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

• 批准号: 10011372
• 负责人: Carlos Zarate
• 金额: $ 245.45万
• 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/10011372
• 关键词: AMPA Receptors; Adverse effects; Age; Agonist; Anti-Anxiety Agents; Antidepressive Agents; Anxiety; Area; Attention; Behavioral; Behavioral Genetics; Biological Availability; Biological Markers; Bipolar Disorder; Body Temperature; Brain; Brain imaging; Brain-Derived Neurotrophic Factor; Canis familiaris; Cessation of life; Chemicals; Clinical Trials; Cross-Over Trials; Data; Diagnosis; Dimensions; Dissociation; Dose; Double-Blind Method; Electroencephalography; Electrophysiology (science); Emotional; Evaluation; Exhibits; Feeling suicidal; Female; Functional Imaging; Functional Magnetic Resonance Imaging; Future; Genes; Genetic; Glutamate Receptor; Glycine; Glycine Receptors; Goals; Hippocampus (Brain); Individual; Infusion procedures; Insula of Reil; Intervention; Intraperitoneal Injections; Investigation; Ketamine; Lead; Life; Magnetoencephalography; Major Depressive Disorder; Measurement; Measures; Mental Depression; Metabolism; Metabotropic Glutamate Receptors; Modification; Montgomery and Asberg depression rating scale; Mood Disorders; Mus; Muscarinic Antagonists; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NMDA receptor antagonist; National Institute of Mental Health; Neurobiology; Neuropsychological Tests; Oral; Oral Administration; Outcome Measure; Participant; Patient Self-Report; Patients; Performance; Pharmaceutical Preparations; Pharmacology; Phenotype; Placebo Effect; Placebos; Plasma; Prefrontal Cortex; Prodrugs; Property; Protocols documentation; Randomized; Rattus; Reaction Time; Receptor Activation; Receptor Inhibition; Receptor Signaling; Refractory; Reporting; Research; Research Domain Criteria; Resistance; Risk Marker; Rodent; Role; Scopolamine; Single-Blind Study; Stimulus; Structure; Suicide; Suicide attempt; Symptoms; Syndrome; Testing; Therapeutic Agents; Validation; Variant; antidepressant effect; behavioral response; collected works; depressed patient; depressive symptoms; design; drug candidate; experience; extracellular; healthy volunteer; improved; inhibitor/antagonist; interdisciplinary approach; male; neural patterning; neurophysiology; new therapeutic target; novel; novel therapeutics; peripheral blood; phenomenological models; preclinical study; prevent; receptor; receptor function; recruit; relating to nervous system; response; side effect; single episode major depressive disorder; suicidal; suicidal behavior; suicidal risk; symptomatology; treatment effect; treatment response; treatment-resistant depression

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); 07-M-0152 (NCT00472576), 09-M-N230; 15-M-0151 (NCT 02484456), 15-M-0188 (NCT02543983), and 19-M-0107 (NCT03973268). Results this past year: 1. Neurophysiological Changes Associated with Antidepressant Response to Ketamine Not Observed in a Negative Trial of Scopolamine in Major Depressive Disorder. This randomized, placebo-controlled, crossover trial examined the antidepressant efficacy of the muscarinic antagonist scopolamine in major depressive disorder subjects with more severe and refractory forms of major depressive disorder relative to previous reports. Participants included 23 medication-free major depressive disorder subjects currently experiencing a major depressive episode. Following a single-blind, placebo lead-in, participants were randomized to receive 2 counterbalanced blocks of 3 i.v. infusions of scopolamine (4 g/kg) and placebo in a double-blind manner. As assessed by both the Montgomery-Asberg Depression Rating Scale and Hamilton Anxiety Rating Scale, scopolamine had no significant antidepressant or anxiolytic effects relative to placebo. No significant drug vs placebo effects were seen in magnetoencephalography gamma power or brain-derived neurotrophic factor plasma concentrations, and brain-derived neurotrophic factor changes did not correlate with change in Montgomery-Asberg Depression Rating Scale score in response to scopolamine. These results do not support the efficacy of scopolamine for more severe or refractory forms of depression. 