A Decisive Blow to the Serotonin Hypothesis of Depression
An exhaustive new review debunks the “chemical imbalance” theory of depression.
- Surveys indicate that 85-90 percent of the public believes low serotonin or a chemical imbalance causes depression.
- Among 237 psychology students interviewed, 46 percent had heard the chemical imbalance explanation from a physician.
- The serotonin hypothesis has been challenged repeatedly and found wanting, even as it remains popular and influential.
- A comprehensive, well-powered, high-quality umbrella review now determines that the theory is “not empirically substantiated.”
The peer-reviewed umbrella review—representing one of the highest forms of evidence in scientific research—was extrapolated from meta-analyses and systematic reviews on depression and serotonin levels, receptors, and transporters involving tens of thousands of participants.
Although “the serotonin hypothesis of depression is still influential,” Moncrieff and coauthors noted, citing widely adopted textbooks published as recently as 2020 and surveys indicating that “85-90 percent of the public believes that depression is caused by low serotonin or a chemical imbalance,” the primary research indicates there is “no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations.”
Among other key findings:
- “Research on serotonin receptors and the serotonin transporter, the protein targeted by most antidepressants, found weak and inconclusive evidence suggestive of higherlevels of serotonin activity in people with depression.” Widespread use of antidepressants is seen as the likely cause.
- The researchers also looked at studies where serotonin levels had been “artificially lowered in hundreds of people” (by depriving their diets of the necessary amino acid that makes serotonin) and found that “lowering serotonin in this way did not produce depression in hundreds of healthy volunteers,” according to a 2007 meta-analysis and several recent studies.
- Numerous other reviews on re-examination were found to provide weak, inconsistent, or nonexistent evidence of a connection between serotonin and depression.
- The researchers also probed well-powered studies involving tens of thousands of patients that focused on gene variation, including the gene for the serotonin transporter. These found “no difference in the genes between people with depression and healthy controls.” As such, “high-quality genetic studies effectively exclude an association between genotypes related to the serotonin system and depression, including a proposed interaction with stress.”
- The researchers also looked at “the effects of stressful life events and found that these exerted a strong effect on people’s risk of becoming depressed—the more of these a person had experienced, the more likely they were to be depressed.”
Legacy Effects of a Discredited Theory
“The popularity of the chemical imbalance idea of depression has coincided with a huge increase in the use of antidepressants,” note Moncrieff and coauthor Mark A. Horowitz in the study’s press release. “Prescriptions for antidepressants have sky-rocketed since the 1990s, going from being rare to a situation now where one in six adults in England and 2 percent of teenagers are prescribed an antidepressant in a given year.”The practical ramifications of the umbrella review are thus vast and consequential, involving millions of people across multiple countries because the findings are tied to a discredited theory that is still fueling mass prescribing on a global basis.
Moncrieff explained in the press release:
Invited to extrapolate the review’s findings for Psychology Today, Moncrieff added:
