PROJECT SUMMARY Depression is a heterogenous and widespread disorder (lifetime prevalence >20%) and confers a substantial societal burden. Current pharmacological therapies are effective for many patients; however, more than 30% fail to achieve remission, and even responders exhibit significant residual symptoms including anhedonia. One pathophysiologic pathway shown to contribute to symptoms of depression is inflammation. Elevated inflammatory markers are observed in both the periphery and central nervous system in a significant proportion of patients with depression, particularly in patients that are resistant to conventional antidepressant therapies. Basic and clinical findings indicate that inflammation can affect striatal dopamine availability and release to contribute to symptoms of anhedonia and reduced motivation. We previously reported a relationship between inflammation and functional connectivity (FC) in dopaminergic reward circuitry in patients with major depressive disorder (MDD) whereby patients with higher plasma C-reactive protein (CRP) concentrations exhibited lower FC between the ventral striatum (VS) and ventromedial prefrontal cortex (vmPFC), which was correlated with symptoms of anhedonia. Preliminary data from our current study demonstrate that VS-vmPFC FC connectivity was increased after acute administration of the dopamine precursor, levodopa (L-DOPA), compared to placebo in patients with high CRP (indexed as CRP >2 mg/L). Clinical and translational evidence from our group and others suggests that inflammation may impact corticostriatal circuits by decreasing the availability and release of dopamine, indicating that increasing dopamine with L-DOPA can reverse the impact of inflammation on this circuit. in MDD patients with high infla We hypothesize that treatment with L-DOPA will improve depressive symptoms mmation and anhedonia by increasing FC in reward circuitry and improving motivation. To determine a dosing strategy for L-DOPA that affects VS-vmPFC FC and behavior in the R61 Phase, medically-stable and medication-free adults with MDD, plasma CRP >2 mg/L, and high anhedonia will receive treatment with three doses of L-DOPA compared to placebo (randomized, double-blind, crossover). Patients will undergo resting-state and task-based functional magnetic resonance imaging (fMRI) to probe FC in reward circuity in relation to bioavailability of L-DOPA at baseline and after 1 week at each dose. Safety and tolerability and data on the effect of L-DOPA on anhedonia and motivation in relation to target engagement in the brain (FC) will also be assessed. If L-DOPA increases VS-vmPFC FC at our Go/No-Go threshold, we will compare the dose of L-DOPA exhibiting optimal target engagement and tolerability to placebo in the R33. Subjects meeting the above criteria will be randomized to L-DOPA or placebo to determine whether L-DOPA has potential for clinical impact (Go/No-Go criteria: change in depression severity) and whether response i...