To gauge chlordiazepoxide’s toxicity to humans, Sternbach performed the first test on himself. He reported feeling “slightly soft in the knees” and a little bit drowsy for a few hours, but otherwise he experienced no ill effects. By the time the FDA approved the drug, on February 24, 1960, Librium had already been administered to some twenty thousand people. The early reports in the medical journals raved about its effectiveness. Patients who had previously found that only electroshock therapy could control their anxiety declared that Librium was equally or more effective. A study published in The Journal of the American Medical Association in January 1960 reported that when 212 outpatients in New Jersey with a range of psychiatric ailments were given Librium, 88 percent of those with “free-floating anxiety” received some degree of relief. The researchers also found that the drug was effective in treating “phobic reactions,” “compulsions” (what we would today label obsessive-compulsive disorder), and “tension.” The lead researcher of a separate study proclaimed the development of Librium to be “the most significant advance to date in the psychopharmaceutical treatment of anxiety states.”
The drug was shipped to American pharmacies in March 1960. The first Hoffmann–La Roche advertisement for Librium said it was for “the treatment of common anxieties and tension.” Within three months, sales of Librium were outpacing sales of Miltown; by the end of the decade, more prescriptions had been written for Librium than for any other medication on earth. Physicians prescribed it for everything from hangovers, upset stomachs, and muscle spasms to all varieties of “tension,” “nerves,” “neurosis,” and “anxiety.” (One doctor noted that Librium had the same range of indications as gin.)
Librium remained the most prescribed drug in America until 1969—when it was displaced by another compound synthesized by Leo Sternbach, this one with the mellifluous chemical name 7-chloro-1, 3-dihydro-1-methyl-5-phenyl-2H-1, 4-benzodiazepin-2-one. This new drug lacked Librium’s bitter aftertaste, and studies found it to be two and a half times as potent. The marketing department at Hoffman–La Roche dubbed it Valium (from the Latin valere, “to fare well” or “to be healthy”), and Valium, in turn, remained America’s most popular drug until 1982.a In 1973, Valium became the first drug in the United States to exceed $230 million in sales (more than $1 billion in today’s dollars)—even as its predecessor, Librium, continued to remain among the five most prescribed drugs in the country. In 1975, it was estimated that one in every five women and one in every thirteen men in America had taken Librium, Valium, or some other benzodiazepine. One study found that 18 percent of all American physicians were regularly taking tranquilizers in the 1970s. Advertisements for the drugs became ubiquitous in the medical journals. “It is ten years since Librium became available,” went the text of a typical Librium advertisement from the 1970s. “Ten anxious years of aggravation and demonstration, Cuba and Vietnam, assassination and a devaluation, Biafra and Czechoslovakia. Ten turbulent years in which the world-wide climate of anxiety and aggression has given Librium—with its specific calming action and its remarkable safety margin—a unique and still growing role in helping mankind to meet the challenge of a changing world.”
By the end of the decade, Librium and Valium had made Hoffman–La Roche—“the house that Leo built”—the biggest pharmaceutical company in the world. The benzodiazepines had become the greatest commercial success in the history of prescription drugs.
But as benzodiazepine sales grew through the 1960s and 1970s, so did the backlash against them. Some doctors warned that the drugs were being overprescribed. In 1973, Leo Hollister, a psychiatrist at Stanford, mused, “Whether the increase [in the use of antianxiety agents] is the result of the generally turbulent times which have prevailed in the past decade, or the introduction of new drugs and their widespread promotion, or of sloppy prescribing practices of physicians is uncertain.” (If 18 percent of doctors were themselves taking Valium, that might account for some of the sloppiness.)
