The Serotonin Theory of Depression: A Systematic Umbrella Review of the Evidence

Summary & key facts

Researchers reviewed many studies that tested whether depression is caused by low serotonin in the brain. They looked at brain scans, experiments that lower serotonin, and large genetic studies. The review found no consistent proof that low serotonin or low serotonin activity causes depression. Some weak or mixed findings appeared, and long-term antidepressant use might lower serotonin, but the studies have limitations. Overall, the simple idea that depression is just a serotonin shortage is not supported by the current evidence.

Key facts:

• The authors combined results from many earlier studies that measured different parts of the serotonin system in people with and without depression.
• Reviews of studies that measured the serotonin transporter in the brain found weak and inconsistent signals of lower transporter binding in some areas. The largest group of these studies included about 1,800 people.
• A set of studies that looked at a particular serotonin receptor included about 560 people and also showed mixed results that were not definitive.
• Experiments that reduce tryptophan, the building block the body uses to make serotonin, showed no clear effect in most healthy volunteers (about 570 people). There was only weak evidence of an effect in people with a family history of depression (about 75 people).
• Two large and high-quality genetic studies with about 115,000 people and about 43,000 people found no link between serotonin-related genes and depression, and no clear interaction between those genes, stress, and depression.
• The reviewers concluded that the main areas of serotonin research do not provide consistent evidence that depression is caused by lowered serotonin activity or lower serotonin concentrations.
• Some findings were consistent with the idea that long-term antidepressant use could reduce serotonin concentration, but the review notes that past antidepressant use was not always ruled out in the studies, which makes interpretation uncertain.
• Because many studies had limits or overlapping samples, the evidence is mixed and does not support the simple claim that depression equals a serotonin deficiency.

Abstract

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.

Topics

Mental Health Research Topics Treatment of Major Depression Tryptophan and brain disorders

Categories

Biological Psychiatry Life Sciences Neuroscience

Tags

Biochemistry Biology Clinical psychology Depression (economics) Economics Internal medicine Macroeconomics Medicine MEDLINE Meta-analysis Psychiatry Psychology PsycINFO Receptor Serotonin Serotonin transporter Systematic review

Conditions & symptoms

Depression Sadness or low mood