SSRI Prescriptions to Youth On Decline Since February
It did not take long for the data on prescriptions of antidepressants to children and adolescents to reflect shifting patterns as physicians reacted last spring to the potential connection between SSRIs and suicidal thoughts and behaviors. Now, serious concerns are being expressed about the probable impact of a “black-box” warning, jointly recommended last month by two Food and Drug Administration (FDA) advisory committees (see page 1).
Data from Medco Health Solutions Inc. show that within roughly six to eight weeks of the FDA's February 2 joint meeting of the Psychopharmacologic Drugs Advisory Committee and Pediatric Advisory Committee investigating a possible connection between antidepressants and increased suicidal thoughts and behaviors in children and adolescents, there was a dramatic decrease in the number of patients under age 18 who filled antidepressant prescriptions.
Medco is one of the nation's largest pharmacy benefit managers, providing prescription benefits to some 60 million Americans a year, 3.5 million of whom are under 18.
The data show that at the end of the first quarter of 2004 (March 31), the number of patients under age 18 receiving antidepressants dropped by 18 percent, compared with the quarter ending December 31, 2003. That decline was followed by an additional 5 percent decrease by the end of the second quarter of 2004 (June 30).
These declines starkly contrast with the steady increases in prescriptions for antidepressant (and other psychotropic) medications each quarter for the last several years. In May Medco released another analysis showing a dramatic 77 percent increase in prescription-drug spending for behavioral conditions in children and adolescents between 2000 and 2003. That analysis attributed the rise to both increased costs and increased numbers of prescriptions.
The Medco analysis, commissioned and first reported by the New York Times on September 21, “appears to support [the idea] that information and education is a powerful tool to improve our health care delivery system,” said Robert Epstein, M.D., Medco's chief medical officer, in a prepared statement.
The Psychopharmacologic Drugs and Pediatric advisory committees' recommendation in favor of a black-box warning—the strongest possible short of a contraindication—was the result of an often impassioned and, by some descriptions theatrical, joint hearing September 13 and 14.
During that meeting, FDA officials presented data from IMS Health that appeared to show not a decrease in antidepressant prescriptions, as do the Medco data, but a 7 percent increase in the six months following the February meeting and the subsequent warnings. Some committee members said they believed the prior warnings had had no effect and wondered whether more drastic warnings were needed.
In the end, the committees' vote on the black-box warning was 15-8 in favor of adding it to the labels of all antidepressants marketed in the United States. While the advisory committees did not discuss specific labeling, they were asked by the agency whether they supported general phrases regarding increased risk and need for closer monitoring and observation.
Members of the committees seemed to take to heart many of the concerns expressed by those speaking during the public-comment portion of the hearing, including several representatives of APA and the American Academy of Child and Adolescent Psychiatry (AACAP). (See box for details on APA and AACAP efforts regarding SSRIs in children.) In a statement issued September 16, APA expressed support for the advisory committees' recommendation that the FDA maintain access to antidepressant medications and noted the hearing “was inclusive and thorough and based on science and concern for patients and parents.”
APA said, “The advisory committees have established a strong case for closer monitoring of patients with depression, especially vulnerable youngsters.”
Specifically, the advisory committees concluded that the finding of an increased risk of suicidal thoughts and behaviors in pediatric patients applied to each of the nine drugs studied so far, since there are no adequate data available to exclude any single antidepressant from the risk. The nine drugs are bupropion, citalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, and venlafaxine. Some committee members specifically worried that if only SSRIs carried the black-box warning, some physicians and/or patients and their caregivers might be falsely led to believe that tricyclics are safer, something committee members stated was not necessarily true.
At the same time, the advisory committees strongly urged the FDA to avoid contraindication of the medications for pediatric depression, noting that“ access to these therapies is important for those who could benefit.”
In addition, the committees recommended that all antidepressants be dispensed with a mandatory patient-information sheet or “medication guide” to ensure that not only prescribers are warned by the black-box labeling, but also patients and their caregivers are appropriately advised of the risks, as well as the benefits, of antidepressant therapy.
The committees also recommended that the results of controlled pediatric trials of depression be included in the labeling for all antidepressant medications.
Variability Is Only Constant
At the core of the advisory committees' hearing and votes was the Columbia University analysis of adverse events from 23 clinical trials of the nine antidepressant medications for major depression, anxiety disorders, and ADHD in children and adolescents. The FDA had asked Columbia last spring to reanalyze patient-level data from the trials in an effort to better understand the significance of the apparent signal seen in the summary data from the clinical trials.
The Columbia analysis, which took four months to complete, involved reclassifying all of the reported serious adverse events noted in any of the trials and was aimed at validating each adverse event as a “suicidal event” or “not related to a suicidal event.” After the Columbia reclassification was forwarded to the FDA in July, the agency turned it over to one of its internal experts for interpretation.
