One flawed 2006 trial roughly doubled fluoxetine's apparent benefit for childhood depression, a 2026 re-analysis finds

Why two influential reviews and a Cochrane review disagreed about fluoxetine for depression in children and teenagers, traced to one small trial.

Significant findings

Fluoxetine (sold as Prozac) is the antidepressant most guidelines name first for depression in under 18s. That rests mainly on two network meta-analyses in Lancet journals, Cipriani 2016 (in this library) and Zhou 2020. Both put fluoxetine ahead of placebo by a standardised effect of 0.51 (95% credible intervals 0.03 to 0.99, and 0.18 to 0.84), with confidence rated "very low". The 2021 Cochrane review (Hetrick, in this library) found a gap of 2.84 points on a 17 to 113 point rating scale, about 0.20 in the same units, and called it small and unimportant.

Lyus, Naudet, van Valkenhoef and Plöderl re-ran both Lancet analyses on their published data. Each carried an unexplained clash between direct and indirect evidence in the fluoxetine, nortriptyline and placebo loop. They traced it to one trial: Attari A, Moghaddam FY, Hasanzadeh A, et al., "Comparison of efficacy of fluoxetine with nortriptyline in treatment of major depression in children and adolescents: a double-blind study", Journal of Research in Medical Sciences 2006;11:24-30. Cochrane had left it out only because it excluded older tricyclic drugs such as nortriptyline.

Without that trial, fluoxetine's edge fell to 0.26 (0.09 to 0.43) in the Cipriani data and 0.29 (0.07 to 0.50) in the Zhou data, close to Cochrane, and the clash went away. In the authors' words: "Discrepancies between the three NMAs were explained by the indirect influence of a single small trial with extreme and unreliable results."

The trial

Forty children and teenagers at one site in Iran, 20 on each drug, no placebo arm. It reported an effect of about 4.2 for fluoxetine; the next largest in the Cipriani dataset was 0.9. Scored from end-of-trial scores instead of changes, the effect was 0.93. To produce the reported figure, before and after scores would have to correlate almost perfectly (r above 0.97): score changes were nearly uniform within each arm. Ethics approval is not mentioned, dropouts were replaced with new cases, and one p-value does not match its data. The authors did not answer two emails. The journal editor forwarded the concerns; the publisher, MedKnow, had not replied when the paper was written. Lancet Psychiatry peer reviewed an earlier version, rejected it and considered the matter closed.

The other direction

Even without the trial, all three analyses still put fluoxetine ahead of placebo beyond chance. The dispute is about size, not existence. The re-analysis was exploratory, had no preregistered protocol, could not exactly reproduce every original estimate, and rebuilt the Cochrane dataset because the full original was not kept. One author works for Cochrane, which the paper says had no role. Andrea Cipriani, a co-author of the 2016 and 2020 reviews, told Nature he agrees the 2006 data are problematic. He said the teams discussed it at the time but had no protocol then for excluding untrustworthy trials, and that both reviews noted concerns and rated confidence in the fluoxetine finding "very low". MedKnow told Nature it has asked the journal's editors to look into it.

What this does not show

The authors do not tell anyone to stop fluoxetine. They say clinicians and patients should know its actual effect and that guidelines should be updated. If your child takes fluoxetine, this is a question for their prescriber, not a reason to stop.

Worth asking

Given the smaller benefit these reviews now agree on, what do we expect fluoxetine to do for my child, and how will we know if it is working?