The serotonin theory of depression: a systematic umbrella review of the evidence
- PMID: 35854107
- PMCID: PMC10618090
- DOI: 10.1038/s41380-022-01661-0
The serotonin theory of depression: a systematic umbrella review of the evidence
Abstract
The serotonin hypothesis of depression is still influential. We aimed to synthesise and evaluate evidence on whether depression is associated with lowered serotonin concentration or activity in a systematic umbrella review of the principal relevant areas of research. PubMed, EMBASE and PsycINFO were searched using terms appropriate to each area of research, from their inception until December 2020. Systematic reviews, meta-analyses and large data-set analyses in the following areas were identified: serotonin and serotonin metabolite, 5-HIAA, concentrations in body fluids; serotonin 5-HT1A receptor binding; serotonin transporter (SERT) levels measured by imaging or at post-mortem; tryptophan depletion studies; SERT gene associations and SERT gene-environment interactions. Studies of depression associated with physical conditions and specific subtypes of depression (e.g. bipolar depression) were excluded. Two independent reviewers extracted the data and assessed the quality of included studies using the AMSTAR-2, an adapted AMSTAR-2, or the STREGA for a large genetic study. The certainty of study results was assessed using a modified version of the GRADE. We did not synthesise results of individual meta-analyses because they included overlapping studies. The review was registered with PROSPERO (CRD42020207203). 17 studies were included: 12 systematic reviews and meta-analyses, 1 collaborative meta-analysis, 1 meta-analysis of large cohort studies, 1 systematic review and narrative synthesis, 1 genetic association study and 1 umbrella review. Quality of reviews was variable with some genetic studies of high quality. Two meta-analyses of overlapping studies examining the serotonin metabolite, 5-HIAA, showed no association with depression (largest n = 1002). One meta-analysis of cohort studies of plasma serotonin showed no relationship with depression, and evidence that lowered serotonin concentration was associated with antidepressant use (n = 1869). Two meta-analyses of overlapping studies examining the 5-HT1A receptor (largest n = 561), and three meta-analyses of overlapping studies examining SERT binding (largest n = 1845) showed weak and inconsistent evidence of reduced binding in some areas, which would be consistent with increased synaptic availability of serotonin in people with depression, if this was the original, causal abnormaly. However, effects of prior antidepressant use were not reliably excluded. One meta-analysis of tryptophan depletion studies found no effect in most healthy volunteers (n = 566), but weak evidence of an effect in those with a family history of depression (n = 75). Another systematic review (n = 342) and a sample of ten subsequent studies (n = 407) found no effect in volunteers. No systematic review of tryptophan depletion studies has been performed since 2007. The two largest and highest quality studies of the SERT gene, one genetic association study (n = 115,257) and one collaborative meta-analysis (n = 43,165), revealed no evidence of an association with depression, or of an interaction between genotype, stress and depression. The main areas of serotonin research provide no consistent evidence of there being an association between serotonin and depression, and no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations. Some evidence was consistent with the possibility that long-term antidepressant use reduces serotonin concentration.
© 2022. The Author(s).
Conflict of interest statement
All authors have completed the Unified Competing Interest form at
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Comment in
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Putting serotonin in its place-again.BMJ. 2022 Oct 5;379:o2357. doi: 10.1136/bmj.o2357. BMJ. 2022. PMID: 36198406 No abstract available.
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Is the serotonin hypothesis/theory of depression still relevant? Methodological reflections motivated by a recently published umbrella review.Eur Arch Psychiatry Clin Neurosci. 2023 Feb;273(1):1-3. doi: 10.1007/s00406-022-01549-8. Eur Arch Psychiatry Clin Neurosci. 2023. PMID: 36790577 Free PMC article. Review. No abstract available.
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Serotonin and depression-an alternative interpretation of the data in Moncrieff et al.Mol Psychiatry. 2023 Aug;28(8):3158-3159. doi: 10.1038/s41380-023-02090-3. Epub 2023 Jun 16. Mol Psychiatry. 2023. PMID: 37322060 No abstract available.
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The serotonin theory of depression.Mol Psychiatry. 2023 Aug;28(8):3157. doi: 10.1038/s41380-023-02091-2. Epub 2023 Jun 16. Mol Psychiatry. 2023. PMID: 37322061 No abstract available.
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Reply to: "The serotonin theory of depression: a systematic umbrella review of the evidence" published by Moncrieff J, Cooper RE, Stockmann T, Amendola S, Hengartner MP, Horowitz MA in Molecular Psychiatry (2022 Jul 20. doi: 10.1038/s41380-022-01661-0).Mol Psychiatry. 2023 Aug;28(8):3153-3154. doi: 10.1038/s41380-023-02093-0. Epub 2023 Jun 16. Mol Psychiatry. 2023. PMID: 37322062 No abstract available.
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Although serotonin is not a major player in depression, its precursor is.Mol Psychiatry. 2023 Aug;28(8):3155-3156. doi: 10.1038/s41380-023-02092-1. Epub 2023 Jun 16. Mol Psychiatry. 2023. PMID: 37322063 No abstract available.
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The serotonin hypothesis of depression: both long discarded and still supported?Mol Psychiatry. 2023 Aug;28(8):3160-3163. doi: 10.1038/s41380-023-02094-z. Epub 2023 Jun 16. Mol Psychiatry. 2023. PMID: 37322064 No abstract available.
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A leaky umbrella has little value: evidence clearly indicates the serotonin system is implicated in depression.Mol Psychiatry. 2023 Aug;28(8):3149-3152. doi: 10.1038/s41380-023-02095-y. Epub 2023 Jun 16. Mol Psychiatry. 2023. PMID: 37322065 Free PMC article.
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