Whether it works and how it works are different questions
Aspirin was sold for about seventy years before anyone could say how it worked. Whether a drug helps is settled by trials, not by the story told about the mechanism - and these trials are large.
We have not finished checking this source. No judgement either way. how we score evidence
Caveat on this rating: Every efficacy number here is contested at the edges, and none of the disputes touches the conclusion this stop rests on. Cipriani 2018's own authors graded certainty moderate to very low and 9% of included trials at high risk of bias; its between-drug ranking is not established and is not used here. Stone 2022's three-class result comes from a statistical model, not an observed grouping, and its reading has been argued over since publication - though its co-author list includes the field's most prominent placebo-effect sceptic, which cuts against overstating benefit rather than for it. Both meta-analyses are dominated by short, largely industry-sponsored acute-phase trials in adults meeting formal criteria for major depression, and neither measures long-term outcomes. Cowen and Browning's emotional-processing account is a hypothesis with supporting experiments, not a settled mechanism. The ANTLER figures describe trial conditions, not any individual reader's risk.
This is the stop that matters most in this trail, and the easiest one to get backwards. "The serotonin explanation was oversimplified" and "the medication does not work" are different claims, resting on different evidence. The second does not follow from the first.
Significant findings
Seven years before the 2022 review, two Oxford psychopharmacologists wrote in World Psychiatry that "simple biochemical theories that link low levels of serotonin with depressed mood are no longer tenable" - and in the same paper set out what the evidence does support: that these drugs shift how the brain appraises emotional information, an effect that "occurs very early in treatment, prior to clinical antidepressant effects". A drug can work while the story about why it works is wrong. Aspirin had been sold for roughly seventy years before John Vane described its mechanism, in 1971.
Whether these drugs work is measured separately, by trials. A network meta-analysis of 522 randomised trials and 116,477 adults found all 21 antidepressants studied more effective than placebo for acute major depression, with odds ratios running from 2.13 (95% credible interval 1.89-2.41) for amitriptyline down to 1.37 (1.16-1.63) for reboxetine (doi:10.1016/S0140-6736(17)32802-7). The same paper rated 46 of those 522 trials at high risk of bias and graded the certainty of the evidence "moderate to very low", and the intervals overlap far too much for the ranking between the drugs to carry weight.
How large is the average effect? An analysis of individual participant data from 232 placebo-controlled trials submitted to the US regulator, 73,388 people, put the drug-placebo difference at 1.75 points on the 17-item Hamilton scale (1.63-1.86) - and found the responses formed not one curve but three, with about 15% of participants showing a large improvement beyond what placebo produced (doi:10.1136/bmj-2021-067606). Modest on average, large for a minority, negligible for another minority. That is a different finding from "it does not work". It is also not what the advertisements said.
Worth asking
Stopping is a measured risk of its own. In a randomised trial of 478 UK primary-care patients who felt well enough to try coming off, 56% of those tapered onto placebo relapsed within a year, against 39% who stayed on their antidepressant (doi:10.1056/NEJMoa2106356). Nothing in this trail is a reason to change anything you take, and any change belongs to you and a prescriber together. If the serotonin sentence is what you were given as a reason to start, the questions worth bringing are about outcome rather than mechanism: what change are we expecting, by when, how would we know it is working, and what happens if it only partly helps?
What to watch for
Evidence quality tells you whether to trust the finding — not whether the treatment is safe. These are the risks this research reports.
- Withdrawal & dependence
Source
What has serotonin to do with depression? — Cowen PJ, Browning M (2015)
Read the source: https://doi.org/10.1002/wps.20229
DOI: 10.1002/wps.20229
How this was scored
- Study design
- not recorded
- Funding
- not recorded
- Published in
- not recorded
- Sample size
- not recorded
- Preregistered
- not recorded
- Conflicts disclosed
- not recorded
- Independent of proponent
- not recorded
- Retracted
- No
We have not finished checking this source, so there is no scoring to show yet. “We have not checked this yet” and “this is disputed” are different statements, so no scored band is shown rather than a low one.
Read the full scoring rubric, including what it can't tell you.
Published September 10, 2026.
Questions
How strong is the evidence behind this?
veisund rates this source "not yet assessed". We have not finished checking this source. No judgement either way. One caveat travels with that badge: Every efficacy number here is contested at the edges, and none of the disputes touches the conclusion this stop rests on. Cipriani 2018's own authors graded certainty moderate to very low and 9% of included trials at high risk of bias; its between-drug ranking is not established and is not used here. Stone 2022's three-class result comes from a statistical model, not an observed grouping, and its reading has been argued over since publication - though its co-author list includes the field's most prominent placebo-effect sceptic, which cuts against overstating benefit rather than for it. Both meta-analyses are dominated by short, largely industry-sponsored acute-phase trials in adults meeting formal criteria for major depression, and neither measures long-term outcomes. Cowen and Browning's emotional-processing account is a hypothesis with supporting experiments, not a settled mechanism. The ANTLER figures describe trial conditions, not any individual reader's risk. 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?
What has serotonin to do with depression? — Cowen PJ, Browning M (2015). DOI: 10.1002/wps.20229. The full source is linked on this page so you can read it yourself.
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.