Did Serendipity Contribute to the Discovery of New Antidepressant Drugs? Historical Analysis Using Operational Criteria.

Objective: 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.

Methods: 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.

Results: 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).

Conclusion: 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).