• Author with professional and personal experience: Psychotherapist Gary Greenberg’s musings on the intersection of science, politics, and ethics have graced the pages of The New Yorker , Wired , and Mother Jones. A longtime sufferer of depression, in 2007 he enrolled himself in a clinical trial for major depression (after his initial application for a minor depression trial was rejected). He wrote about his experience in a Harper’s magazine piece, which received a tremendous response from readers..
• “Am I happy enough?”: This has been a pivotal question since America’s inception. Am I not happy enough because I am depressed? is a more recent version. Greenberg shows how depression has been manufactured—not as an illness, but as an idea about our suffering, its source, and its relief. He challenges us to look at depression in a new way..
• A nation of depressives: In the twenty years since their introduction, antidepressants have become staples of our medicine chests—upwards of 30 million Americans are taking them at an annual cost of more than $10 billion. Even more important, Greenberg argues, it has become common, if not mandatory, to think of our unhappiness as a disease that can, and should, be treated by medication. Manufacturing Depression tells the story of how we got to this peculiar point in our history. .
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Gary Greenberg is a practicing psychotherapist in Connecticut and author of The Noble Lie. He has written about the intersection of science, politics, and ethics for many publications, including Harper's, the New Yorker, Wired, Discover, Rolling Stone, and Mother Jones, where he's a contributing writer.Excerpt. © Reprinted by permission. All rights reserved.:
When Betty Twarog opens the door to her cavernous rooms at the University of Maine’s Darling Marine Laboratory, you’re smacked in the face with mist and the smell of brine, and the sound of water everywhere. Pumped out of Boothbay Harbor, it hisses and sprays and gurgles through pipes overhead and sluiceways underfoot, flowing through huge dark tanks full of sea urchins and starfish and other gnarly marine creatures before pouring back into the harbor. With a finger raised to her lips and a sharp shake of her head, she shushes the questions I shout over the din. At first I think she is afraid I will disturb her spat, the baby clams and scallops gestating in the bucket she’s leaning over. But, she later explains, her job—to measure out precise portions of the three algae concoctions that are bubbling in tall plastic tuns in an adjacent room and feed them to her tiny charges—requires her total focus. So for a half hour, she attends to her task with silent concentration. A slightly built woman with ramrod-straight posture and long dark hair drawn back tightly from a dramatic widow’s peak, she moves with the fluid grace of someone who has been doing chores like these for just over a half century. You wouldn’t know it to look at her, but Betty Twarog is seventy-seven years old.
Something else you wouldn’t know as she tends her mollusks is that Betty Twarog made one of the most important scientific discoveries of the twentieth century, one that changed the course of neuroscience and medicine and set off a revolution in the way we think of ourselves. In 1952, when she was a twenty-five-year-old woman in a man’s world, armed with nothing but a fresh Ph.D. and a hunch about an old scientific mystery, Twarog discovered serotonin in the brain and laid the cornerstone of the antidepressant revolution.
That’s not what she had in mind. All she really wanted to do was to answer a question first posed in 1884 by Ivan Pavlov—yes, that Ivan Pavlov—when he took a brief excursion into the world of invertebrates. Pavlov, on a postgraduate fellowship in Leipzig, was trying to figure out the secrets of digestion. In large part, moving food along the alimentary tract is a matter of smooth muscle functioning, and Pavlov decided to investigate the byssus retractor, the smooth muscle that Mytilus edulis, the common mussel, uses to close its shell. He was particularly interested in how it was possible for the creature to hold its shell shut against the outside world without expending far more energy than it could possibly take in.
His interest in this question didn’t last long, and in the single paper he published on the subject before resuming the inquiries that led to his Nobel Prize (and to his eventual fascination with the salivation reflex in dogs) he offered only the merest hint of an answer. Seventy years later, Betty Twarog, for reasons she can’t quite explain, found the remaining mystery irresistible. And she thought she had the answer, but it was too fantastic, too off the charts to be credible—until Abbott Pharmaceuticals just happened to mail her the means to check out her hunch.
Abbott had offered samples of a compound it had just synthesized to leading scientists around the country, including John Welsh, Twarog’s mentor at Harvard. The molecule didn’t have a name yet, or, more accurately, it had a number of them. Chemists called it 5-hydroxytryptamine after its molecular structure. Some biologists were calling it enteramine because they had found it in the guts of squid and octopi, while the biologists who had found it in blood called it serotonin. Abbott wanted the scientists to use their free samples to figure out what exactly the stuff was, what it did, and how it could be used. The company was hoping to find a way to make a drug, or a target for drugs, out of the new compound. They had no idea what they had stumbled upon.