Tarek Hammad, M.D., Ph.D., a senior medical reviewer in the Division of Neuropharmacological Drug Products at the FDA Center for Drug Evaluation and Research, concluded that not only was the Columbia reclassification methodologically and statistically sound, but also that the end results were not very different from an original FDA review of antidepressant adverseevent data by FDA medical reviewer Andrew Mosholder, M.D. (see page 1).
However, Hammad's analysis of the reclassified data from Columbia involved much more sophisticated statistical analyses to deal with a complex and heterogeneous database that originally had not been developed with any intention of determining an association between treatment and suicidal thoughts and/or behaviors. Some members of the advisory committees noted that the analysis helped to clarify and support the credibility of the review process.
In all, Hammad's analysis of the data estimated “the absolute increase in the risk of the event of interest [suicidal thoughts and behaviors] due to treatment for all SSRIs in pediatric major depressive disorder trials at 2 percent to 3 percent.”
More simply put, Hammad reported, “Out of 100 patients treated, we would expect two or three patients to have some increase in suicidality that is due to shortterm treatment with the drug, beyond what would be expected as a result of the disease itself.”
Hammad calculated that the overall relative risk of suicidal thoughts and/or behaviors fell between a low of 1.37 (citalopram compared with placebo) to a high of 8.84 (venlafaxine compared with placebo).
Data Criticized
Hammad and other FDA officials stressed to the advisory committees that any firm conclusions from the available data are difficult to make because of the extreme variability of the data from one drug to another and between individual trials from the same medication.
In fact, when it came time for the committee to vote, the FDA director of medical policy and acting director of the Office of Drug Evaluation I, Robert Temple, M.D., noted, “We don't have the data to make drug-specific informed decisions. We already know you don't have enough data. Our question is, in the face of these limitations, what is your feeling?”
However, the committee members' “feeling” regarding the data was not good enough for many.
“Notwithstanding the vote of the advisory committees,” noted APA Trustee-at-Large David Fassler, M.D., who delivered APA's testimony at the advisory committees hearing, “the data still seem inconsistent and inconclusive. If you look at `suicidal behavior' or `suicidal thinking' alone, there are no significant differences. If you just look at the studies on depression or the studies on anxiety disorders, there are also no significant differences. Only when you combine suicidal behavior and thinking, and you combine the studies on depression and anxiety disorders, do you find a statistically significant increase. But even when you combine all the studies, there is no significant increase in the `emergence' or `worsening' of suicidal symptoms.”
In addition to the inconsistency of the results, none of the clinical trials on which the reanalysis was based was originally designed to detect the events of interest, noted Peter Jensen, M.D., the Ruane Professor and director of the Center for the Advancement of Children's Mental Health at Columbia University. Jensen was not involved in the Columbia reanalysis project.
“So while there seems to be a `signal' for a potential increase compared with placebo in some of the controlled studies,” Jensen told Psychiatric News, “none of these studies used groups where comparisons were made to the natural course of depression itself and where the person did not see a doctor or get a pill, a placebo, or any therapy.”
What About the Children?
Ironically, it was this highly variable and by some accounts inconsistent and unreliable data that some used to bolster their points.
“Studies show that greater caution is needed when treating pediatric and teen depression with medication, and it is clear that physicians are heeding these warnings,” said Medco Health's Epstein, referring to the reported decrease in antidepressant prescriptions following the February hearing of the advisory committees.
Many psychiatrists may not agree that the reported reductions in prescribing are a good thing. In fact, a significant crosssection of the mental health community is concerned about the potentially grave impact of the proposed black-box warnings.
“I think the black box may be excessive and could do more harm than good, if doctors start to withhold treatments where they may be indicated and, in fact, in some instances lifesaving,” Jensen said.
“I have had parents ask questions about the medications that their children are on, especially those who are doing well and don't want any changes made,” said Paramjit Joshi, M.D., chief of child psychiatry at Children's National Medical Center in Washington, D.C. “Some new patients' parents are reluctant to have their child placed on an SSRI. The pediatricians are definitely feeling more uncomfortable in prescribing these medications, which raises the issue of access to care, given the low numbers of child and adolescent psychiatrists.”
“The sense of reluctance on the part of clinicians to prescribe SSRIs to kids will undoubtedly grow,” added Christopher Kratochvil, M.D., a professor of child and adolescent psychiatry at the University of Nebraska Medical Center. “Pediatricians have been reluctant already. Now this will only serve to cement that feeling.”
Information on the September 13 and 14 hearing is posted online at<www.fda.gov/ohrms/dockets/ac/cder04.html#PsychopharmacologicDrugs>. The FDA's analysis of Columbia University's reclassification of adverse events is posted online at<www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4065b1-10-TAB08-Hammads-Review.pdf>.▪
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Published online: 15 October 2004
Published in print: October 15, 2004
Notes
Conflicting emotions, combined with uncertain data, led to the FDA advisory committees' arriving at a split vote recommending black-box warnings for antidepressants. Now concerns about the drugs' safety could make a difficult situation worse.
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