The Drug Hunters

by Donald R Kirsch

  Henri Laborit was not a psychiatrist and, indeed, knew very little about psychiatry at all. He was a surgeon in the French Navy who served in the Mediterranean squadron during the Second World War. During the war, he became interested in finding new medications to aid in surgery, hypothesizing that a drug that induced artificial hibernation in patients would lessen the dangers of shock following surgery. Pursuing this line of thinking, Laborit speculated that any drug that lowered patients’ temperatures might help induce artificial hibernation.

  Working in a French military hospital in Tunisia, Laborit obtained a new kind of antihistamine compound from a colleague that was believed to lower body temperature, a compound known as chlorpromazine. He tried chlorpromazine out on his surgery patients, hoping to reduce the severity of post-surgical shock. But Laborit noticed that even before he had a chance to administer an anesthetic, the patients’ attitude underwent a dramatic mental change. The chlorpromazine made them indifferent toward the major surgery they were about to undergo, an indifference that continued after the surgery was completed. Laborit wrote about this discovery, “I asked an army psychiatrist to watch me operate on some of my tense, anxious Mediterranean-type patients. After surgery, he agreed with me that the patients were remarkably calm and relaxed.”

  Chlorpromazine, it turned out, did not induce any kind of artificial hibernation and, indeed, has little effect on body temperature. But Laborit was impressed by the unexpected psychological effects of the drug. He began to wonder if the compound could be used to help mitigate psychiatric disturbances. In 1951 Laborit returned to France, where he persuaded a healthy psychiatrist to take an intravenous dose of chlorpromazine in order to describe the subjective effects of the drug. The psychiatrist guinea pig initially reported “no effects worthy of mention, save a certain sensation of indifference.” Then, he abruptly fainted. (Chlorpromazine also has anti-hypertensive effects, reducing blood pressure.) After that, the head of psychiatry at the hospital forbade further experimentation with chlorpromazine.

  Undeterred, Laborit moved to another hospital where he tried to convince the psychiatrists to administer the drug to their psychotic patients. The physicians refused, which was not very surprising considering that most psychiatrists believed that the only way to control (though not treat) schizophrenics was through the use of powerful sedatives—and chlorpromazine was no sedative. But Laborit did not give up. He finally persuaded a psychiatrist to run a test using his “indifference” drug.

  On January 19, 1952, the psychiatrist administered chlorpromazine intravenously to a patient known as Jacques L., a twenty-four-year-old psychotic who was highly agitated and violent. Jacques rapidly settled down and maintained a state of calm for several hours. And then, a miracle. After three weeks of receiving daily doses of the drug, Jacques was able carry out all his normal activities. He could even play an entire game of bridge without any disruptions—something that was previously unthinkable. He recovered so well, in fact, that the astonished physicians discharged him from the hospital. The psychiatrists had just witnessed something completely unheard of in the annals of medicine: a drug had almost entirely eliminated the symptoms of psychosis, enabling a previously uncontrollably violent patient to return to the community.

  Chlorpromazine was marketed to the public by the French pharmaceutical company Rhône-Poulenc in 1952 under the trade name Largactil. The following year it was offered in the United States by Smith, Kline, and French under the trade name Thorazine. It bombed. Nobody prescribed it. Most psychiatrists did not think it was possible even in principle for a drug to treat the symptoms of mental illness. American shrinks dismissed chlorpromazine as a distraction that concealed rather than cured the true childhood sources of a patient’s illness, with several prominent psychiatrists deriding Laborit’s drug as “psychiatric aspirin.”

  Smith, Kline, and French was stunned. They were offering for sale the first miracle drug proven to treat the symptoms of psychosis, yet psychiatrists refused to use it. The pharmaceutical company finally hit upon a solution. Instead of trying to coax psychiatrists into prescribing the drug, Smith, Kline, and French salesmen targeted state governments by arguing that if state-funded mental institutions used chlorpromazine, they would be able to discharge patients instead of warehousing them forever, drastically cutting costs and reducing the state’s bill. A few of these state institutions—more concerned with their bottom line than abstruse debates about the philosophy of mental illness—gave chlorpromazine a try. All but the most hopeless patients exhibited dramatic improvements, and just as Smith, Kline, and French had promised, many were discharged back into society.

