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World J Psychiatry. Apr 19, 2022; 12(4): 588-602
Published online Apr 19, 2022. doi: 10.5498/wjp.v12.i4.588
Role of serendipity in the discovery of classical antidepressant drugs: Applying operational criteria and patterns of discovery
Francisco López-Muñoz, Pilar D’Ocón, Alejandro Romero, José A Guerra, Cecilio Álamo
Francisco López-Muñoz, Faculty of Health, University Camilo José Cela, Villanueva de la Cañada 28692, Madrid, Spain
Francisco López-Muñoz, “Hospital 12 de Octubre” Research Institute (i+12), Avda. de Córdoba, s/n, Madrid 28041, Spain
Pilar D’Ocón, Department of Pharmacology, Faculty of Pharmacy, University of Valencia, Avda. Vicent Andres Estelles, s/n, Valencia 46100, Spain
Alejandro Romero, Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Complutense University, Avda. Puerta de Hierro, s/n, Madrid 28040, Spain
José A Guerra, Department of Pharmacology and Toxicology, Faculty of Pharmacy, Complutense University, Pl. de Ramón y Cajal, s/n, Madrid 28040, Spain
Cecilio Álamo, Department of Biomedical Sciences (Pharmacology Area), Faculty of Medicine and Health Sciences, University of Alcalá, Campus Científico-Tecnológico, Crta. de Madrid-Barcelona, Alcalá de Henares 28871, Madrid, Spain
Author contributions: All authors have contributed to this work; López-Muñoz F and Álamo C designed the study; López-Muñoz F and Guerra JA analyzed the data; López-Muñoz F, D’Ocón P and Romero A wrote the manuscript; López-Muñoz F approved the final manuscript; all authors reviewed and approved the final draft.
Conflict-of-interest statement: Nothing to disclosed.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Francisco López-Muñoz, MD, PhD, Chief Doctor, Dean, Director, Faculty of Health, University Camilo José Cela, C/ Castillo de Alarcón 49, Villanueva de la Cañada 28692, Madrid, Spain. flopez@ucjc.edu
Received: September 6, 2021
Peer-review started: September 6, 2021
First decision: November 8, 2021
Revised: November 22, 2021
Accepted: March 14, 2022
Article in press: March 14, 2022
Published online: April 19, 2022
Processing time: 218 Days and 15.1 Hours
Abstract

The role played by serendipity in the origin of modern psychopharmacology has proven to be controversial in scientific literature. In its original meaning (Walpole), serendipity refers to discoveries made through a combination of accidents and sagacity. We have implemented an operational definition of serendipity based on finding something unexpected or unintended, regardless of the systematic process that led to the accidental observation, and we have established four different patterns of serendipitous attributability. In this paper, we have analyzed the role of serendipity in the discovery and development of classical antidepressant drugs, tricyclic antidepressants and monoamine oxidase inhibitors as well as heterocyclic, “atypical” or “second generation” antidepressants. The discovery of the antidepressant properties of imipramine and iproniazid, the prototypes of tricyclic antidepressants and monoamine oxidase inhibitors, respectively, fits the mixed type II pattern; initial serendipitous discoveries (imipramine was an antipsychotic and iproniazid was an anti-tuberculosis agent) led secondarily to non-serendipitous discoveries. But the other components of these two families of drugs were developed specifically as antidepressants, modifying the chemical structure of the series leaders, thereby allowing all of them to be included in the type IV pattern, characterized by the complete absence of serendipity. Among the heterocyclic drugs, mianserin (originally developed as an antihistamine) also falls into the type II pattern.

Keywords: Serendipity; Antidepressants; Imipramine; Iproniazid; Psychopharmacology; History of neurosciences

Core Tip: In this paper, we have analyzed, for the first time, the role of serendipity in the discovery and development of classical antidepressant drugs through our operational definition of serendipity. We have assigned each of the classic antidepressants its corresponding pattern of serendipitous attributability according to four different patterns.