The Birth of Psychopharmacology
ONE OF THE CRUCIAL FACTORS undermining psychoanalytic hegemony originated not from academia, or from cognitive-behavioral therapists, but from Europe. Its initial impact was felt most powerfully in the least prestigious region of the psychiatric imperium, and it would ultimately provoke a total transformation of the psychiatric enterprise: its therapeutic practices; the settings in which therapists plied their trade; what counted as mental illness and how its various manifestations were to be defined, delimited, and understood; the training of professionals; and the intellectual orientation of the profession’s leading lights. It prompted an influx of research dollars into academic departments that had previously shunned laboratory life and the prestige that bench research might bring. It accompanied, if it did not completely cause, radical changes in the experience of being mentally ill and major shifts in public understanding of the nature of mental illness. It is usually called the psychopharmacological revolution, and that is scarcely an exaggeration. But it was at first a slow-moving revolution, one whose major impacts took decades to materialize.
No one planned the psychopharmacological revolution, and no one understood, in its early years, just how dramatic and far-reaching the effects of the new drug treatments would be. Psychiatrists had often used drugs to help manage their patients. In the early years of the asylum, patients were dosed with cathartics and emetics, among the sheet anchors of an increasingly moribund Hippocratic medicine, whose emphasis on bleeding and purging was soon to disappear. These were eventually supplemented by an array of narcotics: opium and later on morphine, and then, from the 1860s onward, by newer drugs like the sedatives chloral hydrate and bromide.
There was no pretense that these interventions were anything other than management tools, designed to quiet disturbed patients or even render them comatose. During the 1920s, barbiturates were employed as “sleep therapy” and, following the discovery of insulin to treat diabetes, its ability to induce hypoglycemia and comas had likewise been exploited, as we have seen, with extravagant claims for its efficacy belied by the remorseless rise in institutionalized patients. But deep-sleep and insulin therapy, with their associated comas and the risk that these might prove irreversible, bore little relationship to the standard medical practices of the time. By contrast, the drug now introduced to treat psychosis seemed precisely modeled on conventional medical practice. Chlorpromazine, known as Largactil (or “mighty drug”) in Europe, and trademarked as Thorazine in the United States, was the product of research conducted by a French pharmaceutical house, Rhône-Poulenc, and its psychiatric applications were purely serendipitous. Yet within eighteen months of its coming to market in the United States in 1954, two million patients were prescribed Thorazine to treat their mental illness.1
The modern pharmaceutical industry developed in the second half of the nineteenth century, gradually disentangling itself from the excesses of the so-called patent medicine sector, which advertised its secret remedies to a gullible public. “Ethical” drug manufacturers advertised only to the medical profession, and by the end of the nineteenth century, they increasingly allied themselves with the science of chemistry. German chemists were particularly adept at creating new compounds, many of them originally derived from work on new dyes created for the textile industry. These synthetic dyes proved extraordinarily lucrative for the companies that discovered and marketed them. Some of these substances, many derived from coal tar, were accidentally found to have therapeutic applications in medicine, and the companies that had started out making dyes for clothing eventually became major actors in the pharmaceutical industry, as some remain to this day. (Aspirin and the chloral hydrate that was widely used as a sedative in mental hospitals were among the many therapeutic agents discovered largely serendipitously. Bayer and Sandoz [now Novartis] are two important examples of companies that moved from dyestuffs to manufacturing drugs.)2 One of the compounds German scientists synthesized, phenothiazine, had no obvious use at the time but would, in the late 1940s, become of interest to the burgeoning pharmaceutical industry.3
As late as the 1930s, nearly half of all medicines were compounded at small local pharmacies, and most were sold over the counter, without the need for a doctor’s prescription. The pharmaceutical industry had begun to secure a larger presence in the marketplace as the decade wore on, but it was the impact of the war that completely transformed its prospects and importance, most especially, though not exclusively, through the discovery of penicillin’s therapeutic applications in the early 1940s and the solving of the problem of its manufacture on a commercial scale. A scramble was on to locate other antibiotics and to find other magic bullets with commercial possibilities. A period of rapid expansion ensued on both sides of the Atlantic, as pharmaceutical houses began to invest on an ever-larger scale in research, development, and marketing.
