Despite the drug’s momentous impact, I’d wager you’ve probably never heard of it: meprobamate. Originally marketed as Miltown, this synthetic medication alleviated anxiety and elicited a feeling of calm without putting patients to sleep. In the first peer-reviewed article describing meprobamate, the author characterized its effects as “tranquilizing,” giving rise to the name of the first class of psychopharmaceuticals: tranquilizers.
Psychoanalysts denigrated meprobamate as just another chemical distraction that concealed mental illness rather than treating it, but the Freudians were the only ones to pooh-pooh it: meprobamate wasn’t merely the world’s first psychopharmaceutical, it was the world’s first psychotropic blockbuster. By 1956, an astonishing 36 million prescriptions for the tranquilizer had been written; one out of every three prescriptions in the United States was for meprobamate. It was prescribed for everything from psychosis to addiction and came to be associated with overwrought housewives—giving rise to its popular sobriquet, “Mother’s Little Helper,” immortalized by the Rolling Stones.
Meprobamate was superseded in the 1960s by the introduction of Librium and Valium, a new generation of internationally popular tranquilizers. (The bestselling contemporary benzodiazepines are Xanax, for anxiety, and Ambien, for sleep.) All of these drugs trace their origins to Macleod’s deep sleep therapy at the dawn of the twentieth century.
While meprobamate was unquestionably effective in reducing the symptoms of mild anxiety disorders, it was not a pharmaceutical game-changer like antibiotics for bacterial infections, insulin for diabetes, or vaccines for infectious diseases. It had no effect on the disturbing hallucinations, painful melancholy, or frenzied mania of patients locked away in public asylums, so it offered no hope for recovery for those unfortunate souls suffering from severe mental illness. Even after meprobamate become a psychiatric smash hit, the prospect of finding a simple pill that could ameliorate psychosis seemed as fanciful as schizophrenics’ delusions and as remote as the asylums that imprisoned them.
Laborit’s Drug
In 1949 a French surgeon named Henri Laborit was seeking a way to reduce surgical shock—the low blood pressure and rapid heart rate that often occurs after major surgery. According to one of the prevailing hypotheses at the time, surgical shock was due to the excessive reaction of a patient’s autonomic nervous system to stress. (The autonomic nervous system is the unconscious circuitry that controls our breathing, heart rate, blood pressure, and other vital functions of the body.) Laborit believed that if he could find a compound that suppressed the autonomic nervous system, it would increase the safety of surgical procedures.
Working in a French military hospital in Tunisia—not exactly the epicenter of the medical world—Laborit experimented with a group of compounds called antihistamines. Today these drugs are commonly used to treat allergies and cold symptoms, but at the time scientists had just learned that antihistamines affect the autonomic system. Laborit noticed that when he gave a strong dose of one particular antihistamine, known as chlorpromazine, to his patients before surgery, their attitudes changed markedly: They became indifferent toward their imminent operation, an apathy 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. Afterwards, he agreed with me that the patients were remarkably calm and relaxed.”
Impressed by the notable psychological effects of the drug, Laborit wondered if chlorpromazine might be used to manage psychiatric disturbances. Pursuing his hunch, in 1951 Laborit administered a dose of chlorpromazine intravenously to a healthy psychiatrist at a French mental hospital who volunteered to serve as a human guinea pig in order to provide feedback about the drug’s mental effects. At first the psychiatrist reported “no effects worthy of mention, save a certain sensation of indifference.” But then, as he got up to go to the toilet, he fainted—the result of a drop in blood pressure, a side effect. After that, the director of the hospital’s psychiatric service banned further experimentation with chlorpromazine.
Undeterred, Laborit attempted to persuade a group of psychiatrists at another hospital to test the drug on their psychotic patients. They were not particularly enthusiastic about his proposal, since the prevailing belief was that the disruptive symptoms of schizophrenia could only be reduced by strong sedatives, and chlorpromazine was not a sedative. But Laborit persevered and finally convinced a skeptical psychiatrist to try his drug on a schizophrenic patient.
