Selective serotonin reuptake inhibitor

The selective serotonin reuptake inhibitor (SSRI) emerged when the FDA approved fluoxetine in December 1987, ushering in what historians call 'the antidepressant era.' Developed at Eli Lilly under the internal name 'Lilly 110140' and marketed as Prozac, the drug offered a new approach to depression with fewer side effects than tricyclic antidepressants or MAO inhibitors. By the end of 1989, Prozac was the world's most widely prescribed antidepressant.

The adjacent possible opened through 1960s neuroscience. Researchers had established that serotonin—one of the brain's chemical messengers—played a role in mood regulation. The serotonin hypothesis of depression suggested that low serotonin levels contributed to depressive symptoms. Earlier antidepressants affected multiple neurotransmitter systems, causing side effects. The question was whether a drug targeting only serotonin reuptake could be both effective and tolerable.

Work at Eli Lilly began in 1970 as a collaboration between Bryan Molloy and Ray Fuller. David T. Wong joined the team and proposed testing their compounds specifically for serotonin reuptake inhibition using techniques developed by neuroscientist Solomon Snyder. In 1972, Wong, Fuller, Molloy, and Klaus Schmiegel identified fluoxetine as the most potent and selective serotonin reuptake inhibitor in their series.

The path from laboratory discovery to pharmacy shelves took fifteen years. Eli Lilly renamed the compound 'fluoxetine' in 1975 and filed an Investigational New Drug application in February 1977. Belgium approved the drug in 1986. FDA approval came in December 1987, with the US launch in January 1988 under the brand name Prozac.

The cultural cascade from Prozac reshaped how society understood mental illness. Peter Kramer's 1993 book 'Listening to Prozac' explored how the drug seemed to give patients 'better than well' personalities. Direct-to-consumer pharmaceutical advertising, which became legal in the US in 1997, featured antidepressants prominently. The stigma around depression treatment—while not eliminated—diminished as millions openly took SSRIs.

The scientific cascade produced new drug variants. Zoloft (sertraline), Paxil (paroxetine), Celexa (citalopram), and Lexapro (escitalopram) followed, each with slightly different profiles. SSRIs expanded beyond depression to treat anxiety disorders, OCD, panic disorder, and bulimia. By 2024, antidepressants were among the most commonly prescribed medications worldwide.

The SSRI story illustrates pharmaceutical development's long timelines: from 1970s research through 1987 approval to 1990s cultural transformation. Wong, Fuller, and their colleagues at Eli Lilly in Indianapolis created a drug class that changed how humanity treats mental illness.