Blue Dreams

by Lauren Slater

  Remember, Thorazine started its life as an anesthetic potentiator, lauded for its mood-altering properties, its ability to cool patients down, to slow the blood supply to the limbs, and, in so doing, to make surgery easier to perform. Thorazine as we know it was born not when chemists Paul Charpentier and Simone Courvoisier chlorinated the antihistamine promazine, but rather before that, when Henri Laborit observed the indifference in his surgery patients who were under the influence of promethazine, a similar antihistamine, and thus suggested it for psychiatric use. The drug came into being because someone saw it in a new way and dared to dream about uses that were not immediately obvious. In some senses all drug discovery, while clearly the work of scientists, is really done deep in dream, in vision, and proceeds more like the making of a novel than the compounding of chemicals for a clear purpose.

  In their casting about, young Broadhurst and the group of scientists he oversaw gravitated toward the antihistamines because the French, in Thorazine, had given them a big, bright clue. “Eventually,” wrote Broadhurst in his recollection of those times, “the spotlight fell on iminodibenzyl,” a tricyclic substance that, like Thorazine, was descended from a dye—summer blue rather than methylene blue—but was “actually very different in chemical terms.”

  Once the scientists made the choice to focus on iminodibenzyl, they had effectively narrowed their search. At the company’s request, Geigy’s organic chemists created derivatives of the substance, forty-two in all, by making minor alterations in iminodibenzyl’s molecular side chains. The scientists next began testing these derivatives on lab animals—rats, mice, and rabbits—with the goal of discovering which compounds were toxic. Broadhurst, like Cade before him, even went so far as to ingest one of the compounds himself. Eventually the team narrowed in on G22150, the code number given to the least toxic and most sedative of the compounds. Even when administered in heaping doses to the smallest of the animals, the chemical remained nontoxic and efficiently sedating. The thought at Geigy was that it might be developed for clinical use as a hypnotic. Again and again in these accounts one is struck by the arbitrary nature of the entire endeavor of drug research. Insomnia was not a problem the Geigy scientists had set out to treat. They had no specific interest in it. But as often continues to be the case, drugs came first, diseases second.

  Testing the Drug

  In 1950, a year into their efforts, the chemists at Geigy approached a number of psychiatrists, asking if they would be willing to try Geigy’s new substance on some of their insomniac patients. One of these doctors was Roland Kuhn, an esteemed and self-assured psychiatrist at Münsterlingen Hospital, in Switzerland, on the shores of Lake Constance. After considering the proposal, Kuhn, though he was formal and somewhat stern, agreed to test the drug on his sleepless patients.

  Nowadays no drug is tested the way the Geigy scientists sought to test G22150. A drug developer does not home in on a derivative that might have some use and then find a physician willing to give it a whirl, using his or her patients as subjects. The process has become highly regulated, with clinical trials and a double-blind design and an institutional review board overseeing the process. Moreover, the new product is always tested against a placebo, which takes years and years and millions of dollars. The story of imipramine’s development, like Thorazine’s, has an almost fairy-tale quality to it, in a time and a country in which there were no agencies such as the FDA or the DEA—the Drug Enforcement Administration—or institutional review boards. On the one hand, drug development has probably gained from its much stricter surveillance, as patients are at the very least protected by ethical guidelines. Psychiatrists such as Kuhn, however, believed that the best way to test a drug was not through clinical trials that proceed in excruciatingly slow and expensive stages, but rather through careful clinical observation that arises only in the context of an empathic and understanding relationship between patient and practitioner.

  After agreeing to give it a try, Kuhn dutifully dispensed G22150 to Münsterlingen’s insomniac patients, and thus the chemical began its life as a sleeping pill. It was a failure. Some patients slept well; others seemed entirely unaffected. Geigy abandoned G22150 and with it the fleeting desire to help those afflicted with insomnia.