When Rhône-Poulenc began to search for possible therapeutic uses for chemical derivatives of phenothiazine, it had no intention of developing a drug to treat psychiatric illnesses. No such market existed, and few dreamed of creating one. Instead, having previously had some commercial success with an antihistamine, Phenergan, the company decided to explore whether it could find other drugs of this sort. There were suggestions that this class of drugs might prove useful in the treatment of Parkinson’s disease, as a sedative, or as an anti-emetic, and that one or more of them could alleviate the problem of circulatory shock during and after surgery, in part by acting as a catalyst or potentiator for general anesthetics. In December 1950, Rhône-Poulenc’s chemists synthesized a new derivative of phenothiazine. Chlorpromazine, so-called because of the addition of a chlorine atom to the original compound—internally referred to as 4560 RP—was now a drug in search of a disease it could be used to treat, and a broad spectrum of clinical applications was scrutinized for therapeutic and commercial possibilities.
As that search began, Rhône-Poulenc was anxious to find an American corporation willing to buy up rights to its new compound. In the twenty-first century, the pharmaceutical industry is dominated by huge multinational conglomerates, but that consolidation was a long way off. A European corporation seeking to sell its wares in the United States faced substantial structural obstacles, not the least of which was the pronounced skepticism that American physicians exhibited toward European science and medicine. Rhône-Poulenc’s efforts to offset its development costs by selling rights to the American market encountered severe difficulties. The first two corporations it approached rejected its overtures, for this new drug had no obvious market niche they could exploit. But in early April 1952, Smith, Kline & French (SK&F), based in Philadelphia, a company that had been attempting to secure reciprocal deals with Rhône-Poulenc, agreed to buy the North American rights to chlorpromazine. It was a relatively small gamble—the company initially spent a mere $350,000 on research and development costs—but it was a wager that paid off in spades.4
Both Rhône-Poulenc and SK&F were initially quite uncertain as to chlorpromazine’s prospects. There were a number of promising leads. By 1953, trials had been conducted to see whether it could be used as an anti-emetic, as a treatment for skin irritations, as a general sedative, and as an aid in surgery. None of these applications produced sufficiently clear-cut results, though an SK&F internal memorandum dated April 8, 1953, indicated that “nausea and vomiting are still felt to be the most appropriate indications on which to conduct rapid clinical testing to try to get marketing clearance by the F.D.A.”5 That did indeed prove to be a useful market for chlorpromazine. Pediatric journals in the late 1950s are replete with advertisements for its value in treating childhood vomiting—a disturbing phenomenon, given what we now know about the drug’s side effects. But within less than a year, SK&F had rapidly changed tactics, seizing on serendipitous findings in both France and Canada to home in on a very different set of applications for the drug, ones that would massively increase its profits.
SK&F had originally risen to prominence by bringing amphetamines to market in the late 1930s, promoting them as a nasal decongestant, an appetite suppressant, even as an antidote for depression. Such claims rested on extraordinarily flimsy evidence—five published articles reporting on a total of fewer than 150 patients, conducted under conditions that rendered them useless as scientific tests of efficacy.6 Yet despite mounting reports of serious side effects from 1939 onward, ranging from addiction to psychosis and death, the resultant profits had led to the company’s initial rise to prominence, aided by the use of amphetamines by air force pilots in the Second World War to heighten vigilance under combat conditions. Only many decades later would amphetamine abuse and methamphetamine addiction lead to serious regulatory action.7 Chlorpromazine, or Thorazine, to give it its American trade name, came to market in a rather similar fashion.
Few rules constrained the conduct of pharmacological research in the middle decades of the twentieth century, and the standards for assessing the value of new drugs were remarkably lax. Even the trial of streptomycin as a treatment for tuberculosis, often cited as the origin of the later insistence on double-blind, randomized, and placebo-controlled assessments of new therapies, was neither blind nor placebo-controlled. Those exploring the therapeutic possibilities of new drugs had extraordinary latitude in how they proceeded and how they reported their results. Drug companies seeking possible applications for new compounds made them widely available to physicians, often with little serious attention to how they were used. The testing of chlorpromazine conformed to this pattern, and it was precisely this cavalier approach to clinical testing that led to the discovery of its psychiatric applications.
