A new study suggests that depression is associated with low brain blood flow and function, supporting earlier research showing there is no evidence that depression is caused by a chemical imbalance.

Illustration of the brain with streams of blood flow dimming in key regions, reflecting new research findings on depression. Illustration by the author.

For decades, people were told depression came from a “chemical imbalance.” Low serotonin, low dopamine in the brain. But in 2022, a major review in Molecular Psychiatry found no real evidence for it. Now, a new study in JAMA Psychiatry adds weight to that finding, showing that the way blood flows through the brain, and how regions talk to each other, may be the bigger piece of the puzzle.

This wasn’t a small study. Researchers pulled scans from more than 15,000 people, using massive projects like the UK Biobank and the ENIGMA Consortium. Instead of focusing on brain structure, the researchers zeroed in on functional activity. They used something called regional homogeneity, or ReHo. Basically, it measures how well different brain regions “talk” to each other. And this is tied to blood flow and metabolism, so you get a peek at what the brain is actually doing. Not just what it looks like.

What stood out is that in depressed brains, several regions, the cingulate, prefrontal, and temporal lobes, showed less activity and lower blood flow. These functional changes were two or three times stronger than structural ones.

To better quantify these findings, the team developed a Regional Vulnerability Index (RVI) based on ReHo, basically a map of the brain’s weak spots in depression. This could help individuals at risk and potentially guide more personalised treatment approaches.

These results line up perfectly with that 2022 review in Molecular Psychiatry, which found no consistent evidence that low serotonin or a chemical imbalance causes depression. Instead, it looks like the illness is tied more to how the brain is working and how blood moves through it .

The studies suggest that depression is linked to how the brain functions and how blood flows, and not related to chemical imbalances. Understanding these functional patterns might lead to better diagnoses and treatments that actually target the right areas.

This research represents an important step toward a clearer picture of depression’s complex biology, offering hope for better therapies in the future .

Reference: New JAMA Psychiatry study on brain blood flow and function in depression (2025): Chen, J., Xu, T., Qiu, X., et al. (2025). Functional brain alterations and regional vulnerability in major depressive disorder: Evidence from large multi-site datasets. JAMA Psychiatry. Advance online publication. https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2832270

Further Reading: 2022 Molecular Psychiatry review on chemical imbalance: Moncrieff, J., Cooper, R. E., Stockmann, T., et al. (2022). The serotonin theory of depression: A systematic umbrella review of the evidence. Molecular Psychiatry, 27, 1–14. https://www.nature.com/articles/s41380-022-01661-0