Manufacturing depression (26 page)

That idea—that Chemicals ‘R’ Us—is the conceptual backbone of the depression industry. Before you can accept that your mood is merely the symptom of a brain disease, you have to at least implicitly
believe that consciousness is nothing more than the steam that rises off the soup. This notion has been around for more than a century—it was 1874 when Thomas Huxley, Aldous’s grandfather, first compared consciousness to steam (in his case the steam that pours out of a whistle)—but it began to take its current shape as an article of scientific faith in the 1950s, with a series of accidental discoveries about brain chemistry, many of which, as it happens, came about as the result of antidepressant research.

Many of those accidents involved people, like Albert Hofmann, who unexpectedly experienced altered states of consciousness. To a scientist interested in the workings of the mind, these experiences naturally beg for explanation. But if the scientist in question is working for a drug company, more is at stake than mere curiosity. Drugs like LSD and MDMA, with all their psychic fireworks, don’t fit very well with the pharmaceutical paradigm, in which a drug with predictable effects is used—preferably on a frequent basis—to treat a specific illness. To understand the mechanism of these drugs is to harness their power, to domesticate them—which, in the course of the 1950s and 1960s, industry scientists were able to do. In this respect psychopharmacology in general, and antidepressants in particular, are the bastard offspring of mind-altering drugs and the pharmaceutical industry, or, to put it another way, of getting high and making money.

If that sounds like the ravings of a substance abuser, then consider the case of Madame X, a woman who went into a Paris hospital in 1948 for a nose job. For the obvious reason, she couldn’t take anesthetic through a mask, nor was she eager to stay awake for the procedure, so she was given a cocktail containing a newly discovered drug. She remained conscious as the surgeon worked, but she remained perfectly calm.
“I felt the hammer striking
and the scissor cuts, but as if it was happening to someone else’s nose: to me it was indifferent.”

Madame X’s strange state of consciousness was not entirely accidental. Her doctors got the idea for the anesthetic potion from
none other than Paul Ehrlich. In his search for a cure for malaria,
Ehrlich had tried a dye
that lit up that parasite beautifully on slides: methylene blue. It didn’t cure the disease, but in the course of trying, he found something curious. If he injected the dye into frogs, it stained their nerve cells much more vividly than other types of tissue. Methylene blue and nerves, in other words, had a strong affinity for each other; their receptors—structures that Ehrlich had hypothesized to exist but had never seen—were a good match.

Ehrlich was impressed enough to try the dye as an analgesic. It didn’t work, but in 1899, a Genoan doctor,
Pietro Bodoni, started to give methylene blue
to psychotic people. The dye calmed them down, and Bodoni’s colleagues in Italy began to use it in their asylums. Thirty-five years later, an American doctor used methylene blue successfully with schizophrenics, and as late as the 1970s doctors were giving it to manic-depressives. So why haven’t you ever heard of this promising drug? Well, according to psychiatrist/historian David Healy, it’s partly a case of bad luck. Every time doctors got interested in methylene blue, it was eclipsed by more dramatic therapies: barbiturates, which came into vogue just as Bodoni was doing his experiments, the shock treatments of the 1930s, and the more powerful antipsychotic drugs of the last half of the twentieth century. But Healy thinks methylene blue is a victim of a business decision:
“Patents had been obtained
on newer agents and no drug company would market an old drug even if it worked.”

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 depressive 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.