Farber Nuri B
Residency Training, Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, USA.
Handb Exp Pharmacol. 2019;250:287-305. doi: 10.1007/164_2018_165.
Fifteen to thirty percent of patients with major depressive disorder do not respond to antidepressants that target the monoaminergic systems. NMDA antagonists are currently being actively investigated as a treatment for these patients. Ketamine is the most widely studied of the compounds. A brief infusion of a low dose of this agent produces rapid improvement in depressive symptoms that lasts for several days. The improvement occurs after the agent has produced its well characterized psychotomimetic and cognitive side effects. Multiple infusions of the agent (e.g., 2-3× per week for several weeks) provide relief from depressive symptoms, but the symptoms reoccur once the treatment has been stopped. A 96-h infusion of a higher dose using add-on clonidine to mitigate the psychotomimetic effects appears to also provide relief and resulted in about 40% of the subjects still having a good response 8 weeks after the infusion. As this was a pilot study, additional work is needed to confirm and extend this finding. Nitrous oxide also has had positive results. Of the other investigational agents, CERC-301 and rapastinel remain in clinical development. When careful monitoring of neuropsychiatric symptoms has been conducted, these agents all produce similar side effects in the same dose range, indicating that NMDA receptor blockade produces both the wanted and unwanted effects. Research is still needed to determine the appropriate dose, schedule, and ways to mitigate against unwanted side effects of NMDA receptor blockade. These hurdles need to be overcome before ketamine and similar agents can be prescribed routinely to patients.
15%至30%的重度抑郁症患者对靶向单胺能系统的抗抑郁药无反应。目前，N-甲基-D-天冬氨酸（NMDA）拮抗剂正作为这些患者的一种治疗方法而被积极研究。氯胺酮是这类化合物中研究最为广泛的。短暂输注低剂量的该药物能使抑郁症状迅速改善，并持续数天。这种改善在该药物产生其典型的拟精神病性和认知副作用之后出现。多次输注该药物（例如，每周2 - 3次，持续数周）可缓解抑郁症状，但一旦停止治疗，症状会再次出现。使用可乐定作为附加药物以减轻拟精神病性效应，进行96小时的高剂量输注似乎也能缓解症状，并且在输注8周后约40%的受试者仍有良好反应。由于这是一项初步研究，需要更多工作来证实和扩展这一发现。一氧化二氮也取得了积极成果。在其他研究药物中，CERC - 301和rapastinel仍处于临床开发阶段。当对神经精神症状进行仔细监测时，这些药物在相同剂量范围内都会产生相似的副作用，这表明NMDA受体阻断会产生预期和非预期的效果。仍需开展研究以确定合适的剂量、给药方案以及减轻NMDA受体阻断非预期副作用的方法。在氯胺酮及类似药物能够常规开给患者之前，这些障碍需要被克服。
