				Using the search form

IN THE NEWS

Commentary on advances in medicine

The case of the missing evidence: Antidepressant use in children

Theresa Hegmann, MPAS, PA-C

Ms. Hegmann is Clinical Assistant Professor and Director of Curriculum and Evaluation, Physician Assistant Program, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City. The author has indicated no relationships to disclose relating to the content of this article.

We are all aware that depression in children is poorly recognized and undertreated and that depressed adolescents are at significant risk for suicide. In recent years, it has become commonplace for primary care clinicians to start such patients on antidepressant medications while awaiting specialty appointments in an overburdened mental health system. In fact, the use of antidepressant medications in children and adolescents is growing in the United States, with a recent study showing that 56.9% of patients between the ages of 6 and 18 years who received outpatient treatment for depression were prescribed antidepressant medications.¹ Particularly in rural areas, and especially for uninsured or minority patients, access to standard nondrug therapies for childhood depression, such as cognitive and behavioral therapy, is very limited.¹

The past year has brought some surprising news about this common practice, with a long series of well-publicized warnings in the United Kingdom, the United States, and Canada. Thus far, the UK's Medicines and Healthcare products Regulatory Agency (MHRA) has been far more aggressive than the FDA in reacting to new research evidence that suggests a possible link between antidepressant use and an increased incidence of suicidal ideation and attempted suicide. As of December 10, 2003, the MHRA announced that paroxetine (Paxil), venlafaxine (Effexor), sertraline (Zoloft), citalopram (Celexa), and escitalopram (Lexapro) are all contraindicated for use in pediatric major depressive disorder (MDD).²

The FDA response has been more cautious. After many months of study involving repeated requests to pharmaceutical companies for additional analyses of their data on the use of selective serotonin reuptake inhibitors (SSRIs) in children, the FDA issued a Public Health Advisory on March 22, 2004, emphasizing the need to closely observe both adult and pediatric patients on antidepressant medications for worsening depression or the emergence of suicidality.^3,4

But do drugs help depressed children?

The discussion of potential risks of antidepressant use in children raises another critical question: Are the medications effective? As clinicians trying to make a reasonable risk-benefit assessment, PAs must consider both sides of the equation. If the medications work well for a potentially dangerous condition, then it may be reasonable to tolerate more potential side effects. On the other hand, if the clinical benefit is minimal, even small risks become unacceptable. The true art and challenge of clinical decision making lie in appraising and balancing the evidence for efficacy versus the evidence for potential harm.

Both the MHRA and the FDA agree that the available evidence supports the effectiveness of only one medication in the treatment of pediatric MDD: fluoxetine (Prozac).⁵ However, some experts argue that even this use is based on weak evidence.^6,7 In one of the two studies submitted to the FDA in support of this indication, children in the placebo group showed 70% of the improvement seen in the active treatment group, in spite of an experimental design intended to minimize placebo response. Additionally, after an independent statistical review on fluoxetine use in pediatric MDD, the US Center for Drug Evaluation and Research found no statistical difference between placebo and fluoxetine on the primary measures of efficacy that had been specified by researchers at the beginning of the trials.⁸ All claims of efficacy were based on minor improvement in secondary end points. The reanalysis also showed that in the absence of coexisting anxiety, fluoxetine treatment had no advantage over placebo at all.

If drugs don't help much, why prescribe them?

So, if evidence for efficacy is minimal and evidence is growing that SSRIs and similar new-generation antidepressant medications may trigger increased suicidal thoughts and acts of self-harm in children, why are these medications so commonly used in this age group?

The answer to that question is complex. For one thing, clinicians commonly treat children as little adults. For another, the consistently large placebo response rate (40%–60%) seen in studies of antidepressant medications means that even when research evidence for efficacy is lacking, clinicians may have trouble believing that these medicines aren't really making a difference, since their patients are getting better. Additionally, the chemical-imbalance model of depression is finally receiving public acceptance, so that many parents expect clinicians to treat their depressed children with drugs.⁷ And, of course, we live in a country with inadequate, expensive, and poorly distributed mental health resources. In virtually any practice location, prescribing a pill is easier than trying to arrange psychotherapy for a child.

Arguably, however, one of the biggest reasons why newer antidepressant medications continue to be used in children is simple publication bias: Studies showing a significant effect are submitted for publication more often than are studies showing no effect. We also have good recent evidence of another source of bias: Industry-funded research studies are more likely to result in proindustry findings.⁹ What happens to studies that don't support the effectiveness of a medication? Most just don't get published.

