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Inflammation, Depression, and the Gut-Brain Axis

A. C. Applebee, L. N. Combe · March 2026

Abstract

The serotonin deficit hypothesis of depression — the claim that depression results from insufficient serotonin activity in the brain — has been the dominant public and clinical explanation for major depressive disorder for over three decades. In 2022, Moncrieff et al. published a systematic umbrella review in Molecular Psychiatry examining every major line of evidence for this hypothesis. The result was unambiguous: there is no consistent evidence that people with depression have lower serotonin activity than people without depression. The hypothesis, as a causal explanation, is not supported. This paper synthesises the evidence for an alternative framework: depression, or a clinically significant subtype representing approximately 25-50% of cases, is a systemic inflammatory condition with strong gut-brain involvement.

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