  Smith, Kline, and French’s revenues increased eight-fold over the next fifteen years. By 1964, more than 50 million people around the world had taken the drug, which quickly became established as the first line of treatment for any schizophrenic patient. Individuals who were once lost for life in the quasi-dungeons of public asylums could return home and, amazingly, live engaged and productive lives. The success of chlorpromazine also marked the beginning of the end for psychoanalysis and the Freudian dominance of American psychiatry. After all, why would you want to spend week after week for years on end sitting on a shrink’s couch talking about your mother when you could swallow a pill instead—and watch your symptoms disappear?

  All the antipsychotic drugs we use today, including olanzapine (Zyprexa), risperidone (Risperdol), and clozapine (Clozaril), are chemical variants of chlorpromazine. In the more than sixty years since the clinical adoption of chlorpromazine, the scientific community has not been able to come up with a fundamentally better approach. And yet, we still do not have a clear idea of exactly how chlorpromazine mitigates the symptoms of schizophrenia. But that never stopped every pharmaceutical company from trying to make a chlorpromazine knockoff.

  Other drug makers wanted to duplicate the blockbuster success that Rhône-Poulenc and Smith, Kline, and French enjoyed with the world’s first antipsychotic. So they assembled their own teams to try to synthesize their own variation of the chlorpromazine compound. One of these hopeful copycats was the Swiss pharmaceutical company Geigy, a corporate ancestor of Novartis. Geigy executives reached out to Roland Kuhn, a Swiss professor of psychiatry who had a strong interest in finding new treatments for mental illness. Geigy supplied him with a chlorpromazine-like compound that the company had labeled G 22150 and asked him to try it out on his psychotic patients. The drug produced extreme, intolerable side effects, rendering it unfit as a treatment. So in 1954, Kuhn asked Geigy for a new compound to try.

  Kuhn met with Geigy’s head of pharmacology at a hotel in Zurich where Kuhn was presented with a large chart filled with forty hand-scribbled chemical structures. The Geigy executive asked Kuhn to pick one. He pointed to the compound that appeared to be the most similar to chlorpromazine, a compound labeled G 22355. It would prove to be a very fateful choice.

  Kuhn returned to his hospital and administered G 22355 to a few dozen psychotic patients. Not much happened; certainly not the dramatic reduction of symptoms elicited by chlorpromazine. You might expect that Kuhn would have once again returned to Geigy and selected another compound from Geigy’s chart of chemicals. Instead, Kuhn decided to try something else. Without informing Geigy, he decided to give G 22355 to some of his patients suffering from depression.

  It had been just a few years earlier, as we saw, that the first antipsychotic had been discovered—not because of any Big Pharma research project but accidentally, by a surgeon in Tunisia who was trying to reduce surgical shock. And now in Switzerland a psychiatrist decided to ignore the task that he had been hired to do—finding a new antipsychotic—and instead decided to test a failed antipsychotic drug on patients suffering from depression. Why? Because he happened to care a whole lot more about depression than schizophrenia.

  Even in the earliest prescientific days of psychiatry, madness and melancholy were considered distinct conditions. Madness seemed to consist of disruptions of cognition, whil
e depression seemed to consist of disruptions of emotion. There was certainly no medical or pharmaceutical reason to believe that a variation of a compound that dampened the hallucinations of psychotic patients could somehow increase the joy of depressed patients. Indeed, most psychiatrists believed that both psychosis and depression were the result of unresolved emotional conflicts. But Kuhn had quietly developed his own ideas about depression.

  Kuhn rejected the standard psychoanalytic explanation that depression stemmed from repressed anger toward one’s parents, so he rejected psychoanalysis as a treatment. Instead, he had become convinced that depression was the consequence of some kind of biological disturbance in the brain. Since nobody knew how chlorpromazine worked anyway, why not try a chlorpromazine knockoff on a depressed patient and see what happened?

