Large Pediatric Antidepressant Trials Driving High Rate of Placebo Response

Marlene Busko

January 15, 2009

January 15, 2009 — The high rate of placebo response to antidepressants in pediatric populations may be due to an increase in the number of large multicenter trials, new research suggests.

A review of antidepressant drug trials in individuals 6 to 18 years showed that younger age and less severe depression were other factors linked to placebo response to second-generation antidepressants, but the best predictor was a large study.

This is important, since a large placebo response can obscure the efficacy of antidepressants, which are judged in relation to placebo.

"The recent shift toward large multisite trials of antidepressant medications for pediatric major depression may be contributing to an increasing incidence of response to placebo," Jeffrey A. Bridge, PhD, from the Research Institute at Nationwide Children's Hospital, in Columbus, Ohio, and colleagues write.

"Higher placebo response rates in more recent studies were explained by an increasing trend toward large multisite trials and by publication delays and failures to publish some negative trials," they add.

The study is published the January issue of the American Journal of Psychiatry.

Difficult Treatment Decisions

Major depressive disorder is common in children and adolescents and is associated with multiple problems ranging from difficulties in school to increased risk for substance abuse or even suicide, the researchers write.

The high response to placebo in clinical trials of pediatric depression, however, makes it difficult for clinicians to make informed treatment decisions.

In a previous meta-analysis of antidepressants in young people, researchers showed that 50% of youth with major depressive disorder responded to placebo, whereas only 32% of youth with obsessive-compulsive disorder and 39% of youth with other anxiety disorders responded to placebo.

Unlike for adults, factors influencing increased response to placebo in depressed youth have not been well studied.

To examine factors that might predict placebo response in pediatric depression, investigators examined summary data from 12 published and unpublished studies of 2862 patients who were randomized to second-generation antidepressants or placebo. The subjects were aged 6 to 18 years, with a median age of 12.3 years.

Response was defined as a score of 2 or lower on the improvement item in the Clinical Global Impression scale.

Potential predictors of placebo response included age (under age 12 or 13 years vs 12 or 13 years and older), sex, race, study size (number of patients, sites, participants per site), treatment length, study location, presence of placebo run-in, length of depressive episode, first depressive episode, and baseline depression severity.

The researchers found that response to placebo, but not to active medication, was strongly related to the number of study sites.

In addition, participants with less severe baseline depression were more likely to show a placebo response, but this relationship was weaker after the number of study sites was controlled for.

Excluding 1 fluoxetine trial, the rate of response was 54.3% in children and 44.9% in adolescents (P = .02), suggesting that the response may be higher in younger children.

There was no correlation between placebo response and the other potential predictors.

Future Research Suggestions

To better detect differences between active antidepressant treatment and placebo in pediatric depression, future clinical trials should limit study sites to a few specialized centers, use "careful recruitment" to screen out patients who are likely to respond to placebo, and include subjects with at least moderate depression, the researchers suggest.

Future studies should also investigate whether drugs,psychotherapy, or both are best initial treatments for mild depression in young patients.

Placebo Response Should Not be Misinterpreted

"The high rate of response to placebo in multisite clinical trials should not be misinterpreted to mean that childhood depression is not a valid clinical entity or that it does not require vigorous treatment, including use of antidepressant drugs where appropriate," Graham J. Emslie, MD, from the University of Texas Southwestern Medical Center, in Dallas, cautions in an accompanying editorial.

"To that end, the Bridge et al study is an important step toward clarifying issues of trial design that should be modified to increase the likelihood that these important trials identify the children who are most likely to be in need of treatment," he writes.

According to Dr. Emslie, the meta-analysis has 2 main clinical implications.

First, it emphasizes the need for clinicians to carefully evaluate young patients to ensure that their depression is severe enough to warrant antidepressant treatment.

Second, even when placebo-controlled trials of antidepressants fail to provide evidence of efficacy, clinicians should not ignore the study results, since they provide essential information about age-specific adverse effects.

Dr. Bridge has received research support from the National Institute of Mental Health (NIMH) and the American Foundation for Suicide Prevention and has presented on suicide prevention in children and adolescents at a conference supported in part by Eli Lilly and Lundbeck. The financial disclosures of the other authors are listed in the paper. Dr. Emslie receives research support from Biobehavioral Diagnostics, Forest Laboratories, the NIMH, Shire, and Somerset and is a consultant for Biobehavioral Diagnostics, Eli Lilly, Forest Laboratories, Shire, Validus Pharmaceuticals, and Wyeth Pharmaceuticals. The study was supported by the NIMH.

Am J Psychiatry. 2009;166:42-49 Abstract, 1-3. Abstract


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