The serotonin theory of depression: a systematic umbrella review of the evidence.
Level 1 - systematic review of randomized trials
Systematic umbrella review synthesizing systematic reviews, meta-analyses, and large cohort/genetic studies.
PubMed 35854107 · doi:10.1038/s41380-022-01661-0
What was done
Authors conducted a systematic umbrella review across PubMed, EMBASE, and PsycINFO through December 2020 to evaluate evidence on whether depression is associated with lowered serotonin concentration or activity. Eligible designs included systematic reviews, meta-analyses, and large-dataset analyses covering six areas: serotonin and 5-HIAA concentrations in body fluids, 5-HT 1A receptor binding, serotonin transporter (SERT) levels, tryptophan depletion, SERT gene associations, and SERT gene-environment interactions. Quality and certainty were evaluated with AMSTAR-2, STREGA, and a modified GRADE framework.
What was found
Seventeen studies were included. Two meta-analyses of 5-HIAA found no association with depression (largest n = 1,002). A cohort meta-analysis (n = 1,869) found no plasma serotonin relationship with depression, but lowered serotonin was associated with antidepressant use. Meta-analyses on 5-HT 1A binding (largest n = 561) and SERT binding (largest n = 1,845) showed weak and inconsistent evidence of reduced binding, without reliably excluding prior antidepressant use. Tryptophan depletion meta-analyses found no effect in healthy volunteers (n = 566, n = 342, and n = 407 in 10 subsequent studies), with weak evidence in those with a family history of depression (n = 75). Two large genetic studies (n = 115,257 and n = 43,165) found no association between the SERT gene and depression or gene-stress interactions.
Why it matters
This review synthesizes decades of biomarker and genetic evidence to demonstrate that empirical support is lacking for the long-standing theory that depression is caused by serotonin deficiency.
Limits
Meta-analyses were not synthesized quantitatively because of overlapping constituent studies. Included reviews varied in methodological quality, and no systematic review of tryptophan depletion had been performed since 2007. Brain imaging and biomarker studies frequently failed to reliably control for past or current antidepressant exposure.
Cited by
- supports The scientific hypothesis that depression is caused by deficient serotonin activity in the brain has largely been debunked.