Henri Laborit was a young French naval surgeon with few discernible qualifications to conduct academic research and even less interest in abiding by scientific norms. In the casual way of the times, he was given some chlorpromazine to try on his patients. His interest in reducing surgical stress dovetailed with Rhône-Poulenc’s interest in seeing whether the compound might be useful as an anesthetic potentiator. (He would be sent to the United States in November 1953 in an attempt to persuade skeptical American surgeons of the usefulness of chlorpromazine in surgery; the trip turned into a disaster when most of the dogs he was using to demonstrate his technique at Harvard died of heart failure during the operations.) Laborit’s findings were inconclusive, because he mixed 4560 RP with two other drugs to create what he called an artificial hibernation in surgical patients given the mixture. His suggestions that 4560 RP might be useful for an extraordinary range of conditions—treating burns, reducing stress in those suffering from infectious diseases, heart attacks, obesity, and reducing the doses of anesthetic needed in surgery, especially in obstetrics—were seen as idiosyncratic and of little use. But along the way, Laborit had noticed that patients given 4560 RP became uninterested in what was going on around them. He indicated that one of his colleagues thought that “4560 may produce a veritable medicinal lobotomy.”8
Laborit had urged his psychiatrist colleagues at the Val-de-Grâce hospital in Paris to try 4560 RP on their psychiatric patients. A few did so, usually in combination with sleep or shock therapy, though their reports attracted little attention. But a fellow surgeon spoke of Laborit’s findings to his brother-in-law Pierre Deniker, who was a psychiatrist at the Centre Hospitalier Sainte-Anne, the largest psychiatric hospital in Paris, with some 4,000 patients. Deniker persuaded his superior, Jean Delay, that the two of them should use 4560 RP on a broad spectrum of their patients. After a few desultory experiments with artificial hibernation, they began using 4560 RP by itself on a sustained basis.
Jean Delay occupied an important position in French psychiatry. He was a professor of psychiatry at the Faculty of Medicine in Paris, and Chief of Medicine at Ste. Anne’s. He and Deniker produced a series of papers that, somewhat cautiously, touted the merits of the new medication, especially in calming patients displaying violent agitation. Patients given the drug, Deniker noted, “look as though they have been turned to stone.… [T]hey are usually indifferent to themselves and their environment, they are stuporous or prostrate”—a description that resembles Laborit’s observation that chlorpromazine produced a “chemical lobotomy.”9 Delay and Deniker also noted some improvement among the half-dozen schizophrenics to whom they had given the drug but added that “the relatively small number of treated cases and the brevity of the remission do not permit any estimate of the possible usefulness of the method in this most severe affliction.”10
Delay and Deniker painted an optimistic picture of the changes administering chlorpromazine had brought to the atmosphere on their disturbed wards, emphasizing that it had allowed them to eliminate the old means of restraint. Despite their efforts, though, they found that “their work with CPZ [chlorpromazine] in 1952–1953 aroused little interest among their colleagues in Paris” and the drug was slow to take hold in France.11 Rhône-Poulenc, however, was not oblivious to Delay and Deniker’s findings, and it tried to get its sales staff to use reprints of their work to induce other psychiatrists to follow their lead. Oddly, that effort bore little fruit in France but had a major impact in North America, in a curiously roundabout fashion.
Quebec was a deeply divided Canadian province, whose Anglophone elite despised the French-speaking Catholic majority. Yet it was a psychiatrist at the Verdun Protestant Hospital in Montreal, Heinz Lehmann, who took a meeting with the Rhône-Poulenc salesman and subsequently read Delay and Deniker’s publications, by his account while taking a bath.12 A refugee from Nazi Germany who had arrived in Canada in 1937, Lehmann had married a French Canadian and was fluent in three languages. What he read prompted him to obtain samples of chlorpromazine to experiment with, and those experiments did much to encourage SK&F to seek FDA approval for Thorazine as an antipsychotic drug, the first of its kind.
Like Laborit, Lehmann had no training as a researcher—indeed, he had no permanent license to practice medicine in Canada. Only his staff position at a provincial mental hospital allowed him to treat patients. His situation was hardly unique. As the least attractive and most poorly paid part of the profession, institutional psychiatry had a difficult time recruiting physicians to fill vacant posts, and many state hospitals recruited psychiatrists from abroad with training that did not meet American standards. Working for the state allowed these physicians to evade the normal requirements for licensing, but kept them trapped in the state hospital system.
