Initial Treatment on Placebo Not Harmful to Teens in Antidepressant Trials

January 30, 2009 — Initial treatment with placebo in teens participating in antidepressant trials is not harmful, and in fact, adolescents who receive placebo prior to active treatment fare as well as those who receive immediate active treatment, a new study suggests.

Data from the 36-week Treatment for Adolescents With Depression Study (TADS) reveal that teens randomized to 12 weeks of placebo followed by active treatment had adverse events and end-of-study treatment response similar to those who received active treatment for the entire study duration.

"Our findings suggest that patients treated with placebo acutely are not harmed and that placebo is an acceptable intervention in randomized controlled trials with adolescents who have moderate or severe depression," lead author Betsy D. Kennard, PsyD, from the University of Texas Southwestern Medical Center at Dallas, told Medscape Psychiatry.

Parents and clinicians who feel that a child might be an appropriate candidate for a clinical trial can take some comfort from these findings that an initial period of placebo treatment did not diminish outcomes at 9 months, she said.

The study is published online January 15 in the American Journal of Psychiatry.

Concerns About Treatment Delay

"While placebo-controlled trials are necessary to establish the efficacy and safety of medications, concerns have been raised about the long-term impact of delaying active treatment with use of a placebo," the authors write.

A placebo control is not appropriate in a clinical trial where deferring treatment may lead to significant harm, they add. However, in other situations, having a placebo control group means that a smaller study can detect meaningful outcomes.

According to researchers at a recent forum sponsored by the American Academy of Child and Adolescent Psychiatry, placebo controls are acceptable if trial subjects have the potential to directly benefit from placebo, have limited risk of harm from withheld active treatment, and can receive rescue procedures if needed.

To evaluate whether adolescents randomized to initial placebo followed by active treatment had levels of harm or benefits that differed from those in adolescents who received continuous active treatment, the investigators analyzed data from the 36-week TADS trial (March J et al. JAMA 2004;292:807-820).

The study included 439 participants aged 12 to 17 years with depression who were randomized to receive fluoxetine, cognitive behavioral therapy, combination therapy, or placebo.

The 112 subjects in the placebo group received placebo for 12 weeks followed by open active treatment.

"Placebo treatment is not the same as no treatment," said Dr. Kennard. "These teens received a full clinical evaluation, regular visits with a child psychiatrist, and supportive clinical management. So in reality they received quite a bit of treatment."

Thirteen children in the placebo group whose depression worsened before the end of the 12 weeks were removed from this study arm and treated with clinically indicated treatment, she added.

Response to treatment was defined as "very much improved" or "much improved" on the Clinical Global Improvement measure of depressive symptoms relative to baseline. Remission was defined as a Children's Depression Rating Scale-Revised score of less than or equal to 28.

Acceptable Research Study Design

At week 36, 82% of participants in the placebo group vs 83% in the treatment groups achieved a response, and 48% of participants in the placebo group vs 59% of participants in the treatment groups achieved remission.

In addition, patients in the placebo group did not require more rescue procedures or have higher rates of suicidal events or clinical worsening than those in the active-treatment groups.

"Our results demonstrate what we believed all along — that initial assignment to placebo is not associated with higher rates of symptom worsening, study dropout, suicidal events, or diminished response to subsequent treatment," said Dr. Kennard.

"While acceptable for a research study, delaying the onset of meaningful treatment in nonresearch settings is not ethical or clinically appropriate. However, placebo-controlled trials continue to be an important and acceptable research tool for establishing the safety and efficacy of new interventions for depressed adolescents," the investigators write.

Dr. Kennard reports having no competing interests. The financial disclosures of the other authors are listed in the paper. The Treatment for Adolescents With Depression Study is supported by a grant from the National Institute of Mental Health to Duke University Medical Center.

Am J Psychiatry. Published online January 15, 2009. Abstract

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