Sustained effects of repeated levodopa (L-DOPA) administration on reward circuitry, effort-based motivation, and anhedonia in depressed patients with higher inflammation

•Higher CRP has been associated with lower reward circuit FC and anhedonia in MDD.•Evidence shows these relationships may be due to inflammation effects on dopamine.•L-DOPA increased VS-vmPFC FC in MDD with CRP > 2 but not ≤ 2 mg/L in our prior work.•Herein, MDD with CRP > 2 mg/L received repeated L-DOPA (150–450 mg/day/week) and placebo.•L-DOPA caused sustained improvements in VS-vmPFC FC and effort-based motivation. Inflammatory biomarkers like C-reactive protein (CRP) are elevated in a subset of patients with depression and associated with lower functional connectivity (FC) in a ventral striatum (VS) to ventromedial prefrontal cortex (vmPFC) reward circuit and symptoms of anhedonia. Evidence linking these relationships to the effects of inflammation on dopamine is consistent with our recent findings that acute levodopa (L-DOPA) increased VS-vmPFC FC in association with deceased anhedonia in depressed patients with higher but not lower CRP (>2 versus ≤ 2 mg/L). To determine whether repeated L-DOPA administration caused sustained effects on FC and behavior in these patients, medically stable depressed outpatients with CRP > 2 mg/L and anhedonia (n = 18) received one week of three doses of L-DOPA (150–450 mg/day/week with carbidopa) or placebo in a randomized order. Resting-state (rs) and task-based (tb; monetary incentive delay) fMRI, effort-based motivation, and exploratory measures of anhedonia and depression severity were assessed at baseline and after one week of placebo and each dose of L-DOPA. Responses to individual doses of L-DOPA varied across outcomes. For example, VS-vmPFC rs-FC was significantly increased by L-DOPA at 150 and 450 mg/day/week (p