Coming of Age on Zoloft (6 page)

Endogenous depression was believed to be so rare that pharmaceutical companies didn’t even think there would be enough of a market to support a drug for it.
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(Depressive neuroses, while very common, weren’t considered an appropriate target for drug development; since they were thought to be a product of normal psychological functioning, coming up with a drug to treat their causes would have been an idea that just didn’t compute.
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) But in the period of intensive pharmaceutical research and development that followed the end of World War II, interest in drugs for mental illness had begun to stir. Thorazine, the first commercially successful psychopharmaceutical, was discovered in 1950 in France; it was an “antipsychotic” drug used to treat schizophrenia.
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At the time, most people in the industry assumed that the next profitable psychiatric medication would be yet another antipsychotic.
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And that’s just what scientists at the Geigy corporation in Switzerland were looking for when, almost at the same time as T.B. patients in New York were cheering up under the influence of Marsilid, they invented an experimental compound called imipramine. Imipramine proved hopeless as an antipsychotic. In clinical trials, it made schizophrenic patients boisterous and hard to control. But it certainly seemed to have some effect on mood. If the drug could tip schizophrenic patients into mania, some of the researchers reasoned, maybe it could help bring endogenously depressed patients the energy they needed to get well.

The exact origin of the decision to test imipramine on a tiny group of people with endogenous depression is hazy. But the trial, carried out in 1955 at a small country hospital in Switzerland, produced astonishing results. The very first patient recovered from her delusional depression within six days, and the next two also showed vivid improvement.
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Before the trial period was over, the head researcher wrote to imipramine’s manufacturer to state his opinion that the company had discovered a true drug for depression.

This time the psychiatric community took notice. In 1958 imipramine, which had been given the brand name Tofranil, went on the market in Europe as an antidepressant.
13
By this point, some psychiatrists in America had become interested in Marsilid’s antidepressant properties (an early champion, Dr. Nathan Kline, called Marsilid a “psychic energizer”), and it had also gone on sale as a treatment for depression. But neither drug exactly flew off the shelves, largely due to the belief among psychiatrists that endogenous depression was extremely rare. (To give you an idea of the tone of the discourse, an April 1957 article in the
Times
hailed the antidepressant Marsilid as a breakthrough treatment for the “unreachable, severely depressed mental patient.”
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) A few years later, Marsilid was pulled off the market when it was found to cause jaundice in a small number of cases.
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Imipramine, which was the first of what are known as “tricyclic antidepressants,” for their three-ring molecular structure, is actually still on the market in the U.S. and Europe; numerous studies have shown it to be equally or more effective than Prozac.
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Antidepressants had arrived, but the antidepressant revolution was still a few decades off. Before it could hit with full force, our ideas about what depression was would have to undergo their own transformation.

IF YOU CLOSE
your eyes and try to imagine scientists inventing a cure for an illness, you probably assume that they have at least a pretty good idea of how the disease works, and that they use that understanding to take aim at specific targets in the body. That’s more or less how I assumed the story of the development of anti-depressants would go. But in the case of depression, my presumption ran precisely backward. Antidepressants were invented by accident—twice—and scientists drew conclusions about the nature of the illness by investigating the action of the drugs.

Neuroscience is still a young discipline, and it was even younger in the early 1950s. During that decade, researchers in search of a challenge applied themselves to the problem of untangling how the two new classes of antidepressants worked. The first mystery was that while drugs in Marsilid’s family and drugs in imipramine’s family were both effective treatments for endogenous depression, they appeared at first to perform very different actions inside the brain.

