Summary: Levodopa, a commonly prescribed drug for the treatment of Parkinson’s disease that increases dopamine in the brain, has been shown to reverse the effects of neuroinflammation on the reward system and improve symptoms associated with depression.
Source: Emory University
A study from Emory University published in Molecular psychiatry shows that levodopa, a drug that increases dopamine in the brain, has the potential to reverse the effects of inflammation on the brain’s reward circuitry, thereby improving symptoms of depression.
Many labs around the world have shown that inflammation leads to reduced motivation and anhedonia, a central symptom of depression, by affecting the brain’s reward pathways.
Previous research by the Department of Psychiatry and Behavioral Sciences at Emory University School of Medicine has linked the effects of inflammation on the brain to a decrease in the release of dopamine, a chemical neurotransmitter that regulates brain function. motivation and motor activity, in the ventral striatum.
In the study, researchers demonstrated that levodopa reversed the effects of inflammation on functional brain connectivity in reward circuitry and anhedonia (inability to feel pleasure) in depressed people with protein C- reactive (CRP), a blood biomarker produced and released by the liver in response to inflammation.
Inflammation levels can be easily measured by simple blood tests, like CRP, readily available in clinics and hospitals across the United States.
The study included 40 depressed patients with a range of high to low CRP levels who underwent functional brain scans at two visits after receiving in random order either a placebo or the often prescribed drug levodopa. for conditions such as Parkinson’s disease.
Levodopa improved functional connectivity in a classic reward circuit from the ventral striatum to the ventromedial prefrontal cortex, but only in patients with higher levels of CRP. This improvement in the reward circuitry in depressed people with higher CRP was also correlated with a reduction in symptoms of anhedonia after levodopa.
“This research demonstrates the translational potential of using inflammation-related deficits in functional connectivity and may have important implications for future investigations of precision therapies for psychiatric patients with elevated inflammation,” says the researcher. Principal and Lead Author Jennifer C. Felger, Ph.D., Associate Professor of Psychiatry and Behavioral Sciences, Emory School of Medicine.
Felger says the study results are critical for two reasons. First, they suggest that depressed patients with high inflammation may respond specifically to drugs that increase dopamine.
Second, Felger says these findings also provide further evidence that functional connectivity in reward circuitry may serve as a reliable brain biomarker for the effects of inflammation on the brain.
“Furthermore, since the effect of levodopa was specific to depressed patients with higher inflammation, this functional connectivity can be used to assess the responsiveness of the brain to new treatments that might be targeted at this subtype of depressed patients. in future studies and clinical trials,” says Felger.
About this research news in psychopharmacology and depression
Author: Jennifer Johnson McEwen
Source: Emory University
Contact: Jennifer Johnson McEwen – Emory University
Picture: Image is in public domain
Original research: Free access.
“Functional connectivity in reward circuits and symptoms of anhedonia as therapeutic targets in depression with elevated inflammation: evidence from a dopamine provocation study” by Mandakh Bekhbat et al. Molecular psychiatry
Functional connectivity in reward circuits and symptoms of anhedonia as therapeutic targets in depression with high inflammation: evidence from a dopamine challenge study
Increased inflammation in major depressive disorder (MDD) has been associated with low functional connectivity (FC) in corticostriatal reward circuits and symptoms of anhedonia, relationships that may implicate the impact of inflammation on the synthesis and release of dopamine.
To test this hypothesis while establishing a platform to examine target engagement of potential therapies in patients with increased inflammation, medically stable drug-free MDD adult outpatients enrolled to have a range of inflammation (as indexed by the plasma C-reactive protein [CRP] levels) were studied at two visits involving acute challenge with the dopamine precursor levodopa (L-DOPA; 250 mg) and placebo (randomized double-blind order approximately 1 week apart).
The main resting-state (rs) FC outcome in a reward circuit from the classical ventral striatum to the ventromedial prefrontal cortex was calculated using a targeted and a priori approach.
Data available before and after the challenge (not= 31/40) established rsFC stability across visits and determined CRP > 2 mg/L as the threshold for patients with positive (post minus pre) FC responses to L-DOPA by versus placebo (p< 0.01).
A higher post-L-DOPA CF in patients with CRP > 2 mg/L was confirmed in all patients (not= 40) where rsFC data were available after challenge (B= 0.15, p= 0.006), and in those with task-based (tb)FC during reward anticipation (B= 0.15, p= 0.013).
While non-CT effort-based motivation was positively correlated with rsFC regardless of treatment or CRP, change in anhedonia scores was negatively correlated with rsFC after L-DOPA only in patients with CRP > 2 mg/L (r= -0.56, p= 0.012).
FC in reward circuits should be further validated in larger samples as a biomarker of target engagement for potential treatments, including dopaminergic agents in MDD patients with increased inflammation.
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