by Ron Powers
Deinstitutionalization was only the first. Antipsychotics, exuberantly sold to President Kennedy by his Joint Commission as “moral treatment in pill form,” proved utterly useless—as we have seen—in stemming the catastrophe that ensued. The half-century that followed saw an ongoing morality play starring pharmaceutical corporations, the government, a cadre of outraged watchdog writers and journalists, and a grassroots oppositional movement that hardened into an ideological force. Even as they created a market valued beyond $70 billion, the corporate purveyors of antipsychotic drugs have been sued by class-action groups, found guilty in courts of cover-ups and false claims, denounced by civil libertarians, and castigated as evil by victims of schizophrenia who believe that the use of such drugs made them worse instead of better.
No one really set out to find a chemical solution for irrational human behavior. Most intellectuals of the early twentieth century, including scientists, assumed that the Viennese master and his followers had that area covered. The origins of psychopharmacology lay, as they have with so many seminal discoveries, within a search for something else—something entirely different. Scientists have a term for this kind of sublime inadvertence: “serendipity.”
In the mid-1930s, certain French scientists were toiling along what they hoped was the path to a workable antihistamine. Something was needed to neutralize the problematic neurotransmitter histamine. This component in the immune system combats pathogens taken into the body via food and breathing. But the chemical can transform itself into part of the problem, a protopathogen that triggers allergies, such as hives, and damages the heart and smooth muscles. In extreme cases, it can cause the often fatal allergic reaction known as anaphylactic shock.
A series of breakthroughs that took antihistamine research into an unforeseen and revolutionary direction commenced in the late 1930s at the Pasteur Institute in Paris. Among the scientists was a brilliant young Swiss-born scientist with the bony features and intense gaze that called to mind Sherlock Holmes. His name was Daniel Bovet. In 1937, the thirty-year-old Bovet and his twenty-three-year-old colleague Anne-Marie Staub, who had been thinking about leaving biochemistry to become a nun and treat lepers, were trying to develop a “selective antagonist” of histamine that could be safely ingested by human beings. They synthesized an antihistamine with the self-explanatory name thymoxyethyldiethylamine.*
Among the substances whose properties aroused Bovet’s curiosity was a powerful chemical distilled from ergot, a fungus that grows on rye. Other scientists were examining it as well, and it was synthesized in the following year as lysergic acid—the first step along the trail toward LSD. Bovet was the first to extract from it an important truth: that even simple molecules can touch off powerful mood changes and perceptions. As a 2007 review of his career noted, his observations “exerted a marked influence in the field of psychopharmacology, and in particular psychedelic drugs… Bovet’s work helped to shape scientific thought regarding psychoactive drugs that are used in therapy today.”1
Bovet and Staub’s discovery of thymoxyethyldiethylamine set the stage for the use of synthetic drugs in brain therapy. It took time. Refinements of this compound, also (and thankfully) known as 929F, would consume nearly fifteen years before the resulting wonder drug stood revealed. Bovet himself conducted more than three hundred thousand experiments in the four years after discovering 929F to find the right formula.2 His efforts earned him recognition as the founder of psychopharmacology and, in 1957, the Nobel Prize in Medicine.
Bovet and Staub’s new synthetic chemical might have pointed the way only toward a good sneeze medicine, had it not caught the attention of a hovering Parisian pharmaceutical company, Rhône-Poulenc. Rhône-Poulenc, formed just nine years earlier, was interested in the pharmaceutical uses of synthetic textiles. The company formed a collaborative partnership with Pasteur. A chemist named Paul Charpentier incorporated Bovet’s findings into his research toward a usable antihistamine. Within a short time, Charpentier perfected the compound promethazine, which went on the market as Phenergan. This drug not only acted against allergies, it produced a sedative effect as well. Thus it clearly was working upon the central nervous system—changing behavior. But its side effects in some patients—convulsions, increased heartbeat, fatigue, fever—made it a risky bet.
