What was the first antidepressant?

The First Antidepressant

Imipramine was the first tricyclic antidepressant, introduced in the 1950s alongside iproniazid (a monoamine oxidase inhibitor), marking the beginning of modern antidepressant therapy. 1, 2

Historical Development of Antidepressants

• Imipramine and iproniazid were both introduced clinically in the 1950s as the first specifically antidepressant medications 1
• Imipramine is designated as "5-3-(Dimethylamino) propyl-10,11-dihydro-5H dibenz ['b, f]-azepine monohydrochloride" and is the original tricyclic antidepressant 3
• Iproniazid was initially developed as an anti-tuberculosis drug before its antidepressant properties were discovered 4
• The discovery of these medications was largely serendipitous rather than through targeted drug development 2

Significance of Early Antidepressants

• These first antidepressants made two fundamental contributions to psychiatry:
  • A social-health transformation in psychiatric care for depressive patients 1
  • Providing essential research tools for neurobiology and psychopharmacology that led to the first etiological hypotheses of depression 1
• The discovery process involved unexpected observations:
  • Iproniazid's antidepressant effect was noticed when it produced psychostimulation as a side effect in tuberculosis patients 4
  • Imipramine was developed from antihistamines, similar to chlorpromazine (a neuroleptic), and its antidepressant effects were discovered through clinical observation 4

Evolution to Modern Antidepressants

• First-generation antidepressants (tricyclics and MAOIs) were eventually superseded by second-generation antidepressants due to safety concerns 5
• Second-generation antidepressants (including SSRIs, SNRIs, and SSNRIs) have similar efficacy to first-generation drugs but with lower toxicity in overdose 6
• The introduction of fluoxetine (a selective serotonin reuptake inhibitor) in the late 1980s revolutionized depression therapy, opening pathways for new antidepressant families 1

Mechanism of Action

• The discovery of imipramine and iproniazid led to the monoamine theories of depression in the 1960s 2
• Initially, noradrenaline was considered the more important neurotransmitter, but later research emphasized the role of serotonin 2
• All current antidepressants share a similar mechanism of action involving modulation of monoaminergic neurotransmission at the synaptic level 1

Clinical Implications

• Despite newer medications, the original tricyclic antidepressant imipramine remains in clinical use today, demonstrating its enduring efficacy 4
• The concept of an "antidepressant" as a disease-specific treatment emerged rapidly in the 1960s, though evidence for this specificity was limited at the time 7
• Modern antidepressant development continues to focus on improving side effect profiles while maintaining efficacy 8

Historical Context and Impact

• The adoption of antidepressants helped psychiatry integrate with general medicine and move treatment from asylums into community settings 7
• The pharmaceutical industry played a significant role in establishing antidepressants as disease-specific treatments to distinguish them from non-specific drugs 7
• The introduction of these medications fundamentally changed the understanding and treatment approach to depression 1

While both imipramine and iproniazid were introduced around the same time, imipramine is generally recognized as the original tricyclic antidepressant that established this important class of medications, while iproniazid represented the separate MAOI class 3, 1.