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

Background: Fluoxetine is among the most used antidepressants for children and adolescents andfrequently recommended as first-line pharmacological treatment for pediatric depression. However,in contrast to earlier studies and reviews, a Cochrane network meta-analysis from 2021 concludedthat the estimated efficacy of fluoxetine was no longer clinically meaningful.Study aim: To explain the discrepant findings between the recent Cochrane review and earlierreviews and to explore if this was acknowledged in guidelines and treatment recommendationsappearing since then.Methods: Meta-analytical aggregation of trial results over time, exploring potential biases, and anon-systematic search for recent treatment guidelines/recommendations from major medicalorganizations.Results: The estimated efficacy of fluoxetine in clinical trials declined over time into the range ofclinical equivalence with placebo when more recent studies were included in analyses and whenconsidering common thresholds of clinical significance. This remains unacknowledged in treatmentguidelines 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 likelyexplained by biases such as the novelty bias or by variations of expectancy effects.Conclusions: The seeming lack of clinically meaningful efficacy of fluoxetine for the treatment ofpediatric depression needs to be considered by those who develop treatment recommendations aswell as by patients and clinicians. The biases we observed are not only relevant in the evaluation offluoxetine and other antidepressants for pediatric depression, but also for any new treatment.