The History of the Antidepressant Prozac

The drug has had its share of proponents and opponents

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Prozac is the registered trademarked name for fluoxetine hydrochloride, one of the world's most widely prescribed antidepressants. It was the first product in a major class of drugs for depression called selective serotonin reuptake inhibitors—or SSRIs. The drug's history dates to the early 1970s when the role of serotonin in depression began to emerge, according to David T. Wong, K.W. Perry, and F.P. Bymaster, in their September 2005 article, "The Discovery of Fluoxetine Hydrochloride (Prozac)," published in the journal Nature Reviews: Drug Discovery. They add:

"These studies led to the discovery and development of the selective serotonin-reuptake inhibitor fluoxetine hydrochloride (Prozac; Eli Lilly), which was approved for the treatment of depression by the U.S. FDA in 1987."

Prozac was first introduced to the U.S. market in January 1988 and gained its "most prescribed" status within two years.

The Invention of Prozac

The story of Prozac began when biochemist Ray W. Fuller came to work at Eli Lilly in 1963, according to the Science History Institute:

"In his research Fuller had used rats treated with chloroamphetamine, which inhibited the production of serotonin, to measure the effects of other drugs on serotonin levels. Fuller believed that this method would forward research on brain chemistry."

Two other scientists, Bryan Molloy and Wong—who coauthored the article previously mentioned in the introduction—joined Fuller in his work at Eli Lilly. In 1971 both Molloy and Wong attended a lecture on neurotransmission given by Solomon Snyder, a researcher from Johns Hopkins University, the institute notes. Snyder "had ground up rat brains, separated out the nerve endings, and created an extract of nerve endings that worked in the same way as living nerve cells."

Wong then used this technique to test the effects of various compounds, one of which was found to block the reuptake of serotonin with no side effects. The compound, fluoxetine, became the drug that was eventually named Prozac.

Interestingly, Eli Lilly first tested Prozac as a treatment for high blood pressure and then as "an anti-obesity agent," noted Anna Moore in a 2007 article in The Guardian, a British newspaper. Eventually, after further studies by Fuller, Malloy, and Wong, Eli Lilly sought and received FDA approval (in December 1987) and the next month began to market Prozac "as happiness in a blister pack," Moore noted.

Skyrocketing Sales

Sales of the drug took off: By the end of 1988, 2.5 million prescriptions for it were dispensed in America, according to Siddhartha Mukherjee in his article, "Post-Prozac Nation: The Science and History of Treating Depression," published in The New York Times Magazine in April 2002, a year when the number of Prozac prescriptions had risen to more than 33 million annually.

Though other antidepressants have taken over the top spots, Prozac was still the sixth-most popular such drug in the U.S. with 24.5 million annual prescriptions in 2015, according to Tim Hrenchir in his article, "10 Most-Prescribed Antidepressant Medications," published in July 2018 on NewsMax Health.

How It Works

Prozac works by increasing brain levels of serotonin, a neurotransmitter that is thought to influence sleep, appetite, aggression, and mood. Neurotransmitters are chemicals that carry messages between nerve cells. They’re secreted by one cell and picked up by receptor proteins on the surface of another. A neurotransmitter is either destroyed or retrieved into the cell that made it after the message has been delivered. This process is known as reuptake. 

The effect of serotonin is amplified when reuptake is inhibited. Although it's not entirely known why increasing neurotransmitter levels reduces the severity of a depression, it may be that increased levels of serotonin cause changes in the brain's concentration of neurotransmitter-binding receptors. This might make the brain physically more capable of feeling good.

Since it's introduction in the U.S., Prozac has met with mixed reviews by scientists, patients, and doctors, and has provoked its share of debate.

Controversy and Clinical Trials

In her 1994 book “Prozac Nation,” Elizabeth Wurtzel wrote of a nearly "transcendental experience" after she started taking the drug, moving from "an absence of affect, absence of feeling, absence of response, absence of interest" and a “suicidal reverie” to a generally blissful state. Indeed, Wurtzel's book helped the antidepressant gain even greater popularity. Peter Kramer in his 1993 book, "Listening to Prozac" coined the term "better than well" in describing how patients felt after taking the drug.

But others began to question the effectiveness of Prozac, such as psychologist Irving Kirsch who wrote an article in 1998 in the journal Prevention & Treatment titled, “Listening to Prozac but Hearing Placebo,” where he argued that antidepressants, including Prozac, were much less effective than was generally believed. In 2010, he published a book with the same argument called “The Emperor’s New Drugs: Exploding the Antidepressant Myth.”

Clinical trials were conducted that both supported and questioned the efficacy of Prozac. For example, Jay C. Fournier, et al., in a 2010 article published in the JAMA, called "Antidepressant Drug Effects and Depression Severity: A Patient-Level Meta-analysis," evaluated patient data from six trials and found that all antidepressants, including fluoxetine hydrochloride, exhibited "minimal efficacy in mild to moderate depression." Conversely, in a 2009 systematic review of the literature, the National Institute of Care and Clinical Excellence found that strong evidence existed for the efficacy of SSRIs, including Prozac.

Backlash and Continued Use

PBS on the People and Discoveries section of its website notes that reports also emerged that some patients felt more suicidal when they were on Prozac. Other negative references to Prozac also began to emerge in society, PBS notes:

"Lawyers began to defend murder suspects by saying that whatever they did, it was under the influence of a drug -- Prozac."

In all, there were backlashes against Prozac, and later backlashes against the backlashes. The drug eventually settled into the middle of the pack of antidepressants. As noted, Prozac is no longer the most prescribed antidepressant, but it continues to hold a place in the "pharmacist's formulary," as PBS describes it: It is today one of the dozen or so drugs in the U.S. that continue to be prescribed to millions for antidepression.