How a failed antipsychotic became the world's first tricyclic antidepressant

Health · Published 3 October 2026 Swipe more like this →

In short: Originally synthesized in 1951 as a potential antihistamine, imipramine was later tested as an antipsychotic for schizophrenia. It failed that role, but a serendipitous observation of a depressed patient changed everything. Today, this tricyclic antidepressant remains a potent, if complex, tool in modern psychopharmacology and veterinary medicine.

Imipramine, marketed as Tofranil, represents a turning point in medical history. After its initial synthesis in 1951, clinicians attempted to use it to treat psychosis, but it proved ineffective. However, in the mid-1950s, researchers noticed that patients with severe depression showed remarkable improvement while taking the drug. This discovery, occurring around the same time as the emergence of monoamine oxidase inhibitors, helped establish the use of monoaminergic drugs to treat depression. By 1958, it was introduced in Europe, followed by the United States in 1959.

The drug functions by increasing levels of serotonin and norepinephrine while blocking various receptors, including those for histamine and acetylcholine. This broad mechanism makes it highly effective, even for treatment-resistant depression, though it comes with a challenging side-effect profile. Common issues include dry mouth, dizziness, and rapid heart rate. Because it can trigger manic episodes in patients with bipolar disorder, it requires careful clinical management. While newer selective serotonin reuptake inhibitors (SSRIs) have largely replaced it as a first-line treatment due to better tolerability, imipramine remains a vital second-line option.

Beyond psychiatry, imipramine has found diverse applications. It is used in pediatrics to treat nocturnal enuresis by altering sleep stages and has been employed for separation anxiety in dogs and cats. Recent research even suggests potential antiviral properties; studies have shown it can inhibit the feline infectious peritonitis virus by targeting host cholesterol metabolism. From its origins as a failed antipsychotic to its current role in treating everything from chronic pain to viral infections in animals, imipramine remains a uniquely versatile, if demanding, molecule.

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