Glutamatergic Modulators for Rapid and Sustained Antidepressant Effect

本报告涉及根据协议04-M-0222(NCT00088699)收集的工作。 我们的研究表明，谷氨酸能系统参与了快速抗抑郁反应的作用机制。此外，该系统可能是一个可行的目标，用于开发对患有难治性抑郁症和自杀念头的个人具有快速和强大疗效的治疗方法。我们发现，非竞争性NMDA拮抗剂(氯胺酮)具有快速、强劲和相对持久的抗抑郁和抗自杀作用。对氯胺酮的反应在2小时内发生，持续约1周。与现有治疗类似的应答率发生在6-8周，而不是几个小时。 研究：(重度抑郁症快速反应的生物标记物)。 目的：探讨重度抑郁障碍患者对NMDA拮抗剂氯胺酮快速抗抑郁反应的神经相关性。我们发现，单次静脉注射N-甲基-D-天冬氨酸拮抗剂(氯胺酮)可以产生强大而快速的抗抑郁作用；在静脉注射后2小时内起效，并在1周内持续显着。 目的是1)检验氯胺酮的抗自杀作用，以及2)检验氯胺酮对严重抑郁障碍和双相情感障碍的抗抑郁反应的相关性，并包括以下数据/结果指标：临床(例如，家族史)、成像(正电子发射断层扫描PET、磁共振成像/光谱学)、电生理学(脑磁图、脑电图)、神经心理学和生化(例如遗传学、微RNA、脑源性神经营养因子、代谢组学)。 过去一年的结果： 1.锂和丙戊酸盐这两种情绪稳定剂与氯胺酮在难治性双相抑郁中的抗抑郁疗效无关。我们假设氯胺酮的抗抑郁作用将通过治疗性剂量的锂与丙戊酸盐来改善，并且血清锂水平将与氯胺酮的抗抑郁效果呈正相关。在36名接受治疗剂量锂或丙戊酸盐治疗的难治性双相抑郁患者中，我们没有发现锂加强了氯胺酮在难治性双相抑郁中的抗抑郁效果。 2.氯胺酮能迅速产生抗快感作用。我们发现，氯胺酮迅速改善了难治性抑郁症(重度抑郁症和双相情感障碍)患者的快感缺失(缺乏快感)。 3.我们确定了氯胺酮治疗后严重抑郁障碍和双相情感障碍患者快感障碍改变的神经相关因素。快感缺乏症的减少与海马区和背侧扣带回(DACC)的葡萄糖代谢增加以及额叶下回和眶前皮质(OFC)的代谢减少有关。除了缓解整体抑郁症状，氯胺酮还可能在严重抑郁障碍中具有抗快感作用，推测这可能是通过改变海马体、dACC和OFC的代谢活动来调节的。 4.氯胺酮在数小时内迅速产生抗自杀作用，并在单次注射后持续至少一周。 5.我们确定了氯胺酮治疗后重度抑郁障碍和双相情感障碍患者自杀念头变化的神经关联。注射氯胺酮后自杀意念的减少与大脑边缘下皮质局部葡萄糖代谢的降低相关。

This Report involves work collected under protocol 04-M-0222 (NCT00088699). Our research suggests 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 non-competitive NMDA antagonist (ketamine) resulted in rapid, robust and relatively sustained antidepressant and antisuicidal effects. Response with ketamine occurred within 2 hours and lasted approximately 1 week. Comparable response rates with existing treatments occur at 6-8 weeks instead of hours. Study: (Biomarkers of rapid response in major depressive disorder). OBJECTIVE: To determine the neural correlates of rapid antidepressant response to the NMDA antagonist ketamine in subjects with major depressive disorder. We found robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist (ketamine); onset occurred within 2 hours post-infusion and continued to remain significant for 1 week. 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 (positron emission tomography PET, magnetic resonance imaging/spectroscopy), electrophysiological (magnetoencephalography MEG, electroencephalography EEG), neuropsychological, and biochemical (e.g., genetics, microRNA, BDNF, metabolomics). Results in the past year: 1. Lithium and valproate, two mood stabilizers, do not correlate with ketamine's antidepressant efficacy in treatment-resistant bipolar depression. We hypothesized that ketamine's antidepressant effects would be improved by therapeutic doses of lithium versus valproate and that serum lithium levels would positively correlate with ketamine's antidepressant efficacy. In 36 patients with treatment-resistant bipolar depression maintained on therapeutic doses of lithium or valproate, we did not find that lithium potentiates ketamine's antidepressant efficacy in treatment-resistant bipolar depression. 2. Ketamine produces rapid anti-anhedonic effects. We found that ketamine rapidly improves anhedonia (lack of pleasure) in patients with treatment-resistant depression (major depressive disorder and bipolar disorder). 3. We identified the neural correlates of change in anhedonia in patients with major depressive disorder and bipolar disorder following treatment with ketamine. Reduced anhedonia correlated with increased glucose metabolism in the hippocampus and dorsal anterior cingulate cortex (dACC) and decreased metabolism in the inferior frontal gyrus and orbitofrontal cortex (OFC). In addition to alleviating overall depressive symptoms, ketamine could possess anti-anhedonic potential in major depressive disorder, which speculatively, may be mediated by alterations in metabolic activity in the hippocampus, dACC and OFC. 4. Ketamine produces rapid antisuicidal effects within hours and lasts at least one week following a single infusion. 5. We identified the neural correlates of change in suicidal thoughts in patients with major depressive disorder and bipolar disorder following treatment with ketamine. Reductions in suicidal ideation after ketamine infusion were correlated with decreased regional cerebral glucose metabolism in the infralimbic cortex.