  So Kuhn gave G 22355 to three of his patients suffering from severe depression. He waited a few hours, then checked his patients. No improvement. He examined them again in the morning. Still nothing. Since chlorpromazine itself usually produced noticeable improvements within hours or even minutes of administration, it would have made sense for Kuhn to abandon his trials. Instead, for reasons known only to Kuhn, he kept on administering G 22355 to the three patients. Finally, six days after he had started the treatments, on the morning of January 18, 1956, one of these patients, a woman named Paula I., woke up and told the nurse that she was apparently cured of her depression.

  Delighted, Kuhn contacted Geigy and announced that G 22355 “has an obvious effect on depression. The [condition] visibly improves. The patients feel less tired, the sensation of weight decreases, the inhibitions become less pronounced and the mood improves.” In other words, Kuhn had just handed Geigy a silver platter containing what might very well be the world’s first antidepressant. Did the Geigy executives uncork the champagne? Nope. They couldn’t care less about depression. They wanted their own antipsychotic drug to compete with chlorpromazine. They ordered Kuhn to stop testing G 22355 and supplied the compound to another doctor, explicitly instructing him to test it out only on psychotic patients.

  Kuhn tried to take his discovery to other scientists. In September 1957, Kuhn was invited to speak at the Second World Congress of Psychiatry and presented a paper about the effects of G 22355 on depressed patients. Barely a dozen people showed up. No one asked a single question. Frank Ayd, an American psychiatrist and devout Catholic who attended the talk, later reported, “Kuhn’s words, like those of Jesus, were not appreciated by those in positions of authority. I don’t know if anybody in that room appreciated we were hearing the announcement of a drug that would revolutionize the treatment of mood disorders.”

  It looked as if G 22355 was headed for the dustbin of history. But then an influential Geigy stockholder named Robert Boehringer happened to ask Kuhn if he could recommend anything for his wife. She was ill with depression. Kuhn immediately recommended G 22355. Boehringer’s wife recovered. Watching the remarkable improvement in his wife, Boehringer lobbied Geigy to begin marketing the drug. In 1958, Geigy finally began marketing G 22355, naming it imipramine.

  Imipramine became the prototype for dozens of antidepressant drugs that soon followed. Even today, every known antidepressant still shares the same basic mechanism as imipramine, influencing the neurotransmitter serotonin. Even Prozac is a tweaked version of imipramine. Though we still do not have a clear understanding of how antipsychotics or antidepressants bring about their improvements in mentally ill patients, we have a basic awareness of their physiological activity. Both chlorpromazine and imipramine are like shotgun blasts that spray everything in sight, rather than a sniper rifle that hits a single precise target. Chlorpromazine activates at least a dozen different types of neural receptors. Most of these have nothing to do with schizophrenia. It is hypothesized that the antipsychotic effects of chlorpromazine are produced by blocking two or three types of dopamine receptors. But if that was all the drug did, it would produce intolerable side effects, including severe involuntary movements known as dyskinesia. But chlorpromazine, and the many antipsychotic derivatives of chlorpromazine, also block serotonin receptors, a neural effect that fortuitously appears to mitigate the dyskinesia produced by the dopamine receptor blockade. This unusual interaction allows the drug to treat schizophrenia without producing intolerable side effects.

  Imipramine also hits many different receptors in the brain, most of which have nothing to do with depression and several of which produce undesired side effects. But one of the targets of imipramine (and every known antidepressant) is the serotonin reuptake pump, which helps control the amount of the serotonin neurotransmitter in neural synapses. (Prozac and its analogs are known as “selective serotonin reuptake inhibitors,” or SSRIs.) Why does increasing the brain’s available serotonin reduce depression? We still don’t know.

  Why would two compounds that are very similar chemically each turn out to be an effective treatment for two very different mental disorders? There is a broad class of neurotransmitters that includes epinephrine, norepinephrine, and dopamine that are collectively known as biogenic amine substances, because they all share a particular chemical substructure known as ethylamine. This means that other molecules that contain an ethylamine substructure—even synthetic molecules that are not natural to the body—have a high probability of producing some kind of effects in the brain, or possibly multiple effects by activating different sites simultaneously. Scientists call a special chemical structure, like ethylamine, that can activate multiple targets in the body a “privileged structure.”

