Stephen Spotswood U.S. Medicine January, 2007
Silver Spring, Md.-The Food and Drug Administration (FDA) is considering changing the black box warning labels already present on certain antidepressants to include possible dangers to younger adults, as well as children and adolescents.
FDA’s Psychopharmacologic Drugs Advisory Committee met in D.C. Dec. 13 to sort through the results of an ongoing agency meta-analysis of suicidality data from adult antidepressant trials. It was this same committee, that recommended in September 2004 that the agency put a black box warning label on the majority of selective seratonin reuptake inhibitors (SSRIs), a popular class of antidepressant, stating that there was a danger of increased suicidal ideation and behavior among children and adolescents younger than 18 years old who were taking the medication.
Meanwhile the committee’s discussion at their meeting last month revolved around whether to extend that warning to anyone 24 years of age and younger. The topic drew no less interest from members of the public this time around, and the hearing room was full, with nearly 70 people testifying during the open public hearing portion of the meeting. Public testimony was very similar to what was heard in 2004-stories of how antidepressants saved a person’s life told back-to-back with stories to the contrary of how a loved one, shortly after beginning treatment on an antidepressant, unexpectedly committed suicide. This time, though, the stories dealt with people of all ages, not just children and adolescents, and many of the speakers said they were representing thousands of others linked through Web sites and chat rooms.
However, Dr. Robert Gibbons, director of the Center for Health Statistics at the University of Illinois and a former member of the advisory committee, signed up to testify to recent studies performed in the Netherlands that showed that when SSRI rates went up, suicide rates went down. And Dr. Carl Salzman, testifying for the American College of Neuropsychopharmacology (ACNP), said that an ACNP study found no rise in completed suicides with use of the drug and that he was concerned stronger FDA warnings will have the unintended consequence of physicians being wary to provide the drug when it is appropriate for a sick patient.
A lawyer, Derek Braslow, told the committee that his “entire practice is representing people hurt by these drugs,” and scoffed at “the myth that we shouldn’t warn doctors because we’ll discourage treatment.
“The point is to give the doctors the information,” he said. “Your job here is not to promote treatment, but to give doctors the risks and the benefits.”
This was the divide that drove much of the committee’s discussion: whether a stronger warning would scare physicians away from prescribing a drug that might be beneficial to a patient and actually cause more harm than the possible side effects of the medication.
FDA did provide evidence for a wider-ranging signal showing increased suicidal thought and behavior among young adults taking SSRIs. The meta-analysis showed that the odds ratio for suicidal behavior and ideation among those under 18 taking medication versus those not taking medication was 2.22. That ratio dropped to 1.55 in the age group 18 to 24, while still constituting a 50 per cent increase over those not taking the drug in that age group.
According to that meta-analysis, the ratio continues to drop as the age groups progress, to an even ratio for those 25 to 30, a ratio of .77 for those 31 to 64 and a ratio of .39 for those 65 years of age and older. This makes the risk lower for those over 30 in the studies who took the drugs as compared to those over 30 who did not.
Dr. Thomas Laughren, director of FDA’s Division of Psychiatry Products, summarized that FDA was finding that the increased short-term risk for suicidality with antidepressant treatment extended beyond pediatric patients into younger adults up to age 25.
“We’re not seeing that finding extending beyond that age,” he explained. He added that, beyond age 30 antidepressants began to show a “protective effect for suicidality,” which is most pronounced beyond age 65.
“I think what this data says is that there’s something going on with antidepressants that causes suicidality and it’s more prevalent in young adults than older and we can’t ignore it,” Dr. Laughren said.
Dr. Laughren told the committee that FDA was considering changing the black box label to extend the warning language for suicidality risk up to age 25, as well as possibly add in language that explains the protective effects beyond age 30-the latter change to mitigate any unintended discouraging of physicians prescribing the drug if it were appropriate.
Dr. Robert Temple, director of FDA’s Office of Drug Evaluation, said, “If [antidepressant] use has declined, and it seems that it has, you have to ask what is with this black box that scares people off.”
Was it the danger to patients or the suggestion in the label that patients need to be closely monitored? Dr. Temple questioned.
“If it was the [monitoring], I don’t know what you’re going to do,” he said. “I think that everyone agrees that there has been a decline in antidepressant prescribing, especially among young people. But how do we know what the correct rate of prescribing is? Perhaps some people are too casual and [the black box] discourages that.”
The committee seemed resolved to believe in the inevitability that stronger warnings would translate to reduced use of the treatment and urged FDA officials to investigate better ways of communicating, with physicians and the general public, the risks and benefits of, not just antidepressants, but all medications that FDA regulates.
“The way in which we put out this information has to be so inclusive, we should make physicians feel that they can prescribe this drug and they can monitor patients on this drug and that they can include the families,” said committee member and consumer representative Jean Bronstein, RN. “What I’m hearing from the public is that they want more information readily available at their fingertips.”
The greatest concern among the scientists on the committee, however, was that the available data was too limited to make definitive statements about the connection of adverse effects and age, and that age might be little more than a surrogate for an as-yet unidentified biological process.
“We seem to be focusing on these ages as if we think it’s age that’s really doing this,” said Dr. Delbert Robinson, committee member and associate professor of psychiatry at Zucker Hillside Hospital in Glen Oaks, N.Y. “I think age is a proxy for biological mechanism. Magically, 24 is not different from 26 [in regards to] biological mechanisms.”
Any number of variables could be involved in the different reactions patients have to antidepressants, Dr. Robinson explained, including comorbidity and substance abuse, neither of which were factored into any of the analyses that were presented by FDA.
“We have very limited data,” he declared. “Age is just the one that gives us a definite signal in certain groups. “When you’re 26, you’re not [necessarily] safe and when you’re 24 you’re not [necessarily] at risk,” he added. “We don’t know what the real reason is and I think it’s important it doesn’t come across as merely age. Just focusing on age gets people into that false sense of security.”
In the end, the committee voted unanimously to recommend that the labeling be changed, and voted six to two in favor of that change being made in the form of an augmented black box. However, no specific language or even age range was recommended.
Committee Chair Dr. Daniel Pine, Chief of Child and Adolescent Research at the National Institute of Mental Health, said, “The public needs to know more than what has already been said in terms of antidepressants and suicidality
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