Lehmann’s position gave him the freedom to treat patients as he saw fit. He had previously enthusiastically embraced ECT and insulin coma therapy, and he had used barbiturates and paraldehyde to control the agitated and violent. These were, of course, treatments widely used by his professional colleagues, but Lehmann had also shown himself keen to conduct therapeutic experiments on the patients in the Verdun hospital. He had tried subjecting some of them to the inhalation of pure nitrous oxide, causing seizures and loss of consciousness. He then substituted carbon dioxide, which produced extreme fear among those subjected to the experience, but to no avail. He injected sulphur oil to create high fevers, an experiment that proved extremely painful and once again useless. And he injected turpentine into the abdominal muscles of other patients, deliberately creating abscesses in the forlorn hope that an induced infection would somehow drive out the demons of madness.13 Lehmann was, in other words, content to try any novel treatment that struck his fancy and was in a position to do so. Now he had another weapon at his disposal, for Rhône-Poulenc eagerly provided him with a substantial quantity of chlorpromazine.
Nearly two decades later, in an interview with Judith Swazey, Lehmann boasted about how easy it had been to conduct the study: “There were plenty of patients available to us, because none of them were on any other particular therapy.… [W]e didn’t need, or get, the patients’ consent before we started giving them the drug.” Their experiment began in late 1953. Having no clue how long to administer the drug, Lehmann and his resident, T. E. Hanrahan, settled on four weeks, the period they generally allowed for a course of shock therapy. As for dosage, where patients failed to respond to the initial 150 milligrams per day, the experimenters simply upped the dosage till the patient became drowsy, even when that meant giving them “many times the dosage reported in the literature.” Worrying side effects surfaced—three cases of jaundice raising concerns about impaired liver function, and “some Parkinsonian symptoms.… [W]e got the scare of our lives because we had no way of knowing if the symptoms would abate.”14 Undeterred, Lehmann and Hanrahan continued the experiment, and wrote up their findings for the Archives of Neurology and Psychiatry.
One of the most striking things about Lehmann and Hanrahan’s work, besides the fact that the trial on a haphazard collection of seventy-one patients ranging in age from eighteen to eighty-two had employed no criteria of improvement besides the clinical opinion of the two men conducting it, and had no controls, is what they claimed were the major consequences of administering chlorpromazine. Lehmann’s reading of Delay and Deniker’s papers prompted him to see whether the new drug could do a better job “of controlling acute and chronic states of psychomotor excitement—disruptive and uncontrollable behavior on the wards that made the lives of the staff and other patients a misery.” Better, that is, than the existing treatments, principally repeated doses of electroconvulsive therapy (ECT) to produce confusion and somnolence, or deep sleep therapy, with either barbiturates or insulin employed to put the disruptive patients into a coma. Sleep therapies, Lehmann conceded, required enormous medical and nursing resources and were associated with side effects that “are serious and manifold in nature … [including] pneumonia, hyperpyrexia, and cardiovascular collapse.” ECT was simple to administer, but “immediate relapses are frequent”; it has “a disorganizing effect on the higher brain functions [and can produce] confusion, restlessness, and aggression”—not to mention “the unpleasant side-effect of amnesia.”15
Chlorpromazine, by contrast, produced “the most gratifying results,” often within twenty-four hours:
Patients receiving the drug become lethargic. Manic patients often will not object to bed rest, and patients who present management problems become tractable. Assaultive and interfering behavior ceases almost entirely. The patients under treatment display a lack of spontaneous interest in the environment, yet are easily accessible and respond relevantly to questions even if awakened from sleep. As Delay and Deniker described them, they tend to remain silent and immobile when left alone and to respond to questions in a slow monotone.… Although a patient under the influence of chlorpromazine at first glance presents the aspect of a heavily drugged person, one is surprised at the absence of clouding of consciousness.16
Archives of Neurology and Psychiatry sat on Lehmann’s paper for several months and only moved to publish it in 1954 when he threatened to send it elsewhere. In the interim, apprised of the findings, Rhône-Poulenc and SK&F quickly reproduced the paper and circulated it to other psychiatrists practicing in mental hospitals. As the companies immediately recognized, a drug that could ease the management of hundreds of thousands of inpatients had considerable commercial prospects.