On January 19, 1952, chlorpromazine was administered to Jacques L., a highly agitated twenty-four-year-old psychotic prone to violence. Following the drug’s intravenous administration, Jacques rapidly settled down and became calm. After three steady weeks on chlorpromazine, Jacques carried out all his normal activities. He even played an entire game of bridge. He responded so well, in fact, that his flabbergasted physicians discharged him from the hospital. It was nothing short of miraculous: A drug had seemingly wiped away the psychotic symptoms of an unmanageable patient and enabled him to leave the hospital and return to the community.
What distinguished the effects of chlorpromazine so dramatically from sedatives and tranquilizers was its ability to decrease the intensity of psychotic symptoms—the hallucinations, delusions, and disorganized thinking—in the same way that aspirin reduces the pain of a headache or the temperature of a fever. A friend of mine who suffers from schizophrenia, the legal scholar Elyn Saks, writes in her memoir, The Center Cannot Hold: My Journey Through Madness, that antipsychotic drugs act more like a dimmer knob than an on/off switch. When her symptoms are at their worst, they cause her to hear sharp voices hurling painful insults at her or shouting orders she must obey; the meds gradually reduce her symptoms to a point where she still hears voices, but they are distant, faint, receding into the background and no longer distressing or compelling.
Chlorpromazine’s use as an antipsychotic—the first antipsychotic—swept through the mental hospitals of Europe with the force of a tidal wave. In the psychoanalysis-obsessed United States, in contrast, reaction to the miracle med was muted. The Smith, Kline and French pharmaceutical company (a forerunner to GlaxoSmithKline) licensed chlorpromazine for distribution in the U.S., where it was endowed with the American trade name Thorazine (in Europe it was called Largactil), and launched a major marketing campaign to convince medical schools and psychiatry departments to test it on their patients. But American shrinks derided Laborit’s drug as “psychiatric aspirin,” waving it off as just another sedative, like chloral or the barbiturates—a distracting siren song that led gullible psychiatrists away from their true task of digging for neurotic seeds buried in the soil of the unconscious.
At first, Smith, Kline and French was baffled and frustrated by chlorpromazine’s stony reception. They had in their possession a wonder drug proven to treat the symptoms of psychosis for the first time in human history, yet they couldn’t convince anybody in America of its value. They finally stumbled upon a winning strategy: Rather than targeting psychiatrists with promises of a marvelous cure, they targeted state governments using a surprisingly modern argument. Referring to “health economics” and “cost-cutting,” Smith, Kline and French argued that if state-funded mental institutions used chlorpromazine, they would be able to discharge patients instead of warehousing them forever. A few of these institutions—more concerned with the bottom line than with philosophical debates about the ultimate nature of mental illness—tried out Thorazine on their permanent patients. The results were breathtaking, just as French psychiatrists had previously demonstrated and Smith, Kline and French had promised. All but the most hopeless cases improved, and many long-institutionalized patients were sent home. After that, chlorpromazine took American psychiatry by storm. Every asylum and psychiatric hospital began to use Laborit’s drug as the first line of treatment for psychotic patients in their care. Over the next fifteen years, Smith, Kline and French’s revenues doubled three times. By 1964, mo
re than ten thousand peer-reviewed articles had been published on chlorpromazine, and more than fifty million people around the world had taken the drug.
It is hard to overstate the epochal nature of Laborit’s discovery. Like a bolt from the blue, here was a medication that could relieve the madness that disabled tens of millions of men and women—souls who had so very often been relegated to permanent institutionalization. Now they could return home and, incredibly, begin to live stable and even purposeful lives. They had a chance to work, to love, and—possibly—to have a family.
Just as the antibiotic streptomycin emptied sanitariums of tuberculosis patients and the polio vaccine rendered the iron lung obsolete, the widespread adoption of chlorpromazine marked the beginning of the end for the asylums. It also marked the end of the alienists. It is no coincidence that the asylum population began to decline from its peak in the United States in the same year Thorazine was released.
A century and a half after Philippe Pinel freed the inmates of the Parisian Hospice de la Salpêtrière from their physical chains, another French physician released patients from their mental confinement. Psychiatry, after a seemingly interminable struggle, could finally answer the question, “How can we treat severe mental illness?”
