Targeting Dopamine-Mediated Social Reward Sensitivity to Remediate Social Disconnection

针对多巴胺介导的社会奖励敏感性来修复社会脱节

• 批准号: 10572245
• 负责人: Franklin R. Schneier
• 金额: $ 142.37万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10572245
• 关键词: Address; Aftercare; Agonist; Anhedonia; Animals; Anxiety; Anxiety Disorders; Behavior; Behavioral; Biological Assay; Blood; Brain region; Central Nervous System; Clinical; Corpus striatum structure; Cues; Data; Depressive disorder; Diagnostic; Disease; Dopamine; Dopamine Agonists; Dose; Double-Blind Method; Event; Evidence based treatment; Feedback; Goals; Health; Human; Impairment; Individual; Intervention; Magnetic Resonance Imaging; Maintenance; Measures; Mediating; Medicine; Mental Depression; Mental disorders; Meta-Analysis; Modeling; Motion; Motivation; Negative Finding; Negative Valence; Outcome; Outcome Study; Pathway interactions; Patient Self-Report; Patients; Personal Satisfaction; Persons; Pharmacotherapy; Phase; Placebo Control; Placebos; Plasma; Play; Positive Valence; Process; Quality of life; Randomized; Research; Rewards; Role; Sampling; Selective Serotonin Reuptake Inhibitor; Signal Transduction; Social Functioning; Standardization; Symptoms; System; Testing; Time; Trauma; United States National Institutes of Health; behavioral economics; behavioral outcome; behavioral response; confirmatory trial; depressive symptoms; dopamine D3 receptor; dopamine system; experience; improved; incentive salience; insight; interest; neural; neuromelanin; open label; pharmacologic; pramipexol; primary outcome; randomized placebo controlled trial; receptor; recruit; remediation; reward anticipation; reward processing; secondary outcome; social; social attachment; social relationships; tool; treatment effect

Social relationships contribute enormously to our health and well-being. Social disconnection is a common and disabling feature of anxiety and depressive disorders that does not respond sufficiently to our best available treatments. These outcomes suggest first-line treatments do not adequately engage the mechanisms that support positive connections with others. Animal and human research suggests the dopamine system plays an important role in responding to social reward cues and opportunities that drive our motivation and behavior toward connecting with others. Diminished social reward anticipation is observed across anxiety and depressive disorders – pointing to a trans-diagnostic mechanism that may underpin social disconnection. Directly modulating dopaminergic functioning in a dose-dependent manner would provide a strong causal test of social reward-mediated disconnection pathways. This is important because first-line pharmacotherapies for anxiety and depression do not directly target this system, which may explain in part why social disconnection persists for many patients following treatment. The proposed two-phase, milestone-driven project will address this gap by testing the hypothesis that modulating the dopamine system pharmacologically will enhance social reward anticipation (the treatment target) and therefore improve social connectedness (primary outcome) in individuals with clinical levels of anxiety or depression. We will selectively engage this system using pramipexole – a D2/D3 dopamine receptor agonist shown to enhance dopamine signaling in the striatum – thereby providing a strong proof of mechanism test. The R61 project will evaluate dose-dependent effects of pramipexole on striatal activation during social reward anticipation (primary outcome) and opportunities to disclose to others. Secondary outcomes will be measured during dyadic affiliation and shared experiences tasks. Aim 1 will test the hypothesis that pramipexole increases social reward anticipation compared to placebo following 6 weeks of treatment. Aim 2 will determine which dose of pramipexole produces a greater effect on social reward anticipation. Pramipexole blood concentrations will be used to confirm dose-dependent target engagement. If pramipexole is superior to placebo in increasing striatal activation to social reward anticipation, the R33 project will attempt to replicate the R61 findings (Aim 1) and examine whether increases in social reward anticipation are associated with improvements in social connectedness (Aim 2) following a 6-week double-blind, randomized, placebo-controlled trial (dose informed by the R61). Secondary outcomes will be change in positive and negative valence symptoms (e.g., social anhedonia, anxiety, depression). An exploratory aim will examine treatment effects on negative valence processes (e.g., threat sensitivity). Positive findings would validate a new CNS target for remediating social disconnection that could be studied in larger confirmatory efficacy trials. Regardless of study outcomes, important new information will be gained about the role of dopamine-mediated processes that are believed to govern whether and how we connect with others.

社会关系对我们的健康和幸福有着巨大的贡献。社会脱节是一种常见的， 焦虑和抑郁症的残疾特征，对我们现有的最佳治疗没有足够的反应 治疗。这些结果表明，一线治疗不能充分参与这些机制， 支持与他人的积极联系。动物和人类的研究表明，多巴胺系统起着重要的作用。 在响应社会奖励线索和机会，推动我们的动机和行为的重要作用 与他人建立联系在焦虑和焦虑中观察到社会奖励预期减少， 抑郁症-指向一个跨诊断机制，可能会加强社会脱节。 以剂量依赖性方式直接调节多巴胺能功能将提供强有力的因果检验 社会奖励介导的断开途径。这一点很重要，因为一线药物治疗 焦虑和抑郁并不直接针对这个系统，这可能部分解释了为什么社会脱节 许多患者在治疗后仍然存在。拟议的两阶段、里程碑驱动的项目将解决 这一差距通过测试假设，调节多巴胺系统的多巴胺将提高社会 奖励预期（治疗目标），从而改善社会联系（主要结局）， 患有临床焦虑或抑郁水平的个体。我们将有选择地使用这个系统， 普拉克索-一种D2/D3多巴胺受体激动剂，可增强纹状体中的多巴胺信号传导- 从而为机理试验提供了有力的证据。R61项目将评估以下物质的剂量依赖性效应： 普拉克索对社会奖励预期期间纹状体激活的影响（主要结局）和 透露给别人。次要结果将在二元关系和共享经验期间进行测量 任务目的1将检验与安慰剂相比，普拉克索增加社会奖励预期的假设 治疗6周后。目的2将确定哪种剂量的普拉克索对 社会奖励预期普拉克索血药浓度将用于确认剂量依赖性目标 订婚如果普拉克索在增加纹状体对社会奖励预期的激活方面上级于安慰剂， R33项目将尝试复制R61的发现（目标1）并检查社会影响是否增加 奖励预期与6周后社会联系的改善（目标2）相关 双盲、随机、安慰剂对照试验（剂量由R61告知）。次要结局将是 阳性和阴性效价症状的变化（例如，社交快感缺乏、焦虑、抑郁）。一个 探索性目的将检查对负效价过程的治疗效果（例如，威胁敏感度）。积极 研究结果将验证一个新的中枢神经系统目标，以修复社会脱节，可以在更大的研究， 验证性疗效试验。无论研究结果如何，都将获得关于 多巴胺介导的过程的作用，被认为是支配我们是否以及如何与他人联系。