Therapeutic Efficacy of Ketamine Metabolites for Depression Treatment

氯胺酮代谢物治疗抑郁症的疗效

• 批准号: 9502214
• 负责人: Todd D Gould
• 金额: $ 15.34万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9502214
• 关键词: AMPA Receptors; Acute; Address; Adverse effects; Anesthetics; Anhedonia; Animal Model; Antidepressive Agents; Behavior; Behavioral; Behavioral Model; Biochemical; Biological; Brain; Cells; Chronic; Clinical; Data; Development; Disadvantaged; Disease remission; Dose; Drug abuse; Drug usage; Electrophysiology (science); FDA approved; Feeling suicidal; Female; Frequencies; Future; Glutamates; Goals; Human; Individual; Interneurons; Intervention; Intravenous; Ketamine; Lead; Major Depressive Disorder; Measurement; Mediating; Mental Depression; Moods; Mus; N-Methyl-D-Aspartate Receptors; NMDA receptor antagonist; Nature; Neurosciences Research; Outcome; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Pharmacotherapy; Plasma; Play; Population; Preclinical Testing; Property; Psychotropic Drugs; Receptor Inhibition; Refractory; Research; Resistance; Risk; Rodent; Role; Self Administration; Series; Signaling Molecule; Slice; Stereoisomer; Structure; Symptoms; Synapses; Testing; Therapeutic; Therapeutic Effect; Time; Treatment Efficacy; Variant; Work; alpha-bungarotoxin receptor; antidepressant effect; base; behavior test; behavioral study; clinical effect; clinically relevant; depressive symptoms; drug development; endophenotype; experience; experimental study; improved; inhibitor/antagonist; insight; male; next generation; norketamine; novel; patch clamp; pre-clinical; predictive modeling; prepulse inhibition; public health relevance; translational neuroscience

 DESCRIPTION (provided by applicant): Depression afflicts approximately 16% of the world population. Although antidepressant medications are available, many patients remain treatment-refractory, and currently used drugs take several weeks to be effective. A recent finding is that the non-competitive NMDA receptor antagonist ketamine has rapid antidepressant efficacy in treatment-resistant patients. Despite these promising results, ketamine's potential as a long-term antidepressant medication is limited due to its addictive nature, anesthetic properties, and capacity to produce dissociative effects even at low doses. Similar to many existing psychotropic drugs, the full clinical actions of ketamine may be due to more than one target. Ketamine is rapidly and stereospecifically metabolized to various metabolites that have distinct biological activities. These metabolites may be responsible for either the therapeutic or the side effects of ketamine when it is utilized as an antidepressant. Our preliminary data indicate that some metabolites exert antidepressant-like actions and increase AMPA excitatory post-synaptic current frequency in stratum radiatum interneurons, indicative of increases in glutamate release from CA3 Schaffer collateral inputs. The central hypothesis guiding the proposed studies is that a ketamine metabolite or metabolites independently exert clinically relevant actions that substantially explain ketamine's clinical profile. Here, we will use mice to test the antidepressant-like properties and the side effect profile of these compounds. We will first, in Specific Aim #1, define the range of ketamine metabolite's actions on ketamine-sensitive tests related to depression. In addition to utilizing tests to predict rapid and sustained therapeutic antidepressant action in both male and female mice, these studies will assess different endophenotypes associated with depression including helplessness and anhedonia. Quantifying plasma and brain levels at time points relevant to our behavioral studies will permit us to determine the extent to which ketamine's behavioral effects are associated with brain concentrations of its metabolites. In Specific Aim #2, we will assess whether ketamine metabolites account for the side effects of ketamine. We will determine the effects of metabolites in behavioral tests that predict stimulant effects, as well as abuse and psychotomimetic potential. In Specific Aim #3, we will determine the pharmacological activity of ketamine metabolites relevant to their antidepressant actions. We will use whole-cell patch-clamp electrophysiology to determine the cellular mechanisms that underlie the antidepressant actions of ketamine metabolites. Using behavioral approaches we will assess the contribution of identified mechanisms. A comprehensive understanding of how the therapeutic actions of ketamine are exerted is imperative for the development of improved pharmacotherapies that will effectively reproduce the therapeutic benefit of ketamine, but without the unwanted side effects. Completion of the proposed experiments will provide a strong scientific framework to better understand these properties.

 描述（由申请人提供）：世界上约 16% 的人口患有抑郁症。尽管可以使用抗抑郁药物，但许多患者仍然难以治疗，而且目前使用的药物需要几周时间才能发挥作用。最近的一项发现是，非竞争性 NMDA 受体拮抗剂氯胺酮对治疗耐药的患者具有快速的抗抑郁功效。尽管有这些有希望的结果，但氯胺酮作为长期抗抑郁药物的潜力有限，因为它具有成瘾性、麻醉特性以及即使在低剂量下也能产生解离效应的能力。与许多现有的精神药物类似，氯胺酮的全部临床作用可能是由于多个靶点。氯胺酮快速、立体定向地代谢为具有不同生物活性的各种代谢物。当氯胺酮用作抗抑郁药时，这些代谢物可能导致其治疗或副作用。我们的初步数据表明，一些代谢物发挥抗抑郁样作用，并增加辐射层中间神经元中的 AMPA 兴奋性突触后电流频率，表明 CA3 Schaffer 侧支输入的谷氨酸释放增加。指导拟议研究的中心假设是氯胺酮代谢物或代谢物独立地发挥临床相关作用，基本上解释了氯胺酮的临床特征。在这里，我们将使用小鼠来测试这些化合物的抗抑郁样特性和副作用。首先，在具体目标#1中，我们将定义氯胺酮代谢物对与抑郁症相关的氯胺酮敏感测试的作用范围。除了利用测试来预测雄性和雌性小鼠的快速和持续的抗抑郁治疗作用外，这些研究还将评估与抑郁症相关的不同内表型，包括无助和快感缺乏。在与我们的行为研究相关的时间点量化血浆和大脑水平将使我们能够确定氯胺酮的行为影响与其代谢物的大脑浓度相关的程度。在具体目标#2 中，我们将评估氯胺酮代谢物是否会导致氯胺酮的副作用。我们将在行为测试中确定代谢物的影响，以预测兴奋作用以及滥用和拟精神病潜力。在具体目标#3中，我们将确定氯胺酮代谢物与其抗抑郁作用相关的药理活性。我们将使用全细胞膜片钳电生理学来确定氯胺酮代谢物抗抑郁作用的细胞机制。我们将使用行为方法评估已确定机制的贡献。全面了解氯胺酮如何发挥治疗作用对于开发改进的药物疗法至关重要，这种疗法将有效地重现氯胺酮的治疗效果，但不会产生不良副作用。完成所提出的实验将为更好地理解这些特性提供强大的科学框架。