Dong Zhengchao, Grunebaum Michael F, Lan Martin J, Wagner Vashti, Choo Tse-Hwei, Milak Matthew S, Sobeih Tarek, Mann J John, Kantrowitz Joshua T
Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, United States.
Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, NY, United States.
Front Psychiatry. 2021 Jun 2;12:653026. doi: 10.3389/fpsyt.2021.653026. eCollection 2021.
N-methyl-D-aspartate glutamate-receptor (NMDAR) antagonists such as ketamine have demonstrated efficacy in both major depressive disorder (MDD) and bipolar disorder depression (BP-D). We have previously reported that reduction in Glx (glutamate + glutamine) in the ventromedial prefrontal cortex/anterior cingulate cortex (vmPFC/ACC), measured by proton magnetic resonance spectroscopy (H MRS) at 3T during a ketamine infusion, mediates the relationship of ketamine dose and blood level to improvement in depression. In the present study, we assessed the impact of D-cycloserine (DCS), an oral NMDAR antagonist combined with lurasidone in BP-D on both glutamate and Glx. Subjects with DSM-V BP-D-I/II and a Montgomery-Asberg Depression Rating Scale (MADRS) score>17, underwent up to three H MRS scans. During Scan 1, subjects were randomized to receive double-blind lurasidone 66 mg or placebo. During Scan 2, all subjects received single-blind DCS 950 mg + lurasidone 66 mg, followed by 4 weeks of open label phase of DCS+lurasidone and an optional Scan 3. Five subjects received lurasidone alone and three subjects received placebo for Scan 1. Six subjects received DCS+lurasidone during Scan 2. There was no significant baseline or between treatment-group differences in acute depression improvement or glutamate response. In Scan 2, after a dose of DCS+lurasidone, peak change in glutamate correlated negatively with improvement from baseline MADRS (r = -0.83, = 0.04). There were no unexpected adverse events. These preliminary pilot results require replication but provide further support for a link between antidepressant effect and a decrease in glutamate by the NMDAR antagonist class of antidepressants.
N-甲基-D-天冬氨酸谷氨酸受体（NMDAR）拮抗剂，如氯胺酮，已在重度抑郁症（MDD）和双相情感障碍抑郁发作（BP-D）中显示出疗效。我们之前报道过，在3T场强下进行氯胺酮输注期间，通过质子磁共振波谱（H MRS）测量发现，腹内侧前额叶皮质/前扣带回皮质（vmPFC/ACC）中Glx（谷氨酸+谷氨酰胺）的减少介导了氯胺酮剂量和血药浓度与抑郁改善之间的关系。在本研究中，我们评估了口服NMDAR拮抗剂D-环丝氨酸（DCS）联合鲁拉西酮治疗BP-D时对谷氨酸和Glx的影响。符合《精神疾病诊断与统计手册》第五版（DSM-V）BP-D-I/II标准且蒙哥马利-艾斯伯格抑郁量表（MADRS）评分>17的受试者接受了多达三次H MRS扫描。在扫描1期间，受试者被随机分为两组，分别接受双盲鲁拉西酮66 mg或安慰剂。在扫描2期间，所有受试者接受单盲DCS 950 mg +鲁拉西酮66 mg，随后是4周的DCS+鲁拉西酮开放标签治疗阶段，并可选择进行扫描3。5名受试者在扫描1时单独接受鲁拉西酮治疗，3名受试者接受安慰剂治疗。6名受试者在扫描2时接受DCS+鲁拉西酮治疗。在急性抑郁改善或谷氨酸反应方面，治疗组之间在基线时无显著差异。在扫描2中，给予DCS+鲁拉西酮一剂后，谷氨酸的峰值变化与基线MADRS评分的改善呈负相关（r = -0.83，P = 0.04）。未出现意外不良事件。这些初步的试验结果需要重复验证，但为NMDAR拮抗剂类抗抑郁药的抗抑郁作用与谷氨酸减少之间的联系提供了进一步支持。
