The loss of efficacy of fluoxetine in pediatric depression: explanations, lack of acknowledgment, and implications for other treatments

J Clin Epidemiol. 2026 Jan;189:112016. doi: 10.1016/j.jclinepi.2025.112016. Epub 2025 Nov 21.

ABSTRACT

OBJECTIVES: Fluoxetine is among the most used antidepressants for children and adolescents and frequently recommended as first-line pharmacological treatment for pediatric depression. However, in contrast to earlier studies and reviews, a Cochrane network meta-analysis from 2021 concluded that the estimated efficacy of fluoxetine was no longer clinically meaningful. We aimed to explain the discrepant findings between the recent Cochrane review and earlier reviews, and to explore if this was acknowledged in guidelines and treatment recommendations appearing since then.

STUDY DESIGN AND SETTING: Meta-analytical aggregation of trial results over time, exploring potential biases, and a nonsystematic search for recent treatment guidelines/recommendations from major medical organizations.

RESULTS: The estimated efficacy of fluoxetine in clinical trials declined over time into the range of clinical equivalence with placebo when more recent studies were included in analyses and when considering common thresholds of clinical significance. This remains unacknowledged in treatment guidelines and related publications, including some that continue to recommend fluoxetine as first-line pharmacological treatment. Finally, we find that the loss of efficacy over time is likely explained by biases such as the novelty bias or by variations of expectancy effects.

CONCLUSION: The seeming lack of clinically meaningful efficacy of fluoxetine for the treatment of pediatric depression needs to be considered by those who develop treatment recommendations as well as by patients and clinicians. The biases we observed are not only relevant in the evaluation of fluoxetine and other antidepressants for pediatric depression, but also for any new treatment.

PMID:41548966 | DOI:10.1016/j.jclinepi.2025.112016