Levodopa Shows Promise in Treating Depression with Inflammation-Related Motivational Impairments

A study from Emory University suggests that levodopa, a medication that increases dopamine levels in the brain, may help treat individuals with depression who experience motivational impairments due to high inflammation. Researchers found that a common blood test measuring C-reactive protein (CRP), a blood biomarker of inflammation produced by the liver, could help determine which patients are most likely to respond to repeated doses of levodopa.

Findings, published in the March 2025 print edition of Brain, Behavior & Immunity, show that in participants with CRP levels above 2 mg/L, daily administration of levodopa improved connectivity within a key brain reward pathway — the ventral striatum to the ventromedial prefrontal cortex — after just one week of treatment across a range of doses. While about half of the participants responded best to a lower dose of 150 mg/day, the other half required up to 450 mg/day for levodopa to effectively overcome the effects of inflammation on this dopamine-rich reward circuit.

Higher blood levels of CRP indicate increased inflammation in the body, which can affect the brain and lead to behavioral changes such as reduced motivation. CRP and other inflammatory markers can be easily measured through simple blood tests, which are widely available in clinics and hospitals across the U.S.

Previous studies by the Department of Psychiatry and Behavioral Sciences at Emory University School of Medicine linked the effects of inflammation on brain reward circuits in depression with low levels of dopamine, a chemical neurotransmitter that regulates motivation. A single dose of levodopa increased measures of connectivity within the brain's reward systems, as observed through functional magnetic resonance imaging (fMRI), a type of brain scan. Notably, this improvement in reward circuit function was observed exclusively in depressed individuals that had higher levels of CRP (above 2 mg/L).

Importantly, repeated doses of levodopa show promise in improving motivation in depressed patients with higher CRP. These improvements were linked to enhanced activity in the brain's reward centers, as observed through fMRI scans. Early findings also indicate that levodopa could help alleviate symptoms of anhedonia, the inability to feel pleasure, and reduce overall severity of depression in these patients.

“These findings are a significant step forward in the personalized treatment of depression. Targeting specific neurotransmitters affected by inflammation could provide new, effective treatment options, particularly for patients who have not responded well to standard antidepressants,” says principal investigator Jennifer C. Felger, PhD, associate professor of psychiatry and behavioral sciences, Emory School of Medicine.

“This research not only advances our understanding of the connection between inflammation and depression but also illustrates Emory's continued commitment to pioneering new insights into the treatment of depression,” Felger says.

A follow-up randomized clinical trial is underway to determine if a longer, eight-week course of levodopa can further alleviate symptoms of depression and anhedonia compared to a placebo. This ongoing research will help clarify levodopa’s potential as a targeted treatment for individuals with high inflammation-related depression. 

Reference: Bekhbat M, Li Z, Dunlop BW, et al. Sustained effects of repeated levodopa (L-DOPA) administration on reward circuitry, effort-based motivation, and anhedonia in depressed patients with higher inflammation. Brain Behav Immun. 2025;125:240-248. doi: 10.1016/j.bbi.2024.12.026

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