Does Low Serotonin Cause Depression? A Review of the Latest Evidence

Written by: Bhavna Garimella

Edited by: Ayush Halder

Image: Serotonin (Wikipedia, 2025).

The theory that depression is a chemical imbalance of serotonin in the brain is one that has lasted a long time. It has lasted for so long that it trickled its way down from scientific literature to everyday conversation, appearing everywhere from mental health brochures to popular Instagram accounts on psychology and neuroscience. 

 This blog post discusses a paper published in Molecular Psychiatry wherein the authors conducted an umbrella review (which compiles findings from existing systematic reviews and meta-analyses) to find evidence of whether this theory of serotonin and depression holds even today (Moncrieff et al., 2023). 

Based on their review, the authors highlighted six key areas of serotonin research in their paper. While these concepts may seem overly intricate, this blog post will attempt to explain them using understandable analogies.

1. Serotonin and its metabolite 5-HIAA in body fluids

Serotonin levels are often measured in bodily fluids (blood, urine, CSF, etc.). This section investigates whether the serotonin receptors (the 'locks') are functioning in a way that allows serotonin (the 'key') to effectively bind and trigger their signaling pathways.

What the paper found: There were no consistent results to show that serotonin or 5-HIAA levels are lower in the bodily fluids of people with depression. The evidence was termed “weak and inconsistent”, with no clear link between these two. 

Conclusion: Understanding serotonin levels in bodily fluids is not reliable evidence for the previously popular theory.

2. Serotonin receptors (especially 5-HT1A) 

The human brain has serotonin receptors that capture the incoming serotonin. Think of it as a lock and a key. This section tries to investigate whether the lock (serotonin receptors) works properly when the key (serotonin chemical) tries to bind with it. 

What the paper found: Few studies suggested that people with depression have higher levels of 5-HT1A receptors. This means that those with depression have more locks (receptors) on their door; however, the evidence was “inconsistent and methodologically weak”. 

Conclusion: You might be wondering why more receptors do not lead to a better mood. But it is more complicated than that. While there are more receptors, the weak methodology hints at the possibility that some of these receptors might be faulty, not placed correctly, or may not be receiving serotonin at all (Nikolaus et al., 2016). That is why the differences exist, but are not significant enough to be definitive. 

3. Serotonin transporter (SERT) levels

The SERT is a transporter that is like a cleaning crew. It cleans up serotonin after it is used. One theory suggests that if the serotonin transporter is working overtime, then it could possibly lead to the quick depletion of serotonin, leading to depression. 

What the paper found: Older studies suggest that increased SERT activity is associated with depression, but recent and larger, better-designed studies show no such significance. 

Conclusion: This means that there is no consistent evidence to indicate that the transporter is clearing up the excess serotonin, leading to depression. It was reported that there is no significant difference between the transporter levels of those with depression and those without depression. 

4. Tryptophan depletion studies

Tryptophan is a serotonin precursor. Researchers tried to see if reducing the tryptophan levels (thereby reducing the serotonin levels) could lead to symptoms of depression. 

What the paper found: Reducing tryptophan does not cause depression in most people, but it can trigger low mood in those who have a family history of depression or who are already vulnerable. This finding was reported only for a small group. 

Conclusion: Lowering the tryptophan is not significant enough to cause depression, just like turning down the lights in the room does not cause you to sleep. It affects select individuals, but it is not a definitive cause of depression. 

5. SERT gene studies 

Previously, we discussed serotonin transporters. The recipe to make these serotonin transporters is known as the SERT gene. Researchers aimed to investigate if a faulty recipe (faulty SERT gene) could lead to the creation of a faulty serotonin transporter, thereby leading to excessive serotonin clearance. 

What the paper found: Genome-wide studies found no such association between the SERT gene and the risk of depression. 

Conclusion: This means that the recipe (SERT gene) is not the problem, as there is no genetic basis supporting this part of the theory. 

6. Gene–stress interaction studies 

Previously, we covered the possibility of a faulty gene. Researchers took this further to understand whether a faulty gene + stress could equate to depression. 

What the paper found: Older studies suggested the existence of a link, but newer, better-designed studies show no such association upon replication. This interaction between the SERT gene and stress equating to depression is not supported by strong evidence. 

Conclusion: While stress can contribute to depression, the interaction with the serotonin gene does not consistently determine the same risk. 

🧠 Final Takeaway from the Paper 

The age-old theory that low serotonin levels cause depression is not supported by this body of strong evidence evaluated by Moncrieff et al (2023). This does not mean that antidepressants like selective serotonin reuptake inhibitors (SSRIs) do not work; it just means that the popular “chemical imbalance” theory is outdated and oversimplified. 

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References

Moncrieff, J., Cooper, R. E., Stockmann, T., Amendola, S., Hengartner, M. P., & Horowitz, M. A. (2023). The serotonin theory of depression: A systematic umbrella review of the evidence. Molecular Psychiatry, 28(8), 3243–3256. https://doi.org/10.1038/s41380-022-01661-0   

Nikolaus, S., Müller, H. W., & Hautzel, H. (2016). Different patterns of 5-HT receptor and transporter dysfunction in neuropsychiatric disorders–a comparative analysis of in vivo imaging findings. Reviews in the Neurosciences, 27(1), 27-59. https://doi.org/10.1515/revneuro-2015-0014 

Wikipedia. (2025, July 30). Serotonin [Image]. Retrieved August 19, 2025, from https://en.wikipedia.org/w/index.php?title=Serotonin&oldid=1303344192