Leveraging Rapid-Acting Antidepressants for Personalized Response

利用速效抗抑郁药进行个性化反应

• 批准号: 10687872
• 负责人: Neil Savalia
• 金额: $ 5.2万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-16 至 2024-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10687872
• 关键词: Acute; Address; Amygdaloid structure; Anteroventral Thalamic Nucleus; Antidepressive Agents; Axon; Behavior; Behavioral; Biological Assay; Brain; Chronic; Chronic stress; Clinical; Dendritic Spines; Dose; Economic Burden; Feeling suicidal; Foundations; Genetic; Image; Ketamine; Learning; Life; Light; Link; Major Depressive Disorder; Measures; Medial; Mediating; Mental Depression; Mental Health; Modeling; Mus; NMDA receptor antagonist; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Property; Psychological reinforcement; Pyramidal Cells; Research; Rewards; Shapes; Signal Transduction; Site; Source; Specificity; Stress; Sucrose; Symptoms; Synapses; Synaptic plasticity; System; Therapeutic; Therapeutic Effect; Vertebral column; Work; behavioral impairment; behavioral outcome; brain shape; conventional therapy; depressive symptoms; designer receptors exclusively activated by designer drugs; disability; experience; frontal lobe; hippocampal pyramidal neuron; improved; in vivo; in vivo optical imaging; in vivo two-photon imaging; insight; neural; neural circuit; new growth; novel therapeutics; preference; reduce symptoms; response; reward processing; social; social defeat; theories; treatment response; treatment-resistant depression; two-photon

PROJECT SUMMARY At least 1 in 10 people experience debilitating depression in their life, representing major personal, social, and economic burden. In light of this it is troubling that current treatments for depression have been inadequate. A standard first-line antidepressant, for example, is often beneficial but can take weeks to reach an effective dose and will still fail in over half of patients. A key challenge is that while the clinical presentation of depression is heterogeneous across patients—likely due to distinct brain circuit and system-level disruptions underlying their symptoms—current medications are not personalized to one’s specific needs. Recently, compounds with fast- acting antidepressant properties have emerged as potential revolutionizing therapies. One such compound is ketamine, primarily an NMDA receptor antagonist, which at low dose relieves an array of depressive symptoms with rapid onset and sustained response. The therapeutic promise of ketamine led to recent clinical approvals for treatment-resistant depression and acute suicidal ideation. Still, similar to conventional treatments, rapid- acting antidepressants are not effective for all patients nor targeted to one’s specific symptoms. Thus, a critical opportunity to extend and enhance the beneficial actions of ketamine will be addressed here. Several studies now link the behavioral actions of ketamine to the growth of new synapses on frontal cortical pyramidal neurons, but it is unknown which input pathways benefit from this increase in connectivity. The input specificity of ketamine’s plasticity actions is crucial because distinct afferents to frontal cortex are thought to underlie discrete behavioral impairments, such as deficits in reward processing that commonly follow chronic stress. Aim 1 will uncover ketamine’s typical plasticity actions on various inputs to frontal cortex using in vivo optical imaging in the mouse. Next, ketamine-induced synaptic plasticity will be augmented by stimulating one specific pathway during drug administration. Aim 2 will harness this approach to modify a corticocortical pathway with hypothesized relevance to reward-guided behavior. Specifically, an instrumental sucrose preference task recently developed in-house uses principles of reinforcement learning to reveal deficits in reward processing following chronic social defeat. With this paradigm, input-specific stimulation of retrosplenial cortex inputs to medial frontal cortex will be added to ketamine treatment and to improve the rescue of stress-induced deficits in reward sensitivity. Together, this work will reveal if the neural and behavioral actions of rapid antidepressants can be individualized, fueling the critical insights needed to adapt these emerging therapies to best serve patients.

项目摘要 至少有十分之一的人在生活中衰弱的抑郁症，代表了主要的个人，社会， 和经济伯恩。鉴于这种情况，目前对抑郁症的治疗不足是令人不安的。 例如，标准的一线抗抑郁药通常是有益的，但可能需要数周才能实现有效 剂量，仍然会在一半以上的患者中失败。一个关键挑战是，虽然抑郁症的临床表现 在患者之间是异质的，这可能是由于脑电路明显和系统级破坏的原因 症状 - 并不满足特定需求的个性化药物。最近，具有快速的化合物 作用抗抑郁特性已成为潜在的革命疗法。一个这样的化合物是 氯胺酮，主要的NMDA受体拮抗剂，在低剂量下，挽救了一系列抑郁症状 随着快速发作和持续的反应。氯胺酮的治疗承诺导致了最近的临床认可 用于耐治疗的抑郁和急性自杀的想法。尽管如此，类似于常规治疗，快速 作用抗抑郁药对所有患者都不有效，也不针对特定症状。那，一个批判 扩展和增强氯胺酮的有益行动的机会将在这里解决。 现在的几项研究将氯胺酮的行为作用与额叶皮质上的新突触的生长联系起来 锥体神经元，但未知哪种输入途径受益于这种连通性的提高。输入 氯胺酮可塑性作用的特异性至关重要，因为认为额叶皮层的不同传播被认为是 离散的行为障碍是基础的，例如通常遵循慢性处理的奖励处理中定义的障碍 压力。 AIM 1将使用体内的各种输入对额叶皮层的各种输入中的典型可塑性作用 鼠标中的光学成像。接下来，通过刺激一个 药物管理期间的特定途径。 AIM 2将利用这种修改皮层皮质途径的方法 与奖励指导的行为相关性。具体而言，工具性的蔗糖偏好任务 最近开发的内部使用加强学习原理来揭示奖励处理中的定义 慢性社交失败。使用此范式，输入特异性刺激后全民皮质输入到 培养基额叶皮层将被添加到氯胺酮治疗中，并改善应激引起的缺陷的挽救 奖励灵敏度。这项工作将共同揭示快速抗抑郁药的神经和行为作用是否 可以个性化的，从而加剧了适应这些新兴疗法以最好地服务于患者所需的关键见解。