Prozac and Selective Serotonin Reuptake Inhibitors
The search for less toxic neurotransmitter reuptake inhibitors led to the development of second-generation antidepressants known as the selective serotonin reuptake inhibitors (SSRIs). These agents differ from the older tricyclic antidepressants in that they selectively inhibit the reuptake (removal) of the neurotransmitter serotonin into the presynaptic nerve terminals, enhance synaptic concentrations of serotonin, and facilitate sero-tonergic transmission. Initially, AB Astra discovered and marketed an inhibitor for serotonin reuptake, Zimeldine, the prototype of the SSRIs. Unfortunately, a rare but serious side effect, Guillain-Barre syndrome, started to surface after Zimeldine was approved and administered in a large patient base. AB Astra pulled it off the market in the early 1980s.
The discovery of Prozac revolutionized the management of depression. Because it always takes a chemist to first make a drug, I shall begin the story of Prozac with a chemist, Bryan Molloy. In the 1960s, Molloy was a medicinal chemist working at the Eli Lilly Co. in Indianapolis. Born in 1939 in Broughty Ferry, Scotland, Molloy earned his B.S. and Ph.D. degrees in chemistry from the University of St. Andrews in Scotland in 1960 and 1963, respectively. Postdoctoral fellowships then brought him to the United States, where he carried out research at Columbia and Stanford Universities before he was employed by Eli Lilly as a senior organic chemist in 1966. At Lilly, Molloy’s initial assignment was in the cardiac therapeutic area, where he looked into acetylcholine as a regulator of heart action. In 1969, pharmacologist Ray Fuller lured Molloy to the antidepressant project that he was running. Fuller wanted to take advantage of Molloy’s experience with acetylcholine—the side effects of tricyclic anti-depressants arose because they modulate both serotonin and acetylcholine, among others. Antidepressants without acetylcholine modulation would provide cleaner drugs with fewer side effects.
Sir James Black once stated that the most fruitful basis for the discovery of a new drug was to start from an old one. Prozac’s journey began with Benadryl (diphenhydramine, a Parke-Davis over-the-counter drug), an old antihistamine well known for managing stuffy noses and allergies. Molloy began to tweak the molecule by replacing the original substituents on Benadryl with different functional groups. Through a process called structure-activity relationship (SAR) studies, he found out that the Afmethyl ethylamine moiety was necessary to maintain the pharmacological activity (pharmacophore), so he kept that side chain constant. In time, he manipulated the diphenhydramine structure of Benadryl into the phenoxypropylamine series from which fluoxetine hydrochloride (Prozac) would later emerge. In 1970, Molloy made dozens of phenoxypropylamines, some of which blocked the effect of apomorphine-induced hypothermia (decrease of body temperature) in mice tested by his biological collaborator, Robert Rathburn. Apomorphine, a morphine derivative, is a dopamine receptor inhibitor. The animal model using apomorphine-treated mice was thought to reflect the effect of acetylcholine.
In 1971, Molloy ran into David Wong, another important player in discovering Prozac. Wong, a Chinese immigrant, had joined Lilly 3 years earlier following his Ph.D. training in biochemistry at the University of Oregon. At the time, he was growing disenchanted with his research on antibiotics. By the early 1970s, the heyday of antibiotics was pretty much over. A couple of drugs that Wong was involved with did not go anywhere. In 1971, he began to shift his focus to neurochemistry. One day Wong and Molloy attended a seminar on neurotransmission given by Solomon H. Snyder from Johns Hopkins University (the author of a popular book titled Drugs and the Brain). Snyder developed a «binding and grinding» method that enabled isolation of biogenic amines from rat brains. In essence, separating the ground-up products from rat brains would provide some fractions containing nerve endings that would still function chemically. With Snyder’s consultation, Molloy and Wong began their quest to look for a more selective, and thus safer, antidepressant.
Using Snyder’s «binding and grinding» method, Wong initially tested compounds that Molloy deemed most promising—the ones that obliterated the function of acetylcholine according to the apomorphine-treated mouse model. Unfortunately, they all turned out to be duds. They blocked the reuptake of norepinephrine but not serotonin. Wong’s persistence paid off after he started testing the remainder of Molloy’s compounds that had failed in the apomorphine-treated mouse model. One of them (fluoxetine, later to become Prozac) selectively blocked the removal of serotonin while sparing most other biogenic amines. Unlike some of the earlier compounds, it was relatively inactive in the reserpine-induced hypothermia test in mice. In clinical trials, Prozac was found to have a favorable side-effect profile and was much safer in overdose relative to the tricyclics. In 1988 the FDA approved Prozac, which rapidly revolutionized the treatment of depression thanks largely to its safety profile. Prozac transformed debilitating depression into a manageable disease for many patients. In fact, unlike the previous relatively toxic tricyclic antidepressants, which were prescribed primarily by psychiatrists, the much safer Prozac is frequently prescribed by nonpsychiatrists and general practitioners, taking the field of psychiatry more into the open. In 2000, it was the most widely prescribed antidepressant drug in the United States, with worldwide sales of $2.58 billion (which dropped significantly after its patent expired). However, Prozac, and all SS-RIs, are generally not more efficacious than the tricyclic antidepressants and exhibit a marked delay in onset of action. The delay in onset of action is the reason that it takes 2-4 weeks for Prozac and other SSRIs to take effect. In addition, SSRIs also have their own set of side effects that result from the nonselective stimulation of serotonergic receptor sites.
Additional widely known SSRIs are sertraline hydrochloride (Zoloft; Pfizer) and paroxetine hydrochloride (Paxil; GlaxoSmithKline). Zoloft has been available in the United States since 1992 and had worldwide sales of $3.36 billion in 2004. Compared with Prozac, it has a shorter duration of action and fewer central-nervous-system-activating side effects such as nervousness and anxiety. Paxil generated worldwide sales of $3.08 billion in 2003, and its relatively benign side-effect profile favors its use in elderly patients.
It is well known that children and adults do not always respond to medications in the same way. The brains of children and adolescents are quite different from those of grown-ups. SSRIs that have demonstrated efficacy in treating adult depression have peculiar effects on children. In the early 2000s, data started to emerge that suggested that SSRIs may increase the incidents of suicide in children under 18. It underscored the intricacy of human brains and how modulation of serotonin levels could have other effects in different developmental stages. In June 2003, British authorities announced that Paxil should not be used to treat depression in anyone under 18. Shortly after, the FDA followed suit and recommended that pediatric use of Paxil in treating depression be avoided. For juvenile depression, Lilly’s Prozac has the best data and evidence of benefit. In September 2004, the FDA required SSRI antidepressants to carry warnings about the risk of increased suicidal tendencies in young people. Currently, only Prozac is approved for adolescents 9-17 years old.
Due to our genetic disparities, each individual responds differently to different types of antidepressants. Many second- and third-generation an-tidepressants have been discovered and provide a wide variety of choice in managing depression. Behaving similarly to SSRIs, Effexor is one of the serotonin and norepinephrine reuptake inhibitors (SNRIs), whereas Well-butrin is one of the norepinephrine and dopamine reuptake inhibitors (NDRIs), which are also used to help smokers quit. Effexor was Wyeth’s largest selling drug, with over $3 billion in sales in 2004.
