Evidence-Based Reviews

Commentary: Clinical perspective on pediatric depression

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

How the evidence tipped SSRIs’ risk-benefit balance

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.

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With “black box” warnings expected, prescribing antidepressants to children and adolescents is changing. In the past year, information from previously unpublished studies has shown the drugs’ risks to be greater and benefits less in pediatric patients than doctors had believed.

As this article went to press, the FDA said it would adopt tougher labeling for antidepressants, as recommended by its Psychopharmacologic Drugs and Pediatric advisory committees. The advisors voted 15 to 8 at a Sept. 14 hearing in favor of a “black box” for all antidepressants, warning of increased risk of suicidality in pediatric patients.

We reported on the FDA’s Feb. 2 public hearing on increased risk of suicidality with antidepressants (CURRENT PSYCHIATRY, March 2004).¹ This commentary provides a follow-up perspective on:

the Columbia group’s report on classifying suicidality in SSRI clinical trial data
how undisclosed clinical trial data tipped the SSRI risk-benefit balance in pediatric patients
new data on using SSRIs plus psychotherapy for depressed adolescents.

WHAT THE COLUMBIA GROUP FOUND

In March, the FDA requested a warning label on SSRIs and related antidepressants that all patients be “monitored closely for worsening depression or the emergence of suicidality.” The advisory’s text and supporting information is available on the FDA’s Web site.²

The FDA also contracted with Columbia University to classify SSRI clinical trial events—first analyzed by FDA senior epidemiologist Dr. Andrew D. Mosholder—that might represent suicidality. Dr. Mosholder had reviewed pharmaceutical industry data from 22 placebo-controlled trials involving 4,250 pediatric patients and found that youths given antidepressants were nearly twice as likely to become suicidal as those given placebo (Box 1). Suicidality has historically been attributed to depressive illness rather than antidepressant use. Therefore, FDA officials cancelled Dr. Mosholder’s scheduled testimony at the Feb. 2 hearing—a decision that triggered congressional investigations—to allow for further analysis.

Box 1

The Mosholder analysis: ‘Almost twice the risk’ of suicidal behavior

Nearly 2 years ago, FDA senior epidemiologist Dr. Andrew Mosholder requested that paroxetine’s manufacturer analyze suicidal behaviors in its pediatric clinical trial database. In July 2003, the same analysis was requested for eight other antidepressants (bupropion, mirtazapine, fluoxetine, nefazodone, fluvoxamine, sertraline, citalopram, venlafaxine).

The pharmaceutical manufacturers subsequently analyzed data from 22 short-term, placebo-controlled trials involving 4,250 youths—2,298 treated with antidepressants and 1,952 given placebo. Dr. Mosholder reviewed the analyses in September 2003 and found that youths taking antidepressants were nearly twice as likely to become suicidal as those taking placebo. Statistically, the risk of suicide-related events was significantly higher with venlafaxine and paroxetine than with placebo, and data for citalopram approached statistical significance on one measure.

Relative risks for suicide-related events were 0.9 with fluoxetine and 0.5 with mirtazapine, suggesting a possible protective effect (although mirtazapine’s analysis was based on a very small number of events). For all other drugs, relative-risk estimates were >1 or undefined because of lack of events. This association between suicide-related events and active drug treatment was observed only in major depressive disorder treatment trials.

The analyses had limitations; the trials reflected short-term antidepressant use, and each sponsor analyzed its data separately. Based on the evidence, Dr. Mosholder recommended that the FDA discourage use of antidepressants other than fluoxetine in children.

As of Aug. 21, the Columbia group had analyzed data from 25 studies and reviewed 423 adverse events that occurred during the trials’ randomized double-blind phase and/or within 30 days of the last dose of randomized treatment.³ These events included intentional self-injury, suicidal ideation, suicide attempts, accidental injuries, and accidental overdose.

The preliminary evidence suggests that young antidepressant users were 1.8 times more likely to have suicidal thoughts or behaviors compared with patients given placebo⁴—the same conclusion Dr. Mosholder reached nearly 1 year earlier.

RISK VERSUS BENEFIT

Are SSRIs safe in children? In the United Kingdom, a review by the Medicines and Healthcare Products Regulatory Agency (MHRA) of data submitted by paroxetine’s manufacturer revealed an unfavorable risk-to-benefit ratio in children and adolescents. Review of other data on other antidepressants soon followed.

Last December, the MHRA’s Committee on Safety of Medicines and its Expert Working Group on SSRIs advised that the risks and benefits of treating major depressive disorder in patients younger than age 18 were unfavorable for sertraline, citalopram, paroxetine, and escitalopram, and could not be assessed for fluvoxamine.⁵ The MHRA warned British physicians against prescribing paroxetine to depressed patients younger than age 18 and ordered labeling changes for paroxetine contraindicating its use in pediatric major depression.

Fluoxetine is the only SSRI for which the committee considers the risk-benefit balance to be favorable. It cautions British physicians, however, that fluoxetine may benefit only an estimated 1 in 10 pediatric patients.⁵