By the middle of the 1970s, the FDA had collected numerous reports of benzodiazepine dependence. Many patients who had been on high dosages of Valium or Librium for long periods of time would experience excruciating physical and psychological symptoms when they stopped taking the medication: anxiety, insomnia, headaches, tremors, blurred vision, ringing in the ears, the feeling that insects were crawling all over them, and extreme depression—and, in some cases, seizures, convulsions, hallucinations, and paranoid delusions. By the time Ted Kennedy led the 1979 Senate hearings on the hazards of benzodiazepines, critics had a rich literature of horror stories to draw on. Judy Garland’s death, among others, was attributed to a toxic combination of benzodiazepines and alcohol. Fears about benzodiazepines were given a broad airing by Barbara Gordon, a star television writer at CBS who had been nearly destroyed by addiction to Valium. Gordon’s experience with benzodiazepine dependence, as recounted in her memoir, I’m Dancing as Fast as I Can, resonated widely. The book became a New York Times best seller in 1979 and a feature film starring Jill Clayburgh in 1982. That was the year Public Citizen, the organization led by the consumer advocate Ralph Nader, published Stopping Valium, which alleged rampant benzodiazepine addiction.
Social critics worried that the rampant prescription of Valium was papering over the rough edges of society, medicating away radicalism, dissent, and creativity. “One must consider the broader implications of a culture in which tens of millions of adult citizens have come to use psychoactive drugs to alter virtually every facet of their waking (and sleeping) behavior,” warned one doctor at a 1971 academic conference on drug use. “What does that say about the impact of modern technology on our style of life? What changes may be evolving in our value system?”b Marxist intellectuals like Herbert Marcuse attributed widespread pill popping to capitalist alienation. Conspiracy theorists invoked Aldous Huxley’s dystopian Brave New World, alleging that the government was exerting social control by tranquilizing the masses (which was ironic because Huxley himself was an enthusiastic promoter of tranquilizers). An editorial published in the prestigious British medical journal The Lancet in 1973 fretted that at current rates of Valium use, which up to that point had been growing at a clip of seven million prescriptions a year, “the arrival of the millennium would coincide with the total tranquilization of America.”c
The looming expiration of Valium’s patent in 1985 helped spur the rise of a new benzodiazepine, alprazolam, which the Upjohn Company released with the trade name Xanax in 1981. Entering the market just after the DSM-III had introduced anxiety disorders as a clinical category, Xanax got a huge commercial boost from being the first drug specifically approved by the FDA for the treatment of the newly created panic disorder.d
Many patients—and before long I was one of them—found that Xanax cut down on panic attacks and reduced physical symptoms like dizziness, palpitations, and gastrointestinal distress, as well as psychological ones like excessive timidity and feelings of dread. (The poet Marie Howe once told a friend of mine who was afraid to fly after 9/11: “You know that little door in your brain marked Fear? Xanax closes it.”) By 1986, Xanax had overtaken Miltown, Librium, and Valium to become the best-selling drug in history. It has dominated the tranquilizer market ever since.e
Anxiety and tension seem to abound in our modern culture and the current trend is to escape the unpleasantness of its impact. But when has life ever been exempt from stress? In the long run, is it desirable that a population be ever free from tension? Should there be a pill for every mood and occasion?
—FROM A DECEMBER 1956 REPORT BY THE NEW YORK ACADEMY OF MEDICINE
Benzodiazepines have been a leading pharmaceutical treatment for anxiety for more than half a century. But not until the late 1970s did the Italian neuroscientist Erminio Costa—yet another veteran of Steve Brodie’s lab at the National Institutes of Health—finally home in on their salient chemical mechanism: their effect on a neurotransmitter called gamma-aminobutyric acid, or GABA, which inhibits the rate at which neurons fire
.
Some brief and oversimplified neuroscience: A neurotransmitter called glutamate excites neurons, causing them to fire more rapidly; GABA, on the other hand, inhibits neurons, slowing their firing and calming brain activity. (If glutamate is the main accelerator of the brain circuitry, GABA is the main brake.) Costa discovered that benzodiazepines bind to GABA receptors found on every neuron, amplifying GABA’s inhibitory effects and suppressing activity of the central nervous system. In binding to the GABA receptors, benzodiazepines change the receptors’ molecular structure in a way that causes the GABA signal to last longer, which in turn causes the neuron to continue firing at a lower rate, calming brain activity.