Compound G 22355
Envious of the mega-profits generated by chlorpromazine, other pharmaceutical companies searched for their own proprietary antipsychotic throughout the 1950s. They often teamed up with psychiatrists to aid in this search, and the Swiss pharmaceutical company Geigy, a corporate ancestor of Novartis, approached Roland Kuhn, the head doctor at a psychiatric hospital in the Swiss town of Münsterlingen, on the banks of Lake Constance. Kuhn, thirty-eight, was a tall and cultivated psychiatrist who combined an exceptional grasp of the humanities with a background in biochemistry. Geigy offered to provide Kuhn with experimental compounds if he would test them on his patients. Kuhn readily agreed.
In late 1955, Geigy’s head of pharmacology met Kuhn at a hotel in Zurich where he showed him a chart scribbled with the hand-drawn chemical structures of forty different compounds available for testing. “Pick one,” the pharmacologist instructed. Kuhn carefully surveyed the forest of molecules, then pointed to the one that most closely resembled chlorpromazine, a molecule labeled “Compound G 22355.”
Kuhn dosed a few dozen psychotic patients with G 22355, but the drug failed to produce the same dramatic reduction of symptoms as chlorpromazine. Of course, as any pharmacological researcher knows, failure is the usual fate for any experimental compound—most commercial drugs are only discovered after tens of thousands or even hundreds of thousands of chemical candidates are tested and rejected. The most sensible next step would have been for Kuhn to point to a new compound on Geigy’s chart and try again. Instead, Kuhn made a very peculiar decision, one that would affect millions of lives.
The first antipsychotic was not discovered because of any orderly research plan contrived by Big Pharma; it was discovered purely by accident after a solitary physician followed his intuition about an experimental drug for surgical shock. And now a lone psychiatrist decided to ignore the task that he had been assigned—finding a chlorpromazine knockoff—and instead pursued his own private hunch about a disorder he cared about more than schizophrenia: depression.
Even in the earliest days of psychiatry, schizophrenia and depression were almost always considered distinct conditions; madness and melancholia. After all, the worst symptoms of psychosis were cognitive, while the worst symptoms of depression were emotional. When Geigy engaged Kuhn, there was no reason to believe that a class of drugs that dampened the hallucinations of psychotic patients would also elevate the mood of depressed patients. But Kuhn held his own staunch ideas about the nature of depression.
Kuhn rejected the standard psychoanalytic explanation that depressed individuals were suffering from buried anger toward their parents, so he didn’t believe depression should be treated with psychotherapy. On the contrary: he shared the assumption of biological psychiatrists that depression resulted from some unidentifiable neural dysfunction. Nevertheless, Kuhn disliked the prevailing “biological” treatment for depression, sleep therapy; he felt it failed to target the symptoms of depression, instead relying on crude chemical force to bludgeon the patient’s entire consciousness. Kuhn wrote to a colleague, “How often I thought we should improve the opium treatment. But how?”
Without telling Geigy, Kuhn administered G 22355 to three patients suffering from severe depression. After a few days, the patients showed no signs of improvement. This stood in sharp contrast to sedatives like morphine or chloral or even chlorpromazine itself, which produced often drastic effects within hours or even minutes of administration. For reasons known only to Kuhn, he continued administering G 22355 to his patients anyway. On the morning of the sixth day of treatment, January 18, 1956, a patient named Paula woke up feeling quite changed.
The nurses reported that Paula exhibited more energy and was uncharacteristically talkative and sociable. When Kuhn examined her, her melancholy was remarkably improved, and for the first time she expressed optimism for her future. This was just as astonishing as Laborit’s first patient, Jacques L., playing a full game of bridge. Some days after Paula, the other two patients also began to manifest thrilling signs of recovery. Kuhn enthusiastically wrote to Geigy about his unauthorized experiment, “The patients feel less tired, the sensation of weight decreases, the inhibitions become less pronounced, and the mood improves.”
