Leveraging Rapid-Acting Antidepressants for Personalized Response

利用速效抗抑郁药进行个性化治疗

基本信息

批准号：
10490846
负责人：
Neil Savalia
金额：
$ 3.16万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10490846
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 Image Ketamine Learning Life Light Link Major Depressive Disorder Measures Medial Mediating Mental Depression Mental Health Mus NMDA receptor antagonist Pathway interactions Patients Persons Pharmaceutical Preparations Property Psychological reinforcement Pyramidal Cells Research Rewards Signal Transduction Site Source Specificity Stress Sucrose Symptoms Synapses Synaptic plasticity System Therapeutic Therapeutic Effect Vertebral column Work base behavioral impairment behavioral outcome conventional therapy depressive symptoms designer receptors exclusively activated by designer drugs disability exhaustion experience frontal lobe hippocampal pyramidal neuron improved in vivo in vivo optical imaging in vivo two-photon imaging insight neural circuit new growth novel therapeutics preference reduce symptoms relating to nervous system response reward processing social social defeat theories treatment response treatment-resistant depression two-photon

项目摘要

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.

项目概要至少十分之一的人在生活中经历过令人衰弱的抑郁症，代表着主要的个人、社会、鉴于此，目前对抑郁症的治疗还不够充分，这令人不安。例如，标准的一线抗抑郁药通常是有益的，但可能需要数周时间才能达到有效效果。但超过一半的患者仍会失败，一个关键的挑战是抑郁症的临床表现。患者之间存在异质性——可能是由于他们的大脑回路和系统水平中断不同症状——目前的药物并没有根据一个人的具体需要进行个性化治疗，最近，一些化合物具有快速的作用。抗抑郁特性已成为一种潜在的革命性疗法。氯胺酮，主要是一种 NMDA 受体拮抗剂，低剂量可缓解一系列抑郁症状氯胺酮起效快、反应持续，其治疗前景最近获得了临床批准。对于难治性抑郁症和急性自杀意念，与传统治疗类似，快速治疗。抗抑郁药并非对所有患者都有效，也不能针对特定症状。这里将讨论扩大和增强氯胺酮有益作用的机会。现在有几项研究将氯胺酮的行为作用与额叶皮质新突触的生长联系起来锥体神经元，但尚不清楚哪些输入通路受益于这种连接性的增加。氯胺酮可塑性作用的特异性至关重要，因为额叶皮层的不同传入被认为是离散行为障碍的基础，例如慢性病后通常出现的奖励处理缺陷目标 1 将在体内揭示氯胺酮对额叶皮层各种输入的典型可塑性作用。接下来，通过刺激小鼠的光学成像，可以增强氯胺酮诱导的突触可塑性。目标 2 将利用这种方法来修改皮质皮质途径。具体来说，一项工具性蔗糖偏好任务最近开发的内部使用强化学习原理来揭示奖励处理中的缺陷在慢性社交失败之后，压后皮层的输入特异性刺激输入到内侧额叶皮层将被添加到氯胺酮治疗中，并改善对压力引起的缺陷的救援总之，这项工作将揭示快速抗抑郁药的神经和行为作用。可以个性化，激发调整这些新兴疗法以最好地服务患者所需的关键见解。