Is depression caused by low serotonin?
No. A comprehensive umbrella review of 17 studies found no consistent evidence linking depression to lowered serotonin concentration or activity. The review examined six major areas of serotonin research and found no support for the hypothesis that depression is caused by serotonin deficiency, challenging decades of accepted theory.
The review found that evidence across multiple research domains consistently failed to support the serotonin theory, with some findings suggesting long-term antidepressant use may actually reduce serotonin concentration rather than increase it.
What the data show:
- Serotonin levels: No association found between serotonin or metabolite concentrations and depression across multiple studies
- Genetic studies: No evidence of association between serotonin transporter gene and depression in studies with over 115,000 participants
- Receptor binding: Weak and inconsistent evidence, with findings potentially influenced by prior antidepressant use
- Tryptophan depletion: No consistent effect on mood in healthy volunteers or people with depression
A systematic umbrella review published in Molecular Psychiatry examined decades of research across six major areas of serotonin investigation, finding no convincing evidence supporting the serotonin hypothesis of depression that has dominated treatment approaches for decades.
Dr. Kumar’s Take
This review represents a seismic shift in how we understand depression. For decades, we’ve told patients that depression is caused by a “chemical imbalance” of serotonin, but this comprehensive analysis shows that belief isn’t supported by the evidence. This doesn’t mean antidepressants don’t work for some people, but it does mean we need to completely rethink how we explain depression and its treatments. The implications are profound - both for how we conceptualize mental illness and how we approach treatment.
Study Snapshot
This systematic umbrella review searched PubMed, EMBASE, and PsycINFO from inception until December 2020, focusing on systematic reviews, meta-analyses, and large dataset analyses. The researchers examined six key areas: serotonin and metabolite concentrations in body fluids, serotonin receptor binding, serotonin transporter levels, tryptophan depletion studies, serotonin transporter gene associations, and gene-environment interactions. Two independent reviewers extracted data and assessed quality using AMSTAR-2 criteria.
Results in Real Numbers
The systematic umbrella review searched PubMed, EMBASE, and PsycINFO from inception until December 2020, identifying 17 studies that met inclusion criteria: 12 systematic reviews and meta-analyses, 1 collaborative meta-analysis, 1 meta-analysis of large cohort studies, 1 systematic review and narrative synthesis, 1 genetic association study, and 1 umbrella review. The review examined six major areas of serotonin research: serotonin and metabolite concentrations, receptor binding, serotonin transporter levels, tryptophan depletion studies, SERT gene associations, and gene-environment interactions.
Studies examining serotonin and its metabolite 5-HIAA found no association with depression. Two meta-analyses of overlapping studies examining 5-HIAA (largest n = 1,002) showed no association. One meta-analysis of cohort studies of plasma serotonin (n = 1,869) showed no relationship with depression, and found evidence that lowered serotonin concentration was associated with antidepressant use rather than depression itself. Studies of 5-HT1A receptors (largest n = 561) and serotonin transporter binding (largest n = 1,845) showed weak and inconsistent evidence of reduced binding in some areas, but effects of prior antidepressant use were not reliably excluded. Tryptophan depletion studies found no effect in most healthy volunteers (n = 566), with only weak evidence of an effect in those with a family history of depression (n = 75). A subsequent review of 10 recent studies (n = 407) found no effect in volunteers.
The two largest and highest quality genetic studies revealed no evidence of an association between the serotonin transporter gene and depression. One genetic association study included 115,257 participants and found no association with depression. A collaborative meta-analysis included 43,165 participants and also found no evidence of an association, nor any interaction between genotype, stress, and depression. The main areas of serotonin research provide no consistent evidence of 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.
Safety, Limits, and Caveats
While this review challenges the serotonin hypothesis, it doesn’t necessarily invalidate all antidepressant treatments. Some patients do benefit from serotonin-targeting medications, though the mechanisms may be different than previously theorized. The review focused specifically on the serotonin hypothesis and doesn’t address other potential biological mechanisms of depression.
The findings also don’t suggest that depression isn’t a real medical condition or that biological factors aren’t involved. Rather, they indicate that the specific serotonin deficiency model is not supported by current evidence.
Practical Takeaways
- Understand that depression is not simply caused by low serotonin levels, despite decades of this explanation being widely accepted
- Recognize that antidepressant effectiveness, when it occurs, may work through mechanisms other than correcting serotonin deficiencies
- Consider that depression likely involves complex interactions between psychological, social, and biological factors rather than single neurotransmitter imbalances
- Discuss with healthcare providers the current uncertainty about depression’s biological mechanisms and treatment rationales
- Maintain realistic expectations about antidepressant treatments while remaining open to approaches that address multiple aspects of mental health
What This Means for Depression Treatment
This landmark review necessitates a fundamental shift in how depression is conceptualized and explained to patients. Rather than focusing on correcting chemical imbalances, treatment approaches may need to emphasize psychological, social, and lifestyle interventions alongside any medication use.
The findings support more honest discussions about the limitations of current biological understanding of depression and the need for more comprehensive, individualized treatment approaches that don’t rely solely on neurotransmitter theories.
Related Studies and Research
Episode 31: Depression Explained — The Biology Behind the Darkness
Episode 32: Depression Recovery Roadmap: A Step-by-Step, Evidence-Based Plan
FAQs
Does this mean antidepressants don’t work?
No, some people do benefit from antidepressants, but the mechanisms may be different than previously thought and the benefits may not be due to correcting serotonin deficiencies.
If depression isn’t caused by low serotonin, what does cause it?
Depression likely results from complex interactions between psychological, social, environmental, and biological factors, rather than simple neurotransmitter imbalances.
Should people stop taking antidepressants based on this research?
No, medication decisions should always be made with healthcare providers. This research challenges the theoretical basis for antidepressants but doesn’t negate potential benefits for some individuals.
Bottom Line
This comprehensive umbrella review found no convincing evidence supporting the serotonin theory of depression, challenging decades of accepted wisdom about depression’s biological basis. The findings necessitate more honest discussions about depression’s causes and more comprehensive treatment approaches that go beyond simple chemical imbalance models.