Missing evidence and conflicts of interest

Even experts in the area of childhood depression may be surprised to learn that the FDA is basing its ongoing review of suicidality risk of antidepressant medications on data from 24 relatively large, well-designed, randomized, placebo-controlled studies done on nine different medications and involving more than 4,000 patients younger than 18 years.⁵ Most of these studies have not been submitted for publication. The vast majority of these trials were conducted in response to legislation in 1997 and 2001 allowing the FDA to grant additional market exclusivity to pharmaceutical manufacturers who agree to conduct studies of their drugs in pediatric populations. These studies need not show effectiveness in order for the manufacturer to obtain a patent extension, and companies are not required to publish or otherwise make public the results of these (or other) drug trials. Researchers involved in the trials are commonly bound by nondisclosure contracts that forbid any discussion of trial results for many years.⁷

Clearly, companies that invest millions of dollars in developing medications are unlikely to voluntarily publish the results of studies showing their products to be ineffective and possibly unsafe.¹⁰ What company in its right mind would publish data likely to ruin a growing market?

The risks of not knowing

In medicine, what we don't know can hurt us—and more importantly, it can harm our patients. Our ability to base medical care on good research evidence is seriously undermined when that evidence is not available because of publication bias or conflicts of interest in a research arena dominated by pharmaceutical company funding. There can be no evidence-based medicine if the evidence is not available!

So, what conclusions can be drawn about treating depression in children and adolescents? Clearly, at least with respect to drug therapy, we cannot assume that depressed children are similar to depressed adults. More research into the physiologic basis for that difference is undoubtedly necessary. In the meantime, returning to the basics and relying more heavily on proven approaches like cognitive therapy may be prudent. If medication is used, clinicians should stick to FDA-approved uses and take to heart the warning issued by the FDA in March emphasizing the need to monitor both children and adults with MDD very carefully after they are placed on antidepressants. Finally, I would argue that we have a duty to inform both patients old enough to understand and their parents about the mixed and not particularly reassuring evidence regarding the efficacy and safety of SSRI medications for childhood depression.

In the bigger picture, this controversy illustrates that our system of research and development of new pharmaceuticals is seriously flawed. When the best interests of our patients may so easily conflict with those of a large and powerful industry, the potential for tragedy arises on an individual and societal scale. As advocates for our patients and for the public safety, we must expect and demand increased openness in the system used in this country to evaluate the safety and effectiveness of medications. Practicing good medicine requires access to unbiased and complete information about what works . . . and about what doesn't work.

REFERENCES

1. Olfson M, Gameroff MJ, Marcus SC, Waslick BD. Outpatient treatment of child and adolescent depression in the United States. Arch Gen Psychiatry. 2003;60:1236-1242.

2. Committee on Safety of Medications. Selective serotonin reuptake inhibitors (SSRIs): Overview of regulatory status and CSM advice relating to major depressive disorder (MDD) in children and adolescents including a summary of available safety and efficacy data. [updated 4/8/04; cited 7/26/04]. Available at: http://medicines.mhra.gov.uk/ourwork/monitorsafequalmed/safetymessages/ssrioverview_101203.htm. Accessed August 2, 2004.

3. US Food and Drug Administration. FDA Public Health Advisory. March 22, 2004. Subject: Worsening depression and suicidality in patients being treated with antidepressant medications. [Created 3/22/04; cited 7/26/04]. Available at: http://www.fda.gov/cder/drug/antidepressants/AntidepressanstPHA.htm. Accessed August 2, 2004.

4. US Food and Drug Administration. FDA Talk Paper: FDA issues public health advisory on cautions for use of antidepressants in adults and children. [Created 3/22/04; cited 7/26/04]. Available at: http://www.fda.gov/bbs/topics/ANSWERS/2004/ANS01283.html. Accessed August 2, 2004.

5. US Food and Drug Administration Division of Dockets Management. Memorandum dated January 5, 2004: Background comments for February 2, 2004 meeting of Psychopharmacological Drugs Advisory Committee and Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee. [Updated 3/16/04; cited 7/26/04]. Available at: http://www.fda.gov/ohrms/dockets/ac/04/briefing/4006B1_01_ Overview%20Memo.htm" target="_blank">http://www.fda.gov/ohrms/dockets/ac/04/briefing/4006B1_01_ Overview%20Memo.htm. Accessed August 2, 2004.

6. Jureidini JN, Doecke CJ, Mansfield PR, et al. Efficacy and safety of antidepressants for children and adolescents. BMJ. 2004;328:879-883.

7. Garland EJ. Facing the evidence: antidepressant treatment in children and adolescents. CMAJ. 2004;170:489-491.

8. Center for Drug Evaluation and Research. Application number 18-936/SE5-064. Statistical reviews. Fluoxetine. Available at: http://www.fda.gov/cder/foi/nda/2003/18936S064_Prozac%20Pulvules_statr.pdf. Accessed August 2, 2004.

9. Bhandari M, Busse JW, Jackowski D, et al. Association between industry funding and statistically significant pro-industry findings in medical and surgical randomized trials. CMAJ. 2004;170:477-480.

10. The "file drawer" phenomenon: suppressing clinical evidence [editorial]. CMAJ. 2004;170:437.