But what about a new drug based on methylene blue? Now, that you could patent. And in the late 1940s, a French drug company, Rhône-Poulenc, was very interested in expanding its market share of antihistamines, drugs like Benadryl, which had been profitable since 1933. The company had figured out how to extract the nucleus of methylene blue—which it called phenothiazine—in order to make new drugs. None was more effective at treating malaria than methylene blue had been, but they had an overall effect that was interesting. If you gave them to rats that had been trained to climb ropes either to get food or to avoid a shock, they stopped climbing; even stranger, they didn’t seem bothered by the shock. Upon further study, the Rhône-Poulenc scientists concluded that the rats were neither sedated nor impaired; they just didn’t give a rat’s ass.
The drug that helped Madame X keep her head while doctors chiseled away at her nose was a phenothiazine. The psychiatric implications of such a drug were obvious, and soon French doctors were using a particularly strong phenothiazine—RP4560, or chlorpromazine—on their psychotic (mostly schizophrenic) patients. At first, chlorpromazine was administered as an adjunct to a shock treatment popular in France—packing psychotic patients in ice, on the theory that the drug enhanced the hibernation effect, which allegedly cured patients by putting them in a somnolent state. One day, so the story goes, there was no ice on the ward, but the nurses administered the drug anyway. The patients improved, and soon nurses were relieved of the burden, and patients of the discomfort, of the ice treatment.
The drugs became known as tranquilizers, and their effects were immediate and profound—on both the patients and their keepers. One asylum doctor reported:
In the corridors…one no longer passed patients in shirts walking with their straitjackets open with straps undone on the way to the toilets, but patients dressed in heavy blue cloth, strolling decently and quietly…The most evident sign of this extraordinary therapeutic result could be appreciated even from outside the building—there was silence.
Like Rhône-Poulenc’s rats and Madame X, the patients were calm but not sedated. Indeed, previously unresponsive people seemed to wake up, and nearly everyone who took the drug became more oriented and able to engage with others. It was as if chlorpromazine had tamed their inner demons sufficiently to allow them to reenter the world. Or, as another doctor put it, the drug acted like a “pharmacological lobotomy.” He meant that in a good way.
Chlorpromazine was slow to catch on in the United States, where 80 percent of psychiatrists were private practitioners providing therapy to neurotic patients rather than asylum doctors presiding over the psychotic. Smith Kline and French did license the drug in 1953, but only because it happened to reduce nausea and SK&F had just introduced a heart drug that made people vomit; the idea of selling one drug to counteract the side effects of another was irresistible. The company, which named the new drug Thorazine, did manage to prevail upon some leading psychiatrists to try it; they were unimpressed with the results and worried by strange side effects. Finally, however, SK&F got the drug into the hands of the head of New York’s state hospital system, and in 1955, the company sold $75 million worth of Thorazine, most of it for use in asylums across the country. Having found the right target for the phenothiazine effects—whatever they were; scientists couldn’t explain Thorazine any better than shock therapies—psychiatry had its first magic bullet.*
That $75 million figure did not escape the notice of the rest of the pharmaceutical industry. Even before Thorazine hit the market, Geigy Pharmaceuticals, one of the drug companies that started its life as a dye manufacturer in the mid-nineteenth century, had been looking into antihistamines, and SK&F’s sudden success only ramped up the effort. Geigy wasn’t interested in a me-too drug, a version of the compound modified just enough to steer clear of patent infringement. Instead, they looked at another dye that they had on their shelves—summer blue, from which they derived iminodibenzyl, a molecule that, like phenothiazine, showed an affinity for nerve tissue and could be easily modified.
Geigy’s team soon synthesized what they thought was a promising compound, G22355. The youngest member of the team, British pharmacologist Alan Broadhurst, was the first test subject. This was in the days when drug research was almost entirely unregulated. That’s why a company could bring a drug to market just a few months after its first use in humans. It’s also why the trial didn’t come to a sudden halt when Broadhurst fainted as soon as he received the injection.
