Dopaminergic Therapy for Inflammation-Related Anhedonia in Depression

多巴胺能疗法治疗抑郁症中炎症相关的快感缺失

• 批准号: 10872552
• 负责人: Jennifer C Felger
• 金额: $ 70.5万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10872552
• 关键词: Dopaminergic; Therapy; Inflammation; Related; Anhedonia

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.

项目总结 抑郁症是一种异质性和广泛性的疾病(终生患病率为20%)，并赋予大量的 社会负担。目前的药物治疗对许多患者都有效；然而，超过30%的患者 未能获得缓解，甚至应答者也表现出明显的残留症状，包括快感缺失。 炎症是导致抑郁症状的一种病理生理途径。高架 炎症标记物在外周和中枢神经系统中都有相当大的比例。 抑郁症患者，特别是对传统抗抑郁药物治疗有抵抗力的患者。 基本和临床结果表明，炎症可以影响纹状体多巴胺的供应和释放 导致快感缺失和动力减弱的症状。我们之前曾报道过一种关系 大脑血管疾病患者多巴胺能奖赏回路中的炎症和功能连接性 抑郁障碍(MDD)患者血浆C反应蛋白(CRP)浓度较高 在腹侧纹状体(VS)和腹内侧额叶皮质(VmPFC)之间显示较低的FC，这是 与快感缺乏症状相关。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-多巴)后，FC连接性增加。 与高C反应蛋白患者的安慰剂(指数为C反应蛋白和门冬氨酸氨基转移酶2毫克/L)进行比较。临床和翻译证据 来自我们小组和其他人的研究表明，炎症可能通过减少大脑皮质纹状体的 多巴胺的可获得性和释放，表明增加多巴胺与L-多巴可以逆转这种影响 这个环路上的炎症。 MDD患者的高炎症反应 我们假设L多巴治疗会改善抑郁症状。 提高奖赏回路Fc与快感缺失 动力。确定影响VS-vmPFC和R61行为的L-多巴的给药策略 阶段，药物稳定和无药物治疗的成人MDD，血浆C反应蛋白和GT；2 mg/L，并将高度快感乏力 接受三种剂量的L多巴治疗，与安慰剂(随机、双盲、交叉)进行比较。 患者将接受静息状态和基于任务的功能磁共振成像(FMRI)来探测FC L多巴在基线和每次给药1周后的生物利用度的奖赏回路。安全和 L多巴对快感缺乏和目标投入动机影响的耐受性和数据 还将对大脑(FC)进行评估。如果L-DOPA将VS-vmPFC增加到我们的通过/不通过阈值，我们将 比较在R33中表现出最佳靶向结合和对安慰剂耐受性的L-多巴的剂量。 符合上述标准的受试者将随机接受L多巴或安慰剂治疗，以确定L多巴是否 有可能对临床产生影响(通过/不通过标准：抑郁症严重程度的变化)以及反应是否 受FC、快感缺失和/或动机变化的影响。其他基线行为、生物和核磁共振 将收集各种措施，作为反应的可能预测指标，并加强对结果的解释。