Department of Psychiatry, China Medical University Hospital, Taichung, Taiwan; Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
Biol Psychiatry. 2013 Nov 15;74(10):734-41. doi: 10.1016/j.biopsych.2013.02.020. Epub 2013 Apr 3.
Antidepressants, aiming at monoaminergic neurotransmission, exhibit delayed onset of action, limited efficacy, and poor compliance. Glutamatergic neurotransmission is involved in depression. However, it is unclear whether enhancement of the N-methyl-D-aspartate (NMDA) subtype glutamate receptor can be a treatment for depression.
We studied sarcosine, a glycine transporter-I inhibitor that potentiates NMDA function, in animal models and in depressed patients. We investigated its effects in forced swim test, tail suspension test, elevated plus maze test, novelty-suppressed feeding test, and chronic unpredictable stress test in rats and conducted a 6-week randomized, double-blinded, citalopram-controlled trial in 40 patients with major depressive disorder. Clinical efficacy and side effects were assessed biweekly, with the main outcomes of Hamilton Depression Rating Scale, Global Assessment of Function, and remission rate. The time course of response and dropout rates was also compared.
Sarcosine decreased immobility in the forced swim test and tail suspension test, reduced the latency to feed in the novelty-suppressed feeding test, and reversed behavioral deficits caused by chronic unpredictable stress test, which are characteristics for an antidepressant. In the clinical study, sarcosine substantially improved scores of Hamilton Depression Rating Scale, Clinical Global Impression, and Global Assessment of Function more than citalopram treatment. Sarcosine-treated patients were much more likely and quicker to remit and less likely to drop out. Sarcosine was well tolerated without significant side effects.
Our preliminary findings suggest that enhancing NMDA function can improve depression-like behaviors in rodent models and in human depression. Establishment of glycine transporter-I inhibition as a novel treatment for depression waits for confirmation by further proof-of-principle studies.
旨在影响单胺能神经递质传递的抗抑郁药起效慢、疗效有限且顺应性差。谷氨酸能神经传递与抑郁有关。然而，增强 N-甲基-D-天冬氨酸（NMDA）型谷氨酸受体是否可以作为一种治疗抑郁症的方法尚不清楚。
我们研究了肌氨酸，一种增强 NMDA 功能的甘氨酸转运蛋白-1 抑制剂，在动物模型和抑郁症患者中进行了研究。我们在大鼠中进行了强迫游泳试验、悬尾试验、高架十字迷宫试验、新异环境摄食试验和慢性不可预测应激试验，以及在 40 例重性抑郁障碍患者中进行了为期 6 周的随机、双盲、西酞普兰对照试验。每两周评估一次临床疗效和副作用，主要结局为汉密尔顿抑郁量表、总体功能评估和缓解率。还比较了反应时间和脱落率。
肌氨酸可减少强迫游泳试验和悬尾试验中的不动时间，减少新异环境摄食试验中的摄食潜伏期，并逆转慢性不可预测应激试验引起的行为缺陷，这些都是抗抑郁药的特征。在临床研究中，肌氨酸治疗显著改善了汉密尔顿抑郁量表、临床总体印象和总体功能评估的评分，优于西酞普兰治疗。肌氨酸治疗的患者更有可能和更快地缓解，且不太可能脱落。肌氨酸耐受性良好，无明显副作用。
我们的初步发现表明，增强 NMDA 功能可以改善啮齿动物模型和人类抑郁症中的抑郁样行为。进一步的原理验证研究有待证实甘氨酸转运蛋白-1 抑制作为一种新的抑郁症治疗方法的确立。
