López-Muñoz Francisco, D'Ocón Pilar, Romero Alejandro, De Berardis Domenico, Álamo Cecilio
Faculty of Health Sciences - HM Hospitals, University Camilo José Cela, 28692 Madrid, Spain.
HM Hospitals Health Research Institute, 28015 Madrid, Spain.
Alpha Psychiatry. 2025 Apr 28;26(2):40037. doi: 10.31083/AP40037. eCollection 2025 Apr.
Given their great importance, as one of the most prescribed types of therapeutic drugs worldwide, we have analyzed the role of serendipity in the discovery of new antidepressants, ranging from selective serotonin reuptake inhibitors to more contemporary developments.
We carried out a historical analysis of the discovery of new antidepressants, resorting to the original articles published on their development (initial pharmacological and clinical information) and applied an operational criterion of serendipity developed by our group.
Selective serotonin reuptake inhibitors (fluoxetine, fluvoxamine, citalopram, paroxetine, sertraline, and escitalopram), selective dopamine and noradrenaline reuptake inhibitors (bupropion), noradrenaline and serotonin reuptake inhibitors (venlafaxine, milnacipram, duloxetine, and desvenlafaxine), selective noradrenaline reuptake inhibitors (reboxetine), noradrenergic and specific serotonergic antidepressants (mirtazapine), melatonergic agonists (agomelatine), and serotonin modulators and stimulators (vortioxetine, vilazodone, tianeptine) correspond to the type IV pattern. Moclobemide, a reversible monoamine oxidase inhibitor, corresponds to the type II pattern, for which the initial serendipitous findings (i.e., the chance discovery of the inhibitory effects of monoamine oxidase (MAO) whilst being studied for their antihyperlipidemic properties) led to subsequent non-serendipitous discoveries (clinical antidepressant efficacy). Ketamine, a glutamatergic modulator, corresponds to the type III pattern, characterized by a non-serendipitous origin (initial development as an anesthetic agent) leading to a serendipitous observation (the discovery of antidepressant efficacy in individuals illicitly using).
The majority of new antidepressants adhere to a type IV pattern, characterized by a rational and targeted design process where serendipity played no part, except moclobemide (type II pattern) and ketamine (type III pattern).
鉴于其重要性，作为全球处方量最大的治疗药物类型之一，我们分析了意外发现（从选择性5-羟色胺再摄取抑制剂到更现代的药物进展）在新型抗抑郁药发现过程中的作用。
我们对新型抗抑郁药的发现进行了历史分析，参考了关于其研发的原始文章（初始药理学和临床信息），并应用了我们团队制定的意外发现操作标准。
选择性5-羟色胺再摄取抑制剂（氟西汀、氟伏沙明、西酞普兰、帕罗西汀、舍曲林和艾司西酞普兰）、选择性多巴胺和去甲肾上腺素再摄取抑制剂（安非他酮）、去甲肾上腺素和5-羟色胺再摄取抑制剂（文拉法辛、米那普明、度洛西汀和去甲文拉法辛）、选择性去甲肾上腺素再摄取抑制剂（瑞波西汀）、去甲肾上腺素能和特异性5-羟色胺能抗抑郁药（米氮平）褪黑素能激动剂（阿戈美拉汀）以及5-羟色胺调节剂和刺激剂（伏硫西汀、维拉唑酮、噻奈普汀）符合IV型模式。吗氯贝胺，一种可逆性单胺氧化酶抑制剂，符合II型模式，其最初的意外发现（即在研究其抗高脂血症特性时偶然发现单胺氧化酶（MAO）的抑制作用）导致了后续的非意外发现（临床抗抑郁疗效）。氯胺酮，一种谷氨酸能调节剂，符合III型模式，其特点是起源并非意外（最初作为麻醉剂研发），却导致了意外观察结果（在非法使用氯胺酮的个体中发现抗抑郁疗效）。
除吗氯贝胺（II型模式）和氯胺酮（III型模式）外，大多数新型抗抑郁药符合IV型模式，其特点是设计过程合理且目标明确，意外发现未起到作用。
