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COMMENTARY |
Johns Hopkins University School of Medicine, Departments of Psychiatry and Pediatrics, Baltimore, Maryland
Abbreviations: FDA, US Food and Drug Administration • MDD, major depressive disorder • OCD, obsessive-compulsive disorder • SSRI, selective serotonin reuptake inhibitor • MHRA, Medicines and Healthcare Products Regulatory Agency • CDRS-R, Children’s Depression Rating Scale-Revised • TCA, tricyclic antidepressant • CGI-I, Clinical Global Impression–Improvement Scale • AE, adverse event
In January 2003, the US Food and Drug Administration (FDA) approved fluoxetine for the treatment of major depressive disorder (MDD) and obsessive-compulsive disorder (OCD) in youth aged 7 to 18.1 The decision for MDD was based on 2 placebo-controlled clinical trials.2,3 No major expressions of concern were raised at the time, but beginning in June 2003, doubts increasingly arose about the efficacy and safety of selective serotonin reuptake inhibitors (SSRIs) in youth after the United Kingdom Medicines and Healthcare Products Regulatory Agency (MHRA) received pediatric trial data from Glaxo SmithKline on paroxetine. Subsequently, both the FDA and the MHRA reanalyzed both published and unpublished efficacy and safety data from SSRI trials for youth.4,5 Relevant findings from these reanalyses are presented herein.
In reviewing the available age-grouped SSRI data on the treatment of youth with MDD, which used the primary measure of depression, the Children’s Depression Rating Scale-Revised (CDRS-R), it became apparent that all the results covering preadolescents (ie, children) were negative (Table 1). The age-grouped analyses of 7 SSRI/venlafaxine trials for depressive symptoms were reportedly underpowered or not part of the initial outcome assessments; nonetheless, these findings presented no evidence of even a trend favoring any SSRI or venlafaxine over placebo in children with MDD (Table 1). In fact, 2 of these antidepressant-medication outcome analyses related to children favored the placebo, and 1 was nearly significant (P = .052) favoring the placebo (Table 1). Thus, it would be reasonable to conclude that there is no scientific evidence at this time that SSRI and venlafaxine treatments are measurably beneficial for the treatment of MDD symptoms in preadolescent youth.
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A very similar age-grouped conclusion was reached by Hazell et al12 in their Cochrane review on the efficacy of tricyclic antidepressants (TCAs) for the treatment of depression in children and adolescents. It follows: "Data suggest [TCAs] are not useful in treating depression in prepubertal children. There is marginal evidence to support the use of [TCAs] in the treatment of depression in adolescents, although the magnitude of effect is likely to be moderate at best."12 In the Cochrane meta-analysis, the effect size for TCAs in children was –0.15, whereas it was 0.47 in adolescents. The age-grouped effect size for SSRIs based on the CDRS-R data presented in Table 1 (not including the fluoxetine data, which had been recorded only as percent change) was similar: 0.04 for children and 0.42 for adolescents.
Many research assessments of treatment efficacy in pediatric psychiatry have used the Clinical Global Impression–Improvement Scale (CGI-I)13 as a primary outcome measure.11,14 For example, CGI-I ratings have been applied to outcomes in OCD,15,16 social anxiety,17,18 separation anxiety,19 and depression.7,11,14 Blinded CGI-I ratings by clinicians are based on function and are not symptom specific, but they provide quite useful general signals of treatment benefit. However, of the 7 antidepressant trials (listed in Table 1) that grouped their findings by age, only 2 trials6,8 reported CGI-I results specifically for children; both were negative.
In published placebo-controlled clinical trials of SSRIs presenting findings on youth diagnosed with OCD,15,16 social anxiety disorder,17,18 and mixed anxiety disorders,19–21 positive outcomes of the drug over placebo have generally been reported. SSRI studies of treatment for OCD in youth consistently used one primary symptom-specific outcome measure, the Children’s Yale Brown Obsessive-Compulsive Scale.15 For youth treated for anxiety disorders, no single symptom-specific measure has been used consistently.17–21
Unlike the SSRI findings of youth exhibiting depressive symptomatology, none of the analyses of SSRI treatment of youth with OCD or anxiety disorders revealed a significant or meaningful outcome difference according to age group.16,17,19–24 In fact, in a number of studies, children with OCD or anxiety disorders had slightly better SSRI treatment outcome scores than did adolescents.16,23,24
Because 
30% to 40% of youth with MDD have a concurrent anxiety disorder,7,9,11 it is quite possible that SSRI treatment could have a measurable influence on the treatment outcome of depressed youth by impacting on the anxiety symptom dimension. In the FDA’s4(p12) reanalysis of the initial fluoxetine trial of youth (ages 7–17 y) with MDD,2 the subgroup with mixed anxiety/depression had a significant positive outcome (P = .008), whereas those with MDD without rated anxiety did not (P = .278). Only one other subgroup analysis of this type was found; it yielded a similar dichotomous result.25
In comprehensive medication-outcome assessments, efficacy needs to be balanced with treatment-emergent adverse events (AEs) to evaluate a drug’s usefulness (its benefit/risk ratio). In placebo-controlled, age-grouped, published clinical trials of SSRIs, preadolescents experienced 3 times the rate of activation/agitation and 2 times the rate of trial discontinuation resulting from AEs as did adolescents.26 These heightened SSRI AE risks for children occurred over the full range of psychiatric diagnoses.26,27 and have been reported as manic in type28 and as disinhibition.29 In non–age-grouped FDA analyses, Hammad27(pp96–98) presented data indicating that youth with MDD given SSRIs or venlafaxine in clinical trials were over 3 times more likely than those on placebo to experience treatment-emergent agitation or hostility. He also reported that youth who had documented agitation or hostility before or during the studies were 6.6 times more likely to experience treatment-emergent suicidality.27(slide 98) Such findings regarding SSRI AEs have aroused concern.30
In sum, available data from short-term placebo-controlled trials consistently indicate that SSRIs and venlafaxine have not shown a significant reduction in depressive symptomatology above that of placebo in preadolescents with MDD. Furthermore, SSRIs are associated with a greater degree of problematic treatment-emergent AEs in children than in adolescents. Nonetheless, there are clear indications, particularly from the published literature, that children (as well as adolescents) with OCD and anxiety disorders are more likely to benefit from SSRIs than placebos.
In view of age-grouped symptom response and AE differences, it is important that additional SSRI data be obtained in children by new research or be made available from as-yet-unpublished clinical trials to determine if these conclusions are supported. From the available evidence, however, the prescribing of SSRIs for children on the basis of their major depressive symptomatology is not supported. In addition, if SSRIs are used to treat preadolescents for any indication, much caution should be used in view of their increased risk for AEs. Last, the impact of SSRIs on children with concurrent anxiety-depressive symptoms merits additional investigation.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Address correspondence to Daniel J. Safer, MD, 6 Hadley Square North, Baltimore, MD 21218. E-mail dsafer{at}jhmi.edu
The author has indicated he has no financial relationships relevant to this article to disclose.
Opinions expressed in these commentaries are those of the authors and not necessarily those of the American Academy of Pediatrics or its Committees.
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REFERENCES |
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 TOP REFERENCES |
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This article has been cited by other articles:
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  A. Heneghan, A. S. Garner, A. Storfer-Isser, K. Kortepeter, R. E. K. Stein, and S. McCue Horwitz Use of Selective Serotonin Reuptake Inhibitors by Pediatricians: Comparing Attitudes of Primary Care Pediatricians and Child and Adolescent Psychiatrists Clinical Pediatrics, March 1, 2008; 47(2): 148 - 154. [Abstract] [PDF]
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