initially looked at the pediatric and adolescent data and found a pretty clear signal,” he said. “We subsequently looked at adult data and overall did not find a signal. But if you stratify by age, there was a consistent signal in young adults.”
He added, “The important thing to keep in mind is that the point of the warning was not to discourage use of antidepressants but to ensure that clinicians were aware of the need to monitor patients.”
Darrel Regier, M.D., M.P.H., who is the former director of the APA Division of Research and testified at the hearings against the warning, noted that there were in fact no actual suicides among the thousands of teens treated in clinical trials reviewed by the FDA panel. Moreover, the FDA data on suicidal ideation associated with SSRI use was based on spontaneous reports, not on studies prospectively designed to systematically define and identify the incidence of suicidal thoughts or behaviors in teenagers taking the medications.
Regier believes the extraordinary media attention the hearings attracted is a case study in how data pertinent to public health can be obscured or distorted by overinterpretation of spontaneous reporting. “I think it calls into question the FDA’s entire system of spontaneous reporting,” he said.
Regier said a promising step is the agency’s adoption, for use in future phase 3 clinical trials, of the Columbia Suicide Severity Rating Scale for any drug that is thought to have some potential for suicidal ideation (including dermatologic drugs such as Accutane).
“I think the solution is more systematic reporting, which the FDA will start to move toward as the agency begins to have access to electronic health records used by large health systems and HMOs,” Regier said. “This will give the FDA access to phase 4–type data on the long-term effects of medication side effects and associations with suicidal attempts and mortality from all causes.” ■
Rosters, documents, and clinical data reviews from the 2004 meeting are available here.
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Published online: 20 November 2014
Published in print: November 8, 2014 – November 21, 2014
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