【摘要】 重性抑郁障碍（major depressive disorder,MDD）作为抑郁症最常见且典型的临床表现形式，是全球致残的主要原因之一，给社会与个体带来沉重负担。当前临床常用的抗抑郁药物普遍存在起效慢、应答率低及不良反应多等局限，亟需开发更安全、高效的创新疗法。在这一背景下，抗抑郁药物的研发历程经历了4代的演进。第1代药物为单胺氧化酶抑制剂（monoamine oxidase inhibitor,MAOI）和三环类抗抑郁药（tricyclic antidepressant,TCA），此类药物虽具开创性，但因严重的不良反应而临床应用受限。为提升安全性，以选择性5-羟色胺再摄取抑制剂（selective serotonin reuptake inhibitor,SSRI）、5-羟色胺与去甲肾上腺素再摄取抑制剂（serotonin and norepinephrine reuptake inhibitor,SNRI）及去甲肾上腺素与多巴胺再摄取抑制剂（norepinephrine and dopamine reuptake inhibitor,NDRI）为代表的第2代药物应运而生，但仍面临响应不足和性功能障碍等挑战。在此基础上，以基于单胺再摄取抑制与受体调节的多模式抗抑郁药物及5-羟色胺、去甲肾上腺素与多巴胺再摄取抑制剂（serotonin, norepinephrine and dopamine reuptake inhibitor,SNDRI）为代表的第3代药物，在改善快感缺失、认知功能障碍等核心症状和加速起效方面显示出一定优势。近年来，研究突破催生了基于新机制的第4代药物。其中，作用于谷氨酸能系统的艾司氯胺酮、AXS-05与作用于γ-氨基丁酸能系统的祖拉诺龙展现出快速、良好的抗抑郁效果，有效满足了快速缓解症状、降低自杀风险的迫切临床需求。系统回顾了抗抑郁药物自偶然发现到合理设计，乃至超越单胺假说的迭代发展历程，深入剖析了各代药物的研发背景、作用机制、临床优势与局限，旨在为新型药物的研发提供参考与启示。更多还原

【Abstract】 Major depressive disorder(MDD), as the most common and typical clinical manifestation of depression, is one of the leading causes of disability worldwide, imposing a significant burden on both society and individuals. Currently, commonly used antidepressants in clinical practice are characterized by limitations such as slow onset of action, low response rates, and numerous adverse effects, underscoring an urgent need for the development of safer and more effective innovative therapies. Against this backdrop, the research and development of antidepressants have undergone four generations of evolution. The first-generation drugs includes monoamine oxidase inhibitors(MAOIs) and tricyclic antidepressants(TCAs). While these drugs were groundbreaking, their clinical application has been limited due to severe adverse effects. To enhance safety, the second generation of drugs emerged, represented by selective serotonin reuptake inhibitors(SSRIs), serotonin and norepinephrine reuptake inhibitors(SNRIs), and norepinephrine and dopamine reuptake inhibitors(NDRIs). However, these drugs still face challenges such as inadequate response and sexual dysfunction. Building on this, the thirdgeneration drugs, characterized by multimodal antidepressants that combine monoamine reuptake inhibition with receptor modulation, as well as serotonin, norepinephrine, and dopamine reuptake inhibitors(SNDRIs), have shown certain advantages in improving core symptoms such as anhedonia and cognitive dysfunction, and accelerating onset of action. In recent years, research breakthroughs have given rise to the fourth-generation drugs based on novel mechanisms. Among these, esketamine and AXS-05, which act on the glutamatergic system, and zuranolone, which targets the GABAergic system, have demonstrated rapid and robust antidepressant effects, effectively addressing the urgent clinical need for rapid symptom relief and reduction of suicide risk. This review systematically traces the iterative development of antidepressant drugs, from serendipitous discovery to rational design and beyond the monoamine hypothesis. It provides an thoroughly analysis of the R&D background, mechanisms of action, clinical advantages, and limitations of each generation of drugs, aiming to provide references and insights for the development of novel drugs.更多还原