David A. Brent, MD

 The U.S. Food and Drug Administration, after careful deliberation, concluded that antidepressants convey a 1.8-fold increased risk for suicidal ideation or suicide attempt in patients treated with antidepressants. In response, the FDA mandated that all manufacturers of antidepressants place a "black box" warning about this risk to accompany each prescription of an antidepressant. The increased concern about suicidality and antidepressants in the pediatric age group leads to several questions that must be addressed by clinicians, families and patients.

The FDA commissioned Columbia University to convene an international consensus panel of independent experts in adolescent suicidal behavior in order to review and standardize the classification of adverse events in all available placebo-controlled clinical trials for pediatric depression, anxiety and obsessive-compulsive disorder. The FDA then conducted analyses using these classifications to test if there was an association between medication use and suicidality. Their meta-analysis found a 1.8-fold increased risk for new-onset or worsening suicidal ideation or attempt in patients treated with medication versus those treated with placebo (FDA, 2004).

This association between antidepressant use and emergent suicidality was almost never statistically significant within an individual trial. However, this relationship was statistically significant in the FDA's meta-analysis, and the direction of this effect was consistent in enough different individual studies that the FDA's Advisory Panel concluded that this effect, while small, was real. Almost all of the suicidality-related adverse events reported were either new-onset or worsening ideation, with relatively few attempts and no suicide completions among over 4,400 participants. Moreover, it is important to note that, despite a rapid increase in antidepressant prescriptions for adolescents, the adolescent suicide rate has been declining for the past decade.

The increased risk for suicidal adverse events tended to occur relatively early in the course of treatment. Therefore, the FDA underscored the responsibility of prescribing physicians to educate families and patients about the potential risks and to monitor patients closely during the first 12 weeks of treatment: weekly for four weeks, every other week for the next four weeks and again at week 12.

The FDA's decision to strengthen the warning about the possible side effects of antidepressants rather than issue a statement contraindicating them was predicated on the evidence that these agents are efficacious not only for depression, but also for pediatric anxiety and OCD (Birmaher et al., 2003; Pediatric OCD Treatment Study [POTS] Team, 2004; Pediatric Psychopharmacology Anxiety Study Group, 2001). With regard to depression, the evidence supporting efficacy is strongest for fluoxetine (Prozac), for which there are three positive clinical trials, including the Treatment for Adolescents With Depression Study (TADS), which compared cognitive therapy, fluoxetine, the two treatments combined and placebo for adolescent depression (Emslie et al., 2002, 1997; March et al., 2004). In all three of these studies, the response rate for the antidepressant was 52% to 61% versus 33% to 37% for those treated with placebo. Moreover, the TADS study is the only study thus far to compare medication to cognitive-behavioral therapy (CBT), finding that fluoxetine was markedly superior to CBT, which in general did no better than placebo. Thus, not only is fluoxetine superior to placebo, but it also performed better than one alternative, validated psychosocial treatment in this one trial, making the use of antidepressants compared to alternative treatments more compelling.

The TADS trial also allows for a careful analysis of the benefit-risk ratio for antidepressant medication using metrics taken from the evidence-based medicine literature--the number needed to treat (NNT). In the TADS study, the drug-placebo difference was 26%, so that the NNT was 4. In contrast, the incidence of suicidality in fluoxetine versus placebo was 8.3% versus 3.6%, meaning that the analogous number needed to harm (NNH) was 21, so that 5.25 times more participants experienced significant improvement in their depression than had incident or worsened suicidality. Both depression and suicidal ideation and behavior convey markedly increased risks for completed suicide in adolescents of about the same order of magnitude. Thus, if one of the goals of treatment of depression is to prevent suicide, then the 5.25-fold difference between NNT and NNH would suggest a favorable risk-benefit ratio.

Because there is the strongest and most consistent evidence for the use of fluoxetine in the treatment of pediatric depression, it seems reasonable that in the absence of other mitigating circumstances, fluoxetine should be the initial drug of choice. However, only 60% of patients respond to fluoxetine (March et al., 2004), and others cannot tolerate it, meaning that other antidepressants for which there is at least some evidence of efficacy should be considered. Two large clinical trials, when aggregated into one, demonstrated a modest 10% difference in response rate between drug and placebo of sertraline (Zoloft) in pediatric depression (NNT=10) (Wagner et al., 2003). Two studies have been conducted evaluating citalopram (Celexa). One published paper showed a 12% difference between drug and placebo (NNT=8) (Wagner et al., 2004), whereas the other, unpublished study was negative, and had a very high dropout rate (Medicines and Healthcare products Regulatory Agency [MHRA], 2004). Atypically for most pediatric trials, it involved both inpatients and outpatients. Two studies of venlafaxine (Effexor) in pediatric depression have been reported as negative, but a reanalysis of the data stratified by age showed that medication was superior to placebo for adolescents but not for children (Emslie et al., 2004; MHRA, 2004).

