Evidence-Based Reviews

Commentary: Clinical perspective on pediatric depression

Current Psychiatry. 2004 October;3(10):12-23

References

1. Sood AB, Weller EB, Weller RA. SSRIs in children and adolescents: where do we stand? Current Psychiatry 2004;3(3):83-9.

2. Food and Drug Administration. Center for Drug Evaluation and Research. Antidepressant use in children, adolescents, and adults. Available at: http://www.fda.gov/cder/drug/antidepressants/default.htm. Accessed Sept. 2, 2004.

3. Department of Health and Human Services. Public Health Service. Report of the audit of the Columbia suicidality classification methodology [memorandum]. Aug. 16, 2004. Available at: http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4065b1-09-TAB07-Iyasu-Audit_report.htm. Accessed Sept. 2, 2004.

4. Neergaard L. Suicide risk may prompt antidepressant warnings. Associated Press Aug. 21, 2004. Available at: http://chron.com (search archive). Accessed Sept. 15, 2004.

5. Medicines and Healthcare Products Regulatory Agency (UK). Use of selective serotonin reuptake inhibitors (SSRIs) in children and adolescents with major depressive disorder (MDD). Dec. 10, 2003. Available at: www.mhra.gov.uk/news/2003.htm#ssri. Accessed Sept. 2, 2004.

6. Emslie GJ, Rush AJ, Weinberg WA, et al. A double-blind, randomized, placebo controlled trial of fluoxetine in children and adolescents with depression. Arch Gen Psychiatry 1997;54(11):1031-7

7. Emslie GJ, Heiligenstein JH, Wagner KD, et al. Fluoxetine for acute treatment of depression in children and adolescents: a placebo-controlled, randomized clinical trial. J Am Acad Child Adolesc Psychiatry 2002;41(10):1205-15.

8. Wagner KD, Ambrosini P, Rynn M, et al. Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder: two randomized controlled trials. JAMA 2003;290(8):1033-41.

9. Keller MB, Ryan ND, Strober M, et al. Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled study. J Am Acad Child Adolesc Psychiatry 2001;40:762-72.

10. Wagner KD, Robb AS, Findling RL, et al. A randomized, placebo-controlled trial of citalopram for the treatment of major depression in children and adolescents. Am J Psychiatry 2004;161(6):1079-83.

11. Laughren T. Background comments for Feb. 2, 2004 meeting of Psychopharmacological Drugs Advisory Committee (PDAC) and Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee (PedsAC). Available at: http://www.fda.gov/ohrms/dockets/ac/04/brief-ing/4006B1_03_Background Memo 01-05-04.doc. Accessed Sept. 15, 2004.

12. Emslie GJ. Making sense of the research puzzle. AACAP News 2004;35(2):

13. Whittington CJ, Kendall T, Fonagy P, et al. Selective serotonin reuptake inhibitors in childhood depression: Systematic review of published versus unpublished data. Lancet 2004;363:1341-5.Also available at: http://www.thelancet.com/journal/vol363/iss9418 (scroll to article title). Accessed Sept. 2, 2004.

14. Treatment for Adolescents with Depression Study (TADS) team. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression, JAMA 2004;922(7):807-20.

15. Vorstman J, Lahuis B, Buitelaar JK. SSRIs associated with behavioral activation and suicidal ideation. J Am Acad Child Adol Psychiatry 2001;40:1364-5.

16. Food and Drug Administration. Psychopharmacologic Drugs Advisory Committee and the Anti-Infective Drugs Advisory Committee. Briefing information for public hearing Feb. 2, 2004. Available at: www.fda.gov/ohrms/dockets/ac/04/briefing/4006b1.htm. Accessed Sept. 2, 2004.

17. Culpepper L, Davidson JR, Dietrich AJ, et al. Suicidality as a possible side effect of antidepressant treatment. Primary Care Companion: J Clin Psychiatry 2004;6(2):79-86.

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Are SSRIs effective in children? To be labeled for treating depression in children and adolescents, an SSRI must have proven efficacy (statistically and clinically significant improvement) in two independently conducted, double-blind, placebo-controlled trials. Five trials have met this standard—fluoxetine (2),^6,7 sertraline (1),⁸ paroxetine (1-adolescents only),⁹ and citalopram (1)¹⁰—and three trials have not—paroxetine (2) and citalopram (1).¹¹ Thus, only fluoxetine is FDA-approved for treating depressed children and adolescents.