But Twarog did, or so she believed. Pavlov, she thought, had gone much farther toward a solution than he knew. “It’s perfectly beautiful,” Twarog told me, “because to this day his paper summarizes the control of these muscles. He insisted that they contract under nervous stimulation and that they hold that contraction until they are signaled by relaxing nerves that turn it off.” The mussel, that is, didn’t clamp down its byssus retractor and then squeeze it tight like you or I would clench our fist around a quarter; instead, Twarog hypothesized, it closed the shell and threw a lock, which remained latched until a signal opened it like a key.
Twarog, unlike Pavlov, had the benefit of a discovery made in 1921 by a German scientist, Otto Loewi. Loewi wondered exactly how nerves signaled muscles—in particular, whether the process was purely electrical or somehow mediated by chemicals. He claimed that an answer came in a dream on Easter night. He sprang out of bed and rushed to his lab, where he cut the hearts out of two frogs and bathed them separately in salt water. Dissected hearts in saline will continue to beat, and Loewi had left intact the nerves that control the pulse rate—the vagus nerve, which slows it, and the accelerator nerve, which does what you think it does. He sent an electric charge from a battery into the vagus nerve; the heart slowed, just as he expected. But then he took the salt water from that bath and dripped it into the other heart’s solution. When that heart slowed without any electrical stimulation, Loewi concluded that a chemical released from the vagus nerve and into the saline, and not electricity, had slowed down the heart. He repeated the experiment on the accelerator nerve, with the same result, and by 5:00 a.m. on Easter Monday had proved the principle of chemical neurotransmission.
By the time Twarog became intrigued by her mussels, Loewi’s principle had been firmly established, but most scientists had settled into the belief that Loewi’s chemicals—acetylcholine and epinephrine—were the only two neurotransmitters in the body. Twarog, however, was sure that there had to be another—the one that the mussel used to lock and unlock its shell—and she had a hunch that it was the chemical Abbott had sent.
In May 1952, Twarog and Welsh laid out the mussels on a lab bench. As soon as Abbott’s serotonin hit them, the byssus retractors retracted. Twarog was right. Serotonin was the missing neurotransmitter.
As disturbing as the news of a new neurotransmitter might have been to scientific orthodoxy, Twarog’s next idea was downright heretical. She said that serotonin would be found in the mammalian brain, which meant, of course, the human brain. At the time most biologists believed that humans were different from the rest of the animal kingdom, and the brain different from the rest of the body. In particular, they thought that electrical signals leapt around the brain like sparks, a throwback perhaps to René Descartes’ idea that the pineal gland sent out ethereal messengers bearing the soul’s instructions to the body.
Twarog thought this kind of reasoning was “sheer intellectual idiocy.” It didn’t make scientific sense—“what was the difference really between the brain and the rest of the body?” she says, still incredulous after all these years. “This is how nerves worked, no matter where they are.” And, maybe more important, it didn’t make philosophical sense either. “You know Tennyson’s poem ‘Flower in the Crannied Wall’?” She quoted from memory: “‘Little flower—but if I could understand / What you are, root and all / and all in all, I should know what God and man is.’ This is how it had to be.”
Two years later, Twarog moved to Ohio to follow her husband to a university job. Restless, she applied for a position with Irvine Page, a Cleveland Clinic doctor who was trying to understand the role of serotonin in regulating blood pressure. On the day of her interview, it was pouring rain and, she recalls, “I looked like something the cat had dragged in.” Still dripping on Page’s floor, Twarog described her ideal job: a lab, an assistant, and the time to study the distribution of serotonin in the brain. He grilled her—after all, her hypothesis went against everything he’d been taught about the nervous system—but finally agreed to give her the bench space and a technician. Within a year, she had found serotonin in the brains of rats, dogs, and monkeys.
Twarog’s first paper—the one about her experiment at Harvard—didn’t get published until 1954. She didn’t even hear back from the editor of the Journal of Cell Physiology—Detlev Bronk, the president of Johns Hopkins University—until John Welsh, the Harvard professor, called to inquire about the status of the article. Bronk told him that he wasn’t about to ask his peers to review a speculative article by an unknown girl on such an important topic. While the paper was moldering on Bronk’s desk, other scientists, much more prominent than Twarog, were arriving at a similar conclusion about serotonin. Once they had published their findings, it was safe for Bronk to let the girl have her say. Her paper with Irvine Page on cerebral serotonin also had to wait until the big boys said it first. But today no one disputes that she was the first with both discoveries.
