Department of Neurobiology, Maj Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.
Drug Management Department, Institute of Public Health, Faculty of Health Sciences, Jagiellonian University, Krakow, Poland.
Expert Opin Drug Discov. 2022 Oct;17(10):1131-1146. doi: 10.1080/17460441.2022.2111415. Epub 2022 Aug 22.
Major depressive disorder remains a prevalent world-wide health problem. Currently available antidepressant medications take weeks of dosing, do not produce antidepressant response in all patients, and have undesirable ancillary effects.
The present opinion piece focuses on the major inroads to the creation of new antidepressants. These include N-methyl-D-aspartate (NMDA) receptor antagonists and related compounds like ketamine, psychedelic drugs like psilocybin, and muscarinic receptor antagonists like scopolamine. The preclinical and clinical pharmacological profile of these new-age antidepressant drugs is discussed.
Preclinical and clinical data have accumulated to predict a next generation of antidepressant medicines. In contrast to the current standard of care antidepressant drugs, these compounds differ in that they demonstrate rapid activity, often after a single dose, and effects that outlive their presence in brain. These compounds also can provide efficacy for treatment-resistant depressed patients. The mechanism of action of these compounds suggests a strong glutamatergic component that involves the facilitation of AMPA receptor function. Antagonism of mGlu2/3 receptors is also relevant to the antidepressant pharmacology of this new class of drugs. Based upon the ongoing efforts to develop these new-age antidepressants, new drug approvals are predicted in the near future.
重度抑郁症仍然是一个普遍存在的全球性健康问题。目前可用的抗抑郁药物需要数周的剂量，并非对所有患者都能产生抗抑郁反应，并且具有不良的辅助作用。
本专题文章重点介绍了开发新型抗抑郁药的主要进展。这些包括 N-甲基-D-天冬氨酸（NMDA）受体拮抗剂和相关化合物，如氯胺酮、迷幻药如裸盖菇素，以及毒蕈碱受体拮抗剂如东莨菪碱。讨论了这些新型抗抑郁药物的临床前和临床药理学特征。
已经积累了临床前和临床数据来预测下一代抗抑郁药物。与当前的标准抗抑郁药物治疗相比，这些化合物的不同之处在于它们表现出快速的活性，通常在单次给药后，并且其作用持续时间超过其在大脑中的存在时间。这些化合物还可以为治疗抵抗的抑郁患者提供疗效。这些化合物的作用机制表明存在强烈的谷氨酸能成分，涉及 AMPA 受体功能的促进。mGlu2/3 受体拮抗剂也与这一新类药物的抗抑郁药理学相关。基于开发这些新型抗抑郁药的持续努力，预计在不久的将来会有新的药物批准。
