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Neurobiology and Target Validation of Novel Therapeutic Agents in Mood Disorders

情绪障碍新型治疗药物的神经生物学和靶标验证

基本信息

批准号：
9357306
负责人：
Carlos Zarate
金额：
$ 226.07万
依托单位：
NATIONAL INSTITUTE OF MENTAL HEALTH
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9357306
关键词：
Adverse effects Age Agonist Alcohols Animals Anti-Anxiety Agents Antidepressive Agents Biological Markers Bipolar Disorder Brain Brain imaging Clinical Research Complex Data Depressed mood Diagnosis Diazoxide Dimensions Dose Double-Blind Method Electrophysiology (science)Family Feeling suicidal Female Genes Genetic Glutamate Transporter Glutamates Glycine Glycine Receptors Hamilton Rating Scale for Depression Human Image Individual Infusion procedures Inpatients Intervention Intramural Research Program Intravenous Investigation Ketamine Magnetic Resonance Spectroscopy Magnetoencephalography Major Depressive Disorder Measures Mental Depression Montgomery and Asberg depression rating scale Mood Disorders N-Methyl-D-Aspartate Receptors N-Methylaspartate National Institute of Mental Health Neurobiology Neuropsychological Tests Opioid Outcome Measure Patient Self-Report Patients Pattern Pharmaceutical Preparations Phase Phenotype Pilot Projects Placebo Control Placebos Prefrontal Cortex Prodrugs Property Protocols documentation Randomized Recording of previous events Recruitment Activity Reporting Research Research Domain Criteria Resistance Rest Risk Safety Series Site Sleep Suicide Symptoms Syndrome Techniques Technology Therapeutic Agents Time Validation Wakefulness Work antidepressant effect anxious awake collected works depressed patient depressive symptoms design experience glutamatergic signaling improved male neurochemistry neurophysiology new technology new therapeutic target novel novel therapeutics open label peripheral blood phenomenological models pilot trial potential biomarker response suicidal suicidal behavior symptomatology treatment effect treatment response treatment-resistant depression

项目摘要

This Report involves work collected under protocols 01-M-0254 (NCT00024635 ); 08-M-0196 (NCT00759395); 08-M-0150 (NCT00697268); 14-M-0085 (NCT02122562); 07-M-0021 (NCT00397111); 14-M-0041 (NCT02049385); and 07-M-0152 (NCT00472576), 09-M-N230; 15-M-0151 (NCT 02484456), 15-M-0188 (NCT02543983). Results this past year: 1. Antisuicidal response after ketamine infusion is associated with decreased nighttime wakefulness in treatment-resistant depression. In this study, we find a biomarker that predicts who will respond to ketamine and who will not. Here we find that subjects with treatment-resistant depression who have more time awake at later times of the night have more suicidal thinking, and that a single dose of ketamine rapidly eliminates suicidal thinking and restores sleep in depressed patients. The pattern of sleep is no longer different from healthy control subjects. 2. Safety of research into severe and treatment-resistant mood disorders. In this review of 12 years of data of from the intramural program at NIMH, we show that randomized, placebo-controlled drug-free trials in treatment-resistant depression can be performed safely in an inpatient setting. 3. A randomized, placebo-controlled pilot trial of the delta opioid agonist AZD2327 in anxious major depressive disorder. In this double-blind, placebo-controlled pilot study, we show that the delta opioid agonist AZD2327 does not have significant antidepressant property in anxious major depressive disorder. We do find that one of its metabolites appears to have anxiolytic effects. 4. The prodrug 4-chlorokynurenine causes ketamine-like antidepressant, but not side effects, by NMDA/glycineB-site inhibition. This work extends our finding of the rapid antidepressant effects of ketamine. Ketamine modulates the NMDA receptor complex; we believe that such actions are in part responsible for its significant side effects and risk of abuse. We believe that the prodrug 4-chlorokynurenine would more selectively modulate the NMDA receptor complex and thus not result in the liabilities of ketamine (i.e., side effects, risk of abuse). In a series of animal studies we demonstrate the safety of this new compound. A clinical study has begun at the intramural program at NIMH in patients with depression. 5. Reliability of 1H-MRS measured human prefrontal cortex glutamatergic signals at 7 Tesla. We demonstrate the reliability of a new technique for measuring the brain levels of glutamate, believed to be important to rapid antidepressant effects of ketamine. Such technology could help us track the changes in brain glutamate levels before and after ketamine which could help in better understanding antidepressant effects and to develop better treatments. 6. Group differences in MEG-ICA derived resting state networks. We demonstrate using a new technology (magnetoencephalography, MEG), differences in resting state brain networks between patients with depression and healthy controls.

本报告涉及根据方案01-M-0254收集的工作（NCT 00024635）; 08-M-0196（NCT 00759395）; 08-M-0150（NCT 00697268）; 14-M-0085（NCT 02122562）; 07-M-0021（NCT 00397111）; 14-M-0041（NCT 02049385）;和07-M-0152（NCT 00472576），09-M-N230; 15-M-0151（NCT 02484456），15-M-0188（NCT 02543983）。过去一年的成果： 1. 氯胺酮输注后的抗自杀反应与难治性抑郁症患者夜间觉醒减少相关在这项研究中，我们发现了一种生物标志物，可以预测谁会对氯胺酮有反应，谁不会。在这里，我们发现，患有难治性抑郁症的受试者在夜间晚些时候醒来的时间更多，自杀想法更多，并且单剂量氯胺酮迅速消除了自杀想法并恢复了抑郁症患者的睡眠。睡眠模式不再与健康对照受试者不同。 2. 严重和难治性心境障碍研究的安全性。本文回顾了NIMH 12年来的内部研究数据，我们发现，在住院患者中进行随机、安慰剂对照、无药物治疗难治性抑郁症的试验是安全的。 3. 一项δ阿片激动剂AZD 2327治疗焦虑型重性抑郁症的随机、安慰剂对照初步试验在这项双盲、安慰剂对照的初步研究中，我们发现δ阿片受体激动剂AZD 2327在焦虑型重性抑郁症中没有显著的抗抑郁作用。我们确实发现它的一种代谢物似乎有抗焦虑作用。 4. 前药4-氯犬尿氨酸通过NMDA/甘氨酸B位点抑制引起氯胺酮样抗抑郁药，但没有副作用。这项工作扩展了我们对氯胺酮快速抗抑郁作用的发现。氯胺酮调节NMDA受体复合物;我们认为这种作用是其显著副作用和滥用风险的部分原因。我们相信，前药4-氯犬尿氨酸将更选择性地调节NMDA受体复合物，因此不会导致氯胺酮的负债（即，副作用、滥用风险）。在一系列动物研究中，我们证明了这种新化合物的安全性。NIMH的一项临床研究已经开始在抑郁症患者中进行。 5. 1H-MRS在7特斯拉下测量人类前额叶皮层神经元能信号的可靠性我们证明了一种测量大脑谷氨酸水平的新技术的可靠性，这种技术被认为对氯胺酮的快速抗抑郁作用很重要。这种技术可以帮助我们跟踪氯胺酮前后大脑谷氨酸水平的变化，这有助于更好地了解抗抑郁作用并开发更好的治疗方法。 6. MEG-ICA导出的静息态网络中的组差异。我们使用一种新技术（脑磁图，MEG）证明了抑郁症患者和健康对照者之间静息状态脑网络的差异。