Dopaminergic Therapy for Inflammation-Related Anhedonia in Depression

项目摘要 抑郁症是一种异质性和广泛的疾病（终生患病率>20%）， 社会负担。目前的药物治疗对许多患者有效;然而，超过30%的患者在治疗过程中会出现并发症。 不能达到缓解，甚至应答者也表现出显著的残留症状，包括快感缺乏。 炎症是导致抑郁症状的一种病理生理学途径。升高 在外周和中枢神经系统中都观察到炎性标记物 抑郁症患者，特别是对传统抗抑郁治疗有抵抗力的患者。 基础和临床研究结果表明，炎症可以影响纹状体多巴胺的可用性和释放， 会导致快感缺失和动力不足我们之前报道过 多巴胺能奖励回路中的炎症和功能连接（FC） 抑郁症（MDD），患者血浆C反应蛋白（CRP）浓度较高 在腹侧纹状体（VS）和腹内侧前额叶皮质（vmPFC）之间表现出较低的FC， 与快感缺乏症的症状有关我们目前研究的初步数据表明，VS-vmPFC 急性给予多巴胺前体左旋多巴（L-DOPA）后，FC连接性增加， 与安慰剂相比，在具有高CRP（索引为CRP >2 mg/L）的患者中。临床和翻译证据 来自我们小组和其他人的研究表明，炎症可能会通过减少皮质纹状体回路， 多巴胺的可用性和释放，表明增加多巴胺与左旋多巴可以逆转的影响， 在这条赛道上的炎症。 在伴有高度炎症的MDD患者中， 我们假设左旋多巴治疗可以改善抑郁症状 通过增加奖赏回路中的FC和改善 动机确定影响VS-vmPFC FC和R61中行为的左旋多巴给药策略 阶段性、药物稳定和无药物治疗的MDD、血浆CRP >2 mg/L和高度快感缺乏的成人将 与安慰剂相比，接受三种剂量的左旋多巴治疗（随机、双盲、交叉）。 患者将接受静息状态和基于任务的功能性磁共振成像（fMRI），以探测FC 在基线时和每一剂量1周后，与L-DOPA生物利用度相关的报酬循环。安全和 L-DOPA对快感缺失和与靶向参与相关的动机的作用的耐受性和数据 还将评估大脑（FC）。如果左旋多巴在我们的Go/No-Go阈值下增加VS-vmPFC FC，我们将 在R33中，将表现出最佳靶点接合和耐受性的L-DOPA剂量与安慰剂进行比较。 符合上述标准的受试者将被随机分配至左旋多巴或安慰剂组，以确定左旋多巴是否 是否具有潜在的临床影响（进行/不进行标准：抑郁严重程度的变化），以及缓解是否 受FC、快感缺乏和/或动机变化的影响。其他基线行为、生物学和MRI 将收集衡量标准，用作可能的反应预测指标，并加强对结果的解释。

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 is influenced by change in FC, anhedonia and/or motivation. Additional baseline behavioral, biological and MRI measures will be collected for use as possible predictors of response and to enhance interpretation of results.