Betty Twarog soon returned to marine biology, her first love. But many of the others went on to figure out the biology of neurotransmission, establishing within a decade that electricity really didn’t fly from neuron to neuron like angels, that the brain really ran on chemicals like the rest of the body. And more than a half century later, new neurotransmitters are still turning up under the microscope, the subtleties of their metabolism still emerging.
None of these discoveries would be of much interest outside the lab were it not for some chance observations made in the early 1950s—that, for instance, an antitubercular drug that had induced an unexpected (although not unwelcome) euphoria inhibited an enzyme that breaks down serotonin, or that lysergic acid diethylamide (LSD), already famous for its profound effects on consciousness, has a chemical structure similar to serotonin. Out of these and other findings, scientists began to cobble together a theory: that mental illness in general and depression in particular are caused by imbalances in neurotransmitters, and especially in serotonin. This theory was of obvious interest to pharmaceutical companies, and by 1958 drugs had come to market designed to cure depression by fixing these supposed imbalances. In 1988, Prozac was introduced, and by 2005, the last year for which reliable figures are available, 27 million Americans—10 percent of the adult population—were taking antidepressants, most of which act on serotonin, at an annual cost of more than ten billion dollars. It was a success far beyond anything Abbott could have dreamed of when they sent their serotonin to John Welsh’s lab.
This is how the best science stories start—with a chance discovery that leads to a vast change in our everyday lives. Take the brilliant insight, the dogged determination, and the sheer good fortune behind an achievement like Betty Twarog’s, throw in the poignant contrast between her anonymity and the significance of the knowledge she uncovered, add to it some gee-whiz-interesting science, and the next thing you know you have not only a great tale, but also an excellent example of the way that scientists take us up toward Parnassus—in this case the heights of happiness and health. A good science story can make you feel even better about progress and the prospects for humankind.
That’s not the kind of story I’m going to tell in this book.
The invention of antidepressants is not the kind of achievement that contributes unambiguously to the betterment of our species. You probably already suspect that. Unless you’ve been living off the grid for the last half century, and especially the past two decades, you already know that serotonin has become a household word and Prozac and its chemical cousins—known collectively as selective serotonin reuptake inhibitors, or SSRIs—have become staples of the American medicine chest. And you know about the controversies that have ensued. You’ve had conversations about them with friends or family—or with yourself, when you wondered if your unhappiness or worry were signs of the disease we call depression, or when your doctor wrote a prescription for you and you hesitated to fill it, or when you took the pills, felt better, and wondered what that meant about you. And you’ve probably found that these discussions leave you just as confused as you were before. One thing antidepressants don’t do is end confusion about antidepressants. You’d need a different drug to do that.
You’ll also need a different book to do that. I’m not going to end this confusion for you. In part, that’s because my subject is not the drugs so much as the condition they purport to treat, the disease of depression. But it’s also because ongoing uncertainty is a hazard of reading a book by an old-fashioned psychotherapist like me, who believes that when it comes to important and complex questions, the best approach is to leave yourself in doubt for as long as possible, to live with inner conflict rather than to end it, to withstand yourself rather than to become someone different, to understand how you arrived at an important juncture rather than strike out down a road simply for the sake of getting on with life.
In this case, the crossroads that we’ve all arrived at is as crucial as it gets, and what I will do in this book is to show you how we arrived here, how we got to a point in our history where it is common, if not mandatory, to think of our unhappiness as a disease. And I’m going to do something else here: to try to convince you that what is at stake with antidepressants and the disease they treat isn’t only the question of whether or not to take drugs for our unhappiness, or even whether or not it’s really a good idea to call our unhappiness clinical depression. What’s at stake is who we are, what kind of people we want to be, what we think it means to be human.
If that seems like a stretch, then you should listen to Peter Kramer.
One of the strangest things about the antidepressant revolution, and one indication that more is going on here than biochemistry, is that the drugs that started it—the SSRIs, which first appeared in the United States in 1988—are no more effective at treating depression than the generation of drugs invented in the immediate aftermath of Betty Twarog’s discovery. And that’s not very effective. Nearly half the time, the drugs fail to outperform placebos in clinical trials. In real life (which generally lasts longer than a clinical trial and allows for modifications in dosage and brand), they seem to make a positive difference in perhaps 60 percent of the people who take them. You would think that if depression were really biochemical in nature and the drugs were really targeted at the culprit, they’d work better than that. Of course, the first part of that statement remains speculative: despite their best efforts—and notwithstanding what doctors tell their patients when they prescribe them antidep...
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