Moncrieff J, Cooper RE, Stockmann T, Amendola S, Hengartner MP, Horowitz MA. The serotonin theory of depression: a systematic umbrella review of the evidence. Mol Psychiatry. 2023 Aug;28(8):3243-3256. doi: 10.1038/s41380-022-01661-0. Epub 2022 Jul 20. PMID: 35854107; PMCID: PMC10618090.

Moncrieff, J., & Horowitz, M. (2022, July 20). No evidence that depression is caused by low serotonin levels, finds comprehensive review. University College London. https://www.ucl.ac.uk/news/2022/jul/no-evidence-depression-caused-low-serotonin-levels-finds-comprehensive-review

Ohio State University, Columbus

The serotonin theory claims that depression and other mental disorders are caused from an imbalance of serotonin in the brain, leading to a widespread use of SSRIs. This theory was first proposed in the 1960's and was publicized in the 1990's. SSRIs aim to increase serotonin levels in the synaptic cleft by blocking the reuptake of serotonin. However, the theory has been questioned in recent years, as studies haven’t consistently found a clear link between low serotonin and mental illnesses like depression.

The Serotonin Theory

References for the Serotonin Theory

The glutamate hypothesis of depression states that abnormalities in glutamate activity (especially extremities) may be the underlying cause of depressive disorders as chronic stress or trauma may lead to excess glutamate release. This can lead to neurotoxicity, impaired synaptic plasticity, and structural brain changes such as dendritic atrophy in key regions like the prefrontal cortex and hippocampus. Unlike the slower effects of traditional SSRIs, glutamatergic modulators demonstrate rapid antidepressant effects due to their influence on NMDA receptor activity and synaptic signaling pathways.

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