The relay baton was passed on to Henri Laborit, a dashing, dark-pompadoured physician, artist, movie actor (as himself), and wartime man of action. This summer of 1949 found Laborit, at age thirty-five, serving as a naval neurosurgeon at the Bizerte Naval Hospital at the port in Tunis. He was searching for some new medication that would reduce postoperative shock in victims of severe war wounds. He would soon light the spark to the combustible chain of research begun by Bovet and blast the psychotropic era into existence.
Laborit opened a package one day and found samples of Charpentier’s new mixture from Rhône-Poulenc. Laborit took the compound into the lab, tested its properties, and intuited that its sedative powers offered possibilities beyond curing infection and runny noses. It produced hypothermia, or what Laborit called “artificial hibernation”—a kind of drug-induced anesthesia. Returning to Paris, he asked Charpentier for additional compounds that might increase the potency and reduce the side effects. In one of those tests, on December 11, 1950, Charpentier added a chlorine atom to the promazine molecule and produced chlorpromazine (CPZ).
Laborit continued his lab tests before trying it out on a living person. In February 1952, he and others administered some trial doses at the Val-de-Grâce military hospital in Paris. The doses, he reported, did not automatically put his patients to sleep. But they did produce an indifference to what was going on around them, and to their own pain.
In that year, Laborit recommended CPZ for use on patients in emotional or mental pain, though he still saw it mainly as an anesthetic. Rhône-Poulenc made it available by prescription in France as Largactil (“large in action”). In that same year the small, flailing American firm Smith, Kline & French (SKF) took a chance on buying license rights for the substance in the United States.
The thing was that still, nobody knew exactly what to do with it. Smith Kline invited Laborit to come to America and show off its “artificial hibernation” capacities to surgeons. This time, his magic went missing. His experimental dogs kept dying after their doses. Laborit went back home. He turned to writing and produced more than twenty books on science and evolutionary psychology. His ideas about free will and memory attracted the attention of Alain Resnais, a pioneer in the French school of New Wave filmmaking. He played himself in Resnais’s mold-breaking 1980 movie Mon oncle d’Amérique, starring Gérard Depardieu. He faced the camera at intervals in this story of three characters groping for their destiny yet conditioned by their past, their lives implicitly compared to white rats in a lab cage. The film won the Grand Prize at Cannes. Laborit died in 1995.
As for Smith Kline, it began to think it had bought the rights to something like a failed high school chemistry experiment. Before cutting its losses, the little company decided to invite one last French scientist to come over and see what he could do. This was Pierre Deniker. Deniker was a colleague of Laborit’s and one of the first to understand the true value of chlorpromazine. With his square, white crew-cut head, dark brows, and tight little grin, he called to mind a small-town police chief. Unlike Laborit, who had the appearance of a man who might at any moment don a beret and drag a woman across a cabaret stage, Deniker projected a businesslike demeanor. Like Laborit, he possessed a brilliant mind.
Deniker had already proved his knack for selling the new compound. Early in 1952, Rhône-Poulenc dispatched him to the Sainte-Anne Psychiatric Hospital in Paris, where he wowed the staff with a confident air. As recounted by the psychological historians Steve D. Brown and Paul Stenner, Deniker arrived one morning at Sainte-Anne, “from where the mentally ill, whom the Paris police have picked up the night before, are distributed. ‘How many do you want for the clinic this morning?’ the charge nurse asks… N
ormally these patients were not ‘particularly welcome’ on the wards… Nonetheless, Deniker… tells her he will take them all. He says to the nurse, ‘We have found a trick that works.’”3
It did work. Not that day, but within a week or so, the “mentally ill” subjects (none of whom, of course, had been clinically diagnosed for schizophrenia; nor, for that matter, been cured of it by Deniker) had improved dramatically in their behavior. Shackles and restraints were no longer necessary. They were recognizably “normal” again. Or nearly so. Or so it seemed.
Soon after that, Deniker was taking his “trick” on the road in the United States, at hospitals and academies along the eastern seaboard. Again, he coaxed dubious professionals into listening to his claims and then witnessing the remarkable calm that descended upon their patients within several days. Demonstrating that he intuited where the real power lay, Deniker also looked into state mental institutions, dosing selected inmates and persuading their administrators that the wonder drug could radically diminish their overcrowded wards. Again, the results were amazing. The wardens, eager to impress state legislatures, sent the word along.
