Demystifying the black box warning on antidepressants: A protocol for safe prescribing in your practice

DR. FERREN is assistant clinical professor of psychiatry and child and adolescent psychiatry at the University of California, San Francisco and based in the Child and Adolescent Services clinic at San Francisco General Hospital.

Staff editors: KAREN BARDOSSI, Senior Editor, and JOHN BARANOWSKI, Editor, Contemporary Pediatrics

The author, manuscript reviewers, and staff editors have nothing to disclose in regard to affiliations with, or financial interests in, any organization that may have an interest in any part of this article.

Although the black box warning, which is rare on medications for pediatric use, is the strongest caution from the FDA to prescribers and patients regarding possible adverse effects, it is not a contraindication to using antidepressants in children. Antidepressant medication is an important treatment for the appropriate pediatric patient. American children and families cannot afford to have pediatricians withdraw from prescribing antidepressants when they are indicated; the risk of psychiatric morbidity and mortality for depressed and anxious children is far greater than the comparatively rare risk of developing suicidal ideation.

As one of the approximately 7,000 child and adolescent psychiatrists in the US,² I commend those of you in primary care pediatrics who screen children for depression and anxiety, develop treatment plans for these disabling disorders, and prescribe antidepressant medication when it is appropriate. It is no surprise to any of you who have tried to refer a patient to a member of my specialty that we are few and far between, depending on where you practice, and we often have a long waiting list or a full practice. The American Academy of Child and Adolescent Psychiatry (AACAP) has been working tirelessly to address the tremendous work force shortage, but no easy solution exists. As a result, more American children are prescribed antidepressants by general practitioners and pediatricians than by child psychiatrists.³ The guidelines presented here are designed to decrease your anxiety about prescribing antidepressants and encourage you to continue to provide this important intervention to children who may otherwise have no access to medical treatment for psychiatric disorders.

A chronology of the SSRI controversy

In May 2003, the FDA and the United Kingdom's Medicines and Healthcare Products Regulatory Agency received a report from GlaxoSmithKline regarding the efficacy and safety of paroxetine (Paxil) in pediatric populations. One of three clinical trial data sets submitted suggested an increased risk of "possibly suicide related" events and "suicide attempts."⁴ Subsequently, the FDA issued its first Public Health Advisory recommending that paroxetine not be used in children and adolescents with depression and requested data on eight other antidepressants.⁴

When summary data did not provide conclusive answers, the FDA solicited patient-level pediatric data; sought an independent, external review and classification of suicidality events by experts at Columbia University; and issued a second Public Health Advisory and talk paper noting "an excess in reports of suicidality for several antidepressants."⁴ By July 2004, the completed Columbia University analysis concluded that there was a small but real effect. Two months later, the discussion moved from the scientific community to the political arena when the US House of Representatives' Energy and Commerce Committee's Subcommittee on Investigations and Oversight held its first hearing on disclosure and publication of the clinical trials data. In addition, the FDA's Psychopharmacologic Drugs and Pediatric Advisory committees recommended a black box warning, and the House subcommittee demanded immediate FDA action. Lastly, two representatives threatened to introduce legislation banning the prescribing of antidepressants to anyone under 18 years of age if the FDA did not "act forcefully and swiftly to protect America's children."⁴ This culminated in the issuance of the black box warning on October 15, 2004.

The evidence for using antidepressants in children

Two months before the FDA issued the black box warning, the Journal of the American Medical Association published the Treatment for Adolescents with Depression Study (TADS), which provides the strongest evidence to date of the effectiveness of antidepressants in pediatric patients. TADS concluded that 71% of adolescents studied responded positively to a combination of cognitive behavioral therapy (CBT) and fluoxetine (twice the 35% placebo rate), and 60% responded positively to fluoxetine alone.⁵ For every three patients treated, therefore, one will improve from the effects of medication, one will improve because of a placebo effect, and one will not improve. This study is especially significant because demonstrating efficacy in pediatric patients presents a number of challenges:

Because of these challenges, TADS has become a professional counterargument to the sociopolitical forces that fuel the decline in prescribing antidepressants to children.

The rationale behind the black box warning

The Columbia University experts on suicidality consulted by the FDA retrospectively conducted a meta-analysis of 24 placebo-controlled trials of nine antidepressants of less than four months duration that enrolled 4,400 pediatric patients with major depressive, obsessive compulsive, and other psychiatric disorders. They concluded that the average risk of developing suicidal ideation while taking antidepressant medication was 4%, compared to a 2% risk while taking placebo.¹ One in 50 children, therefore, developed suicidal ideation that could be attributed to antidepressant medication-although there were no completed suicides among the 4,400 patients.

In the opinion of one epidemiologist-general pediatrician member of the FDA Pediatric Advisory Committee, published to coincide with the issuance of the FDA directive: "Some FDA staff and committee members expressed reservations about the data used for this analysis. For example, there was a relatively small number of events, the trials had not been designed to evaluate suicidality, and the methods of ascertainment and classification of the events in the various trials were not uniform. To me, however, these concerns only made the results more compelling. Inadequate sample size and misclassification of outcomes make it more-not less-difficult to detect differences between outcomes in randomized, blinded trials. The fact that an association emerged from the meta-analysis with a p value of 0.00005, for an outcome that the sponsors of the trials were not looking for, and presumably did not wish to find, was quite convincing."⁶

Two weeks after the FDA's directive, the president of the AACAP sent a letter to members asserting: "It should be noted that only 78 of the 4,400 patients experienced suicidal thinking or suicidal behavior, but no suicides occurred in these trials.... The FDA research has shown a 2% increase [in suicidal ideation] over that created by the use of placebo...[Coupled with the findings of the TADS study,] on average each practitioner would need to treat just three patients to see a strong response to fluoxetine...in contrast to the need to treat over 50 patients in order to see evidence of the medication causing suicidal ideation or suicidal behavior."⁷

These opinions from professionals in leadership positions regarding the risk-benefit ratio of antidepressants for children illustrate the two poles of the ongoing debate.

Professional organizations respond

Soon after the FDA issued the black box warning, the American Academy of Pediatrics (AAP) voiced its support but urged the FDA to reconsider and alter the warning to preserve patient safety and decrease liability concerns.⁸ Specifically, the AAP expressed concern that:

The Assembly of Regional Organizations of Child and Adolescent Psychiatry, a subgroup of AACAP, wrote: "This decision will frighten and confuse parents, families, and legal guardians and reduce the likelihood that they will seek treatment for their children with psychiatric disorders. Others may discontinue effective treatment...We are also concerned that pediatricians and family practice physicians will become more reluctant to prescribe these medications, only further restricting the availability of help to youngsters in need."⁹