Role of serendipity in the discovery of classical antidepressant drugs: Applying operational criteria and patterns of discovery

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

Figure 1

Diagram of the four patterns of serendipitous attribution in the discovery of pharmacological agents. ¹They usually, but not always, relate to findings in laboratory animals; ²Findings relating to clinical efficacy.

Figure 2

Historical process of the discovery of tricyclic antidepressants during the 1950s. TCAs: Tricyclic antidepressants.

Figure 3

Historical process of the discovery of monoamine oxidase inhibitors during the 1950s. APA: American Psychiatric Association; MAOI: Monoamine oxidase inhibitors.