As other studies of chlorpromazine accumulated, the initial assessment of the potential market would prove to be an underestimate of major proportions. As late as December 1953, SK&F had tested the drug on only 104 psychiatric patients (all in uncontrolled trials), whereas its potential value as an anti-emetic, for use in treating motion sickness or the side effects of anesthesia or chemotherapy, had been tested on over a thousand patients. Finding psychiatrists willing to test the drug was a source of enormous frustration within the company. It reflected the skepticism of most, who doubted that pharmaceutical remedies would be useful for disorders that the bulk of the profession now believed to have a psychodynamic origin. In Heinz Lehmann’s words, “No-one in his right mind in psychiatry was working with drugs. You used shock or various psychotherapies.”17
It is a measure of how lax the FDA’s procedures were in those years that by March 26, 1954, SK&F had secured federal approval to market the substance it now called Thorazine for use as an anti-emetic and antinausea drug and also as a drug to treat psychiatric illnesses.18 Fortunately for SK&F, in the years before the Thalidomide tragedy, the standard they had to meet was not a demonstration of efficacy, but rather one of safety, and apart from some internal worries about the potential for liver toxicity, nothing had yet surfaced to raise questions for the FDA staff. The major side effects would only come to light some years after Thorazine had come to market.
Within a year of its introduction, Thorazine had increased SK&F’s total sales volume by more than a third. A major portion of the corporation’s subsequent growth, from net sales of $53 million in 1953 to $196 million in the two years after Thorazine came to market, and $347 million in 1970, was directly attributable to this enormously profitable product. The overwhelming bulk of these sales came not from its use as an anti-emetic, but from its psychiatric applications.19 That explosive growth was no accident. SK&F’s senior management grasped very early on the financial bonanza that this novel marketplace represented, and they moved aggressively to create and dominate it, though the first advertisement for Thorazine’s psychiatric applications did not appear until July 1955. Significantly, it touted the medicine’s value in suppressing the outbursts of violent and disruptive patients, as a replacement for earlier management techniques. “Thorazine,” the company boasted, “reduces the need for electroshock therapy.”20
Company strategies often remain opaque to outsiders. In this case, however, the architects of the program were keen to enlighten the public. They shared their account of how they proceeded with the author of a celebratory study of the drugs revolution, Judith Swazey. The product manager for Thorazine, Charles Bolling, and the head of the hospital sales department, Frazier Cheston, spoke at length about the approach they adopted.21 At that time, SK&F’s total sales force numbered 300 people. When the decision was made to promote the use of Thorazine for psychiatric illnesses, they told Swazey, “We found that this group was not adequate to deal with the introduction of Thorazine into mental hospitals, in terms of geographic distribution, the special funds needed for this type of work, or the specialized knowledge and communications network that would be needed. A professional representative, we discovered, could make no inroads at a single hospital. We had to work with the whole system, from the legislature in a state through the entire public mental hospital system and civic groups.”22 To accomplish this massive task, the best fifty salesmen were selected to form a task force whose full-time job was to create the market and sell the drug.
From the outset, SK&F had essentially written off working with “office practice” psychiatrists. They were generally separable into two groups: the electroshock people, and the analysts and related psychotherapists, both with a great commitment to their years of experience and basic training philosophy and some resistance to the use of drugs. Mental hospitals, which in the early 1950s contained more than half a million patients, were seen as a much more promising market, and the early reports of Thorazine’s ability to calm the agitated and the violent, and to make patient management infinitely easier, had an obvious attraction to beleaguered hospital psychiatrists. But sunk in “a heavy atmosphere of custodial care” and lacking any money to spend on drugs, the hospital authorities had little ability to respond to SK&F’s marketing efforts: “[We] saw there would be a need to educate supervisors, business managers, and staff people about the potential therapeutic value of Thorazine and the vast administrative savings it offered in reduced damage to plant and reduced inpatient population. We also saw that we would have to go to work with, and similarly educate, state legislators of the need for higher drug budgets for the state hospitals.”23
The task force was kept in place for six years. The propaganda efforts were sophisticated and sustained. Films were made to demonstrate Thorazine’s dramatic effects. A speakers’ training bureau was set up to coach hospital administrators on how to approach their political masters and persuade them to provide the necessary funds for drug purchases. Statistics were created to show how “factors such as less staff turnover, and less cost for such things as broken windows and damaged furniture” were correlated with various dosage levels of Thorazine. And, to encourage mass prescription of the drug, states were offered quantity discounts.
Still, the SK&F executives commented, there was resistance in many quarters:
We found that some individual legislators, and in certain cases entire state legislatures, were so apathetic to the idea of funding intensive-treatment programs that the Task Force sometimes had to use “drastic” procedures. In one state, for example, through the efforts of SK&F and other interested groups, a special legislative session took place at one of the state mental hospitals, with the governor’s and the legislative leaders’ blessings. The entire session was filmed by the “Today” show, and, in that state, it was the breakthrough that eventually committed the legislature to funding an intensive-treatment program for the state hospital system.
