In the history of psychiatry, a few discoveries can be said to have forever changed the landscape of the discipline: the development of psychoanalysis by Freud; the discovery of electroconvulsive therapy by Ugo Cerletti; the (re-)discovery of lithium's effectiveness in bipolar mood disorders by John Cade. Among these gamechangers undoubtedly lies the introduction of fluoxetine (Prozac) by Eli Lilly and Company in 1987.
The search for a drug specifically targeting depression began with the work of the pioneering psychopharmacologist Nathan S. Kline in the 1950s. Kline, director of research at Rockland Hospital in Rockland County, New York, grew intrigued by reports of the psychological effects of the antitubercular drug iproniazid (Marsilid) and began his own investigation of the drug with depressed patients. His 1957 report with psychoanalyst Mortimer Ostow, presented at the annual meeting of the American Psychiatric Association, showed promising results. Kline and Ostow theorized that Marsilid acted as a "psychic energizer," using Freudian psychoanalytic theory to explain the effects of the drug. (This was important since the majority of psychiatrists at the time were either formally trained in analysis or were analytically-oriented in their persuasion.) With Kline and Ostow's research, a new class of drug was born: the antidepressant.
Following Roland Kuhn's near-simultaneous work in Switzerland on imipramine (Tofranil) and the development of amitriptyline (Elavil) in 1960, a "catecholamine hypothesis of affective disorders" began appearing in the professional literature (see, for example, Schildkraut, 1965). (Norepinephrine, a target of these drugs, contains a chemical group known as catechol, and is a monoamine. Thus, neurotransmitters of this type are known as catecholamines). For a period of time in the 1960s and 1970s, norepinephrine took center stage as psychiatry's focus in mood disorders. Serotonin's role was minimized and seen only as ancillary to norepinephrine.
This all changed with Prozac. In the early 1970s, the pharmaceutical company Eli Lilly began to investigate the possibility of developing an antidepressant drug that avoided the potential cardiovascular risks associated with some of the earlier tricyclic antidepressants (like imipramine and amitriptyline). The Lilly team, which included the Hong Kong-born biochemist David Wong, synthesized several chemicals derived from an antihistamine called diphenhydramine (found in Benadryl and over-the-counter sleeping aids like Tylenol PM). Wong, who was familiar with European research implicating serotonin in mood regulation, encouraged the team to screen their newly synthesized chemicals for any that might selectively inhibit the reuptake of serotonin (Wong, Horng, Bymaster, Hauser, & Molloy, 1974). On July 24, 1972, they found one.
Eli Lilly originally identified the chemical as "Lilly 110140" but renamed it "fluoxetine" in 1975. A couple of years later, the company filed an application with the FDA to investigate fluoxetine's potential as a treatment for clinical depression. Initial expectations were modest. A 1983 Wall Street Journal article quoted an Eli Lilly spokesperson who reported that fluoxetine was not expected to be a major hit (Phillips, 1983). Still, stockholders need not be concerned; the company would still make money with their new Elizabeth Arden cosmetics line and their medical device business.
In December 1987, fluoxetine (which had now been branded as Prozac) received FDA approval for the treatment of major depression. Within a few months, Prozac sales outpaced the market leader Pamelor (a tricyclic), as physicians believed that Prozac was both safer and avoided the weight gain common with the tricyclics. In fact, many patients seemed to lose weight on Prozac. By 1990, much to Lilly's surprise, Prozac became the best-selling antidepressant of all time.
With Prozac's mass success, a new type of depressed patient emerged: the mildly depressed (see Shorter, 2013). For hundreds of years, depression (historically termed melancholia), was considered a rare and serious disease, usually only observed in psychiatric inpatients (see Ruffalo, 2020). Because Prozac was so safe—and the risk of drug-drug interactions minimal—doctors began prescribing it to patients with milder symptoms, those to whom they might have hesitated to prescribe a tricyclic. Patients who would have been treated in psychotherapy instead started on Prozac. A biological revolution was well underway.
While the idea of a "chemical imbalance" causing depression is often credited to Eli Lilly's marketing of Prozac, it was actually Pfizer—the manufacturer of Zoloft, a drug introduced in 1992—which spearheaded this claim in drug advertising (Harrington, 2019). [It is worth noting here that the "chemical imbalance" theory was never seriously propounded within academic psychiatry, as Pies (2019) has extensively and repeatedly noted.] Nevertheless, the general public—inundated with direct-to-consumer advertising in the U.S.—came to believe that depression and other mental illnesses reflected, quite simply, an imbalance of certain chemicals in the brain.