2. (2R,6R)-hydroxynorketamine exerts mGlu2 receptor-dependent antidepressant actions. Currently approved antidepressant drugs often take months to take full effect, and 30% of depressed patients remain treatment resistant. In contrast, ketamine, when administered as a single subanesthetic dose, exerts rapid and sustained antidepressant actions. Preclinical studies indicate that the ketamine metabolite (2R,6R)-hydroxynorketamine (2R,6R)-HNK is a rapid-acting antidepressant drug candidate with limited dissociation properties and abuse potential. We assessed the role of group II metabotropic glutamate receptor subtypes 2 (mGlu2) and 3 (mGlu3) in the antidepressant-relevant actions of (2R,6R)-HNK using behavioral, genetic, and pharmacological approaches as well as cortical quantitative EEG (qEEG) measurements in mice. Both ketamine and (2R,6R)-HNK prevented mGlu2/3 receptor agonist (LY379268)-induced body temperature increases in mice lacking the Grm3, but not Grm2, gene. This action was not replicated by NMDA receptor antagonists or a chemical variant of ketamine that limits metabolism to (2R,6R)-HNK. The antidepressant-relevant behavioral effects and 30- to 80-Hz qEEG oscillation (gamma-range) increases resultant from (2R,6R)-HNK administration were prevented by pretreatment with an mGlu2/3 receptor agonist and absent in mice lacking the Grm2, but not Grm3 -/-, gene. These findings highlight that (2R,6R)-HNK exerts antidepressant-relevant actions via a mechanism converging with mGlu2 receptor signaling and suggest enhanced cortical gamma oscillations as a marker of target engagement relevant to antidepressant efficacy. Moreover, these results support the use of (2R,6R)-HNK and inhibitors of mGlu2 receptor function in clinical trials for treatment-resistant depression either alone or in combination. 3. Antidepressant-relevant concentrations of the ketamine metabolite (2R,6R)-hydroxynorketamine do not block NMDA receptor function. Preclinical studies indicate that (2R,6R)-hydroxynorketamine (HNK) is a putative fast-acting antidepressant candidate. Although inhibition of NMDA-type glutamate receptors (NMDARs) is one mechanism proposed to underlie ketamine's antidepressant and adverse effects, the potency of (2R,6R)-HNK to inhibit NMDARs has not been established. We used a multidisciplinary approach to determine the effects of (2R,6R)-HNK on NMDAR function. Antidepressant-relevant behavioral responses and (2R,6R)-HNK levels in the extracellular compartment of the hippocampus were measured following systemic (2R,6R)-HNK administration in mice. These data demonstrate the stereoselectivity of NMDAR inhibition by (2R,6R;2S,6S)-HNK and support the conclusion that direct NMDAR inhibition does not contribute to antidepressant-relevant effects of (2R,6R)-HNK. 4. Functional Imaging of the Implicit Association of the Self With Life and Death. A critical need exists to identify objective markers of suicide ideation. One potential suicide risk marker is the Suicide Implicit Association Task (S-IAT), a behavioral task that uses differential reaction times to compare the implicit association between the self and death to the implicit association between the self and life. Individuals with a stronger association between the self and death on the S-IAT are more likely to attempt suicide in the future. To better understand the neural underpinnings of the implicit association between self and either life or death, a functional magnetic resonance imaging (fMRI) version of the S-IAT was adapted and piloted in healthy volunteers. An fMRI version of the S-IAT was administered to 28 healthy volunteers (ages 18-65, 14F/14M). Behavioral results were comparable to those seen in non-scanner versions of the task. The task was associated with patterns of neural activation in areas relevant to emotional processing, specifically the insula and right ventrolateral prefrontal cortex. Performance on the S-IAT fMRI task may reflect scores obtained outside of the scanner. In future evaluations, this task could help assess whether individuals at increased risk of suicide display a different pattern of neural activation in response to self/death and self/life stimuli. 5. Mouse, rat, and dog bioavailability and mouse oral antidepressant efficacy of (2R,6R)-hydroxynorketamine. (R,S)-ketamine has gained attention for its rapid-acting antidepressant actions in patients with treatment-resistant depression. However, widespread use of ketamine is limited by its side effects, abuse potential, and poor oral bioavailability. The ketamine metabolite, (2R,6R)-hydroxynorketamine, exerts rapid antidepressant effects, without ketamine's adverse effects and abuse potential, in rodents. We evaluated the oral bioavailability of (2R,6R)-hydroxynorketamine in three species (mice, rats, and dogs) and also evaluated five candidate prodrug modifications for their capacity to enhance the oral bioavailability of (2R,6R)-hydroxynorketamine in mice. Compared to intraperitoneal injection in mice, the relative oral bioavailability of (2R,6R)-hydroxynorketamine was 62%, which was not improved by any of the candidate prodrugs tested. Following oral administration, (2R,6R)-hydroxynorketamine readily penetrated the brain, with brain to plasma ratios between 0.67-1.2 in mice and rats. These results demonstrate that (2R,6R)-hydroxynorketamine has favorable oral bioavailability in three species and exhibits antidepressant efficacy following oral administration in mice.

