Fluoxetine - History

History

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 Robert Rathbun. It was known at that time that the antihistamine diphenhydramine shows some antidepressant-like properties. 3-Phenoxy-3-phenylpropylamine, a compound structurally similar to diphenhydramine, was taken as a starting point, and Molloy synthesized dozens of its derivatives. Testing the physiological effects of these compounds in mice resulted in nisoxetine, a selective norepinephrine reuptake inhibitor currently widely used in biochemical experiments.

Later, 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. This test, carried out by Jong-Sir Horng in May 1972, showed the compound later named fluoxetine to be the most potent and selective inhibitor of serotonin reuptake of the series. Wong published the first article about fluoxetine in 1974. A year later, it was given the official chemical name fluoxetine and the Eli Lilly and Company gave it the trade name Prozac. In February 1977, Dista Products Company, a division of Eli Lilly & Company, presented a new drug request to the U.S. Food and Drug Administration (FDA) for fluoxetine.

Fluoxetine appeared on the Belgian market in 1986. After over a decade, the FDA gave its final approval in December 1987, and a month later Eli Lilly began marketing Prozac; annual sales in the U.S. reached $350 million within a year.

In 1989, Joseph Wesbecker shot and killed eight people and injured 12 others before killing himself at his place of work in Kentucky. Wesbecker had been taking fluoxetine for four weeks before these homicides, and this led to a legal action against Eli Lilly. The case was tried and settled in 1994, and as part of the settlement a number of pharmaceutical company documents about drug-induced activation were released into the public domain. Subsequent legal cases have further raised the possibility of a link between antidepressant use and violence. The Prozac Survivors Support Group created a report on 288 individuals who had suffered adverse effects from Fluoxetine during 1991 and 1992. It showed that most of the cases led to violence against self or other individuals. There were 164 cases in the suicide and suicide ideation category, including 34 complete suicides. There were also 133 cases of crime and violence, which featured 14 murders, nine attempted murders, 39 violent actions, 54 violent preoccupations and 17 crimes. The report also showed that 13 individuals had become addicted to Fluoxetine and 14 cases of alcoholism forming or worsening. However, Mayo Clinic psychiatrist Daniel K. Hall-Flavin is of the opinion that people cannot get addicted to antidepressants, stating "Addiction represents harmful, long-term chemical changes in the brain. It's characterized by intense cravings and the inability to control your use of a substance.".

"...the efficacy of Prozac could not be distinguished from placebo in 6 out of 10 clinical trials (Moore, 1999)..."

A controversy ensued after Lilly researchers published a paper titled "Prozac (fluoxetine, Lilly 110140), the first selective serotonin uptake inhibitor and an antidepressant drug" claiming fluoxetine to be the first selective serotonin reuptake inhibitor (SSRI). Two years later they had to issue a correction, admitting that the first SSRI was zimelidine developed by Arvid Carlsson and colleagues.

Eli Lilly's U.S. patent on Prozac (fluoxetine) expired in August 2001, prompting an influx of generic drugs onto the market. Prozac was rebranded "Sarafem" for the treatment of PMDD in an attempt to stem the post-patent decrease in Eli Lilly's sales of fluoxetine.

A meta-analysis published in February 2008 combined 35 clinical trials of four newer antidepressants (fluoxetine, paroxetine (Paxil), nefazodone (Serzone) and venlafaxine (Effexor)). These antidepressants belonging to three different pharmacological groups were considered together, and the authors did not analyze them separately. The authors concluded that "although the difference easily attained statistical significance", it did not meet the criterion for clinical significance, as used by the UK's National Institute for Health and Clinical Excellence, "for any but the most severely depressed patients". Some articles in the press using the titles "The creation of the Prozac myth" and "Prozac does not work in majority of depressed patients" presented these general findings about the relative efficacy of antidepressants and placebo as the findings about ineffectiveness of fluoxetine. In a follow-up article, the authors of the meta-analysis noted that "unfortunately, during its initial coverage, the media often portrayed the results as “antidepressants do not work”, which misrepresented our more nuanced pattern of findings".

As of April 2, 2010, fluoxetine is one of four antidepressant drugs that the FAA allows pilots to take. The others are sertraline (Zoloft), citalopram (Celexa), and escitalopram (Lexapro).

There has been research on possible effects of fluoxetine on marine life.