Cochrane 2021: newer antidepressants cut depression in children and teens by a small and unimportant amount
Across 26 trials in 6 to 18 year olds, fluoxetine beat placebo by 2.84 points on a 17 to 113 point scale, which Cochrane rated small and unimportant. Sertraline, escitalopram and duloxetine were in the same range.
Reasonable evidence with real limitations. how we score evidence
Caveat on this rating: Read from the abstract and plain language summary only. Most included trials excluded young people at risk of suicide; suicide-related estimates are low certainty with wide intervals. The 2026 re-appraisal authors report that the full dataset behind this review was not retained.
The Cochrane review of newer antidepressants for depression in children and teenagers, and the one that disagreed with the Lancet reviews on fluoxetine.
Significant findings
Hetrick and colleagues pooled 26 randomised trials of newer antidepressants in 6 to 18 year olds with major depression, searched to March 2020. Older drugs (tricyclics and MAO inhibitors) were not included. On the clinician-rated CDRS-R scale (17 to 113 points), most drugs gave a "small and unimportant" drop in symptoms compared with placebo. Fluoxetine: 2.84 points (95% CI 1.56 to 4.12), moderate certainty. Sertraline (3.51), escitalopram (2.62), duloxetine (2.70) and paroxetine (1.43) were in the same range. Differences between most of the drugs were also "small and unimportant".
No trial reported the two primary outcomes, diagnosis by clinical interview and suicide. Suicide-related outcomes were uncommon and the estimates wide. For fluoxetine the odds ratio was 1.27 (0.87 to 1.86): low certainty that it may at least slightly raise those odds. Most trials excluded young people at risk of suicide, so the review cannot speak for them.
The other direction
The review does not say these drugs are useless. Averages hide people who respond more. The authors say sertraline, escitalopram, duloxetine and fluoxetine "could be considered as a first option", with close monitoring of treatment effects and suicide-related outcomes, and that therapy, particularly CBT, remains important. They also say methodological shortcomings in the trials make the findings hard to interpret.
Why it matters now
Because it left out tricyclics, this review did not include a small 2006 trial of fluoxetine against nortriptyline. A 2026 re-analysis (Lyus and colleagues, in this library) found that trial is what made fluoxetine look larger in the two Lancet reviews, including Cipriani 2016 (also in this library). Without it, all three land close to this review's estimate.
What this does not show
It does not tell any family whether to start, keep or stop a medicine. If your child takes fluoxetine, this is a question for their prescriber, not a reason to stop.
Worth asking
What size of change should we expect, how will we measure it, and how will suicide-related thinking be watched?
Source
New generation antidepressants for depression in children and adolescents: a network meta-analysis — Hetrick SE, McKenzie JE, Bailey AP, Sharma V, Moller CI, Badcock PB, Cox GR, Merry SN, Meader N (2021)
Top-tier peer-reviewed journal
Read the source: https://doi.org/10.1002/14651858.CD013674.pub2
DOI: 10.1002/14651858.CD013674.pub2
How this was scored
- Study design
- Meta-analysis of randomised trials
- Funding
- Funding not disclosed
- Published in
- Top-tier peer-reviewed journal
- Sample size
- not recorded
- Preregistered
- not recorded
- Conflicts disclosed
- not recorded
- Independent of proponent
- not recorded
- Retracted
- No
Read the full scoring rubric, including what it can't tell you.
Published October 7, 2026.
Where we put this study in context
Questions
How strong is the evidence behind this?
veisund rates this source "moderate evidence". Reasonable evidence with real limitations. It scores 66 out of 100 on our published rubric. One caveat travels with that badge: Read from the abstract and plain language summary only. Most included trials excluded young people at risk of suicide; suicide-related estimates are low certainty with wide intervals. The 2026 re-appraisal authors report that the full dataset behind this review was not retained. The score is calculated from recorded facts about the source — study design, funding, publication venue, sample size, preregistration — not typed in by an editor.
What is the source for this?
New generation antidepressants for depression in children and adolescents: a network meta-analysis — Hetrick SE, McKenzie JE, Bailey AP, Sharma V, Moller CI, Badcock PB, Cox GR, Merry SN, Meader N (2021). Published in: Top-tier peer-reviewed journal. DOI: 10.1002/14651858.CD013674.pub2. The full source is linked on this page so you can read it yourself.
Who paid for this research, and does that matter?
Study design: Meta-analysis of randomised trials. Funding: Funding not disclosed. Independence from the proponent is not recorded. Industry sponsorship is one of the most reliably measured biases in medicine, which is why funding carries real weight in the score rather than sitting in a footnote.
Is this medical advice?
This is information to bring to your prescriber, not medical advice and not a reason to change anything on your own. Nothing here is an instruction to stop or reduce a medication. If you are in crisis, call or text 988.
This is information to bring to your prescriber, not medical advice and not a reason to change anything on your own. Nothing here is an instruction to stop or reduce a medication. If you are in crisis, call or text 988.