Glutamatergic Modulators for Rapid and Sustained Antidepressant Effect

谷氨酸能调节剂具有快速和持续的抗抑郁作用

• 批准号: 10703926
• 负责人: Carlos Zarate
• 金额: $ 382.11万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 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/10703926
• 关键词: AMPA Receptors; Acute; Affect; Amygdaloid structure; Anesthetics; Anger; Anterior; Antidepressive Agents; Antioxidants; Attention; Biochemical; Biological Markers; Bipolar Depression; Bipolar Disorder; Brain; Brain region; Brain-Derived Neurotrophic Factor; COVID-19 pandemic effects; Cerebrospinal Fluid; Cessation of life; Chronic; Coupling; Data; Data Collection; Distress; Dose; Electroencephalography; Electrophysiology (science); Emotional; FOS gene; Face; Family; Fatigue; Feeling suicidal; Frequencies; Functional Magnetic Resonance Imaging; Gene Mutation; Genes; Genetic; Genetic Transcription; Glutamates; Health Personnel; Hippocampus (Brain); Homeostasis; Hour; Human; Human Volunteers; Image; Immediate-Early Genes; Impairment; Individual; Inflammatory; Infusion procedures; Investigation; Ketamine; Life; Link; Magnetic Resonance Imaging; Magnetoencephalography; Magnetometries; Major Depressive Disorder; Measures; Medical; Mental Depression; Mental Health; MicroRNAs; Molecular; Molecular Target; Montgomery and Asberg depression rating scale; Mood Disorders; Mus; N-Methylaspartate; Neurons; Neuropsychology; Nitric Oxide Signaling Pathway; Oxidative Stress; Parietal Lobe; Participant; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Pharmacology; Phase; Placebos; Plasma; Post-Traumatic Stress Disorders; Power Sources; Property; Protocols documentation; Public Health; Rattus; Recording of previous events; Recovery; Recurrence; Regulation; Relapse; Research; Resistance; Sampling; Sensory; Sleep; Slow-Wave Sleep; Sphingolipids; Stimulus; Suicide; Suicide attempt; Symptoms; Synapses; Synaptic plasticity; System; Therapeutic; Time; Transcription Process; Transcriptional Activation; Work; antagonist; antidepressant effect; arm; cellular targeting; clinical outcome measures; comparative; coronavirus disease; depressive symptoms; drug action; follow-up; frontal lobe; gene network; glutamatergic signaling; healthy volunteer; improved; indexing; interest; intravenous administration; metabolome; metabolomics; neural correlate; pleasure; preclinical study; premature; primary outcome; randomized trial; resilience; response; severe mental illness; spectroscopic imaging; standard care; suicidal behavior; transcription factor; transcription regulatory network; transcriptome sequencing; treatment-resistant depression

Our results indicate that the glutamatergic system is involved in the mechanism of action of rapid antidepressant response. In addition, this system may be a feasible target for developing treatments that have rapid and robust efficacy in individuals who have treatment-resistant depression and suicidal thoughts. We found that the glutamatergic modulator ketamine resulted in rapid, robust and relatively sustained antidepressant, antisuicidal, and antianhedonic effects. Response with ketamine occurred within 2 hours and lasted approximately 1 week. Study: (Biomarkers of rapid response in major depressive disorder): protocols 04-M-0222 (NCT00088699), 17-M-0060 (NCT03065335), and 19-M-0107 (NCT 03973268). OBJECTIVE: To identify the neural correlates and cellular and molecular targets of rapid antidepressant response to the NMDA antagonist ketamine in subjects with major depressive disorder. Aims are 1) to examine the antisuicidal effects of ketamine, and 2) to examine correlates of antidepressant response to ketamine in both major depressive disorder and bipolar disorder and include these data/outcome measures: clinical (e.g., family history), imaging (magnetic resonance imaging/spectroscopy), electrophysiological (magnetoencephalography MEG, electroencephalography EEG), neuropsychological, and biochemical (e.g., genetics, microRNA, BDNF, metabolomics), 3) To demonstrate more robust neuropharmacodynamic effects measured by neuropharmacodynamic imaging (fMRI+EEG and MEG) of ketamine 0.5 mg/kg as compared to placebo administered over 40 minutes, and 4) To understand the involvement of AMPA receptors in ketamine's antidepressant response. Secondary aims: To determine if increases in synaptic plasticity, using electrophysiological measures in response to TMS and in association with sleep (i.e., slow wave sleep EEG activity) are associated with better antidepressant response. Results in the past year: 1. Magnetoencephalography biomarkers of suicide attempt history and antidepressant response to ketamine in treatment-resistant major depression. This study examined magnetoencephalographic (MEG) correlates of suicidal ideation (SI) and suicide attempt history in patients with treatment-resistant major depression (TRD) at baseline and