Once they got the dosage problem straightened out, the Geigy scientists sought out patients on whom to test their drug. Fortunately for them, Roland Kuhn, who ran an asylum in Switzerland, was just then getting tired of paying top dollar for chlorpromazine. He had worked for Geigy before, and when he heard about G22355, he offered his patients as subjects in return for a free supply of the drug. It quickly became apparent that G22355 wasn’t going to compete with chlorpromazine, no matter how cheap it was. If anything, it made schizophrenics more delusional. Broadhurst remembers one case in which a patient, in an unwitting reprise of Albert Hofmann’s bicycle trip, “rode, in his nightshirt, to a nearby village, singing lustily, much to the alarm of the local inhabitants. This was not really a very good PR exercise for the hospital.” Broadhurst added, “And I can’t say it endeared the hospital to Geigy either.”
The scientists, according to Broadhurst, “stumbled around considering a variety of unlikely hypotheses and mechanisms” to explain these untoward results until finally they began to realize—with what Broadhurst now calls the “most naïve scientific reasoning…something which I now look back on with a kind of embarrassment”—that if they switched their focus, they just might have a valuable drug on their hands. “If the flat mood of schizophrenia could be lifted to hypomania by the drug,” they reasoned, “then could not in a similar fashion a depressed mood be elevated also?” If G22355 got people high, in other words, then why not use it with people who were low?
In 1956, Geigy decided to answer that question. The company asked Roland Kuhn to give G22355 to his depressed patients, and within weeks, he reported back that depressed patients taking the drug felt much better. In 1957, he sang the drug’s praises to the readers of a Swiss medical journal and to the International Congress of Psychiatry at their meeting in Zurich. A year later, he repeated the performance at Galesburg State Hospital in Illinois, a talk published by the American Journal of Psychiatry at year’s end. His data was overwhelming, his enthusiasm even stronger, but G22355—by then known as imipramine—was hardly taking the world by storm, and Kuhn was roundly ignored. Indeed, according to one doctor active in the late 1950s, psychiatrists compared him to Ichabod Crane, an outsider with an inflated sense of himself and his ideas.
Reading Kuhn’s paper now, it’s easy to see why his colleagues isolated him. At a time when psychoanalysis was the mainstay of psychiatry, he was arguing that imipramine could “bring a complete change in the situation within a few days, which could not be achieved by intensive prolonged psychotherapy.” In the immediate wake of Thorazine’s success, he had advanced the claim that a closely related drug would have the opposite effect—stimulating rather than tranquilizing patients. These notions were heresy enough, but even more jarring was Kuhn’s idea that imipramine cured an illness that few doctors had even heard of: endogenous depression, in which unhappiness seems without external cause and thus can be presumed to be biological in origin. This “vital disturbance,” Kuhn claimed, is what imipramine was uniquely suited to treat.
Endogenous depression was easy to miss in part because its primary symptoms—“a general retardation in thinking and action, associated with fatigue, heaviness, feeling of oppression, and a melancholic or even despairing mood”—were less florid than the delusions and mania of the affective psychoses. But the disease was also insidious. It hid in the plain light of more obvious problems—anxiety, phobias, hysteria, insomnia, impotence, homosexuality; indeed, according to Kuhn, “Almost any neurotic symptom can be caused by a depr
essive state or be maintained because of the simultaneous occurrence of a depression.” It could even be the cause of reactive or, as the Freudians were calling it, neurotic depression—the reason that those external factors kindled a melancholic response to a loss in the first place. Worst of all, endogenous depression came on slowly and imperceptibly, manifesting in “mild disturbances, which hardly appeared pathological at the time.” You could be endogenously depressed—indeed, if you were suffering from a “neurotic symptom,” you very likely were—and not even know it.
Until you took the drug, that is, and realized, as many of Kuhn’s patients told him, that you “had not been so well for a long time.” This was no mere euphoria, Kuhn assured his skeptical colleagues, and imipramine was no simple amphetamine, which doctors had been using for thirty years to lift people’s moods; people didn’t develop tolerance and craving for it. Imipramine “completely restore[d] what the illness…impaired—the power to experience.” Imipramine didn’t simply improve your mood; it changed something underlying it, the endogenous, and presumably biochemical, problem that gave rise to your mood—in short, your disease. Amphetamines only made you feel better, but imipramine made you feel well—which meant that you must have been sick all along. The drug had revealed the contours of a disease.