Through a series of ingenious experiments, researchers discovered that while the two types of drugs do work in different ways, they lead to virtually the same end result. Each drug causes higher concentrations of the neurotransmitter norepinephrine to be present in the synapses—the tiny spaces in between the nerve cells that make up the brain, across which brain cells communicate with each other by chemical signals.
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,
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Drugs in impiramine’s family, the tricyclics, do this by blocking the re-absorption, or reuptake, of norepinephrine from the synapse back into the nerve cells around it. Drugs in Marsilid’s family, which came to be known as “MAO inhibitors,” or MAOIs, do it by dampening the action of an enzyme that breaks down certain neurotransmitters, norepinephrine included. MAO inhibitors also boost brain levels of another neurotransmitter, serotonin.
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Later research confirmed that tricyclic antidepressants do so too.
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Once scientists knew how the antidepressants worked, it was just about impossible to resist drawing up some new theories about what depression was. In 1965, a psychiatrist named Joseph Schildkraut pulled all that was known about antidepressant action into just such a theory. He used a process of simple reasoning backward: the known antidepressants, he observed, worked by raising the level of biogenic amines (a class of compounds that includes norepinephrine and serotonin) in the brain. Depression, he concluded, would therefore seem to be related to a deficiency of these same compounds—in other words, a chemical imbalance.
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Schildkraut’s ideas were known as the “amine hypotheses,” and the
American Journal of Psychiatry
paper in which he introduced them went on to become one of the most cited in the history of the field.
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“Thanks to Schildkraut,” reads his 2006 obituary in the
Times
of London, “it was generally accepted that depression is a medical illness and that many mental disorders are related to imbalances in chemicals in the brain.”
23

In the 1960s, multiple types of each antidepressant went on the market. Nardil, Pamelor, and Elavil joined the other treatments in psychiatrists’ arsenals. And psychiatrists did begin prescribing them to their most severely depressed patients. By 1987, about 1.8 percent of Americans purchased an antidepressant each year. That’s not nothing, but it’s hardly the explosive proliferation that would begin in the 1990s. Antidepressants might have remained a relatively specialized treatment, and the amine hypotheses just another piece of wonky scientific knowledge, lodged deep within its field. After all, endogenous depression was rare. Companies that made antidepressants didn’t expect them to be big sellers, and they weren’t. But changes were about to take place that would allow Schildkraut’s amine hypotheses to take root and grow, subsuming the old distinction between endogenous and neurotic depression, and ultimately becoming one of those big ideas that seems to take society by storm.

WHEN SCHILDKRAUT WAS
coming up with his amine hypotheses, the dominant framework in American psychiatry wasn’t biochemical but psychoanalytic. During the 1940s, 1950s, and 1960s, most people who had nonpsychotic mental problems and could afford to pay a professional for help would have gone to a psychoanalyst with a more or less Freudian orientation, who would have understood their problems as some variety of psychological reaction and would have treated them with talk therapy.
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Psychiatrists and the educated public alike assumed that most mental disturbances, even serious ones, were the result of intrapsychic processes involving inner conflicts and subconscious desires. Neurotic depressions and the like were understood as disorders of the emotions, but not diseases as such; in fact, Freud had used the term “neurosis” specifically to refer to a mental problem that was primarily psychological and not the result of any structural or functional problem in the brain.