However, lacking two positive trials does not necessarily indicate that a medication is not effective, especially when only two trials were conducted.¹² Also, unpublished data now becoming available show inconsistencies with the published data.¹³

PUBLISHED VS. UNPUBLISHED DATA

In a meta-analysis by Whittington et al,¹³ data from five published, randomized, controlled trials of SSRIs (fluoxetine, paroxetine, sertraline and venlafaxine) were compared with data from unpublished reports found in the United Kingdom’s Committee on Safety of Medicines’ review. In the unpublished data, for example, paroxetine had a significantly lower response rate and more-pronounced placebo effect than the published data indicated.

As a result, these investigators concluded that the favorable risk-benefit profiles of paroxetine, sertraline, and venlafaxine for children and adolescents should be switched to unfavorable. They recommended against using these three antidepressants in youth because of possible increased risk of suicidal ideation and serious adverse events—findings that corresponded to the MHRA’s 2003 decisions.

Tipping the balance? Discrepancies between published and unpublished data raise alarms about nonreporting of negative trials. Except for one paroxetine trial, one early fluoxetine trial, and one more-recent fluoxetine trial funded by the National Institute of Mental Health (NIMH),¹⁴ the FDA’s “pediatric rule” of 1997 has produced all emerging data on SSRIs in children and adolescents. This rule gives pharmaceutical companies an additional 6 months of patent protection (which translates to millions of dollars) for conducting minimal research to collect data on medications’ safety in pediatric populations.

The subsequent Pediatric Research Equity Act of 2003 (PREA) requires pharmaceutical companies to conduct pediatric studies as part of nearly every new drug application filed since Jan. 1, 1999. Unfortunately, PREA does not regulate the quality of that research nor require that negative studies be disclosed.

TADS: FLUOXETINE PLUS CBT

The recently reported Treatment for Adolescents with Depression Study (TADS)¹⁴—funded by the NIMH—showed the benefit of combining fluoxetine with cognitive-behavioral therapy (CBT) for depressed children and adolescents. In the 12-week, multi-site, double-blind, placebo-controlled trial, 439 adolescents ages 12 to 17 diagnosed with major depressive disorder received fluoxetine, 10 to 40 mg/d; CBT alone; CBT with fluoxetine, 10 to 40 mg/d; or placebo. Response rates were:

fluoxetine alone, 61% (95% confidence interval [CI], 51-70%)
CBT alone, 43% (95% CI, 34-52%)
fluoxetine with CBT, 71% (95% CI, 62- 80%)
placebo, 34.8% (95% CI, 26-44%).

The two treatments containing fluoxetine were statistically more effective than CBT alone or placebo, as measured by the Clinical Global Impression scale. Clinically significant suicidal thinking—in 29% of the adolescents at baseline—improved significantly in all treatment groups, with fluoxetine plus CBT showing the greatest reduction (P = 0.02). Seven of 439 patients (1.6%) attempted suicide; there were no completed suicides.

Box 2

Is activation synonymous with suicide risk?

An association between SSRIs and suicidal ideation in children and adolescents was first reported in the early 1990s.¹⁵ In theory, agitation and nervousness that occur in some children treated with SSRIs might increase their risk of self-injury or of harming others. Agitation, hyperkinesia, mania, and hypomania tend to be more frequent among patients treated with SSRIs (including fluoxetine) than among those receiving placebo (1 to 6% vs 0 to 4%).¹⁶

Clinicians should watch carefully for activation during SSRI treatment. The following symptoms may occur in activation syndromes: anxiety, agitation, panic attacks, hostility, impulsivity, akathisia (severe restlessness), insomnia, hypomania, irritability, or mania.¹⁷

On the other hand, no evidence has shown that increased agitation with SSRIs is synonymous with suicidal behavior, and no suicides have occurred in more than 4,000 children and adolescents studied in SSRI clinical trials. In fact, increased SSRI prescribing for children ages 10 to 19 appears to parallel a significant decrease in suicide in this population. With each 1% increase in SSRI use among adolescents, the number of suicides has declined by 0.23 per 100,000 adolescents per year.¹⁸ continued

WHAT ARE CLINICIANS TO DO?

Depression is a known risk factor for suicidal ideation or behavior, and subjects with serious suicidal ideation or suicide attempts are always excluded from clinical trials of antidepressant therapy. Suicide is also relatively rare. Thus, a strong association between SSRI treatment and suicide is difficult to demonstrate. Dozens of controlled trials with thousands of pediatric subjects would be required to show definitively that suicide is associated with antidepressant use.