In 1954 CPZ appeared as an American prescription drug, approved by the FDA and licensed and distributed by Smith, Kline & French (today, GlaxoSmithKline). Its proprietary name was Thorazine.
Nothing like this could have been dreamed, or even conceptualized, by those generations of luckless inmates at Bedlam, or their keepers. “Technological solutions to mental disorders,” as it has been described, was at the threshold of history.
Antipsychotics work as suppressants. Another generic name for them is “neuroleptics,” because they function by producing neurolepsis in the brain through blocking certain transmissions. Neurolepsis is a condition of emotional quiescence, indifference to surroundings, and the tamping down of “psychomotor” function—that is, the effect on physical movement of thought impulses. These results are quite similar to the symptoms of negative schizophrenia.
The target of most neuroleptics is the neurotransmitter dopamine. More specifically, the target is one of dopamine’s five receptors, D2, “the primary site of action for all antipsychotics,” in the phrasing of one paper.4 Receptors are proteins that bind to neurotransmitters and move chemical information along through neural pathways. Dopamine, through its receptors, influences nearly every function of the body, regulating the flow of information from anatomical areas to the brain. Its signals enable us to pay attention, to learn, and to remember. It regulates bodily movement and augments immune systems. Its release enables people to experience pleasure from food, sex, recreation, and the abstract series of vibrations known as music. Dopamine is the Self’s Dr. Jekyll.
Except when it is transformed into Mr. Hyde. This can occur when its balance is disrupted—when there is either too much or too little of it. Stress is a leading cause of dopamine oversupply. Lack of sleep is another. Drugs, even prescription drugs and certainly “recreational” ones, are common causes. The consequences can be heightened anxiety, paranoia, adrenaline rushes, and hyperactivity—at its extreme, tardive dyskinesia, or uncontrollable grimacing and tongue-thrusting and other movements in the lower face. Given the right genes (that is, the wrong genes), all of this can produce schizophrenia.
Stress, a truly insidious state, can also lower the dopamine supply; as can obesity, a bad diet, and too much alcohol intake. Lower dopamine can result in Parkinson’s disease, depression, too much sleep, a lowered libido, aggressive behavior, and a lack of concentration, among other things. Antipsychotics are aimed at oversupply; they are “antagonists” to it.
Another important neurotransmitter is serotonin, discovered in 1948 by the Italian pharmacologist Vittorio Erspamer. Serotonin is known as “the happy chemical”: “Happy” because the molecule is believed to safeguard the balance of mood in much the same way as dopamine. That, and because it is the leading receptor for LSD.
Unlike dopamine, serotonin is manufactured in two distinct regions of the body, and the chemicals from each do not cross the other’s boundaries. Up to 90 percent of the chemical is located in the gastrointestinal system, where it regulates bowel movements, aids the formation of blood clots that result from wounds, and hastens the expulsion of toxic food and drink via vomiting and diarrhea. Serotonin’s smaller but at least equally vital production point is the hypothalamus, deep inside the limbic system of the brain—the delicate collection of many tiny structures that govern human emotion and memory. From this region, serotonin patrols the same territory as dopamine: mood, appetite, memory, sleep, and libido.
In the constantly pruning and regenerating adolescent brain, serotonin is believed to be a critical gatekeeper of thought and behavior. If there is not enough of it, the chemical is thought to be incapable of inhibiting impulses to anger, aggression, anxiety, panic, fear, and depression. Raising serotonin levels is the goal of the many antidepressant medications originally known as “mother’s little helpers,” the tranquilizers that arrived and proliferated on a parallel trajectory with antipsychotics. Miltown, introduced in 1955, was the first, working its way into thirty-six million prescriptions in two years. It was followed by Prozac, Zoloft, Paxil, and the rest. These medications are known collectively as SSRIs—selective serotonin reuptake inhibitors. “Reuptake” refers to the absorption of neurotransmitters by the same nerves that released them. SSRIs block this process and leave more serotonin available for action.
