Report 10 of the Council on Scientific Affairs (A-05)

Safety and Efficacy of Selective Serotonin Reuptake Inhibitors (SSRIs) in Children and Adolescents

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Summary

Objective.  This report reviews approaches used in the United States to enhance pediatric prescription drug labeling; summarizes recent regulatory actions related to the prescription drug labeling of antidepressants and their use in children and adolescents;  evaluates the apparent safety and efficacy of antidepressants, particularly the selective serotonin reuptake inhibitors (SSRIs) in children and adolescents; and reviews the evidence on whether these drugs may have a causal role in the emergence of suicidality or other harmful behavior during  treatment.

Methods.  Literature searches were conducted in the MEDLINE database for English-language articles published between 1990 and April 2005 using the search terms antidepressant, serotonin reuptake inhibitor, SSRI, fluoxetine, paroxetine, sertraline, citalopram, or fluvoxamine, in combination with suicide or self-harm  and child, teen, or adolescent.  This search yielded 986 references, 306 of which were deemed relevant to this report. The background material, presentations, and proceedings from the deliberations of the U.S. Food and Drug Administration (FDA) Psychopharmacologic Drugs and Pediatric Advisory Committees and the U.K. Medicines and Healthcare products Regulatory Agency (MHRA) also were consulted. 

Results.  The use of antidepressants in children and adolescents has increased significantly over the last 15 years, primarily the SSRIs.  Pilot studies and some larger clinical trials have failed to demonstrate the efficacy of older tricyclic antidepressants in pediatric patients.  Several trials have been conducted in children and adolescents using SSRIs for major depressive disorder (MDD), obsessive compulsive disorder (OCD), and other anxiety disorders.  Several SSRIs are approved for  use in OCD, but only fluoxetine has gained FDA approval for pediatric MDD.   Individual trials of other SSRIs show some evidence of efficacy in pediatric MDD but substantive, replicative studies are lacking.  A detailed review of adverse event reports from 8- to 12-week clinical trials of antidepressants in children and adolescents that excluded subjects who were a serious suicide risk concluded that the use of antidepressants is associated with a doubling in the number of reports indicative of suicidal thinking and behavior in children and adolescents with MDD and other psychiatric disorders.  Most, but not all, data from ecological studies, forensic analysis, and drug discontinuation studies support the notion that the prescription of antidepressants, including SSRIs, reduces suicidal behavior and completed suicide attempts overall and in adolescents, although the risk of such behavior appears to be highest during the initial course of drug therapy.  The results obtained from patient-level controlled observational studies emanating from general practice are variable but found some evidence of an increased risk for suicide or suicidal behavior for SSRIs with respect to age or specific drug.  

Conclusion.  Controversy continues to exist regarding the strength of the evidence base supporting the efficacy of SSRIs in pediatric MDD.  A causal role for antidepressants in increasing suicides in children and adolescents has not been established.  There is a pressing need for properly designed and powered pragmatic studies of antidepressants in children and adolescents, which could test the concerns raised by the MHRA and FDA analyses.  Meanwhile, these drugs should continue to be available, with their use guided by prudent clinical judgment.

RECOMMENDATIONS

The following statements, recommended by the Council on Scientific Affairs, were adopted by the AMA House of  Delegates as AMA policy and directives at the 2005 AMA Annual Meeting:

The AMA:

1. Recommends that selective serotonin reuptake inhibitors (SSRIs) should remain available for use in children and adolescents, including unlabeled uses, subject to the exercise of prudent clinical judgment and development of clinical guidelines for treatment.  Current clinical evidence indicates that fluoxetine is an effective SSRI in children and adolescents with major depressive disorder. (Policy)
2. Urges the Food and Drug Administration (FDA) to ensure that studies conducted by sponsors in pursuit of pediatric exclusivity be adequately designed and of sufficient duration to answer clinically relevant efficacy and/or safety questions that have evolved in a particular therapeutic area. (Directive)
3. Recognizes that the current product labeling (package insert) of antidepressant drugs, including the Black Box warnings, is a precautionary statement intended to reinforce the need for careful monitoring of patients with depression and other psychiatric disorders during the initiation of treatment.  This product labeling should not be interpreted in a way that would decrease access for patients who may benefit from these drugs. (Policy)
4. Urges the FDA to evaluate the impact of labeling changes mandated by the Agency for antidepressants, including the Black Box warning and Patient Medication Guide on treatment patterns, patient compliance, and patient access. (Directive)

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