Efficacy of an Antiglutamatergic Agents in Treatment-Resistant Depression

迫切需要新的目标来开发治疗难治性重度抑郁症的新疗法。谷氨酸能系统是开发更好的情绪障碍治疗方法的重要目标。在以前的工作中，我们发现谷氨酸调节剂利鲁唑(谷氨酸释放的抑制剂，AMPA转运和谷氨酸重摄取的促进剂)对治疗难治性单相和双相抑郁有效。这些数据表明，谷氨酸能系统可能在抑郁症的病理生理和治疗中发挥关键作用，调节这一神经递质系统的药物可能代表着一类新的抗抑郁药物。 我们研究了42名TRD患者(18-65岁)，MADRS评分为22分，单次静脉滴注氯胺酮(0.5 mg/kg)。在输液后4至6小时，受试者被随机分成两组，分别服用利鲁唑(100-200 mg/天；n=21)或安慰剂(n=21)，为期4周。每天对抑郁症状进行评级。MADRS评分较基线有显著改善(P&lt；0.001)。氯胺酮的改善作用最初很大，在28天的试验中一直保持中等水平。总体而言，27%的氯胺酮应答者在单次注射氯胺酮后4周内没有复发。平均复发时间为13.2天。然而，利鲁唑组和安慰剂治疗组之间的差异并不显著，这表明利鲁唑与氯胺酮联合治疗并不会显著改变单独使用氯胺酮的抗抑郁反应过程。我们继续招募受试者，寻找治疗反应的生物标记物。初步数据表明，a)有酒精使用障碍家族史的人比没有酒精使用障碍家族史的人对氯胺酮的抗抑郁反应更好，以及b)有焦虑性抑郁症的人比没有焦虑抑郁的人对氯胺酮的抗抑郁反应更好。研究正在检查遗传学、氯胺酮代谢物和其他可能与治疗反应相关的生物标志物。确定反应的生物标志物最终将促进药物的发现和开发，并使治疗干预措施个体化或个人化。

Novel targets for developing new treatments for treatment-resistant major depression are urgently needed. The glutamatergic system stands as an important to target to pursue in the developing improved treatments for mood disorders. In previous work, we found that the glutamate modulating agent riluzole (inhibitor of glutamate release, and enhancer of AMPA trafficking and glutamate reuptake) was effective in treatment-resistant unipolar and bipolar depression. These data suggest that the glutamatergic system might have a key role in the pathophysiology and treatment of depression, and that agents which modulate this neurotransmitter system, may represent a novel class of antidepressants. We studied 42 subjects (18-65) with TRD and a MADRS score of 22 received a single intravenous infusion of ketamine (0.5 mg/kg). Four to six hours post-infusion, subjects were randomized to double-blind treatment with either riluzole (100-200 mg/day; n=21) or placebo (n=21) for 4 weeks. Depressive symptoms were rated daily. A significant improvement (P<0.001) in MADRS scores from baseline was found. The effect size of improvement with ketamine was initially large and remained moderate throughout the 28-day trial. Overall, 27% of ketamine responders had not relapsed by 4 weeks following a single ketamine infusion. The average time to relapse was 13.2 days. However, the difference between the riluzole and placebo treatment groups was not significant, suggesting that the combination of riluzole with ketamine treatment did not significantly alter the course of antidepressant response to ketamine alone. We have continued to enroll subjects in the search of biomarkers of treatment response. Preliminary data indicates that subjects with a) family history of alcohol use disorders have a better antidepressant response to ketamine than subjects without a family history of alcohol use disorders, and b) subjects with anxious depression have a better antidepressant response to ketamine than subjects without anxious depression. Studies are examining genetics, ketamine metabolites, and other biomarkers that might be associated with treatment response. Identifying biomarkers of response would ultimately facilitate drug discovery and development and to individualize or personalize treatment interventions.