Incredibly, Geigy expressed no interest in Kuhn’s discovery. The company was fixated on finding an antipsychotic to compete with chlorpromazine, not exploring some radical and unknown treatment for melancholia. Ignoring Kuhn completely, Geigy hurriedly sent G 22355 to other psychiatrists and ordered them to test the compound exclusively on schizophrenics, never mentioning its potential effects on depression. Geigy executives snubbed Kuhn again the next year, when he attended a psychopharmacology conference in Rome and repeated his request to pursue G 22355 as a depression-fighting drug. Kuhn’s lonesome discovery seemed destined for the scrap heap of medical history.
He tried to interest other academics, but they, too, collectively shrugged their shoulders. When Kuhn presented a paper on G 22355 at a scientific meeting in Berlin, only a dozen people showed up. After he finished his talk—in which he described the world’s first effective pharmacological treatment for depression—none of the attendees asked a single question. One person in the audience was Frank Ayd, an American psychiatrist and devout Catholic, who told me years later, “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.”
But as with Laborit’s drug, fate—or blind luck—intervened once again. An influential Geigy stockholder and business partner named Robert Boehringer knew of Kuhn’s expertise in mood disorders and asked if he could suggest anything for his wife, who was suffering from depression. Without hesitation, Kuhn recommended G 22355—and made sure to point out that the stockholder’s company was refusing to develop the drug. After taking the experimental compound for a week, Mrs. Boehringer’s depression lifted. Delighted, Boehringer began lobbying Geigy executives to develop the drug as an antidepressant. Under pressure from such an influential partner (Boehringer also owned his own pharmaceutical enterprise), Geigy changed course and began formal human trials of G 22355 on depressed patients and finally bestowed the compound with its own name: imipramine.
In 1958, Geigy released imipramine to the public. It was the first of a new class of drugs known as tricyclic antidepressants—so named because the compounds’ molecular structure is composed of three joined molecular rings. (When a drug is named after its chemical structure rather than its physiological mechanism, it’s a sure sign that nobody knows how it works. Another class of antidepressants are known as selective serotonin reuptake inhibitors, or SSRIs; needle
ss to say, scientists have since learned they produce their effects by inhibiting neurons’ reuptake of the neurotransmitter serotonin.) Unlike chlorpromazine, imipramine was an instant global success, equally embraced by psychiatrists in Europe and America. Other pharmaceutical companies soon released a flood of tricyclic antidepressants, all knock-offs of imipramine.
It’s not possible to overstate the prodigious impact of chlorpromazine and imipramine on the practice of psychiatry. Less than a decade after the release of Thorazine in the United States, the entire profession was utterly transmogrified. Two of its three flagship illnesses, schizophrenia and depression, were reclassified from “wholly untreatable” to “largely manageable.” Only manic-depressive illness, the final mental scourge of humanity, remained bereft of treatment and hope.
Serendipity Down Under
As these accidental discoveries of miracle medications were occurring in Europe, an unknown doctor in an obscure corner of the medical world was quietly pursuing his own professional hobbyhorse: a cure for mania. John Cade was initially trained as a psychiatrist, but during World War II he served as a surgeon in the Australian Army. In 1942, he was captured by the Japanese during their conquest of Singapore and locked up at Changi Prison, where he observed many of his fellow prisoners of war exhibiting the unhinged behavior that so often accompanied combat trauma. They trembled, they shrieked, they babbled mindlessly. Struck by what he perceived as the similarity between these war-induced symptoms and those produced by mania, Cade hypothesized that the prisoners’ quasi-manic behavior might be caused by a stress-induced toxin produced by the body. Perhaps such medical speculations helped him endure the sweltering nights in his dank, cramped cell.
Cade was eventually released, and after the war he pursued his toxin theory of mania at the Bundoora Repatriation Mental Hospital in Melbourne. His experiments were straightforward, if somewhat crude: He injected urine from manic patients into the abdomen of guinea pigs. Uric acid, found in urine, is a naturally occurring metabolite in humans. Excessive uric acid causes gout, and Cade guessed that uric acid might also cause mania if it accumulated in the brain. After the guinea pigs received a gut-full of human urine, Cade recorded that they exhibited “increased and erratic activity.” He interpreted these manic-like behaviors as confirmation of his toxin theory, though an alternative interpretation might be that any creature will exhibit erratic activity after getting a syringe of foreign urine in its belly.
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