following subanesthetic-dose ketamine infusion. Twenty-nine drug-free patients with TRD participated in a crossover randomized trial of ketamine. MEG data were collected during an attentional dot probe task with emotional face stimuli at baseline and several hours post-ketamine infusion. Synthetic aperture magnetometry was used to project source power in the theta, alpha, beta, and gamma frequencies for angry-neutral, happy-neutral, and neutral-neutral face pairings during a one-second peristimulus period. Ketamine significantly reduced SI and depression across the sample. Post-ketamine, attempters had improved accuracy and non-attempters had reduced accuracy on the task. SI was positively associated with gamma power in regions of the frontal and parietal cortices across groups. In an extended amygdala-hippocampal region, attempters differed significantly in their emotional reactivity to angry versus happy faces as indexed by theta power differences, irrespective of drug. Ketamine significantly reduced the association between alpha power and SI for angry compared with happy faces in a fronto-insular/anterior cingulate region important for regulating sensory attentiveness. The findings highlight key differences in band-limited power between attempters and non-attempters and reinforce previous findings that ketamine has distinct response properties in patients with a suicide history. 2. Transcriptional Activation, Deactivation and Rebound Patterns in Cortex, Hippocampus and Amygdala in Response to Ketamine Infusion in Rats. In this molecular-pharmacological investigation in the rat, we used short- and longer-term infusions of high dose ketamine to stimulate neuronal transcription processes. We hypothesized that a progressively stronger modulation of neuronal gene networks would occur over time in cortical and limbic pathways. A continuous intravenous administration paradigm for ketamine was developed in rat consisting of short (1 h) and long duration (10 h, and 10 h + 24 h recovery) infusions of anesthetic concentrations to activate or inhibit gene transcription. Transcription was measured by RNA-Seq in three brain regions: frontal cortex, hippocampus, and amygdala. Induction of a shared transcriptional regulatory network occurred within 1 h in all three brain regions consisting of (a) genes involved in stimulus-transcription factor coupling that are induced during altered synaptic activity (immediate early genes, IEGs, such as c-Fos, 9-12) and (b) the Nrf2 oxidative stress-antioxidant response pathway downstream from glutamate signaling per brain region. By 10 h of infusion, the acute results were further reinforced and consisted of more and stronger gene alterations reflecting a sustained and accentuated ketamine modulation of regional excitation and plasticity. After 24 h recovery, we observed overshoot of transcriptional processes rather than a smooth return to homeostasis suggesting an oscillation of plasticity occurs during the transition to a new phase of neuronal regulation. These data elucidate critical molecular regulatory actions during and downstream of ketamine administration that may contribute to the unique drug actions of this anesthetic agent. These molecular investigations point to pathways linked to therapeutically useful attributes of ketamine. 3. Comparative metabolomic analysis in plasma and cerebrospinal fluid of humans and in plasma and brain of mice following antidepressant-dose ketamine administration. Preclinical studies found that (2 R,6 R;2 S,6 S)-hydroxynorketamine (HNK), a major circulating metabolite of ketamine, elicits antidepressant effects similar to those of ketamine. To help determine how (2 R,6 R)-HNK contributes to ketamine's mechanism of action, an exploratory, targeted, metabolomic analysis was carried out on plasma and CSF of nine healthy volunteers receiving a 40-minute ketamine infusion (0.5 mg/kg). Ketamine and (2 R,6 R)-HNK both affected multiple pathways associated with inflammatory conditions. In addition, several changes were unique to either the healthy human volunteers and/or the mouse arm of the study, indicating that different pathways may be differentially involved in ketamine's effects in mice and humans. Mechanisms of action found to consistently underlie the effects of ketamine and/or (2 R,6 R)-HNK across both the human metabolome in plasma and CSF and the mouse arm of the study included LAT1, IDO1, NAD+, the nitric oxide (NO) signaling pathway, and sphingolipid rheostat. 4. The Mental Health Impact of COVID-19 Pandemic on Healthcare Workers Protocol (P205022: PI: Zarate, Carlos) completed initial baseline data collection and one month follow-up, and will re-contact participants for 2 month follow-up ratings. In total, over 900 HCWs completed ratings related to COVID exposure, distress, resilience and mental health symptoms including PTSD.