本报告涉及根据协议 01-M-0254 (NCT00024635) 收集的工作； 08-M-0196 (NCT00759395); 08-M-0150 (NCT00697268); 14-M-0085 (NCT02122562)； 07-M-0021 (NCT00397111)； 14-M-0041 (NCT02049385)； 07-M-0152 (NCT00472576), 09-M-N230; 15-M-0151 (NCT 02484456)、15-M-0188 (NCT02543983) 和 19-M-0107 (NCT03973268)。 去年的结果： 1. 在东莨菪碱治疗重度抑郁症的阴性试验中未观察到与氯胺酮抗抑郁反应相关的神经生理学变化。这项随机、安慰剂对照、交叉试验检查了毒蕈碱拮抗剂东莨菪碱对患有更严重和难治性抑郁症的重度抑郁症受试者的抗抑郁功效。参与者包括 23 名目前正在经历重度抑郁发作且未接受药物治疗的重度抑郁症受试者。在单盲安慰剂导入后，参与者被随机接受 2 组平衡组，每组 3 次静脉注射。以双盲方式输注东莨菪碱（4 g/kg）和安慰剂。根据蒙哥马利-阿斯伯格抑郁量表和汉密尔顿焦虑量表的评估，东莨菪碱相对于安慰剂没有显着的抗抑郁或抗焦虑作用。与安慰剂相比，在脑磁图伽马功率或脑源性神经营养因子血浆浓度方面没有观察到显着的药物效应，并且脑源性神经营养因子的变化与东莨菪碱反应的蒙哥马利-阿斯伯格抑郁量表评分的变化不相关。这些结果并不支持东莨菪碱对更严重或难治性抑郁症的疗效。 2. (2R,6R)-羟基去甲氯胺酮发挥 mGlu2 受体依赖性抗抑郁作用。目前批准的抗抑郁药物通常需要数月才能完全发挥作用，并且 30% 的抑郁症患者仍然对治疗有抵抗力。相比之下，氯胺酮当以单次亚麻醉剂量给药时，可发挥快速且持续的抗抑郁作用。临床前研究表明，氯胺酮代谢物 (2R,6R)-羟基去甲氯胺酮 (2R,6R)-HNK 是一种速效抗抑郁候选药物，具有有限的解离特性和滥用潜力。我们使用行为、遗传和药理学方法以及小鼠皮层定量脑电图 (qEEG) 测量，评估了 II 组代谢型谷氨酸受体亚型 2 (mGlu2) 和 3 (mGlu3) 在 (2R,6R)-HNK 抗抑郁相关作用中的作用。氯胺酮和 (2R,6R)-HNK 均可阻止 mGlu2/3 受体激动剂 (LY379268) 诱导的缺乏 Grm3 基因（而非 Grm2 基因）的小鼠体温升高。 NMDA 受体拮抗剂或限制 (2R,6R)-HNK 代谢的氯胺酮化学变体无法复制这种作用。通过使用 mGlu2/3 受体激动剂进行预处理，可防止因 (2R,6R)-HNK 给药而产生的与抗抑郁药相关的行为效应和 30 至 80 Hz qEEG 振荡（伽玛范围）增加，并且在缺乏 Grm2 基因的小鼠中不存在，但在缺乏 Grm3 -/- 基因的小鼠中则不存在。这些发现强调，(2R,6R)-HNK 通过与 mGlu2 受体信号传导相融合的机制发挥抗抑郁相关作用，并表明增强的皮质伽马振荡是与抗抑郁功效相关的靶标参与的标志。