Thus, one can make the case that antidepressant medication should still play an important role in the management of pediatric depression. Many clinicians would agree that antidepressants have an important role for patients whose depression is chronic, recurrent or severe, with accompanying difficulties in motivation, energy, concentration and sleep that make it more difficult for a patient to participate fully in psychotherapy.

The single most significant contraindication for antidepressant medication is that the patient and family are opposed to it. Our role as physicians is to present different treatment possibilities and help the family and patient to make a decision based on risks and benefits. In the treatment of pediatric depression, psychotherapeutic techniques that have been proven to be efficacious are clearly viable alternatives. Although much more work needs to be done to clarify the optimal management of bipolar depression and depression in youth at risk for bipolar disorder, use of psychotherapeutic approaches prior to use of antidepressants may be a reasonable alternative, given the risk of induction of mania or a mixed state, particularly in younger patients with depression (Martin et al., 2004).

Many patients with a first episode of mild-to-moderate depression respond to education and support. Two specific psychotherapeutic approaches for which there are studies supporting efficacy for adolescent depression are CBT and interpersonal therapy (IPT) (Rossello and Bernal, 1999; Mufson et al., 1999). It is hard to reconcile the results of these studies with the TADS findings, but the difference in outcome could be accounted for by the greater severity of depression in the TADS trial, possible positive expectations of the TADS participants vis--vis medication and difference in the style and delivery of CBT in TADS versus other trials. There is growing evidence supportive of IPT as a treatment for moderate depression in adolescents, although IPT has never been compared to medication (Mufson et al., 1999).

The evidence base for the treatment of prepubertal depression is not as well developed as our knowledge about the treatment of adolescent depression. There are no tested psychotherapeutic approaches for this population, and, while the results of some trials are supportive of the use of antidepressants for prepubertal depression (e.g., citalopram, fluoxetine, sertraline), the results of others are not (e.g., venlafaxine).

It is the responsibility of the physician to educate the family about depression as an illness, about the risks and manifestations of suicidality, and the benefits and risks of medication and psychotherapy. We must be honest in declaring the limits of our knowledge, but at the same time, we need to provide a framework for collaboration between physicians and families in making decisions. For more severe, recurrent or chronically depressed patients, the benefits of antidepressant treatment may outweigh the risk. For those with milder depression, education, support and one of the indicated psycho-therapies may be more appropriate. Sometimes patients with milder depressions do not want to engage in psychotherapy, just as those who are more severely depressed may indicate a wish to begin with psychotherapy alone. It is reasonable to commence with second-choice treatments, as long as the treatment contract allows for a careful definition of symptomatic and functional goals, a timetable for reaching those goals, and a framework for reviewing treatment options if the first treatment fails to deliver.

Families and patients need to be taught how to monitor symptoms of depression and suicidality, and also to be on the lookout for common side effects of antidepressants that may be related to incident suicidality: irritability, hostility, disinhibition, agitation and hypomania. The physician should develop a safety plan with the adolescent and family about how to anticipate, mitigate and communicate about increased suicidality, with an agreement from the patient to keep themselves safe and to contact a responsible adult if suicidal urges become too strong to resist. The clinician or a proxy must be available 24 hours a day so that emergencies can be dealt with expeditiously.

It is vitally important for physicians to listen to patients and families. None of us like to believe that the medications we give to patients have undesirable side effects, but we must be open to the realization that "any medication can do anything to anyone," and if the timing of a side effect seems coincident with the initiation or increase in dosage of a medication, then that side effect is related to the medication until proven otherwise.

The rate-limiting step in our effectiveness is our patients' and families' ability to accurately describe their mood, function, suicidality and any side effects. Thus, education to help families and patients to be able to track relevant information is vital to build the partnership required for a successful outcome.

