AMPA Receptor Components of the Antidepressant Response to Ketamine in Humans

人类抗抑郁药对氯胺酮反应的 AMPA 受体成分

• 批准号: 10734845
• 负责人: NAOMI R DRIESEN
• 金额: $ 83.74万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-03 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734845
• 关键词: AMPA Receptors; Acids; Anesthetics; Animal Model; Antidepressive Agents; Attenuated; Biological; Biological Markers; Brain; Calibration; Cerebral cortex; Cerebrum; Clinical; Crossover Design; Data; Distress; Dose; Excitatory Amino Acid Antagonists; FDA approved; Functional Magnetic Resonance Imaging; Glutamate Receptor; Glutamates; Half-Life; Hamilton Rating Scale for Depression; Hour; Human; Impairment; Individual; Infusion procedures; Ketamine; Literature; Maps; Measures; Medial; Mental Depression; Metabolic; N-Methylaspartate; Neurobiology; Neuronal Plasticity; Oxygen; Patients; Pharmaceutical Preparations; Placebos; Receptor Activation; Rest; Safety; Saline; Symptoms; Synapses; Testing; Therapeutic; Therapeutic Effect; Time; antagonist; antidepressant effect; base; clinically significant; density; depression model; depressive symptoms; disability; follow-up; imaging biomarker; improved; information gathering; intravenous administration; metabolic rate; neural; pre-clinical research; preclinical study; prevent; response; restoration; single episode major depressive disorder; treatment-resistant depression

Project Summary Treatment resistant depression (TRD) is a major cause of distress and disability. The discovery of the antidepressant effects of ketamine, an N -Methyl- D -aspartate glutamate receptor (NMDAR) antagonist, has brought new hope to TRD patients. The search for the biological bases underlying the antidepressant effects of ketamine is a key priority. Preclinical studies suggest that, in the subcallosal cortex (SCC), ketamine activates cortical circuits, increasing glutamate release, stimulating α-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid glutamate receptors (AMPAR), and engaging downstream neuroplasticity mechanisms. In animal models of depression, AMPAR blockade prevents the antidepressant effects of ketamine. However, it is unclear whether this applies to humans with TRD. With the availability of the first FDA-approved AMPAR antagonist, perampanel, we can now test this hypothesis. Aim 1 evaluates whether perampanel pretreatment prevents the reduction in depression symptoms produced by ketamine in TRD patients. Aim 2 tests whether perampanel pretreatment augments ketamine-related increases in SCC resting state functional connectivity. Aim 3 assesses whether perampanel blocks ketamine-associated increases in SCC cerebral metabolic rate of oxygen relative to the pre-ketamine baseline. These metabolic increases may subserve restoring synaptic connectivity in TRD patients. Together these aims would provide an important test of a central hypothesis related to the mechanism underlying the therapeutic effects of ketamine and could inform efforts to develop alternatives to ketamine as a treatment for TRD.

项目摘要 难治性抑郁症(TRD)是困扰和残疾的主要原因。发现了 氯胺酮和N-氯胺酮的抗抑郁作用 -甲基- D -天冬氨酸 谷氨酸受体(NMDAR)拮抗剂， 给TRD患者带来了新的希望。寻找抗抑郁药的生物学基础 氯胺酮的影响是一个关键的优先事项。临床前研究表明，在扣带下皮质(SCC)， 氯胺酮激活皮质环路，增加谷氨酸释放，刺激α-氨基-3-羟基-5- 甲基-4-异恶唑丙酸谷氨酸受体(AMPAR)，下游接合 神经可塑性机制。在抑郁症动物模型中，AMPAR阻断可防止 氯胺酮的抗抑郁作用。然而，目前还不清楚这是否适用于患有TRD的人类。使用 FDA批准的第一种AMPAR拮抗剂perampanel的可用性，我们现在可以测试这一点 假设。目的1评估潘生丁的预处理是否能阻止抑郁症的减轻 TRD患者的氯胺酮所致症状。Aim 2测试电热板前处理 增加与氯胺酮相关的SCC静息状态功能连接的增加。AIM 3评估是否 帕金森可阻断氯胺酮相关的SCC脑氧代谢率的增加 氯胺酮前基线。这些代谢的增加可能有助于恢复TRD的突触连接 病人。这些目标加在一起，将是对与 氯胺酮治疗效果的潜在机制，并可能为开发替代品的努力提供信息 将氯胺酮作为治疗TRD的方法。