Ray W. Fuller, David T. Wong, and Bryan B. Molloy

Left to right: David Wong, Ray Fuller, and Bryan Molloy. © Copyright Eli Lilly and Company. All rights reserved. Used with permission.

Left to right: David Wong, Ray Fuller, and Bryan Molloy. © Copyright Eli Lilly and Company. All rights reserved. Used with permission.

Since its introduction by Eli Lilly and Company in 1988, Prozac (fluoxetine) has been hailed as a wonder drug, a safe antidepressant that is more effective than those of previous eras. Though questions were raised about Prozac’s side effects and true level of efficacy, it became one of the most prescribed antidepressants, with worldwide annual sales in the $2 to $3 billion range until the expiration of its patent in 2001 and the rise of competition from other pharmaceutical companies, ultimately including manufacturers of generic drugs. Prozac and similar drugs enabled many of the estimated 10 million people in the United States suffering from depression to lead normal lives. The development of this groundbreaking drug was undertaken by three Eli Lilly researchers: Ray W. Fuller (1935–1996), David T. Wong (b. 1935), and Bryan B. Molloy (b. 1939).

During the 1950s a class of antidepressants known as tricyclics was developed. Although effective, these drugs also cause a variety of undesirable side effects, including dizziness, blurred vision, and constipation. The next generation of antidepressants was known as monoamine oxidase inhibitors, or MAOIs. Unfortunately, MAOIs can be highly. Further research was needed to develop an effective antidepressant with low toxicity and a low incidence of side effects. A giant breakthrough occurred in 1974, when Eli Lilly scientists reported on their studies of fluoxetine, the first in a class of antidepressants known as selective serotonin reuptake inhibitors, or SSRIs.

Most antidepressants work in the same manner: they increase the amount of neurotransmitters in the brain. Neurotransmitters are the chemicals released by nerve cells to stimulate neurons, thereby passing impulses through the nervous system. It is believed that depression is especially affected by levels of the neurotransmitters serotonin and norepinephrine. Antidepressants differ in respect to which neurotransmitters they increase and how they do it. MAOIs inhibit the enzyme monoamine oxidase from destroying the neurotransmitters norepinephrine, serotonin, and dopamine, thereby increasing the levels of all three. Tricyclics inhibit the reuptake (reabsorption), for reuse, of norepinephrine and serotonin already released in the brain. This means that greater amounts of these neurotransmitters are left in the brain, increasing their effects. Tricyclics also often affect the neurotransmitter acetylcholine, which causes a variety of side effects. SSRIs—including Prozac, Pfizer’s Zoloft (sertraline), and SmithKlineGlaxo’s Paxil (paroxetine)—work much like tricyclics, except that they are more selective; by affecting only serotonin, they cause fewer side effects.

The story of Prozac begins in the 1960s, when Ray Fuller came to work at Eli Lilly. Fuller was born and raised in Illinois. He earned a bachelor’s degree in chemistry in 1957 and a master’s degree in microbiology in 1958, both from Southern Illinois University. Fuller worked his way through college as an employee at a state mental hospital; there he developed his interest in the brain and therapies for treating mental disorders. In 1961 he earned his Ph.D. in biochemistry from Purdue University. Shortly thereafter he accepted a post as director of the biochemistry research laboratory at the Fort Wayne State Hospital for Mentally Retarded Children. In 1963 he joined Eli Lilly as a pharmacologist and was set to work testing potential new antidepressants.

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 and sought to entice Bryan Molloy, another Eli Lilly scientist, to this line of research.

Molloy was born in 1939 in Broughty Ferry, Scotland. He received his B.S. in chemistry in 1960 from the University of St. Andrews, and three years later earned his Ph.D. in chemistry from the same institution. In 1963 he came to the United States to conduct postdoctoral research at Columbia and Stanford Universities, and three years later joined Eli Lilly as a senior organic chemist. Molloy’s research interests centered on the neurotransmitter acetylcholine and its effect on the heart. Fuller suggested that he abandon his cardiac work and take up a related line of research: looking for an antidepressant that did not affect acetylcholine. A new medication with that trait would not have many of the side effects that tricyclics had.

After accepting this proposal, Molloy began to research possible compounds for his project. Knowing that antihistamine research had led to some of the first antidepressants, including chlorpromazine (see Paul Charpentier et al.), Molloy developed compounds whose chemical structures closely resembled those of antihistamines.

David Wong, another Eli Lilly researcher with an interest in neurochemistry, joined the antidepressant project in 1971. Born in Hong Kong in 1935, Wong was the son of a machinist. As a youth, he was encouraged by his family to find a career helping people. He began his higher education at National Taiwan University, majoring in chemistry, and in 1957 he traveled to the United States to study at Seattle Pacific College, where he earned his B.S. in chemistry in 1960. In 1964 Wong earned an M.S. in biochemistry from Oregon State University. Two years later he received a Ph.D. in biochemistry from the University of Oregon. He joined Eli Lilly as a research biochemist in 1968.

In 1971 both Molloy and Wong attended a lecture at Eli Lilly on neurotransmission given by Solomon Snyder, a researcher from Johns Hopkins University. Snyder had developed a technique that would prove immensely useful to the Lilly team. He 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 used this technique to test the effects of Molloy’s compounds, one of which was found to block the reuptake of serotonin while affecting virtually nothing else. The compound was further tested in Fuller’s chloroamphetamine-treated rat and was again found to block the reuptake of serotonin. This compound was fluoxetine.

Prozac was introduced in 1988, to great acclaim by doctors and patients alike. It is as effective as other antidepressants on the market, but it does not induce as many side effects. Furthermore, SSRIs are not lethal in overdoses. In the past decade Prozac has been shown to be effective in treating other conditions, including obsessive-compulsive disorder and bulimia nervosa.

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