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16 minute read
Michael D. Lemonick

For Chicago journalist Susan Schwendener, the symptoms were as familiar as the runny nose of a cold or the scratchiness of a strep throat. “You can’t sleep, you can’t eat, you lose weight because your mood’s so blue.” Schwendener, 33, suffered her first bout of depression as a teenager. She started taking Prozac 10 years ago. “The pain,” she says, “sort of evaporated over time.” By the age of 21, Beth Herwig, now an executive assistant in St. Louis, Mo., tipped the scales at more than 500 lbs. At 29, after years of yo-yo dieting, she was carrying 545 lbs. on her 5-ft. 4-in. frame. Then Herwig went on a combination of fenfluramine and phentermine, popularly known as fen/phen. “It’s not that I don’t want that Twinkie still,” says Herwig. “But before, I would see it, and there was almost nothing that could stop me.” Today she weighs just 265 lbs.

Brian Goodman, 20, is obsessed with the idea that disaster and death are about to strike his family. The only way to stave off catastrophe, his mind tells him, is to follow self-imposed rituals to the absolute letter: making coffee in a way that never varies, driving around Los Angeles along the same route every day. A classic victim of obsessive-compulsive disorder, Goodman has been in treatment since he was seven, without much change. Now he is on Zoloft. “Before the medicine,” he says, “it was like living in hell.”

At first glance, these stories seem completely unrelated–three profoundly different disorders treated with three different drugs. Yet all three medications have one crucial element in common: they target the brain chemical serotonin. Though serotonin has been known to researchers for nearly a half-century, only in recent years have neuroscientists begun to understand how important this one substance is to the functioning of the human psyche. Serotonin, or the lack of it, has been implicated not only in depression, uncontrollable appetite and obsessive-compulsive disorder but also in autism, bulimia, social phobias, premenstrual syndrome, anxiety and panic, migraines, schizophrenia and even extreme violence.

The growing awareness of serotonin’s central role in mood and emotion has been paralleled–and in some cases driven–by a boom in drugs that target serotonin more or less specifically. Among them are such popular antidepressants as Elavil, Prozac, Zoloft and the hot new herbal medication St. John’s wort; powerful appetite suppressants including Redux and fenfluramine; and antipsychotics such as clozapine. Like every other drug, the ones that zero in on serotonin have side effects. Elavil makes people sleepy. Zoloft can trigger headache and nausea. Zoloft and Prozac may cause sexual dysfunction. All these symptoms are annoying, to be sure, yet they are a price that many sufferers have been willing to pay.

But last week it became startlingly clear that monkeying with the chemistry of the human mind can trigger problems much more serious than a dull sex life. Just 1 1/2 years after it approved Redux for treatment of obesity, the FDA issued a warning advising patients to stop taking it and its close chemical cousin fenfluramine immediately. At the same time, the drugs’ manufacturers and distributors, Wyeth-Ayerst Laboratories, told physicians to stop prescribing them and took the dramatic step of pulling both medications from the market. The reason for such haste: new evidence had revealed that as many as 30% of Redux and fen/phen users could develop abnormalities in the shape of their heart valves–changes that could eventually lead to serious cardiac weakness and perhaps even death.

These were not the first lethal side effects associated with Redux and fenfluramine. When Redux was approved, both Wyeth-Ayerst and the FDA already knew that the medication could lead to a potentially fatal lung condition known as primary pulmonary hypertension. But this problem seemed to affect only a small minority of users, and morbid obesity carries significant risks of its own: heart disease, diabetes, high blood pressure and stroke. On balance, the benefits seemed to outweigh the risks.

Why did the equation suddenly seesaw the other way? Partly because clinical trials reveal only the most obvious side effects; the heart-valve changes discovered over the summer do not initially cause visible symptoms in most patients. Also, many doctors went overboard, giving Redux and fen/phen to patients who were merely overweight, not obese, a violation of the FDA and drug-company prescription criteria that couldn’t help skewing the risk-benefit ratio.

