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Restoring the two pivotal fluoxetine trials in children and adolescents with depression
Peter C Gøtzsche1, David Healy2
1Institute for Scientific Freedom, Hørsholm, Denmark.
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.
Insights
This review of fluoxetine trials for pediatric depression found the drug to be unsafe and ineffective. Key efficacy outcomes were biased, and precursors to suicidality occurred more frequently with fluoxetine.
Area of Science:
- Psychiatry
- Pediatric Mental Health
- Clinical Pharmacology
Background:
- Fluoxetine's approval for pediatric depression was based on two trials (X065, HCJE).
- Concerns exist regarding potential misreporting of these pivotal trials.
- This study aims to systematically review the original clinical study reports and publications.
Approach:
- Systematic review of clinical study reports and publications.
- Primary outcomes included efficacy, suicidal events, and precursors to suicidality or violence.
- Analysis focused on identifying missing information and numerical inconsistencies.
Key Points:
- Efficacy outcomes were biased by differential dropouts and missing data; patient ratings found fluoxetine ineffective.
- Suicidal events were omitted from publications and reports; precursors to suicidality/violence were more frequent with fluoxetine.
- Fluoxetine was associated with adverse events, including harm, reduced growth, and QT interval prolongation.
Conclusions:
- Reanalysis indicates fluoxetine is unsafe and ineffective for treating depression in children and adolescents.
- Significant data discrepancies and biases were identified in the original trial reporting.
- The findings challenge the established efficacy and safety profile of fluoxetine in pediatric populations.
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