In 1993, Brown University psychiatrist Peter D. Kramer published the book Listening to Prozac, which became a New York Times bestseller and remains one of the most well-known popular books on psychiatry ever written. In the book, Kramer offered a nuanced view of Prozac and related antidepressants (by now, dubbed "selective serotonin reuptake inhibitors"), specifically the use of these drugs as "personality enhancers." Kramer raised the possibility that, in addition to lifting depression, Prozac could also brighten a dull personality, assist an ambitious employee in climbing the corporate ladder, and make a shy person lively and outgoing. Kramer termed the use of drugs in this fashion "cosmetic psychopharmacology," while remaining somewhat ambivalent on the practice.
With Listening to Prozac's literary success, public interest in the drug piqued, and in 1993 sales of the drug increased a remarkable 15 percent (Harrington, 2019). A series of "me-too" SSRIs were subsequently released, including Pfizer's Zoloft and SmithKline Beecham's Paxil—with continued financial success. This was followed by the release of the so-called SNRI ("serotonin-norepinepherine reputake inhibitors") drugs in the late 1990s. It was clear that the "Decade of the Brain" had also become the decade of the antidepressant.
The excitement surrounding Prozac and the other antidepressants in the 1990s led to something of a paradigm shift in psychiatric training. As psychiatrist Daniel Carlat described in his controversial 2010 book, Unhinged: The Trouble with Psychiatry, the general consensus in psychiatry at the time was that biology held all the answers to the problem of mental illness. Carlat, trained in the early 1990s at the Harvard-affiliated Massachusetts General Hospital, described his experience in psychiatric residency as one that emphasized biological understanding and treatment and minimized—and, at times, confidently dismissed—the role of psychotherapy. Claims of Freud's demise—clearly premature—were being asserted, both inside and outside of the profession.
At the time of this writing, SSRI antidepressants—the first of which being Prozac—remain first-line pharmacotherapy for major depression and are also first-line in anxiety disorders, obsessive-compulsive disorder, and posttraumatic stress disorder, among some other psychiatric conditions. Despite much criticism in recent years, these drugs have unquestionably helped hundreds of thousands of patients deal with the listlessness and despondency of depression. Their discovery, ushered in by Prozac, is an event of significant medical importance.
Prozac's status as a landmark drug will indeed forever be enshrined in the history of psychiatry. Yet, its effectiveness as an antidepressant is only one facet of its legacy. Perhaps of equal significance is Prozac's role in reshaping the public perception of mental disorders, redefining the concept of clinical depression, and reorienting psychiatry—at least temporarily—away from psychotherapy and toward biological treatment.
For a more thorough reading of the history of antidepressant therapy, and of psychiatry in general, I suggest Anne Harrington's 2019 book Mind Fixers: Psychiatry's Troubled Search for the Biology of Mental Illness.
Carlat, D. (2010). Unhinged: The trouble with psychiatry. Free Press.
Harrington, A. (2019). Mind fixers: Psychiatry's troubled search for the biology of mental illness. W. W. Norton.
Kramer, P. D. (1993). Listening to Prozac: A psychiatrist explores antidepressant drugs and the remaking of the self. Viking Press.
Pies, R. W. (2019, August 2). Debunking the two chemical imbalance myths, again. Psychiatric Times. https://www.psychiatrictimes.com/depression/debunking-two-chemical-imba…
Ruffalo, M. L. (2020, January 24). Restoring melancholia as a diagnostic entity. Psychology Today. https://www.psychologytoday.com/nz/blog/freud-fluoxetine/202001/restori…
Phillips, C. (1983, August 31). Eli Lilly facing a shortage of new products as three drugs develop serious problems. Wall Street Journal, 23-24.
Schildkraut, J. J. (1965). The catecholamine hypothesis of affective disorders: A review of supporting evidence. American Journal of Psychiatry, 122(5), 509-522.
Shorter, E. (2013). How everyone became depressed: The rise and fall of the nervous breakdown. Oxford University Press.
Wong, D. T., Horng, J. S., Bymaster, F. P., Hauser, K. L., & Molloy, B. B. (1974). A selective inhibitor of serotonin uptake: Lilly 110140, 3-(p-trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine. Life Sciences, 15(3), 471-479.