  Their scientists, however, soon identified a new focus, G22355, which shared many chemical similarities with Thorazine. Broadhurst and others at Geigy were becoming aware that Thorazine had slipped from surgery into psychiatry in France, and that Jean Delay and Pierre Deniker were getting outstanding results in treating schizophrenics. Even though Geigy’s scientists did not want to develop a “me too” drug, they could not help but wonder if their new darling might also be a successful treatment for psychosis. “The road to Münsterlingen was already well trodden,” Broadhurst recalled, “and soon we were retracing our steps to the psychiatric hospital there to ask Dr. Kuhn if he would try out our new drug in schizophrenia.”

  Despite the failure of G22150, Kuhn was willing to give this new drug a chance. Schizophrenic patients who were currently on Thorazine (or Largactil, as it was called in Europe), which was growing too expensive for regular use, were pulled off, and Kuhn assembled a group of drug-free schizophrenics as well. All were administered G22355. Despite their scant knowledge of the compound, the Geigy scientists, the staff at Münsterlingen, and Kuhn himself all thought that this drug, so similar in structure to Thorazine, would work, and that when it did, there would be a second antipsychotic to add to the arsenal.

  Thus the whole team—everyone involved with the trial except the patients themselves—waited expectantly, hoping that this time would be an arrow straight into the bull’s-eye of their patients’ intense suffering. As the drug flowed through the patients’ veins, the nurses watched closely for just a flicker of change, although they knew that no drug, not even Thorazine, could instantly alter an illness as severe and static as schizophrenia. A silence descended over Münsterlingen in the days during which this new drug was being transmitted to patients—the silence of suspension, of something held aloft.

  Eventually, in a period ranging from a few days to several weeks, the patients who had been given the new drug began to show some behavioral changes that “were not only fascinating,” according to Broadhurst, but also, “in some patients, quite alarming.” What happened is this: a group of usually quiet, sedate schizophrenic patients began to pace, showing increasing agitation. Some became energized, but the energy was disorganized and senseless. They skipped in small circles, or sang nonsense songs. Row row row your boat. Down the dock. Made of rock. Hackensack. Believe your back. Life is but a dream. One patient, charged up with insane energy, managed to get hold of a bicycle and, one night, with the stars wheeling over the mountaintops, pedaled over to an adjacent village in his nightclothes, singing at the top of his voice. The sleeping denizens rose from their beds and parted their curtains to see a sweating man speeding down the street with his head tipped back and his voice tumbling and trembling as the songs spewed forth and billowed into the air like smoke.

  The Geigy scientists, the nursing staff, even Kuhn himself—all were crestfallen. Clearly the drug had had an effect, but it surely did not organize schizophrenics. There were a few patients, those with a depressive streak in their illness, in whom some improvement was noted. But only some improvement. Nothing like the huge home runs that had been happening with Thorazine in France. “Our disappointment was intense,” wrote Broadhurst. In dismay, they abandoned the clinical trial and “spent many agonizing hours trying to find an explanation as to what might have happened to precipitate such a reaction in certain patients. We stumbled around, examining a number of unlikely hypotheses and mechanisms.”

  These stumbling sessions took place at Geigy’s headquarters in Basel, where the scientists cast about for an answer. But they were all ambition, no vision. They had not even an inkling of what it was they might want to try next. As they huddled around a table one day, trying to make sense of why it was that their antipsychotic had fa
iled so miserably while Thorazine, so similar, was such a spectacular success, an idea crystallized. Who spoke it first is unclear—Broadhurst believes it may have been his colleague Paul Schmidlin—but the scientists began to speculate on the reasons for the drug’s tremendous energizing effect. Those pacing schizophrenics had acted as though they were wearing battery packs. And that bicycle man, the one with his song streaming out of him beneath a starry sky—he was a man without an orbit, wavering and wobbling, but happy. Yes, some of the patients had seemed oddly happy on G22355, had they not, or if not happy, then at least endowed with an intention that made them circle and pace. The drug had bestowed on almost every patient who took it some sort of motivation, and thus…could it be, might it be…an antidepressant?

