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Selective serotonin reuptake inhibitors (SSRIs) have infiltrated the lives of so many Americans they are almost a cultural paradigm. Whole books have been written about the wonders of Prozac: how it brought people back from the edge of despair when nothing else could, and how formerly inhibited and self-effacing people became social dynamos under its influence. Still other books denigrate Prozac as a "zombie-maker" of formerly passionate and innovative people. Some say that Prozac's side effects are so debilitating that people would be better off grappling with severe depression than trying to live with the tremors, tics, and sexual dysfunction associated with its use.

Oddly, there is a mystique about Prozac, even as it becomes more and more commonplace in people's lives. More and more prescriptions are filled every year, often by family doctors with

A mind not to be chang'd by place or time. The mind is its own place, and in itself Can make a Heaven of Hell, a Hell of Heaven

John Milton Paradise Lost little knowledge of psychology, and the prescriptions are often for behaviors not related to mood, such as kleptomania, weight gain, or neuropathic pain. Is Prozac truly a panacea for such a wide scope of problems and populations? Or is the hype of Prozac over-reaching its powers? This chapter will attempt to pull the curtain away from Prozac mythology with a discussion of SSRI benefits and drawbacks.


The SSRIs were the first family of antidepressants not discovered by chance. Their development was planned according to what was known about the neurochemistry of depression, which partially explains their lack of side effects and efficacy of action.

David Wong, an antibiotics researcher at Eli Lilly, had just learned a new technique that allowed him to measure uptake of chemical messengers (neurotransmitters) in neurons. Since Wong knew that current antidepressants' side effects (such as those seen in tricyclics) were mostly due to norepinephrine uptake rather than serotonin, he decided to look for compounds that would alter serotonin uptake only, in hopes of developing a drug that would cure depression but not cause the undesirable side effects associated with the earlier classes of antidepressants. After experimenting with several obscure compounds, Wong found that a tri-fluoridated (containing three fluoride atoms) molecule called fluoxetine had the most specific serotonin uptake inhibition. After years of tests on animal models and then in human clinical trials, Eli Lilly released fluoxetine under the trade name Prozac in the late 1980s. Prozac went on to become the best-known and best-selling antidepressant of our time. Other companies quickly hopped onto the SSRI bandwagon, with the release of Paxil (paroxetine), Luvox® (fluvoamine), Zoloft® (sertraline), and Celexa® (citalopram). Each of these drugs had the capacity for selective serotonin uptake inhibition but also had other individual characteristics that made some better or worse than others for individual cases of depression. In fact, studies have shown that success rates for SSRIs in alleviating moderate depression are only around 40-60 percent, and even lower for major depression. Often psychiatrists must prescribe a few SSRIs in succession to find one that works best.


The SSRIs are, like the MAOIs, named for their predominant function: selective serotonin reuptake inhibition. As detailed in the first chapter, the synapse is where the brain's electrical messages move chemically into different neurons. The chemical message is conveyed through neurotransmitters. If the electrical message is particularly strong (high current), then a high concentration of neurotransmitters will be released, but if the message is weak, then a small amount will be released. After being released into the synapse, the neurotransmitters bind to receptors at the other side of the synapse. Then the receiving neuron either conveys the message to other neurons or stimulates the expression of genes that may alter neuronal functioning. At the same time this is occurring, special pumps along the surface of the synapse are also moving the neurotransmitters back inside the neuron so that they can no longer stimulate the receptors. SSRIs block this uptake process by binding to the pumps, which allows more serotonin to activate receptors in the synapse (Figure 3.1). Indeed, studies have shown that, within a few hours of taking an SSRI, extracellular serotonin levels rise to seven times the amount normally found outside the neurons. Thus serotonin receptors on neurons are being continually stimulated. However, even though serotonin levels go up immediately, there is no instantaneous eradication of depression. Instead, gradually over time, this chronic stimulation translates into changes in the activity patterns of the brain which then causes depression to dissipate.

This description of SSRI action on the brain explains merely the first few steps in alleviating depression. How increasing serotonin levels within the synapse can bring about a

Drug Sertraline Mechanism Action
Figure 3.1 How Prozac (fluoxetine) blocks reuptake of serotonin. Normally the serotonin reuptake transporter carries serotonin back into the neuron. Prozac binds to the transporter, causing serotonin to build up outside the neuron.

therapeutic benefit is not entirely known, although scientists have a few clues on underlying mechanism involved. They know, for example, that simply stimulating receptors with serotonin agonists does not bring about therapeutic changes in mood. Nor does giving large amounts of SSRIs expedite the therapeutic effects. In fact, there is no way to speed up the process, which makes scientists think that the therapeutic changes must be genetic. One idea that has gained popularity is that SSRIs "cure" depression by increasing the amount of serotonin autoreceptors on neurons. Autoreceptors are like thermostats on neurons, for the rate at which these receptors are stimulated indicates how much serotonin is outside the neuron. When levels of serotonin go up (due to the presence of SSRIs), neurons respond by decreasing (or down regulating) receptors. Scientists have found that autoreceptor and transporter down regulation can take several weeks, the same time that it takes for therapeutic results. Because of these findings, many researchers have focused on understanding the signaling that goes on inside the neuron after serotonin receptors are stimulated.

One intracellular signaling molecule, cyclic AMP (cAMP), has been shown to be an important mediator of signaling cascades that control gene expression. Scientists are looking at ways different levels of cAMP may allow some genes to be expressed over others. The idea is that, once we discover intra-cellular pathways that are important for depression, drugs could be developed that act on these pathways only. Targeting an intracellular pathway molecule such as cAMP will allow potential drugs to be more specific in their action, with less debilitating side effects. These new kinds of drugs will be discussed further in Chapter 6.


Biologists have already found intracellular pathways and genes important in mediating relief from depression. Two researchers, Jessica Malberg and Richard Duman, both of

Princeton University, have shown that chronic treatment with Prozac (fluoxetine) causes new neurons to be born in the hippocampus, a region important for memory formation. This discovery is fascinating because it implies that depression may be caused by decreases in neuronal birth.

Several brain-imaging studies have shown that the hip-pocampal areas of depressed patients were actually smaller than those in normal patients. Initially, scientists believed that the cause of shrinkage was loss of old neurons, but only recently have scientists begun to realize that neurons are continually being born (albeit in minute amounts) in the adult brain. Less than a decade ago, it was believed that only developing fetuses and babies could grow new brain cells. The discovery that neurons were, indeed, being born in discrete regions in the adult brain was a major revolution in neuroscience. And since we now know that depression is hindering the birth of new neurons, we can look for ways to develop antidepressants that stimulate new neurons.

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  • Maik
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