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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：
10387133
负责人：
Neil Savalia
金额：
$ 3.09万
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/10387133
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 Pharmaceutical Preparations Property Psychological reinforcement Pyramidal Cells Research Rewards Signal Transduction Site Source Specificity Stress Structure 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.

项目总结