The abrupt change also reflects a deeper truth about serotonin: despite years of study and impressive breakthroughs, researchers are only beginning to understand the chemical’s complex role in the functioning of the body and brain–and how doctors can make adjustments when serotonin levels go out of balance. So far, the tools used to manipulate serotonin in the human brain are more like pharmacological machetes than they are like scalpels–crudely effective but capable of doing plenty of collateral damage. Says Barry Jacobs, a neuroscientist at Princeton University: “We just don’t know enough about how the brain works.”

Still, there is plenty that researchers do understand. At the most basic level, they have been aware for more than two decades that without serotonin, dopamine, norepinephrine and the hundreds of other known neurotransmitters, the brain could not process information or send out instructions to run the rest of the body. That is because neurons, or nerve cells, do not actually touch one another; they are separated by gaps known as synapses. When the electrical impulses that carry information through the nervous system reach the end of a neuron, they have nowhere to go. The circuit is broken.

It would be, that is, if not for the neurotransmitters. These chemicals are stored in tiny sacs known as vesicles, located at nerve endings. When an electrical signal reaches the vesicles, they release their load. The neurotransmitter molecules navigate across the synapse and lock into receptors on the neighboring nerve cell–an action roughly equivalent to flipping on a light switch. The second nerve cell wakes up and sends off a jolt of electricity to pass the message along. Their job completed, the neurotransmitter molecules detach and are ferried back to be reabsorbed or destroyed.

That’s the simple version of the story. In practice, things are a bit more complicated. To start with, different neurons specialize in releasing different neurotransmitters. Many carry messages that convey facts about the outside world–incoming sounds, patterns of light and so on–and integrate them into useful information. Some neurotransmitters also carry messages of action, telling muscles when to release or contract.

But a small subset of these brain chemicals, especially serotonin, evidently serves an entirely different purpose. As Steven Hyman, director of the National Institute of Mental Health, describes it, “These neurotransmitters modulate raw information and give it its emotional tone.” Northwestern University psychiatrist James Stockard puts it more poetically: “A person’s mood is like a symphony, and serotonin is like the conductor’s baton.” Other neurotransmitters help us know our stomachs are full; serotonin tells us whether we feel satisfied. Other chemicals help us perceive the water level in a glass; serotonin helps us decide whether we will think of it as half empty or half full.

With such a broad neurological portfolio, it is no wonder these mood-changing brain chemicals have been implicated in so many mental disorders. And it is not surprising that serotonin appears to be especially important–the first among equals, in a sense. The nerve cells that specialize in serotonin production originate in the raphe nuclei, in a region right atop the spine that nimh’s Hyman calls “the deep basement of the brain.” From there, these neurons extend vinelike projections called axons up through the brain and down into the spinal column. The axons form a sort of neurological interstate-highway network, over which serotonin supplies are sent to all parts of the nervous system. Other neurotransmitters are restricted to certain regions of the brain or the body; serotonin is just about everywhere.

Its effects vary widely, however, depending on a variety of factors. To begin with, each neurotransmitter can latch onto more than one kind of receptor. As many as 15 distinct receptors have been identified for serotonin alone. And since a given nerve cell may have more or fewer receptors, depending on where in the brain it is located, a jolt of a particular neurotransmitter can generate electrical signals of widely varying strengths. Small wonder, therefore, that serotonin can affect everything from satiety to depression.

It is also not surprising that serotonin deficits can give rise to very different illnesses, depending on what part of the brain is affected. Obsessive-compulsive disorder, for example, probably arises in the striatum, a part of the brain that controls voluntary movements. Princeton’s Jacobs believes that, based on experiments with cats, repetitive motor activity–walking, chewing, breathing–stimulates the release of serotonin, which improves mood. That might explain why people are soothed by gum chewing and why obsessive-compulsives perform such ritualistic acts as hand washing over and over; they may simply be self-medicating to overcome a serotonin deficit.

Anxiety disorders, on the other hand, probably reflect serotonin deficits in the amygdala, the part of the brain that processes fear and other emotions. For depression, bulimia, obesity and the rest of the serotonin-related disorders, however, no one knows for sure what part of the brain is involved or exactly why the drugs work. “There is,” says Hyman, “a bit of mystery here.”