Knowing even this superficial bit of neuroscience has given me a serviceable metaphor for understanding how my brain produces anxiety and how Xanax reduces it. When my anxiety mounts, my autonomic nervous system gets kicked into fight-or-flight mode, my thoughts start racing, and I start imagining all kinds of catastrophic things; my body feels like it’s going haywire. I imagine the firing of my synapses getting faster and faster, like an overheating engine. I take a Xanax, and about thirty minutes later, if I’m lucky, I can almost feel the GABA system putting on the brakes as the benzodiazepines bind to their receptors and inhibit neuronal firing. Everything … slows … down.
Of course, this is a rather reductionist metaphor. Can my anxiety really be boiled down to how effectively gated my chloride ion channels are or to the speed of neuronal firing in my amygdala? Well, yes, at some level it can. Rates of neuronal firing in the amygdala correlate quite directly with the felt experience of anxiety. But to say that my anxiety is reducible to the ions in my amygdala is as limiting as saying that my personality or my soul is reducible to the molecules that make up my brain cells or to the genes that underwrote them.
In any case, I have a more practical concern: What is this long-term reliance on benzodiazepines doing to my brain? By this point, I have taken benzodiazepines (Valium, Klonopin, Ativan, Xanax) at varying doses and frequencies for more than thirty years. For several years during that time, I have been on tranquilizers around the clock for months at a time.
“Valium, Librium, and other drugs of that class cause damage to the brain. I have seen damage to the cerebral cortex that I believe is due to the use of these drugs, and I am beginning to wonder if the damage is permanent,” David Knott, a physician at the University of Tennessee, warned back in 1976. In the three decades since then, scores of articles in scientific journals have reported on the cognitive impairment observed in long-term benzodiazepine users. A 1984 study by Malcolm Lader found that the brains of people who took tranquilizers for a long time physically shrank. (Subsequent studies have shown that different benzodiazepines seem to concentrate the shrinkage in different parts of the brain.) Does this explain why at the age of forty-four, after several decades of intermittently continuous tranquilizer consumption, I feel stupider than I used to?
* * *
* I’ve just listed ten of the thirteen DSM criteria for a panic attack; the other three symptoms are feelings of depersonalization or unreality, fear of losing control or going crazy, and fear of dying. At least four of these thirteen symptoms must be present for a panic attack to have occurred, according to the DSM.
† Another way of characterizing this was as a victory of the neo-Kraepelinians over the Freudians. Many scholars consider Emil Kraepelin, not Sigmund Freud, to be the crucial figure in the history of psychiatry. Psychoanalysis, these scholars say, was just a blip; Kraepelin’s system of disease classification both predated Freudianism and outlasted it.
In 1890, when Freud was setting up his practice in Vienna, Kraepelin, then a thirty-four-year-old physician, took a professorship in psychiatry at Heidelberg University. While there, Kraepelin became interested in the symptoms of various mental illnesses. He and his residents would draw up a note card for each patient who entered his clinic at Heidelberg and would record on it symptoms and a preliminary diagnosis. Each card would then be placed in the “diagnosis box.” Every time a new symptom appeared, and every time a diagnosis was revised, the patient’s card would be taken from the box and updated. When the patient was released from the hospital, his or her disposition and final diagnosis would be recorded. Over the years, Kraepelin accumulated many hundreds of such cards, which he would take on vacation to study. “In this manner we were able to get an overview and see which diagnoses had been incorrect and the reasons that had led us to this false conception,” he wrote.
This systematic recording of patient symptoms and diagnoses may not seem novel today, but no one had attempted to apply such thorough observation and classification to mental illness before Kraepelin. (Actually, one exception here was astrologers. Through the Enlightenment, astrologers kept meticulous medical records so they could chart symptoms against astrological alignments, looking for correlations that would be useful to them in future diagnoses and treatments. This record keeping may in fact have made astrologers better able to prognosticate the course of diseases than doctors, who acted on intuition rather than systematic observation. Astrologers, in other words, may have been more likely to provide evidence-based medicine than doctors were.) Diagnoses were haphazard and random. Kraepelin’s goal in gathering all this data was to try to cleave nature at the joints—to identify the cluster of symptoms that characterized each mental disease and to project their development over the life course. Unlike Freud (who was ambiguous about whether mental illness was a medical disease or a psychosocial problem of “adjustment”), Kraepelin came to believe strongly that psychiatry was a subfield of medicine. Emotional disorders were biological entities that could be identified and differentiated the way measles and tuberculosis were.
