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Cited by 960Neurotransmitter Receptor Influence on BehaviorTreatment of Major DepressionTryptophan and brain disorders

The serotonin theory of depression: a systematic umbrella review of the evidence

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Moncrieff, Joanna, Cooper, Ruth E., Stockmann, Tom, Amendola, Simone, Hengartner, Michael P., Horowitz, Mark A.·2023·Molecular Psychiatry
DOI 10.1038/s41380-022-01661-0PMC PMC10618090
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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-HT 1A 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-HT 1A 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.

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  • The serotonin deficit hypothesis postulates lowered serotonin in affective disorders and that SSRIs alleviate symptoms by normalizing serotonin levels.

    “Another point of contention is the “serotonin deficit hypothesis” which postulates lowered serotonin in affective disorders and that SSRIs alleviate symptoms by normalizing serotonin levels (Moncrieff et al., 2023).”

    From Revisiting the SSRI vs. placebo debate in the treatment of social anxiety disorder: the role of expectancy effects, neural responsivity, and monoamine transporters (2025) · cites this paper as Moncrieff et al., 2023

    The Introduction describes the proposed link between lowered serotonin and depression and the assumption that SSRI effects implicate serotonin. The Results section on the serotonin transporter says SSRIs are thought to increase serotonin in the synaptic cleft. The paper does not extend the hypothesis to affective disorders generally or state that symptom relief occurs by normalizing serotonin levels; its Discussion says the serotonin theory of depression is not empirically substantiated. (LLM, conf=0.83)

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Authors
Moncrieff, J., Cooper, R. E., Stockmann, T., Amendola, S., Hengartner, M. P., & Horowitz, M. A.
Affiliations
  • North East London NHS Foundation Trust (GB)
  • University of Greenwich (GB)
  • Sapienza University of Rome (IT)
  • ZHAW Zurich University of Applied Sciences (CH)
Corresponding author
Moncrieff, Joanna
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2022-07-20
Volume
28
Issue
8
Pages
3243-3256
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/s41380-022-01661-0
PMC
PMC10618090
OpenAlex
W4285891880
Cited by
960
References
13
Citations by year
2026: 180 · 2025: 226 · 2024: 256 · 2023: 228 · 2022: 68
FWCI
27.77
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion, cc-by)
  • FOCUS The Journal of Lifelong Learning in Psychiatry (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion)
  • Zürcher Hochschule für Angewandte Wissenschaften digital collection (Zurich University of Applied Sciences) (submittedVersion, cc-by-nc-nd)
  • UCL Discovery (University College London) (submittedVersion)
  • IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
  • Research Portal (King's College London) (submittedVersion, other-oa)
  • ZHAW Digital Collection
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Keywords
depression, serotonin, 5-hydroxyindoleacetic acid, serotonin transporter, 5-HT1A receptor, tryptophan depletion, gene-environment interaction, antidepressant use, plasma serotonin, postmortem brain, serotonin metabolites, bipolar depression, genetic association studies, antidepressant response prediction, treatment-resistant depression, depression subtypes
MeSH terms
Antidepressive Agents, Depression, Humans, Hydroxyindoleacetic Acid, Serotonin, Tryptophan, Receptor, Serotonin, 5-HT1A, Serotonin Plasma Membrane Transport Proteins

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