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Can fluoxetine's diminished efficacy in pediatric depression be explained by study sites, baseline severity, age, and

Martin Plöderl1, Richard Lyus2, Florian Naudet3

  • 1Center for Inpatient Psychotherapy and Crisis Intervention, University Clinic for Psychiatry/Psychotherapy/Psychosomatics, Paracelsus Medical University, Salzburg, 5020, Austria.

Journal of Psychiatric Research
|August 19, 2026
PubMed

Insights

Trial characteristics like number of study sites (NOSS), age, or severity did not explain declining fluoxetine efficacy in pediatric depression. An outlying trial influenced early findings, but overall, these factors don't account for reduced effectiveness.

Area of Science:

  • Child and Adolescent Psychiatry
  • Psychopharmacology
  • Clinical Trial Methodology

Background:

  • Fluoxetine's effectiveness in pediatric depression trials has decreased, approaching placebo levels.
  • Investigating trial characteristics to explain this trend is crucial for understanding treatment efficacy.

Purpose of the Study:

  • To determine if changes in trial characteristics explain the declining efficacy of fluoxetine in pediatric depression.
  • To explore the impact of number of study sites (NOSS), participant age, baseline depression severity, and psychological interventions on fluoxetine's efficacy and placebo response.

Main Methods:

  • Secondary exploratory analysis of meta-analyses of pediatric fluoxetine depression trials.
  • Meta-regression used to assess associations between NOSS, age, severity, and psychological interventions with efficacy and placebo response.
  • Symptom change measured using the Children's Depression Rating Scale Revised (CDRS-R).

Main Results:

  • Number of study sites (NOSS) increased over time but was not significantly associated with outcomes.
  • Initial associations between log-transformed NOSS and decreased efficacy/increased placebo response were driven by a single high-risk-of-bias trial.
  • Participant age, baseline severity, and psychological interventions did not significantly impact efficacy or placebo response.

Conclusions:

  • The apparent decline in fluoxetine efficacy is not explained by changes in NOSS, age, baseline severity, or psychological interventions.
  • An outlying trial with high risk of bias influenced early findings regarding NOSS.
  • These trial characteristics do not substantially account for the observed meta-analytic efficacy estimates of fluoxetine in pediatric depression.
Abstract

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