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

Abstract (PubMed)

The serotonin hypothesis of depression is still influential. We synthesised and evaluated evidence on whether depression is associated with lowered serotonin concentration or activity in a systematic umbrella review. PubMed, EMBASE and PsycINFO were searched until December 2020. 17 studies were included: 12 systematic reviews and meta-analyses. The review was registered with PROSPERO (CRD42020207203). Two meta-analyses of 5-HIAA showed no association with depression. One meta-analysis of plasma serotonin showed no relationship with depression. Meta-analyses of 5-HT1A receptor and SERT binding showed weak and inconsistent evidence. Tryptophan depletion found no effect in most healthy volunteers. Meta-analyses of SERT gene and gene-environment interactions showed no association with depression. The main areas of serotonin research provide no consistent support for the hypothesis that depression is caused by lowered serotonin activity or concentrations.