It is important to remember that depression is a potentially fatal disease, posing a very high risk for completed and attempted suicide. The FDA black box warning helps physicians, patients and families to focus on the importance of closely monitoring symptomatic response, suicidality and side effects, especially during the initial three to six months of treatment.

Finally, the entire series of events leading up to the FDA review and the black box warning could have been circumvented had there been rapid and complete disclosure of the results of all clinical trials. Physicians and medical centers should not participate in clinical trials unless there is a commitment to publish and disclose the results regardless of whether they are favorable or not. A national policy that mandates full disclosure and maintenance of a public registry is necessary so that patients, families and physicians are making treatment decisions with full awareness of all available information--both about risks and benefits.

Dr. Brent is professor of psychiatry, pediatrics and epidemiology and has an Endowed Chair in Suicide Studies at the University of Pittsburgh School of Medicine. He is also academic chief in child and adolescent psychiatry at Western Psychiatric Institute and Clinic. Dr. Brent participated in the panel reviewing adverse events in the FDA-sponsored meta-analysis of pediatric clinical trials.

Birmaher B, Axelson DA, Monk K et al. (2003), Fluoxetine for the treatment of childhood anxiety disorders. J Am Acad Child Adolesc Psychiatry 42(4):415-423.

Emslie GJ, Findling RL, Yeung PP et al. (2004), Efficacy and safety of venlafaxine extended release in children and adolescents with MDD. NR470. Presented at the 157th Annual Meeting of the American Psychiatric Association. New York; May 1.

Emslie GJ, Heiligenstein JH, Wagner KD et al. (2002), Fluoxetine for acute treatment of depression in children and adolescents: a placebo-controlled, randomized clinical trial. J Am Acad Child Adolesc Psychiatry 41(10):1205-1215.

Emslie GJ, Rush JA, Weinberg WA et al. (1997), A double-blind, randomized, placebo-controlled trial of fluoxetine in children and adolescents with depression. Arch Gen Psychiatry 54(11):1031-1037

FDA (2004), FDA talk paper. Available at: www.fda.gov/bbs/topics/ANSWERS/2003/ANS01256.html. Accessed March 24, 2005.

March J, Silva S, Petrycki S et al. (2004), Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression. Treatment for Adolescents With Depression Study (TADS) randomized controlled trial. JAMA 292(7):807-820 [see comments].

Martin A, Young C, Leckman JF et al. (2004), Age effects on antidepressant-induced manic conversion. Arch Pediatr Adolesc Med 158(8):773-780.

MHRA (2004), Report of the CSM Expert Working Group on the safety of selective serotonin reuptake inhibitor antidepressants. Available at: http://medicines.mhra.gov.uk/ourwork/monitorsafequalmed/safetymessages/SSRIfinal.pdf. Accessed March 30, 2005.

Mufson L, Weissman MM, Moreau D, Garfinkel R (1999), Efficacy of interpersonal psychotherapy for depressed adolescents. Arch Gen Psychiatry 56(6):573-579.

Pediatric OCD Treatment Study (POTS) Team (2004), Cognitive-behavior therapy, sertraline and their combination for children and adolescents with obsessive-compulsive disorder: The Pediatric OCD Treatment Study (POTS) randomized controlled trial. JAMA 292(16):1969-1976.

Pediatric Psychopharmacology Anxiety Study Group (2001), Fluvoxamine for the treatment of anxiety disorders in children and adolescents. The Research Unit on Pediatric Psychopharmacology Anxiety Study Group. N Engl J Med 344(17):1279-1285 [see comments].

Rossello J, Bernal G (1999), The efficacy of cognitive-behavioral and interpersonal treatments for depression in Puerto Rican adolescents. J Consult Clin Psychol 67(5):734-745.

Wagner KD, Ambrosini P, Rynn M et al. (2003), Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder: two randomized controlled trials. JAMA 290(8):1033-1041 [see comments].

Wagner KD, Robb AS, Findling RL et al. (2004), A randomized, placebo-controlled trial of citalopram for the treatment of major depression in children and adolescents. Am J Psychiatry 161(6):1079-1083.

Articles

The FDA has issued a "black box" warning about the use of all antidepressants in the pediatric population due to a 1.8-fold increase in suicidality on drug compared to placebo. Yet these medications can be an effective tool in treating depression. How should parents and patients be educated, considering this information?

David A. Brent, MD

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Shedding Light on the 'Black Box': Treating Pediatric Depression