  In hindsight, when everything appears so obvious, it seems incredible that the scientists took so long coming to their conclusion. But as Healy points out, the word “antidepressant” was not really in existence when imipramine was first discovered, a lack of language that may shed some light on why the insight that was finally wrought from their tortured speculations did not occur to them earlier. According to Broadhurst, “In retrospect, it all seems so naïve, so preposterous, so mechanistic, and yet so simple, but we wondered if the apparent mood elevation seen in the schizophrenic patients might also occur in depressed individuals, but in this case with a beneficial outcome.”

  So it was that the scientists returned to Münsterlingen for the third time, asking Kuhn once again if he would be willing to try G22355, only this time on his depressed patients. “I well remember the look of suspicious disbelief on his face,” wrote Broadhurst. But eventually Kuhn was persuaded to undertake a new clinical trial, which began in late 1955. First intramuscularly and then orally, G22355 was administered to a group of asylum patients with severe vegetative depression. Forty patients altogether were given the drug, after which came, once again, the waiting game, the empty silence, the staring, with no evidence of effect as the days dripped by and everyone waited—most especially the patients, who had the most to gain and the most to lose. Unlike the previous patients who had taken the drug, these were not the walking wounded. Nor were they schizophrenics lost to the world. They were cognizant of their condition, trapped in a terrible paralysis. Patients hospitalized for depression in the 1950s tended to be seriously stuck, immobilized by their relentless pain, entirely unable to cope but nevertheless harboring clear memories of who and what they had been prior to their descent, the knowledge of the cruel contrast difficult to bear.

  As with the earlier trial of G22355, this one was also entirely uncontrolled. The scientists simply gave some samples to Kuhn, who in turn administered those samples to the patients he picked. But the simplicity that may appear distressing or careless was not necessarily so. While Kuhn had never employed a double-blind study, placebos, a statistical treatment of data, or any of the other accoutrements of clinical trials that today are paramount, he “examined each patient individually, often every day, on several occasions, and questioned each patient again and again.”

  The first patient to show a change was forty-nine-year-old Paula J.F., who had been depressed and deluded for years. She began treatment with G22355 on January 12, 1956, and only days later appeared completely well. About three weeks after the start of the trial, both the scientists and Kuhn were able to see incredible results in many other patients as well. “It was clear that G22355 was producing a dramatic, and this time beneficial, response,” wrote Broadhurst. “About two-thirds of the patients showed marked reduction in their depressive symptoms. Individuals with biological—or as Dr. Kuhn described them, ‘vegetative’—symptoms tended to do best.”

  Resistance

  Like Thorazine, which found success through large public mental health hospitals, G22355 was slow to make inroads into the psychiatric community, again at least in part because the 1950s were the heyday of psychoanalysis and psychodynamic therapies, an era in which depression was seen as internalized rage, sublimated sexual distress, or even the externalization of a psychological snarl the patient had yet to work through. It was one thing to calm a psychotic person through chemical means, but treating depression with drugs was antithetical to the zeitgeist. Drug treatment, it was widely believed, would slow down or short-circuit the patient’s effort to get to the heart of his trouble and was therefore to be avoided at all costs.

  Certainly I harbored these notions as I stood on the street outside the apothecary that snowy night, rolling my just-filled bottle of imipramine back and forth in my ungloved hand, watching the flakes form on its curved surface, until the bottle was furred with snow and the ink ran black, staining the pristine white. I clearly remember later on, back at my dorm, placing two of the tiny candy-coated pills on the pad of my tongue and washing them down with water, followed by a sweet aftertaste and then the swale of sleep drenched in contorted dreams full of clowns with melting mouths and clouds rolling on the ground, the red scream of a siren, a swan in full flight, bones in a bag, the dagger of an icicle with a drop of water trembling at its tip. My hesitations and the extreme side effects of the drug that set in the very next morning—fuzziness, sweating, a tacky mouth and tongue—did not, however, stop me from taking it, because I had already tried, unsuccessfully, to dredge up my rotten rage, to blame my mother, to deeply weep, and it had all come to naught. So what other choice did I have, exactly? I have to think that, twenty years earlier, just as G22355 was being tested, the patients taking it must have felt similarly.