More than a bit. In fact, the entire history of serotonin and of drugs that affect it has been largely a process of trial and error marked by chance discoveries, surprise connections and unanticipated therapeutic effects. The chemical was not even first discovered in the brain. It was stumbled on in the late 1940s by U.S. and Italian researchers, working independently, in blood platelets and in the intestines, respectively. The Italians called it enteramine, the Americans serotonin (sero for blood, tonin for muscle tone)–and when the two groups compared notes, they found their compounds were identical.

At first, the effects of serotonin seemed confined to the body alone: it was found to trigger contractions in the muscles and intestines and to regulate blood pressure by forcing blood vessels to constrict. But experiments at the National Institutes of Health in the 1950s revealed that compounds that depressed serotonin levels depressed patients as well. Not long after, researchers found two more clues to the serotonin-depression connection. The first was that reserpine, an anti-blood-pressure medicine that depresses serotonin levels, can sometimes trigger depression. The second came from iproniazid, originally developed as an anti-tuberculosis agent. The medicine worked against TB, which naturally made patients happy. When the euphoria did not wear off, however, scientists began to suspect that it was not entirely natural.

They were right. Iproniazid is what is known as a monoamine oxidase inhibitor (MAO). In the brain, scientists have subsequently learned, monoamine oxidase’s job is to destroy leftover neurotransmitters that are floating around loose after they have done their work. By inhibiting the action of monoamine oxidase, drugs like iproniazid let neurotransmitters circulate and keep stimulating neurons longer than they normally would. An extended soaking in serotonin and norepinephrine evidently made for a happier patient, and MAO inhibitors became the first antidepressants.

In the 1960s, a second class of antidepressants emerged. By tinkering with the chemical structure of antihistamines, a Swiss psychiatrist, Ronald Kuhn, created a drug called imipramine, first of the so-called tricyclic antidepressants. At the time no one had any idea why these medicines worked. Researchers have since learned that they keep excess serotonin and other neurotransmitters from being reabsorbed into the nerve cells they originally came from: same extended neurotransmitter bath as the MAO inhibitors, different mechanism.

Both types of antidepressant had major side effects, though, including profound drowsiness and heart palpitations. The reason, scientists generally agreed, was that they affected brain chemistry too broadly. The research seemed to point to serotonin as the most important mood-enhancing chemical, though not the only one, and so neurochemists set about looking for a drug that would boost the influence of serotonin alone. In 1974, after a decade of work, Eli Lilly came up with Prozac, first of the so-called selective serotonin reuptake inhibitors, or SSRIS, and it was finally approved by the FDA in 1987.

But the serotonin trail led scientists down a number of other interesting paths as well. One involved LSD: clinicians discovered that people on MAO inhibitors were much less sensitive to the drug than normal. The consensus is that LSD mimics serotonin in the brain and latches onto the same neuronal receptors. With MAO inhibitors keeping more serotonin in circulation, the acid cannot elbow its way in.

Another line of investigation revealed that serotonin may play a role in sleep. Destroy the raphe nuclei in cats, and they develop permanent and total insomnia. Give the wakeful cats a shot of serotonin, and they immediately go to sleep. In humans the amino acid L-tryptophan, which is converted to serotonin in the brain, is sometimes used as a sleeping pill. (A bad batch of L-tryptophan killed several people in the late 1980s and effectively killed the craze.) In another experiment, researchers discovered that when they stimulated raphe cells to release extra serotonin not in the brain but in the spinal cord, test subjects experienced pain relief.

In yet another series of studies in the 1970s, scientists discovered links between serotonin and aggressive behavior. Monkeys with high levels of serotonin by-products in their blood, it turns out, tend to be feistier, and drugs that boost serotonin activity tend to calm them down. The serotonin-violence link appears to hold for humans as well. In 1979 psychiatrist Frederick Goodwin, now at George Washington University, discovered that Navy enlisted men with low levels of serotonin byproducts often had a history of aggression. Subsequent studies discovered similar evidence in Marines discharged for excessive violence, in people who became violent after drinking alcohol and in children who tortured animals.

Finally, the development of Prozac led to a number of surprises–the discovery that it was good for obsessive-compulsive disorder, for example, as well as for panic disorder and social phobias. Clinicians also noticed that Prozac patients tended to lose weight, an intriguing finding, considering how many Americans are obese. But the weight loss was transitory, so Lilly scientists went back into the lab to see if they could reformulate Prozac as an effective obesity drug.