此外，这些结果支持在临床试验中单独或联合使用(2R,6R)-HNK 和 mGlu2 受体功能抑制剂治疗难治性抑郁症。 3. 抗抑郁药相关浓度的氯胺酮代谢物 (2R,6R)-羟基去甲氯胺酮不会阻断 NMDA 受体功能。临床前研究表明 (2R,6R)-羟基去甲氯胺酮 (HNK) 是一种公认​​的速效抗抑郁候选药物。尽管抑制 NMDA 型谷氨酸受体 (NMDAR) 是氯胺酮抗抑郁和副作用的一种机制，但 (2R,6R)-HNK 抑制 NMDAR 的效力尚未确定。我们采用多学科方法来确定 (2R,6R)-HNK 对 NMDAR 功能的影响。在小鼠体内全身施用 (2R,6R)-HNK 后，测量了海马细胞外区室中抗抑郁药相关的行为反应和 (2R,6R)-HNK 水平。这些数据证明了 (2R,6R;2S,6S)-HNK 抑制 NMDAR 的立体选择性，并支持直接 NMDAR 抑制不会导致 (2R,6R)-HNK 的抗抑郁相关作用的结论。 4. 自我与生死的内隐联系的功能成像。迫切需要确定自杀意念的客观标志。一个潜在的自杀风险标记是自杀内隐关联任务（S-IAT），这是一项行为任务，使用不同的反应时间来比较自我与死亡之间的内隐关联和自我与生命之间的内隐关联。在 S-IAT 中，自我与死亡之间的关联性较强的个体未来更有可能尝试自杀。为了更好地理解自我与生或死之间隐含关联的神经基础，对 S-IAT 的功能性磁共振成像 (fMRI) 版本进行了调整，并在健康志愿者中进行了试点。对 28 名健康志愿者（18-65 岁，14F/14M）进行了 S-IAT 的功能磁共振成像版本。行为结果与非扫描仪版本的任务中看到的结果相当。该任务与情绪处理相关区域的神经激活模式有关，特别是岛叶和右腹外侧前额叶皮层。 S-IAT fMRI 任务的表现可能反映在扫描仪之外获得的分数。在未来的评估中，这项任务可以帮助评估自杀风险增加的个体是否表现出不同的神经激活模式来响应自我/死亡和自我/生命刺激。 5. (2R,6R)-羟基去甲氯胺酮的小鼠、大鼠和狗的生物利用度和小鼠口服抗抑郁功效。 (R,S)-氯胺酮因其对难治性抑郁症患者的快速抗抑郁作用而受到关注。然而，氯胺酮的广泛使用因其副作用、滥用可能性和口服生物利用度差而受到限制。氯胺酮代谢物 (2R,6R)-羟基去甲氯胺酮在啮齿类动物中发挥快速抗抑郁作用，且没有氯胺酮的不良反应和滥用潜力。我们评估了 (2R,6R)-羟基去甲氯胺酮在三个物种（小鼠、大鼠和狗）中的口服生物利用度，还评估了五种候选前药修饰在小鼠中增强 (2R,6R)-羟基去甲氯胺酮口服生物利用度的能力。与小鼠腹腔注射相比，(2R,6R)-羟基去甲氯胺酮的相对口服生物利用度为62%，任何测试的候选前药均未改善该生物利用度。口服给药后，(2R,6R)-羟基去甲氯胺酮很容易渗透到大脑，在小鼠和大鼠中，脑与血浆的比率在0.67-1.2之间。这些结果表明，(2R,6R)-羟基去甲氯胺酮在三个物种中具有良好的口服生物利用度，并且在小鼠口服给药后表现出抗抑郁功效。