The medication fluoxetine, sold under the brand name Prozac, is recommended as a treatment for depression in children and adolescents in several clinical guidelines.Credit: Jb Reed/Bloomberg via Getty
A single clinical trial of 40 children in Iran, published in 2006, might have wrongly swayed medical evidence in favour of using Prozac (fluoxetine) to treat depression in children and adolescents, a group of researchers say. They’re now calling that trial’s findings into question and suggest that, in their opinion, Prozac’s recommendation in paediatric clinical guidelines isn’t sufficiently supported by the evidence — although they stop short of calling for clinicians to stop prescribing Prozac for depression in children.
Instead, “guideline committees should review their recommendations, acknowledge the evidence we have clarified and go through their process of weighing up whether use can still be justified”, says Richard Lyus, a consultant child and adolescent psychiatrist in Cambridge, UK, and a co-author of the study, which was published this month in Cochrane Evidence Synthesis and Methods1.
The finding shows how a single ‘zombie’ trial — that is, one with data so flawed as to be untrustworthy — can corrupt the evidence base for a frontline medical treatment, says Florian Naudet, a psychiatrist at the University of Rennes in France, and another co-author of the study.
Scientists have repeatedly warned that flawed studies are affecting the results of systematic reviews in medicine and other fields, but it’s rare to find such a clear example, Naudet says.
The researchers who conducted the controversial trial did not respond to repeated email enquiries from Naudet’s team and did not contact him or his colleagues when they posted a preprint to medRxiv describing their analysis in September last year. Nor did they respond to Nature’s request for comment.
Excluding outliers
Prozac is one of the most frequently prescribed antidepressants in children. Many national prescribing guidelines recommend the drug on the basis of a 2016 meta-analysis published in The Lancet2, which found that Prozac is better than placebo for treating depression in children and adolescents. A 2020 meta-analysis in The Lancet Psychiatry supported those findings3. But, in 2021, a meta-analysis published in Cochrane Database of Systematic Reviews4 found that Prozac had only a ‘small and unimportant’ advantage over placebo, and that it was probably no better than other antidepressants.
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In the latest study, Naudet and his colleagues found that the reason that the meta-analyses disagreed comes down to whether they included or excluded just one clinical trial, conducted in Iran and published in 20065. This trial found that Prozac had an enormous advantage over another antidepressant, nortriptyline. The effect size of this result was so big as to be unheard of in biomedical science, says Martin Plöderl, a clinical psychotherapist at Paracelsus Medical Private University in Salzburg, Austria, and a co-author of the latest study. “It’s the kind of effect size you only get if you ask people whether they prefer chocolate or faeces,” he says.
Plöderl, Naudet and their colleagues re-ran the 2016 and 2020 meta-analyses while excluding the data from the 2006 trial and found that Prozac’s outsized benefits disappeared. The 2021 analysis happened to leave out the 2006 trial because it chose to exclude comparison studies with a class of antidepressants that contains nortriptyline.
Elia Abi-Jaoude, a psychiatrist and clinician at the Hospital for Sick Children in Toronto, Canada, calls the paper a “slam-dunk study”. “I hope it will get wide exposure” he says.
Trial disagreements
No other trial of Prozac for paediatric depression has found an effect size close to the one reported in the 2006 study. The researchers say that the trial’s findings also seem implausible because the data reported imply that in the group of children taking Prozac every participant’s depression score changed by a similar amount. And that was also true for the group taking nortriptyline. Such an orderly shift is rare in clinical trials. The trial also included no description of its ethics-approval process.
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MedKnow, the publisher of the journal in which the trial appeared, says that it has asked the journal’s editorial team to look into the issue, and that it expected a delay due to the issues currently faced by Iran.
In the past five years, the Cochrane group, a network of clinicians, patients, carers and health researchers that guides gold-standard medical reviews, has grown sufficiently worried by the influence of flawed trials that it has brought in a protocol for researchers to assess whether trials are “untrustworthy” — and to potentially exclude them from reviews in such cases. On those grounds, the 2006 trial should be removed from the evidence base for Prozac, Plöderl and others say.
Andrea Cipriani, a psychiatrist at the University of Oxford, UK, and a co-author of the 2016 and 2020 meta-analyses that found that Prozac is better than placebo for treating depression in children and adolescents, told Nature that he agrees that the 2006 trial data are problematic. He says that the meta-analysis teams did discuss it at the time, but that, without the current protocol for dealing with untrustworthy trials, they couldn’t find a justification for excluding it from analysis. In their write-ups, the teams did note concerns about poor methods and risk of bias, and added in an appendix to the 2016 study that potential biases in evidence meant that there was “very low” confidence in the Prozac findings, Cipriani says, a warning that was repeated in the 2020 study.
