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: 9417095
• 负责人: Todd D Gould
• 金额: $ 47.98万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9417095
• 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; predictive test; 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（由适用提供）：抑郁症折磨约16％的世界人口。尽管有抗抑郁药可用，但许多患者仍在治疗治疗，目前使用的药物需要几周才能有效。最近的发现是，非竞争力NMDA受体拮抗剂氯胺酮在耐药患者中具有抗抑郁剂的效率。尽管有这些希望的结果，但氯胺酮作为长期抗抑郁药的潜力受到限制，由于其添加性，麻醉特性以及即使在低剂量下也产生分离效应的能力。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一个以上的靶标。氯胺酮迅速和立体定义为具有不同生物学活性的各种代谢产物。这些代谢物可能是氯胺酮用作抗抑郁药时的治疗或副作用。我们的初步数据表明，某些代谢产物发挥抗抑郁药样作用，并增加了辐射层中神经元中突触后电流频率的增加，这表明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，氯胺酮代谢产物或代谢产物独立发挥了与临床相关的作用，从而实质上解释了氯胺酮的临床特征。在这里，我们将使用小鼠测试这些化合物的抗抑郁样性质和副作用曲线。首先，在特定的目标＃1中，我们将定义氯胺酮代谢产物对与抑郁症有关的氯胺酮敏感测试的作用范围。除了使用测试预测雄性和雌性小鼠中的快速和持续的治疗抗抑郁作用外，这些研究还将评估与抑郁症有关的不同内膜型，包括无助和抗抗反感。在与我们的行为研究有关的时间点上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脑浓度有关。在特定的目标＃2中，我们将评估氯胺酮代谢物是否解释了氯胺酮的副作用。我们将确定代谢物在预测刺激作用以及滥用和心理图的行为测试中的影响。在特定的目标＃3中，我们将确定氯胺酮代谢物与抗抑郁药相关的药物活性。我们将使用全细胞斑块钳电生理学来确定氯胺酮代谢物抗抑郁作用的基础的细胞机制。使用行为方法，我们将评估确定机制的贡献。对如何开发改进的药物疗法，必须有效地再现氯胺酮的治疗益处，但没有不必要的副作用，对氯胺酮的治疗作用进行了全面的了解至关重要。拟议的实验的完成将提供一个强大的科学框架，以更好地了解这些特性。