Restoring the two pivotal fluoxetine trials in children and adolescents with depression.

Background: Fluoxetine was approved for depression in children and adolescents based on two placebo-controlled trials, X065 and HCJE, with 96 and 219 participants, respectively.

Objective: To review these trials, which appear to have been misreported.

Methods: Systematic review of the clinical study reports and publications. The primary outcomes were the efficacy variables in the trial protocols, suicidal events, and precursors to suicidality or violence.

Results: Essential information was missing and there were unexplained numerical inconsistencies. (1) The efficacy outcomes were biased in favour of fluoxetine by differential dropouts and missing data. The efficacy on the Children's Depression Rating Scale-Revised was 4% of the baseline score, which is not clinically relevant. Patient ratings did not find fluoxetine effective. (2) Suicidal events were missing in the publications and the study reports. Precursors to suicidality or violence occurred more often on fluoxetine than on placebo. For trial HCJE, the number needed to harm was 6 for nervous system events, 7 for moderate or severe harm, and 10 for severe harm. Fluoxetine reduced height and weight over 19 weeks by 1.0 cm and 1.1 kg, respectively, and prolonged the QT interval.

Conclusions: Our reanalysis of the two pivotal trials showed that fluoxetine is unsafe and ineffective.