This summary comprises the accepted understanding of how antipsychotics work—accepted at least for a while. After all, it was only in 1975 that the Canadian researcher Philip Seeman discovered the D2 receptor. Before that, no one really knew how the new wonder drugs worked. They just worked. More or less.
And it appears that no one knows still.
Sales of Thorazine exploded on impact. Two million patients regarded as mentally disturbed ingested it by prescription in the first eight months. Smith, Kline & French, not a firm to let a single golden egg go uncracked, set an enduring pharmaceutical template by marketing its product as if it were a—product. It launched a barrage of print advertising in 1954 depicting Thorazine as the answer for just about anything that could ail a body short of dishpan hands: Arthritis. “Acute” alcoholism. “Severe” asthma. “Severe” bursitis. Behavior disorders in children. (It would be years before state and federal agencies started cracking down on indiscriminate and ethically reckless claims that psychotherapeutic drugs could help children, whose delicate neurochemistry is far more vulnerable to chemical distortion than adults’.) Menopausal anxiety. Gastrointestinal disorders. Psoriasis. Nausea and vomiting. Senile agitation. And, brushing once more against the border of ethical responsibility, even cancer.
These display advertisements set the stage for decades of charges that Big Pharma manipulated its customers’ expectations via weaselly marketing techniques. Nearly all of them avoided direct claims that Thorazine would cure the complaint in question, including schizophrenia. They insinuated cure, but they were really selling relief—relief from symptoms. The modifying adjectives acute and severe served subtle notice of this, as did the small print that preceded the big scare words. The display ad for Thorazine as the enemy of cancer, for example, was presented as follows:
relief from the suffering and
mental anguish of
CANCER5
Among the small handful of ads that did make absolute claims was the one that trumpeted “Another dramatic use of ‘Thorazine’”: in eight out of ten patients, it stopped hiccups.6
By 1955 the drug had rocketed around the Western world, trailing clouds of money: to Switzerland, England, Canada, Germany, Hungary, Latin America, Australia, and the USSR. Within a year Thorazine increased the company’s sales volume by a third. SKF net sales increased from $53 million in 1953 to $347 million in 1970. In 1957, Deniker, Laborit, and their colleague Heinz Lehmann, who had supervised the first CPZ experiments in North America, shared the prestigious Albert Lasker Award for medical research.* The age of “
miracle drugs” was under way.
Psychiatrists began to survive by transitioning from “talk therapy” with their patients to being de facto agents of the drug industry. Their classic roles as methodical counselors of troubled people, their time-consuming search to locate the causes of those troubles in traumas suffered earlier in life—these pursuits evaporated, to be replaced by medical expertise. This was by way of prescribing proper medications to control symptoms of discontent by altering brain function. “Brain disease” replaced “the unconscious” as a near-consensus truth. (Or, as the pioneering child psychiatrist Leon Eisenberg joked, American psychiatry shifted from brainlessness to mindlessness.) And once that ambiguous truth was settled or at least agreed upon, commerce’s doors swung open to admit the stampede of new pharma-entrepreneurs.
Haloperidol (Haldol) was synthesized in Belgium in 1958; lithium, an alkali metal with multiple adaptive uses in weapon-grade nuclear fusion, airplane-engine grease, ceramics, optics, polyester clothing, and air purification, was adapted and put on the market for use against bipolarity in 1970. The list increased steadily: Mellaril, Prolixin, Navane. The number of antipsychotics available today, in widely varying degrees of effectiveness and public awareness, approaches fifty. And then came clozapine, a watershed drug in several ways.
Clozapine appeared a few years after Haldol. It was developed in the early 1960s by the Swiss company Sandoz and promoted as a drug that succeeded with patients who seemed unreachable by Thorazine and the other early meds. Further, its developers declared it to be effective against suicidal tendencies in patients. A serotonin antagonist, clozapine could block both dopamine and serotonin receptors, which multiplied its control of overflow. But not long after its debut, clozapine disappeared. It did not reappear for a decade. It was pulled because of the problem that has bedeviled the “wonder drug” makers virtually from the outset; that has cost them millions of dollars in fines and settlements and the stigma of scandal even as their revenues soared into the billions; that has done damage to many patients, and has never been eradicated. The problem was side effects.