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We appreciate Dr. Pitts’ comments on our article. He appears to take issue with the implication that antidepressants as a class are of questionable efficacy in the treatment of adolescents with depression, arguing in particular that there is moderate to strong evidence of fluoxetine’s efficacy and that providers should not be afraid to use it. While Restoring Study 3291 and our commentary apply only to imipramine and paroxetine, we do believe the larger body of existing literature similarly calls into question the efficacy of treating adolescent depression with antidepressant medications generally, including fluoxetine.
Dr. Pitts cites the recent meta-analysis by Cipriani et al, examining 34 double-blind randomized trials involving 14 antidepressant medications and 5,260 children and adolescent participants.2 Thirteen of the 14 antidepressants were found to be no better than placebo for the primary outcome of improvement in depressive symptoms. Indeed, fluoxetine was the single medication found to be superior to placebo. However, Cipriani et al note that the upper limit of the 95% confidence interval for fluoxetine is close to the point of no difference, raising “the question of whether this estimate is robust enough to inform clinical practice.” Using the GRADE criteria, the authors rated the evidence for primary outcomes in the comparison of fluoxetine to placebo at very low quality. It is also important to note that 8 of the 10 fluoxetine trials meeting...
Dr. Pitts cites the recent meta-analysis by Cipriani et al, examining 34 double-blind randomized trials involving 14 antidepressant medications and 5,260 children and adolescent participants.2 Thirteen of the 14 antidepressants were found to be no better than placebo for the primary outcome of improvement in depressive symptoms. Indeed, fluoxetine was the single medication found to be superior to placebo. However, Cipriani et al note that the upper limit of the 95% confidence interval for fluoxetine is close to the point of no difference, raising “the question of whether this estimate is robust enough to inform clinical practice.” Using the GRADE criteria, the authors rated the evidence for primary outcomes in the comparison of fluoxetine to placebo at very low quality. It is also important to note that 8 of the 10 fluoxetine trials meeting criteria in the Cipriani study received industry funding. Given the well documented biases of industry data reporting, would the precarious benefit of fluoxetine remain if subjected to a comprehensive review of unpublished fluoxetine trial data?
While much effort has been spent attempting to establish the efficacy for antidepressant medications, their harms have been understudied and underreported. Similar to the Restoring Study 329 methodology, scrutiny of regulatory documents and other sources of unpublished clinical trial data are being used to shed light on potential harms. For example, one recent analysis using previously unpublished data from 70 placebo controlled trials found that prescription of SSRIs (including fluoxetine) to adolescents and children was associated with a doubling in risk of suicidality and aggression.3 That such critical, damning data are routinely left out of industry trials and brought to light only by diligent, independent researchers post-hoc is alarming.
Let there be no doubt that adolescent depression is a serious condition. Suffering teens, their families, and their medical providers need tools to help them. This includes better access to mental health services, including evidence-based psychotherapy. However, in the absence of balanced, comprehensive data demonstrating that the benefits of medication outweigh the harms, it seems hard to justify the rising frequency of pharmacologic prescriptions for adolescents suffering from depression.
1. Le Noury J, Nardo JM, Healy D, Jureidini J, Raven M, Tufanaru C, et al. Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence. Bmj. 2015;351:h4320.
2. Cipriani A, Zhou X, Del Giovane C, Hetrick SE, Qin B, Whittington C, et al. Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: a network meta-analysis. Lancet (London, England). 2016;388(10047):881-890.
3. Sharma T, Guski LS, Freund N, Gotzsche PC. Suicidality and aggression during antidepressant treatment: systematic review and meta-analyses based on clinical study reports. Bmj. 2016;352:i65.
My comment addresses points raised in the recent Pediatrics article by Coon et al titled “Update on Pediatric Overuse”. The section of the article in question is titled “Antidepressants for Adolescents Are Determined to Be Ineffective and Possibly Harmful in Reanalysis of a Pivotal Trial.” This section highlights the recent “Restoring Study 329”, which raises major methodological concerns about an important original paroxetine and imipramine trial performed in the mid-late 1990s (Study 329). Coon et al conclude that the “current widespread use of antidepressants in adolescents may have been driven in part by misleading results from the initial [Study 329] trial in 2001” and correctly argues for improved data transparency in antidepressant research.
While Coon et al should be applauded for highlighting concerns raised by “Restoring Study 329”, their conclusion on antidepressants as a medication class does not seem to consider the broader context of major depression management in adolescents. The notion that paroxetine is not efficacious in adolescents has been well established from other previous studies. A recent network meta-analysis on anti-depressant use in children and adolescents also re-confirmed this finding.
Importantly, this same meta-analysis also confirmed the established evidence that fluoxetine is often efficacious for acute treatment of adolescents with major depressive disorder (MDD). It also finds that among the pediatric populatio...
Importantly, this same meta-analysis also confirmed the established evidence that fluoxetine is often efficacious for acute treatment of adolescents with major depressive disorder (MDD). It also finds that among the pediatric population, fluoxetine is better tolerated than many other antidepressants. Importantly, the findings in favor of fluoxetine were observed in both industry-sponsored and non-industry-sponsored trials. This knowledge has largely informed major depression practice parameters that have been in place for the better part of a decade.
USPSTF systematic reviews from 2009 and 2016 describe evidence of good symptom response to combination psychotherapy and fluoxetine in adolescents with MDD. Due to the body of evidence, fluoxetine in addition to psychotherapy is recommended for consideration in moderate to severe depression by both the Royal Australian and New Zealand and the British NICE guidelines for diagnosing and managing depression in pediatrics.
Restoring Study 329 raises important concerns about research ethics and the importance of revisiting trial data to reach appropriate conclusions in pediatric research. Likewise, Coon et al crucially identify the need for better trial data transparency to ensure accurate evidence-based antidepressant prescribing practices for adolescents. At the root, however, Coon et al use specific evidence against paroxetine in adolescents to raise concern about the overuse of antidepressants as a class. They do not seem to acknowledge that fluoxetine is used far more often than paroxetine due to strong evidence that suggests it should be considered as first line therapy for many adolescents with major depression. Based on the body of the literature, there is moderate to strong evidence that fluoxetine in combination with psychotherapy is an efficacious and safe option for adolescents with moderate to severe depression. Prescribing this antidepressant a teenager should be strongly considered when indicated. Primary pediatricians and mental health specialists should not be afraid to utilize fluoxetine as a tool when an adolescent truly needs help.
Brian H. Pitts, MD (Res), Department of Pediatrics, University of North Carolina
1. Coon, E. R. et al. Update on Pediatric Overuse. Pediatrics 139, e20162797 (2017).
2. Cipriani, A. et al. Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: a network meta-analysis. The Lancet 388, 881–890 (2016).
3. Williams, S. B., O’Connor, E. A., Eder, M. & Whitlock, E. P. Screening for Child and Adolescent Depression in Primary Care Settings: A Systematic Evidence Review for the US Preventive Services Task Force. PEDIATRICS 123, e716–e735 (2009).
4. Forman-Hoffman, V. et al. Screening for Major Depressive Disorder in Children and Adolescents: A Systematic Review for the U.S. Preventive Services Task Force. Ann. Intern. Med. 164, 342 (2016).
5. Malhi, G. S. et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders. Aust. N. Z. J. Psychiatry 49, 1087–1206 (2015).
6. Hopkins, K., Crosland, P., Elliott, N. & Bewley, S. Diagnosis and management of depression in children and young people: summary of updated NICE guidance. Br. J. Sports Med. 50, 184–186 (2016).
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