Therapeutic Efficacy of Ketamine Metabolites for Depression Treatment

 描述（由申请人提供）：抑郁症困扰着大约16%的世界人口。虽然抗抑郁药物是可用的，但许多患者仍然是治疗难治性的，目前使用的药物需要几周才能有效。最近的一项发现是，非竞争性NMDA受体拮抗剂氯胺酮在治疗抵抗性患者中具有快速的抗抑郁疗效。尽管有这些有希望的结果，氯胺酮作为长期抗抑郁药物的潜力是有限的，因为它的成瘾性，麻醉特性，即使在低剂量下也能产生解离作用。与许多现有的精神科药物相似，氯胺酮的全部临床作用可能是由于超过一个靶点。氯胺酮快速立体特异性代谢为具有不同生物活性的各种代谢物。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的原因。我们的初步数据表明，一些代谢产物发挥抗抑郁剂样作用，并增加AMPA兴奋性突触后电流频率在放射层中间神经元，表明谷氨酸释放增加CA3谢弗侧支输入。指导拟定研究的中心假设是，氯胺酮代谢物或代谢物独立发挥临床相关作用，这在很大程度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药样特性和副作用。我们将首先在具体目标#1中定义氯胺酮代谢物对与抑郁症相关的氯胺酮敏感性试验的作用范围。除了利用测试来预测雄性和雌性小鼠中快速和持续的治疗性抗抑郁作用外，这些研究还将评估与抑郁症相关的不同内在表型，包括无助和快感缺乏。在与我们的行为研究相关的时间点定量血浆和脑水平将使我们能够确定氯胺酮的行为效应与其代谢物的脑浓度相关的程度。在具体目标#2中，我们将评估氯胺酮代谢物是否导致氯胺酮的副作用。我们将确定代谢物在行为测试中的作用，预测兴奋剂的作用，以及滥用和拟精神病的潜力。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学活性。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。使用行为的方法，我们将评估所确定的机制的贡献。全面了解氯胺酮的治疗作用是如何发挥的，对于开发有效重现氯胺酮治疗益处但没有不必要的副作用的改进药物疗法至关重要。完成拟议的实验将提供一个强大的科学框架，以更好地了解这些属性。

 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.