Effects of Dopaminergic Therapy with Levodopa (L-DOPA) on Fear and Anxiety-Related Circuits and Symptoms in Patients with Depression and Higher Inflammation.

Inflammatory biomarkers such as cytokines and C-reactive protein (CRP) are reliably elevated in patients with major depressive disorder (MDD) as well as fear and anxiety-related disorders. Moreover, inflammatory biomarkers have been associated with lower functional connectivity (FC) in reward and threat-related circuits that contribute to symptom severity. Prior work has linked low FC in reward circuitry and symptoms of anhedonia to inflammation effects on striatal dopamine (DA), including our studies involving administration of the DA precursor, levodopa (L-DOPA). Nevertheless, the mechanisms of inflammation associations with fear and anxiety-related circuits and symptoms are not fully understood. Given recent interest in DA in the amygdala in anxiety and the effects of inflammation, we examined a potential role for DA in relationships between inflammation, lower right amygdala-ventromedial prefrontal cortex (vmPFC) FC, and symptoms of anxiety and post-traumatic stress disorder (PTSD). Leveraging data from our studies in medically-stable, unmedicated adults with a primary MDD diagnosis, we tested the hypothesis that acute (250 mg; Study 1, n = 30) and sub-chronic (150-450 mg/day/week; Study 2, n = 18) L-DOPA (administered with carbidopa) versus placebo would increase right amygdala-vmPFC resting state (rs)FC (using a targeted, a priori approach) in patients with higher (but not lower) inflammation, in relation to comorbid anxiety and PTSD symptoms. In patients enrolled to have a range of CRP concentrations and rsFC before and after acute, within-subject challenge with both L-DOPA and placebo (double-blind, randomized order ∼ 1-week apart; Study 1), a CRP by treatment interaction (F[1,28] = 1.33, p < 0.05) revealed that right amygdala-vmPFC rsFC was increased by L-DOPA versus placebo only in patients with CRP > versus ≤ 2 mg/L (p < 0.05). In MDD patients recruited to have CRP > 2 mg/L in Study 2, L-DOPA increased right amygdala-vmPFC rsFC versus placebo (F[1,12] = 9.24, p < 0.05), with two of three L-DOPA doses (150 and 450 mg/day) increasing rsFC versus placebo at a predetermined threshold of ≥ 20 %. Repeated L-DOPA versus placebo further decreased self-reported anxiety symptoms and state anxiety (F[2,16] = 11.87, p < 0.01), with all three L-DOPA doses significantly decreasing state anxiety (p < 0.05). Right amygdala-vmPFC rsFC responses to L-DOPA also associated with greater reductions in state anxiety (r = -0.72, p < 0.05). Similarly, L-DOPA decreased PTSD symptom severity versus placebo across all four PTSD symptom clusters (B-E) in patients with significant PTSD symptoms at baseline (n = 11; all p < 0.05), with right amygdala-vmPFC rsFC responses to L-DOPA versus placebo negatively correlating with improved Intrusion symptoms (r = -0.81, p < 0.05). These findings suggest a role for DA in the effects of inflammation on fear and anxiety-related circuits and symptoms, while supporting the use of right amygdala-vmPFC rsFC as a modifiable brain biomarker for future investigation of new therapies in patients with higher inflammation.