It’s hard to appreciate now how thoroughly ingrained psychoanalytic ideas had become. It was true to the extent that Nathan Kline, a famous American psychiatrist who tried to popularize antidepressants in the 1950s, first described those drugs’ effects in
Freudian terms
: he hypothesized that MAOIs increased a person’s vital energies by reining in the ego, which was responsible for keeping in check the primal, libidinous id. By freeing up a burst of raw power from the id, Kline said, the medication would whet a person’s appetites for food, sex, and stimulation of all kinds, leading to a feeling of joyfulness and well-being.
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But by the 1960s, the psychoanalytic “establishment” was, as powerful incumbents will, attracting its share of criticism. Frustrated patients began to grouse that psychoanalysis was expensive and time-consuming. The technique didn’t always seem to produce a marked improvement. And it was notably bad at helping the people who needed help most, people with schizophrenia or other psychotic illnesses. (Indeed, reading about psychiatrists’ attempts to use the “talking cure” on its own to heal patients with severe mental illness is a poignant experience, and one that can put any critique of modern psychiatry into perspective.) Some people blasted analysts for being arrogant, always ready to blame a patient’s failure to improve on that patient’s subconscious “resistance,” rather than on the shortcomings of their own method.
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Also, beginning in the 1950s, medications began to compete with talk therapy for the first time. These weren’t antidepressants, which hadn’t become popular enough to make waves, but prescription drugs meant to alleviate the symptoms of neurotic anxiety. Miltown, launched in 1955, was the first prescription antianxiety drug. In 1960 it was joined by Librium and Valium, members of a new drug family called the benzodiazapenes. Originally marketed to ease the strains of corporate life for hard-driving businessmen, “tranquilizers” turned into a phenomenon. Some estimates claim that by the mid-1970s, about 15 percent of the adult population of the United States was using them.
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According to one apocryphal story, early demand for the pills was so great that ransacked drugstores were forced to hang out signs that read:
NO MILTOWN TODAY
.
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Eventually the tranquilizers’ popularity made them an object of mass cultural awareness, discussed and debated and joked-about in their era in much the same way that SSRIs have become in ours.

On the one hand, the tranquilizer explosion made psychiatry even more prominent and more influential. The availability of an easy fix for a common mental problem brought many new cases out of the woodwork, and demand for psychiatric ser-vices increased. On the other hand, tranquilizers could be read as a challenge to the psychoanalytic psychiatry of the day. They could be, and often were, prescribed by ordinary doctors rather than by expert psychiatrists.
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And while no one presented tranquilizers as a true cure for anxiety or anything else—their effects lasted just a few pleasant hours, and then you had to take another dose—they did seem to make an end run around the psychoanalytic method. Why spend long years analyzing your problems when you can pop a pill and watch them melt away?

By the 1970s, the backlash against psychiatry had intensified. Psychiatrists became the butt of criticism from the countercultural movement, which saw them as rigid and authoritarian. In 1975 Miloš Forman released his film version of Ken Kesey’s anti-psychiatry novel
One Flew over the Cuckoo’s Nest,
to critical acclaim. Two years earlier, a psychologist named David Rosenhan had humiliated the profession by performing an experiment in which perfectly healthy people presented themselves at mental hospitals, acting completely normal besides reporting that they had heard a voice saying the word “thud.” The subjects were admitted, diagnosed as schizophrenic, and held, often for weeks and sometimes against their will; Rosenhan had his results published in the prestigious journal
Science
.
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Many psychiatrists watched unhappily from the inside as their specialty threatened to descend into a national joke. Psychiatry, it seemed clear to many, needed to rehabilitate its image and bring itself in line with the times.

Some of them located the problem within psychiatry’s comparatively unscientific nature. Psychiatry is a medical specialty, and all psychiatrists have MDs. But psychiatry had long been seen as something like the redheaded stepchild of medicine. Unlike other doctors, psychiatrists didn’t perform surgeries or look at germs under microscopes; instead, they sat all day and
talked
to people. Plenty of analysts liked the subjective, interpersonal nature of their work just fine; for many, psychiatry’s humanistic bent was what had drawn them to it in the first place. But an increasingly energetic group believed that for psychiatry to find its way again and regain the respect of the public, it needed to become more rigorous and empirical, more like other branches of medicine. They wanted their discipline to ease out of its tweed jacket and slip into a white lab coat.

A group of these reformers, mostly based at Washington University in Saint Louis, got control of the American Psychiatric Association committee that was charged with revising the
Diagnostic and Statistical Manual of Mental Disorders
. First published in 1952, the DSM was meant to classify all known mental disorders, in order to aid psychiatrists in their process of diagnosis.
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To date, the book hadn’t carried a lot of weight in the field. The second edition, from 1968, which was the one up for revision, is a pamphlet slim enough to be read from cover to cover in an afternoon. Its words illustrate the psychoanalytic leanings of American psychiatry at the time. For instance, here’s how my condition in the fall of 1997 would have looked in DSM-II: