The umbrella review, and the fight about it
A 2022 review of 17 studies found no support for depression being caused by low serotonin. Thirty-five authors replied in the same journal that the review was too leaky to show it. Both stand; neither is withdrawn.
We have not finished checking this source. No judgement either way. how we score evidence
Caveat on this rating: This stop is the dispute, so the caveat is about what it does NOT establish. It does not establish that the serotonin hypothesis is disproved: the review's own framing is absence of support, and Jauhar and colleagues argue that its method manufactures that absence. It does not establish that the rebuttal is correct either. The two sides also disagree about what tryptophan depletion is for - whether the test is inducing depression in healthy people, or worsening it in people with a history - and that disagreement is unresolved rather than adjudicated here. Four further published critiques and a second author reply appeared in 2024 and are named in the body only as "a second exchange", because their full texts are paywalled with no PMC deposit and this library does not quote a paper it has only read about. Declared interests are printed for both sides precisely because neither set of interests decides the science.
Two papers, eleven months apart, in the same journal. Reading only one of them is how people end up certain about this.
Significant findings
In July 2022 Molecular Psychiatry published an umbrella review - a review of reviews - covering six areas of serotonin research across seventeen studies (doi:10.1038/s41380-022-01661-0). Its conclusion, in its own words: the evidence provides "no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations".
Its strongest results are the genetic ones. The largest study of the serotonin transporter gene found an odds ratio of 1.000 against lifetime depression in 115,257 people; the largest collaborative meta-analysis found 1.00 (95% CI 0.95-1.05) in 21,135. The gene-by-stress interaction that was once among psychiatry's most cited findings replicated in neither.
In June 2023 the same journal published a reply with thirty-five authors, led by Jauhar and with Cowen as its senior author. Their summary: "the methodology is inconsistent with an umbrella review, with substantial bias created by the authors' chosen quality criteria, selective reporting, and interpretation of results." They also charge a specific technical error - that the review treats 5-HT1A receptors as exclusively the pre-synaptic kind when most are not - and they press hardest on tryptophan depletion, the experiment that temporarily removes serotonin's dietary building block. In the very meta-analysis the review cites, they note, the effect in depressed people not taking antidepressants, across eight samples, "was large" - Hedges' g = -1.9, 95% CI -3.02 to -0.78.
The review's authors replied in the same issue. That subgroup, they write, "was presented in Table 1 but not described in the text because the main point of tryptophan depletion is to establish whether it induces depression in people without depression" - and on people without depression, "we all agree the data is consistent and tryptophan depletion has no effect" (doi:10.1038/s41380-023-02094-z). A second exchange followed in 2024.
Who is arguing matters in both directions, and both sides declared it. Two of the review's authors are co-chairs of the Critical Psychiatry Network and two others declare interests in antidepressant-discontinuation work. Among the thirty-five signatories of the reply, one is a part-time employee and shareholder of a drug manufacturer, and many declare consultancy or speaking fees from industry. Neither list settles anything; both are on the record, which is the point.
Worth asking
Nothing here was retracted. A contested review and a contested rebuttal both stand, which is what an unsettled question looks like from the inside. If you were told your depression was a serotonin deficiency, the useful question is not who won this argument. It is what your prescriber is actually watching to tell whether your treatment is working.
Source
A leaky umbrella has little value: evidence clearly indicates the serotonin system is implicated in depression — Jauhar S, Arnone D, Baldwin DS, Bloomfield M, Browning M, Cleare AJ, Corlett P, Deakin JFW, Erritzoe D, Fu C, Fusar-Poli P, Goodwin GM, Hayes J, Howard R, Howes OD, Juruena MF, Lam RW, Lawrie SM, McAllister-Williams H, Marwaha S, et al. (35 authors; senior author Cowen PJ) (2023)
Read the source: https://doi.org/10.1038/s41380-023-02095-y
DOI: 10.1038/s41380-023-02095-y
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: This stop is the dispute, so the caveat is about what it does NOT establish. It does not establish that the serotonin hypothesis is disproved: the review's own framing is absence of support, and Jauhar and colleagues argue that its method manufactures that absence. It does not establish that the rebuttal is correct either. The two sides also disagree about what tryptophan depletion is for - whether the test is inducing depression in healthy people, or worsening it in people with a history - and that disagreement is unresolved rather than adjudicated here. Four further published critiques and a second author reply appeared in 2024 and are named in the body only as "a second exchange", because their full texts are paywalled with no PMC deposit and this library does not quote a paper it has only read about. Declared interests are printed for both sides precisely because neither set of interests decides the science. 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?
A leaky umbrella has little value: evidence clearly indicates the serotonin system is implicated in depression — Jauhar S, Arnone D, Baldwin DS, Bloomfield M, Browning M, Cleare AJ, Corlett P, Deakin JFW, Erritzoe D, Fu C, Fusar-Poli P, Goodwin GM, Hayes J, Howard R, Howes OD, Juruena MF, Lam RW, Lawrie SM, McAllister-Williams H, Marwaha S, et al. (35 authors; senior author Cowen PJ) (2023). DOI: 10.1038/s41380-023-02095-y. 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.