This statement was coded as being contradictory to the peer-reviewed literature, with one coder noting, “No, fluoxetine is approved for age 8 and older.” This statement further illustrates the problems with the study methods. The US Food and Drug Administration (FDA) approval only means that there is a statistically significant difference between the medication and placebo, and a closer look at the data and methods is necessary if one wishes to understand the clinical significance of the results. In 1 of the 2 studies submitted to the FDA for fluoxetine's approval, in addition to a commonly practiced placebo run-in phase, there was a fairly unique medication run-in phase to ensure that only children who were medication responders were allowed into the study. Yet, even with this advantage, for the prospectively defined primary outcome measure, 65% of the children taking Prozac had a beneficial response compared with 53% of the patients taking placebo, a result that was not statistically significant. It was only by looking at other measures that clinical significance was found; on the patient- and parent-rated scales there was no advantage to Prozac, but on 1 of the clinician-rated scales there was a slight advantage to Prozac. Although Russell Katz, MD, of the FDA wrote, “one could argue that this post hoc choice of primary outcome is inappropriate,” the FDA accepted the post hoc change and approved Prozac for children.
3
In fact, there is perhaps no more contentious and complex issue in medicine right now than the use of antidepressants in young children. Even in adults there is an ongoing debate about the efficacy of antidepressants.
4 In the case of antidepressants there is evidence of selective reporting,
5 ghostwritten papers, and a well-documented difference between the published and unpublished clinical trial data.
6 Several years ago, an editorial in
The Lancet summarized the peer-reviewed research on pediatric antidepressant use as “confusion, manipulation, and institutional failure.”
7 In reference to the pediatric use of antidepressants, Healy referred to the difference between the published data and the actual raw clinical trial data as the “greatest known divide in all of medicine.”
8
In 2004, a study in the
BMJ examined the methods and reporting of the published trials of the newer antidepressants in children younger than 18 years.
9 According to these researchers, the drugs offered only a modest benefit over placebo but had significant risks. In their conclusions they noted that: “Antidepressant drugs cannot confidently be recommended as a treatment option for childhood depression.” These researchers also noted that in the original Prozac pediatric trials submitted to the FDA, Prozac did not show efficacy over placebo on the primary end points.