The suggestion that doctors had misunderstood the nature of depression, and the controversy it inspired, were not new. But by 1958, the arguments among Kraepelin and his colleagues, and between them and the rest of the psychiatric profession, had been forgotten. Freud’s nosology and his contention that psychological suffering arose out of personal history had sent Kraepelin into eclipse—a “world-wide ignorance,” that Kuhn bemoaned.
Kuhn’s affinity for Kraepelin is obvious. His theory was Kraepelinian logic on drugs. Endogenous depression was exactly the disease that imipramine cured, and the proof that you had been sick was that imipramine cured you. Imipramine wasn’t only a cure; it was the chemical that assayed for the presence of the disease. Kuhn was pushing psychiatry closer to fulfilling Kraepelin’s promise that mental illnesses would be found in nature. After all, if a chemical could identify and fix the problem, then doesn’t it stand to reason that it was chemistry that was broken in the first place?
You would think that, especially in a permissive regulatory climate, a drug company would sit up and take notice when a doctor informs it that its new drug is a magic bullet for a widespread, if hitherto under-recognized, disease, puts that assertion on what appears to be a firm scientific footing, and then adds that “therapy must be maintained as long as the illness lasts”—which, since the problem was “endogenous,” may well be a lifetime. But Geigy was mostly unimpressed with Kuhn’s reports; the company’s marketing experts said that depression was too small a market to bother with. It would take thirty years before the ideas really caught fire that a disease could show up in nearly any malady and be a problem before the patient even knew it, that not feeling well enough was an illness that could be remedied by a prescription.
By then, of course, marketing experts had gotten more savvy and drug companies more determined. They wouldn’t, for instance, have let the fact that an antidepressant drug was derived from a substance called summer blue pass them by, or be dissuaded by ethical concerns about convincing people that they are sick. But that’s not to say that the first generation of antidepressants were without their hucksters. It’s just that they weren’t to be found in the Old World, but in the United States.
In 1952, a story appeared on the front page of the New York Times reporting on a drug for tuberculosis that was being tested on patients at Sea View Hospital on Staten Island. The drug—iproniazid, or as Hoffman–La Roche called it, Marsilid—was having some remarkable effects. Not only was it healing people’s lungs, but according to doctors, it was also relieving their pain enough for them to give up narcotics and, at least sometimes, instilling in them a “euphoria” that after three or four weeks leveled off into a “normally optimistic instead of a depressed attitude.” In fact, as doctors soon discovered, the drug was capable of making patients feel better than their X-rays said they were. “This suggested,” wrote the Times reporter, “the use of the chemical in conditions other than tuberculosis.”
Iproniazid was invented when the stocks of hydrazine, Germany’s primary fuel for their V-1 and V-2 rockets, went to Roche at the end of World War II. There was some evidence that hydrazine could be modified into an antihistamine that might be particularly effective against tuberculosis, but once the psychological side effects made themselves known, it didn’t take a rocket scientist to figure out what to do next. It also didn’t take a drug company executive—Roche was as lukewarm as Geigy about the commercial prospects of an antidepressant. What it took was Nathan Kline, an American psychiatrist known as “an international wheeler-dealer, a flamboyant, buccaneering fellow [who] would try anything on his patients.” And that was according to one of his friends.
Kline was honest about his own ambitions and the love of power from which they came. “Research scientists are wide-eyed manipulators,” he once wrote.
When an observant brat discovers for the first time that he can push buttons, turn faucets, open doors, dial phone numbers and exploit his parents, he is astonished and delighted to uncover and control the physical and social environment. Some of us never recover.
