Link Between Serotonin and Depression Questioned

Hypothesis that depression is caused by low serotonin not supported; some evidence shows decrease in serotonin with antidepressant use

THURSDAY, Aug. 11, 2022 (HealthDay News) — Evidence is lacking for an association between serotonin and depression, according to a systematic umbrella review published online July 20 in Molecular Psychiatry.

In a systematic umbrella review, Joanna Moncrieff, M.D., from University College London, and colleagues evaluated evidence on whether depression is associated with lowered serotonin concentration or activity. Data were included from 17 studies, 12 of which were systematic reviews and meta-analyses; the studies had variable quality.

The researchers observed no association with depression in two meta-analyses of overlapping studies that examined the serotonin metabolite 5-HIAA. No association with depression was seen in a meta-analysis of cohort studies of plasma serotonin, while there was evidence for lowered serotonin concentration in association with antidepressant use. Weak and inconsistent evidence of reduced binding in some areas was seen in two meta-analyses of overlapping studies examining the 5-HT_1A receptor and three meta-analyses of overlapping studies examining SERT binding; this could be consistent with increased synaptic availability of serotonin in people with depression, but the effects of prior antidepressant use were not reliably excluded. Tryptophan depletion studies showed no effect in most healthy volunteers, but weak evidence was seen in those with a family history of depression. No evidence of an association with depression was seen in the two largest and highest-quality studies of the SERT gene, one genetic association study, and one collaborative meta-analysis.

“We suggest it is time to acknowledge that the serotonin theory of depression is not empirically substantiated,” the authors write.

One author disclosed being cofounder of a company that aims to help people safely stop antidepressants; two authors are co-chairs of the Critical Psychiatry Network.