Kraepelin used the symptom data he accumulated on his cards as the basis of the psychiatry textbook he published in 1883. Revised multiple times over the years, his Compendium der Psychiatrie came to be the most influential psychiatric textbook ever published. By the time of the sixth edition in 1899, it had become the urtext of psychiatric classification.
Even through the middle years of the twentieth century, when psychoanalysis pushed Kraepelin’s biological psychiatry to the margins, the Kraepelinian and Freudian systems of disease classification existed side by side. When the first edition of the Diagnostic and Statistical Manual was published in 1952, it divided diseases into different illness categories based on symptom clusters, very much the way Kraepelin’s nineteenth-century textbooks had. But the terminology that described most of those illnesses was psychoanalytic, so almost everything in the first two editions of the DSM blended together into a soup of medical and psychoanalytic nomenclature.
‡ I will say more about this in chapter 7.
§ The distinction between, say, generalized anxiety disorder and panic disorder lies not in how the disease is acquired—whether by genes or childhood trauma or unreleased libido—but on whether a person experiences a certain minimum number of symptoms from a checklist.
‖ Recall from chapter 2 that some genetic research suggests there is in fact no meaningful difference between depression and generalized anxiety disorder.
a Sternbach would also develop flurazepam (marketed as Dalmane) and clonazepam (marketed as Klonopin). Klonopin, like Valium, is still frequently prescribed today as a long-acting benzodiazepine.
b Feminists had related concerns. A series of ads run by Roche in the early 1970s presumed to offer a treatment for spinsterhood: “35, single and psychoneurotic,” began a typical full-page advertisement, this one telling the sad story of Jan. “You probably see many … Jans in your practice,” the ad went on. “The unmarrieds with low self-esteem. Jan never found a man to measure up to her father. Now she realizes she’s in a losing pattern—and that she may never marry.” The cure? Valium. (“You wake up in the morning, and you feel as if there’s no point in going on another day like this,” Betty Friedan had written in 1963 in The Feminine Mystique. “So you take a tranquilizer because it makes you not care so m
uch that it’s pointless.”)
c As it turned out, Valium use peaked in 1973.
d This approval was not without controversy. The first favorable studies of Xanax’s effect on panic were published in the Archives of General Psychiatry, whose editor at the time, Daniel Freedman, turned out to be on Upjohn’s payroll as a member of its Division of Medical Affairs. Critics said this had unduly biased him and that the studies should not have been published because they were poorly constructed and therefore did not actually demonstrate that the drug was effective.
e In 2010, Xanax was the twelfth most commonly prescribed drug in America and the most frequently prescribed psychotropic medication—more widely prescribed than Prozac or any other single antidepressant.
CHAPTER 7
Medication and the Meaning of Anxiety
When Valium came along, both patients and their doctors were willing to define their problems in terms of anxiety.… When Prozac, a drug for depression, arrived on the scene, the accent fell on depression as the hallmark of distress.
—EDWARD SHORTER, A History of Psychiatry (1997)
In the spring of 1997, after a difficult year—my parents’ divorce, an unhappy job situation, a bad romance—and some months off psychiatric medications, I began, at my therapist’s urging, to take Paxil, an SSRI whose generic name is paroxetine.
After a week or so on Paxil, I experienced an infusion of energy that bordered on manic: I slept fewer and fewer hours, but without feeling tired during the day; I could, for the first time in my life, regularly awake in the morning feeling energetic. The mild mania passed, but what followed was a slow brightening of my mood. I ended—finally, after several unsuccessful attempts—my codependent and dysfunctional relationship with my girlfriend of nearly two years. I got a promotion at the small magazine where I was working. I started dating.
My Age of Anxiety: Fear, Hope, Dread, and the Search for Peace of Mind Page 24