Their efforts failed, but Richard Wurtman, an M.I.T. neurologist and Lilly consultant, took a different approach. Instead of using Prozac as a starting point, he turned to fenfluramine, a European weight-loss drug. Because fenfluramine acts on both serotonin and dopamine, it has the unfortunate side effect of putting its users to sleep. That is why doctors came up with fen/phen; the “phen” (phentermine) is an amphetamine-like drug that wakes the patient up again and boosts the metabolism to burn calories faster. Wurtman separated fenfluramine into its two component chemicals, levofenfluramine and dexfenfluramine. The latter has revealed itself to be a powerful weight-loss medication. He patented the drug for M.I.T., founded a company called Interneuron Pharmaceuticals to manufacture it under license to Wyeth-Ayerst and began moving the drug, dubbed Redux, through the FDA-approval process.

From the start, it was clear that Redux has serious potential side effects. One is primary pulmonary hypertension, a rare form of high blood pressure that strikes the blood vessels of the lungs. Another, considered even more serious by some of Redux’s critics, was the possibility of brain damage. When fed to monkeys, dexfenfluramine can destroy neurons. Says John Harvey of the Allegheny University of Health Sciences in Philadelphia, who edits the Journal of Pharmacology and Experimental Therapeutics: “Any of us who were pharmacologists knew this was a dirty drug. None of us was surprised.”

Some critics claim that Interneuron steamrollered Redux through the FDA and that the agency acted irresponsibly in approving it, charges that the company and the agency vigorously deny. What nobody on either side considered, though, was the possibility that either Redux or its parent compound fenfluramine might damage heart valves.

But why would they? After all, other serotonin enhancers, such as Prozac, have never caused heart problems. There is a crucial difference, however, between Prozac and Redux-fenfluramine. The former, like the other SSRIS, keeps serotonin in circulation longer than it would otherwise be, thus helping the brain get the most out of its normal output. The latter do the same, but they also force nerve cells to boost the levels of serotonin that go into circulation. It is this unnatural bath of excess serotonin, some scientists theorize, that causes heart-valve defects and also triggers brain damage–in monkeys, at the very least–by overdosing neurons and burning them out.

But if Redux and fenfluramine are too powerful for the body to handle–a proposition not fully accepted by some doctors despite the FDA and manufacturers’ action–research into serotonin-boosting drugs is hardly slowing down. If anything, the discovery of a new set of side effects will spur researchers to hone their pharmacological handiwork even more, to create medicines that will not just fine-tune the way serotonin is used in the brain but might target specific serotonin receptors as well or act on only specific parts of the brain and nervous system.

For example, says Solomon Snyder, the Johns Hopkins neuroscientist who discovered several of the brain’s serotonin receptors, while antidepressants are reasonably effective against chronic pain, it is easy to imagine a serotonin drug that could target chronic pain more directly than today’s antidepressants do. It is also possible that pharmacologists could build a serotonin sleeping pill, a serotonin jet-lag pill, or even an appetite suppressant that doesn’t have Redux’s dangerous side effects. Just as the first antidepressants were refined into safer, more effective and relatively side effect-free drugs like Prozac, so might Redux or fenfluramine yield to similar but safer alternatives.

As neurophysiologists continue to unravel the secrets of serotonin, they will also be looking at other neurotransmitters that influence mood and emotion. Already psychiatrists are buzzing with news of reboxetine, which totally ignores serotonin and goes after norepinephrine, the neurotransmitter Prozac left behind. Approved in England just this past summer, it works quickly, has relatively mild side effects (constipation, dry mouth, low blood pressure) and might eventually be the therapy of choice for people with especially severe depression. However, the new drug has so far gone through clinical trials on only a few hundred people; fenfluramine was used in Europe for more than 20 years before any heart problems showed up.

Advanced mood-enhancing medicines such as reboxetine and the next generation of serotonin boosters may eventually revolutionize psychiatry, self-improvement and health care in general. But in the wake of the Redux-fenfluramine debacle, it could be many years before the FDA is ready to approve the new drugs. Or before the rest of us are ready to swallow them.

–Reported by Elaine Lafferty/Los Angeles, J. Madeleine Nash/Chicago, Alice Park/New York and Dick Thompson/Washington

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