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New review suggests there is “no convincing evidence” that low serotonin levels cause depression

A widely held belief about the relationship between serotonin and depression is being contested by a University College London research group. (Credit: Bryan Bruno/MidCityTMS)

The serotonin theory of depression postulates serotonin deficiency as the underlying reason for depression. Although a recently debated topic, the idea that this neurotransmitter imbalance is responsible for depression is still a widely held belief.

In a recently published review, a group of researchers from University College London (UCL) assessed 17 studies— including meta-analyses, systematic reviews, and genetic association studies— that looked at the relationship between serotonin levels and depression.

The UCL research team analyzed reviews that focused on the topics of 5-HIAA, a serotonin metabolite, and its relationship with depression, serotonin receptor and serotonin transporter (SERT) levels in depressed patients, and tryptophan (precursor of serotonin) depletion and its effects on depression.

The researchers told UCL News, “There has been extensive research on the serotonin system since the 1990s, but it has not been collected systematically before. We conducted an “umbrella” review that involved systematically identifying and collating existing overviews of the evidence from each of the main areas of research into serotonin and depression. Although there have been systematic reviews of individual areas in the past, none have combined the evidence from all the different areas taking this approach.”

The recently published systematic umbrella review found that out of the three studies included that assessed the relationship between serotonin, which was measured using 5-HT and 5-HIAA, and depression, none of the studies showed a statistically significant relationship after adjusting for multiple comparisons. However, one of the meta-analyses reported that 5-HT levels were lower in patients who took antidepressants when compared to controls (p<0.0001). This finding suggests that long-term SSRI use may lead to the opposite of its intended effect.

In the two meta-analyses that looked at the relationship between acute tryptophan depletion (ATD) and mood, which assessed the outcomes of seventy-three (73) different studies, they found that ATD had no significant effect on mood in healthy volunteers with no family history of depression. ATD in patients with a family history of depression did, however, lower mood regardless of antidepressant use status.

Genetic studies detailing the relationship between the serotonin transporter (SERT) gene and depression has been a major topic of interest in the field of mood disorder research. A common variation in the promoter region of the SERT gene, 5-HTTLPR, leads to decreased SERT expression resulting in increased synaptic serotonin levels. The new systematic review identified two large studies— one being a genetic association study totaling 115,257 participants, and the other being a meta-analysis which looked at 43,165 individuals— which both showed no relationship between lifetime major depressive disorder (MDD) diagnosis and 5-HTTLPR polymorphism (p=0.919, p=0.95).

The study’s authors concluded by stating, “[Our] review suggests that the huge research effort based on the serotonin hypothesis has not produced convincing evidence of a biochemical basis to depression. This is consistent with research on many other biological markers. We suggest it is time to acknowledge that the serotonin theory of depression is not empirically substantiated.”

The study was published in Molecular Psychiatry on July 20th, 2022.

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.

Moncrieff, J., Cooper, R.E., Stockmann, T. et al. The serotonin theory of depression: a systematic umbrella review of the evidence. Mol Psychiatry (2022). https://doi.org/10.1038/s41380-022-01661-0

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