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

Table 1 Classification of classical monoaminergic antidepressants according to action mechanism and historical perspective on their clinical introduction

Family	Mechanisms of action	Acronym	Prototype substance	Period
Tricyclic antidepressants	5-HT and NA reuptake inhibitors with blocking action of diverse receptors	TCA	Imipramine	1957-1980
Monoamine oxidase inhibitors	Irreversible MAO inhibitors	MAOI	Phenelzine	1958-1965
Heterocyclic or “second generation” antidepressants	NA reuptake inhibitors with blocking action of diverse receptors		Maprotiline	1967-1980
	Antagonists of α2 auto-receptors		Mianserin	1970-1980
	DA and NA reuptake inhibitors		Nomifensine	1970-1980
	5-HT reuptake inhibitor and antagonist of 5-HT2 receptors		Trazodone	1970-1980

5-HT: Serotonin; NA: Norepinephrine; DA: Dopamine; TCAs: Tricyclic antidepressants; MAOIs: Monoamine oxidase inhibitors.

Table 2 Attribution of serendipity in the discovery of classical antidepressant drugs

Group/Family	Drug	ATC code	Date of discovery (psychiatric introduction)	Effect/primary properties1	Effect/secondary properties2	Pattern of discovery
TCAs	Imipramine	N06AA02	1951 (1957)	S	NS	II
	Amitriptyline	N06AA09	1958 (1961)	NS	NS	IV
	Trimipramine	N06AA06	1964 (1966)	NS	NS	IV
	Butriptyline	N06AA15	1964	NS	NS	IV
	Desipramine	N06AA01	1964	NS	NS	IV
	Clomipramine	N06AA04	1963 (1970)	NS	NS	IV
	Nortriptyline	N06AA10	1963 (1967)	NS	NS	IV
	Protriptyline	N06AA11	1967	NS	NS	IV
	Iprindole	N06AA13	1967	NS	NS	IV
	Doxepin	N06AA12	1969	NS	NS	IV
	Dibenzepin	N06AA08	1970	NS	NS	IV
	Maprotiline3	N06AA21	1967 (1973)	NS	NS	IV
	Dosulepin	N06AA16	1977	NS	NS	IV
	Amineptine	N06AA19	1978	NS	NS	IV
	Amoxapine	N06AA17	1980	NS	NS	IV
	Quinupramine	N06AA23	1983	NS	NS	IV
	Lofepramine	N06AA07	1989	NS	NS	IV
MAOI	Iproniazid	N06AF05	1952 (1957)	S	NS	II
	Isocarboxazid	N06AF01	1959	NS	NS	IV
	Phenelzine	N06AF03	1960	NS	NS	IV
	Tranylcypromine	N06AF04	1961	NS	NS	IV
	Nialamide	N06AF02	1988	NS	NS	IV
OCA	Trazodone	N06AX05	1966 (1973)	NS	NS	IV
	Nomifensine	N06AX04	1977	NS	NS	IV
	Mianserin	N06AX03	1966 (1979)	S	NS	II

¹Usually, but not always, correspond to discoveries in laboratory animals.

²Discoveries related to clinical efficacy.

³Maprotiline is the first tetracyclic antidepressant and is included in the group of “second generation antidepressants.” Antidepressant drugs were classified by the Anatomical Therapeutic Chemical classification system controlled by the World Health Organization Collaborating Centre for Drugs Statistics Methodology. This system classifies the active ingredient of a drug into groups according to the organ or system on which they have their effect. https://www.whocc.no/atc_ddd_index/?code=N06AX&showdescription=no.

NS: Non-serendipitous discovery; S: Serendipitous discovery; TCAs: Tricyclic antidepressants; MAOIs: Monoamine oxidase inhibitors; OCA: Other classical antidepressants; ATC: Anatomical Therapeutic Chemical.