History of

Fluoxetine

The work which eventually led to the discovery of fluoxetine began at Eli Lilly and Company in 1970
as a collaboration between Bryan Molloy and Ray Fuller.[142] It was known at that time that
the antihistamine diphenhydramine showed some antidepressant-like properties. 3-Phenoxy-3-
phenylpropylamine, a compound structurally similar to diphenhydramine, was taken as a starting
point. Molloy and fellow Eli Lilly chemist Klaus Schmiegel synthesized a series of dozens of its
derivatives.[143][144] Hoping to find a derivative inhibiting only serotonin reuptake, another Eli Lilly
scientist, David T. Wong, proposed to retest the series for the in vitro reuptake of serotonin,
norepinephrine and dopamine, using a technique developed by neuroscientist Solomon Snyder.
[142]
This test showed the compound later named fluoxetine to be the most potent and selective
inhibitor of serotonin reuptake of the series.[145] The first article about fluoxetine was published in
1974.[145] A year later, it was given the official chemical name fluoxetine and the Eli Lilly and Company
gave it the brand name Prozac. In February 1977, Dista Products Company, a division of Eli Lilly &
Company, filed an Investigational New Drug application to the U.S. Food and Drug
Administration (FDA) for fluoxetine.[146]
Fluoxetine appeared on the Belgian market in 1986.[147] In the U.S., the FDA gave its final approval in
December 1987,[148] and a month later Eli Lilly began marketing Prozac; annual sales in the U.S.
reached $350 million within a year.[146] Worldwide sales eventually reached a peak of $2.6 billion a
year.[149]
Lilly tried several product line extension strategies, including extended release formulations and
paying for clinical trials to test the efficacy and safety of fluoxetine in premenstrual dysphoric
disorder and rebranding fluoxetine for that indication as "Sarafem" after it was approved by the FDA
in 2000, following the recommendation of an advisory committee in 1999. [150][151][152] The invention of
using fluoxetine to treat PMDD was made by Richard Wurtman at MIT; the patent was licensed to
his startup, Interneuron, which in turn sold it to Lilly.[153]
To defend its Prozac revenue from generic competition, Lilly also fought a five-year, multimillion-
dollar battle in court with the generic company Barr Pharmaceuticals to protect its patents on
fluoxetine, and lost the cases for its line-extension patents, other than those for Sarafem, opening
fluoxetine to generic manufacturers starting in 2001.[154] When Lilly's patent expired in August 2001,
[155]
generic drug competition decreased Lilly's sales of fluoxetine by 70% within two months.[150]
In 2000 an investment bank had projected that annual sales of Sarafem could reach $250M/year.
[156]
Sales of Sarafem reached about $85M/year in 2002, and in that year Lilly sold its assets
connected with the drug for $295M to Galen Holdings, a small Irish pharmaceutical company
specializing in dermatology and women's health that had a sales force tasked to gynecologists'
offices; analysts found the deal sensible since the annual sales of Sarafem made a material financial
difference to Galen, but not to Lilly.[157][158]
Bringing Sarafem to market harmed Lilly's reputation in some quarters. The diagnostic category of
PMDD was controversial since it was first proposed in 1987, and Lilly's role in retaining it in the
appendix of the DSM-IV-TR, the discussions for which got under way in 1998, has been criticized.
[156]
Lilly was criticized for inventing a disease in order to make money,[156] and for not innovating but
rather just seeking ways to continue making money from existing drugs.[159] It was also criticized by
the FDA and groups concerned with women's health for marketing Sarafem too aggressively when it
was first launched; the campaign included a television commercial featuring a harried woman at the
grocery store who asks herself if she has PMDD.