  Chlorpromazine and imipramine both contain an ethylamine substructure, which is why they have such broad and diverse effects on neural receptors in the brain. Purely by accident, Henri Laborit and Roland Kuhn had armed themselves with drugs that induced a wide range of changes in the brain, and merely got lucky that there were more positive changes than negative ones.

  There’s an old adage, “It’s better to be lucky than smart.” A drug hunter has the best chance of success when they are both lucky and smart—and Laborit and Kuhn were both.

  Conclusion

  The Future of the Drug Hunter

  The Chevy Volt and the Lone Ranger

  Is drug development more like engineering … or filmmaking?

  “For success in drug hunting one needs ‘four Gs’: Geld, Geduld, Geschick … and Glück.”

  —Paul Ehrlich, 1900

  In the fall of 2002, General Motors knew it was in trouble. It had predicted hybrid vehicles would never catch on with the public—after all, consumers loved GM’s gas-guzzling SUVs, so there was little financial motivation to invest in the development of electric cars. But then, a bomb dropped. Toyota introduced the Prius, a gasoline-electric hybrid that quickly became a sales sensation and made Toyota the undisputed world leader in hybrid production. General Motors was suddenly staring into a future much different than what they expected or were equipped for.

  Nevertheless, as with most industries that rely on engineering and science—including the computer industry, kitchen appliance industry, and telecommunications industry—the automobile industry usually offers a chance for a properly incentivized company to catch up to a market leader or, at the very least, carve out their own market share. All General Motors needed to do was design its own hybrid vehicle.

  So GM assembled a team of their brightest scientists and engineers and commanded them to build a vehicle that fulfilled two design objectives: first, the ability to drive across the entire country on gasoline; and second, the ability to commute to work without using any gasoline at all. Now let’s pause here for one moment. Toyota had a head start of about ten years in terms of developing the Prius. General Motors, meanwhile, needed to figure out how to build their own version of an electricity-powered car from scratch. Nevertheless, even though nobody expected GM to design a vehicle as popular as the Prius, neither industry insiders nor ordinary consumers were especially skeptical that GM could build some kind of hybrid car. After all, the company had hi
ghly trained scientists and engineers who were well-versed in the technical knowledge required to achieve their goal. Their collective expertise covered battery technologies, electric motors, internal combustion engines, chassis engineering, and automobile design. They knew the manufacturing techniques for different parts and they knew the cost of materials.

  So after eight years of effort, when GM’s hybrid-design team rolled out the Chevy Volt—a vehicle that fulfilled both of its design objectives—it was certainly a triumph, but it was not a particularly astonishing achievement. After all, shouldn’t GM, the world’s largest automobile maker, know how to design a car?

  In the end, the Volt did not sell very well, and it did not make a meaningful dent in the sales of Prius. But from an engineering standpoint, the sales are almost beside the point. The Volt did what it was supposed to do. In a relatively short period of time, General Motors had taken a vague design idea—let’s create our own plug-in hybrid!—and actually crafted a product that turned the idea into reality. Now think how different this process is from engineering a Hollywood movie.

  In 2007, Disney director and producer Jerry Bruckheimer was riding high on the success of three consecutive Pirates of the Caribbean films, each one a global smash hit. They thought they had figured out how to design a blockbuster, so when Bruckheimer bought the rights to a new movie he began putting it together according to the same design principles—namely, a supernatural action comedy script penned by the same writing team behind the Pirates trilogy, a huge special-effects-laden budget, some romance, a happy ending, and Johnny Depp in a scenery-chewing starring role. Disney agreed that these were the right ingredients for success and funded the project. Yet, even though the producers diligently followed the ordained formula for commercial movie production, the final product failed to fulfill its basic design objectives: making an audience laugh, applaud, and feel genuine thrills. Instead, The Lone Ranger became one of the biggest flops of the past decade.