  And it may be that some psychiatrists felt similarly too. Broadhurst recalls Hilda Abraham, one of psychiatry’s distinguished psychoanalysts, “the last person [he] would have expected to be interested in the drug treatment of depression,” contacting him about getting G22355 so she could begin a trial of it. Abraham was known for doing what my psychiatrist did, namely, trying to transform patients using insight and catharsis alone. One of Abraham’s colleagues set her up with a real trial, using a control group and a double-blind design. “I remember how amazed Abraham was,” wrote Broadhurst, “when nearly two-thirds of her depressed patients recovered with the drug.”

  Credit

  Who gets credit for scientific discoveries is always a complex question. In the case of Thorazine—the first psychiatric drug ever created, the drug that moved the field from the mere management of severe and persistent mental illness to, in many cases, at least partial remissions so long as the drug was continued—it was unclear, in large part because no one could figure out who had held the crucial key. Was it Paul Charpentier, who, in his laboratory at Rhône-Poulenc, first chlorinated promazine and came up with chlorpromazine, later christened Thorazine? Or was it his colleague Simone Courvoisier, who, in her experiments with lab rats, first noted Thorazine’s central effects? Was it Henri Laborit, who, perhaps more significantly, not only noted the indifference that his surgery patients displayed when under the influence of both promethazine and later Thorazine, but also avidly pushed psychiatrists at the Val-de-Grâce military hospital to try Thorazine on their patients? Or was it Delay and Deniker, the first psychiatrists to use Thorazine widely and without additional drugs or ice, thereby discovering that Thorazine was in its own right and by virtue of its own actions a steadfast antipsychotic?

  Similarly, G22355, which became imipramine, was another huge breakthrough and, as in the case of Thorazine, it is difficult to assess who should get credit for what. Without a doubt Broadhurst and his colleagues at Geigy, including the chemists who concocted those forty-two derivatives of iminodibenzyl, played a pivotal role. Yet they have more or less dropped out of view, their names seldom mentioned when the topic of the discovery of antidepressants is broached. Instead it is Kuhn who is usually credited with singlehandedly discovering imipramine, which is not at all the case, though it is true that at this point in our story, once the very first clinical trials have been run, the Geigy team recedes and Kuhn steps forward to play a bigger part.

  He was not well liked, by his colleagues a
t least. Some found him curmudgeonly, others tightfisted. He published broadly but sometimes failed to put others’ names on the papers, despite the fact that they were clearly collaborative. He sought recognition and was consistently disappointed that more did not come his way. He was not always invited to crucial conferences.

  Kuhn had been born on March 4, 1912, in the small town of Biel, Switzerland, northwest of Bern, where he would later train in psychiatry at the university, with the great Jakob Klaesi, who pioneered deep-sleep therapy, a treatment that relied primarily on the notion that in states of prolonged rest accomplished with hypnotics and barbiturates, patients’ nervous systems would have the chance to recalibrate and right themselves. (Deep-sleep therapy swept Europe in the early to mid-twentieth century, though it never really caught on in the States.) Kuhn apprenticed himself to Klaesi for some years. When he was done with his training, he left Klaesi’s practice and went to work at Münsterlingen, a state hospital which housed seven hundred inpatients along with an expanding outpatient population.

  Klaesi understood some forms of mental illness to be a biological phenomenon, and when one looks closely at Kuhn, Klaesi’s fingerprints become apparent, as Kuhn took on his mentor’s views concerning the biological basis of depression. Nevertheless, Kuhn’s proclivities as a clinician, despite the fact that he would later achieve renown for the imipramine drug trials, were more psychodynamic and existential, probably because he was also heavily influenced by Ludwig Binswanger, a Swiss psychoanalyst and existential philosopher whom he considered “a genius in his understanding of mood disorder.” Like Binswanger, Kuhn probed his patients for the psychological paradigms that might have caused or contributed to their mental illnesses. In his work he stressed empathic listening with existential insight into the profoundly problematic human condition, as his patients struggled, as we all do, with the knowledge that ultimately we live and die alone.