我们的结果表明，谷氨酸能系统参与了快速抗抑郁反应的作用机理。此外，该系统可能是开发具有耐药性抑郁症和自杀思想的个体具有快速且效率强大的治疗方法的可行目标。我们发现，谷氨酸能调节剂氯胺酮会导致快速，健壮和相对持续的抗抑郁药，抗杀虫剂和抗雄性作用。对氯胺酮的反应发生在2小时内，大约持续了1周。 研究：（重度抑郁症的快速反应生物标志物）：方案04-M-0222（NCT00088699），17-m-0060（NCT03065335）和19-m-0107（NCT 03973268）。 目的：确定对主要抑郁症受试者中NMDA拮抗剂氯胺酮快速反应反应的神经相关性，细胞和分子靶标的。 目的是1）检查氯胺酮的抗杀菌作用，以及2）检查主要抑郁症和双相情感障碍中抗抑郁药对氯胺酮反应的相关性，包括这些数据/结果指标：临床（例如，家族史），成像（磁性共鸣/分光镜）（磁性成像），电子物理学的绘制学效果，磁性成像（磁性共鸣）神经心理学和生物化学（例如遗传学，microRNA，BDNF，代谢组学），3）表明，通过与40分钟相比，与40分钟相比，通过神经药物动力学成像（fMRI+EEG和MEG）进行了神经药物动力学成像（fMRI+EEG和MEG）所测量的更强大的神经药物动力学效应，并显示出40分钟的受体。在氯胺酮的抗抑郁药反应中。 次要目的：为了确定突触可塑性的增加，使用电生理措施响应TMS并与睡眠有关（即慢波睡眠脑电图活性）与更好的抗抑郁药反应有关。 过去一年的结果： 1。自杀尝试史和抗抑郁药对氯胺酮在耐治疗的重度抑郁症中的磁脑化生物标志物。这项研究检查了基线耐药性重大抑郁症（TRD）的患者以及酮症下HANESTHETHETHETY剂量酮类输注后，自杀意念（SI）和自杀尝试史的磁脑摄影（MEG）相关性。 29例无药物TRD患者参加了氯胺酮的分频随机试验。在注意力点探测任务中收集了MEG数据，并在基线时进行了情绪刺激和酮胺后几个小时。在一秒钟的时间内，使用合成的光圈磁力测定法用于theta，alpha，beta和伽马频率中的源功能，用于愤怒中性，中性和中性中性的面部对配对。氯胺酮在样品中显着降低了SI和抑郁症。酮后，Attempter的精度提高了，非攻击者的任务准确性降低了。 SI与跨组额叶和顶叶皮质区域的伽马功率呈正相关。在一个扩展的杏仁核 - 海马地区，attempter在对愤怒的面孔和快乐面孔的情感反应性上有很大差异，如theta力量的差异所索引，而与药物无关。氯胺酮显着降低了Alpha Power和Si对愤怒的关联，与额额/前扣带中的快乐面孔相比，对于调节感官的关注很重要。这些发现突出了Attempters和非攻击者之间的限制能力的关键差异，并加强了先前的发现，即氯胺酮在自杀病史的患者中具有不同的反应特性。 2。响应大鼠氯胺酮输注的皮质，海马和杏仁核的转录激活，停用和反弹模式。在大鼠的分子 - 药理学研究中，我们使用了高剂量氯胺酮的短期和长期输注来刺激神经元转录过程。我们假设在皮质和边缘途径中，随着时间的流逝，神经元基因网络的调节逐渐更强。在大鼠中开发了氯胺酮连续的静脉内给药范例，由短持续时间（1 h）和长时间（10 h）（10 h和10 H + 24 h恢复）输注麻醉浓度，以激活或抑制基因转录。通过RNA-Seq在三个大脑区域中测量转录：额叶皮层，海马和杏仁核。 Induction of a shared transcriptional regulatory network occurred within 1 h in all three brain regions consisting of (a) genes involved in stimulus-transcription factor coupling that are induced during altered synaptic activity (immediate early genes, IEGs, such as c-Fos, 9-12) and (b) the Nrf2 oxidative stress-antioxidant response pathway downstream from glutamate signaling per brain region.到输注10小时，急性结果得到了进一步的加强，并包括更多，更强的基因改变，反映了持续而强调的区域激发和可塑性的氯胺酮调节。恢复24小时后，我们观察到转录过程的过冲，而不是平稳回到体内平衡，表明在过渡到新的神经元调节阶段时发生可塑性的振荡。这些数据阐明了氯胺酮给药期间和下游的关键分子调节作用，这可能有助于这种麻醉剂的独特药物作用。这些分子研究指向与氯胺酮治疗有用属性相关的途径。 3。抗抑郁剂剂量氯胺酮给予人类血浆和脑脊液的比较代谢组学分析。临床前研究发现（2 r，6 r; 2 s，6 s） - 羟基苯丙胺（HNK）是氯胺酮的主要循环代谢产物，引起与氯胺酮相似的抗抑郁作用。为了帮助确定（2 R，6 R）-HHNK如何对氯胺酮的作用机理有助于探索性，有针对性的，代谢组分分析，对接受40分钟氯胺酮输注（0.5 mg/kg）的九名健康志愿者的血浆和CSF进行。氯胺酮和（2 R，6 R） - HHNK都影响了与炎症条件相关的多个途径。此外，健康的人类志愿者和/或研究的小鼠臂是独有的，这表明不同的途径可能与小鼠和人类的氯胺酮作用不同。作用机制始终是氯胺酮和/或（2 r，6 r）-HHNK在血浆和CSF中的人类代谢组中的影响以及研究的小鼠组包括LAT1，IDO1，NAD+，一氮氧化物（NO）（NO）信号途径，以及sphinghingolipid rheeostat。 4.Covid-19-19对医疗工人协议的心理健康影响（P205022：PI：ZARATE，CARLOS）完成了初始基线数据收集和一个月的随访，并将重新接触参与者进行2个月的随访评级。总共有900多个HCW完成了与包括PTSD在内的共同暴露，困扰，韧性和心理健康症状有关的评级。