Iproniazid wasn’t the first button that Kline had put his finger on. In 1954, he’d gotten hold of reserpine, a drug that Geigy had recently synthesized. Reserpine was the active ingredient of Rauwolfia serpentina, or snakeroot, an herb known for centuries to India’s ayurvedic physicians, who called it sarpagandha, as a cure for many complaints, and to holy men as pagal-ki-dawa, a remedy for insanity. Kline gave it to more than seven hundred psychiatric inpatients and found that it calmed down most of them—enough, he said, that the glaziers at his hospital reported that they had fewer shattered windows to replace.
Given what John Gaddum and other researchers were saying about LSD and serotonin, Kline and other scientists speculated that reserpine was increasing serotonin levels in the brain. Experiments carried out at the National Institutes of Health, however, showed that reserpine lowered levels of serotonin in rabbits’ brains even as it made them sleepy and immobile. But the idea that a simple brain glitch was the cause of mental illness was too pleasing to be discarded because of one experiment, and soon scientists were talking about serotonin imbalances rather than deficiencies; insanity could now be a problem of excess or deficient serotonin.
As you’ll see in a moment, this new theory was even more wrong than the one it replaced, but before anyone knew that, Kline had already taken it a step further, using the same “naïve” reasoning that embarrassed Alan Broadhurst. If a drug could depress mental functioning—a good thing in the case of people who were agitated and hallucinating—what about a drug that did the opposite? A “psychic energizer,” as Kline named it,
would relieve simple depression and…the sadness and inertia of melancholia…reduce the sleep requirement and delay the onset of fatigue…increase appetite and sexual desire…Motor and intellectual activity would be speeded up. It would heighten responsiveness to stimuli, both pleasant and noxious.
In 1956, Kline heard that scientists had given iproniazid along with reserpine to lab animals, which, far from being sedated, had become hyperactive. The possibility that the drug could reverse the reserpine effect, Kline said, “immediately led me to speculate whether this was the psychic energizer for which we had all been looking.”
That’s how Kline told the story in 1970 anyway. Like Zarate thirty-five years later, he mostly left out the part about how the drug was already known to make people high in favor of a story about scientists reaching conclusions through sober reasoning. It’s not clear which version Kline told to the research director at Roche, but by then the company had become disenchanted with iproniazid as a tuberculosis treatment—those darned side effects!—and they remained uninterested.
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��Here indeed was a fairly unique situation!” Kline wrote years later. “A group of clinical investigators were trying to convince a pharmaceutical house that they had a valuable product rather than the other way around.” Kline was in a good position to mount his campaign for iproniazid. The drug was already on the market, and he was the director of research at New York’s Rockland State Hospital. In 1957, he put together a team that quickly launched a study of iproniazid treatment for seventeen hospitalized schizophrenics and nine of Kline’s office patients who were depressed. When the depressed patients seemed to be getting better, Kline arranged to testify to Congress on the subject of iproniazid and to have his work published in the Congressional Record—a move that at once avoided peer review and guaranteed publicity. He also used his position as the head of the American Psychiatric Association’s committee on research to secure a spot at a regional conference in Syracuse, New York, to present his findings. He parlayed this relatively obscure gig into a preconference interview with a New York Times correspondent, who dutifully reported that “a side effect of an anti-tuberculosis drug may have led the way to chemical therapy for the unreachable severely depressed mental patient.”
Kline’s showmanship paid off, at least temporarily. In the next year, Roche, which had all but abandoned iproniazid as an antitubercular, sold the drug to four hundred thousand presumably happy, or at least less unhappy, customers.
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It is impossible to know how many of these patients would have impressed Kuhn as endogenously depressed, or, for that matter, how many American doctors rendered an official diagnosis of depression before reaching for the prescription pad. In part, that’s because diagnostic specificity and the record keeping it allows were still a thing of the future. The DSM in use in 1958 was a mere 132 pages and counted among its 125 diagnoses inadequate personality and imbecility, diseases whose eye-of-the-beholder vagueness could only support the prevailing view that, as one doctor put it in 1960, “a disease is what the medical profession recognizes as such.” It’s enough to make you grateful for the faux objectivity of the more recent DSMs.
Manufacturing depression Page 20