It was, Bolling and Cheston insisted, “not lobbying per se” but rather “a true educative effort.”24
SK&F’s “education” of politicians and state hospital psychiatrists played a major role in the psychopharmaceutical revolution, and, as the first mover, the company enjoyed a substantial initial advantage in the marketplace. Not content to watch from the sidelines, other pharmaceutical companies rapidly sought to enter the fray. Just as chlorpromazine was coming to market, a potential rival appeared on the scene: reserpine, a drug synthesized from Rauwolfia serpentina, a plant known as Indian snakeroot, or Devil Pepper. It was the subject of experiments run by an ambitious young psychiatrist, Nathan Kline, at Rockland State Hospital in suburban New York.
Traditional Indian medicine had long used concoctions of Rauwolfia to treat a wide variety of ailments, including hypertension and insanity. Another New Jersey drug company, CIBA, had derived reserpine from the original plant material and begun exploring whether it could be used to treat hypertension. Hearing of this, Kline obtained a supply to experiment with on his psychiatric patients. His report of promising results appeared in 1954, just six weeks after Thorazine came to market, and for a time some psychiatrists tried both drugs.25 But reserpine’s effects were slower to materialize, and, unlike Thorazine, it had no massive marketing campaign behind it. Moreover, its use was associated with dangerous drops in blood pressure, and in the early stages of treatment it produced restlessness and agitation, in contrast to the initially calming action of Thorazine. In short order, reserpine faded from view.
It turned out that phenothiazine, the drug from which Thorazine had been developed, was readily susceptible to other manipulations in the laboratory. Soon a number of copycat drugs that were claimed to possess similar antipsychotic properties were on the market. Hospital psychiatrists reported enthusiastically that “the atmosphere of disturbed wards has been completely revolutionized. Patients now remain clothed; they are quiet; they do not annoy each other; they conform to the conventions, take an interest in their personal appearance and in the appearance of the ward.”26 Testimony of this sort reinforced the sense that a dramatic change had occurred. The impression was strengthened by further papers suggesting that besides their success as major tranquilizers, the drugs were also effecting positive changes among schizophrenic patients, previously among the most refractory and troublesome patients. Major drug companies—SK&F, Rhône-Poulenc, CIBA, Sandoz, Geigy—helped to create this mounting optimism, funding a series of national and international conferences designed to highlight the new drugs and to encourage the creation of the new discipline of psychopharmacology.27
For several years, the vast majority of the scholarly literature on the phenothiazines, while highly favorable, was deeply flawed. Tests of the drugs’ efficacy continued to be conducted on the basis of nonblind or single-blind designs (in which only the patient was nominally unaware of whether he or she was receiving either the active substance or the placebo). Reported sample sizes were extremely small, sometimes just a single patient, and sometimes the number of patients under treatment was not even recorded. All sorts of potentially relevant confounding factors—duration of illness, previous and concomitant treatments, differential treatment of treated and untreated patients—were ignored, and assessments of whether improvement had taken place were frequently purely subjective. Most reports also covered only brief periods, with long-term follow-up studies notable by their absence.28 As studies began to be undertaken in a more systematic fashion, and double-blind assessments became the norm, early estimates of the drugs’ efficacy began to decline.
The initial enthusiasm was not entirely misplaced. Thorazine and its competitors did indeed calm severely disturbed patients. They decreased the hallucinations and delusions that, along with distortions of perception and peculiar thoughts, are the most conspicuous manifestations of psychosis. The diminution of violence and destructive acting out that mental hospitals had long struggled to contain were not inventions of the professional mind. Those forms of symptomatic relief were real and dramatic, and their importance should not be minimized. Revolutionary in their way, they continue to underpin psychiatry’s faith in psychopharmacology to this day.
But, as gradually became apparent, the symptomatic relief was far from universal. Many patients failed to respond to the drugs, and even among those who did, many paid a heavy price in side effects—an issue to which I shall return. Worse still, the phenothiazines turned out to be largely ineffective in treating the less dramatic, but in many ways more devastating deficits that are characteristic of schizophrenia—those that psychiatrists term “negative” symptoms. The blunted affect, the poverty of speech, the absence of spontaneity and initiative, the failure to connect with others, the anhedonia, or apparent inability to experience or feel pleasure: cumulatively, these have catastrophic effects on people’s quality of life and their ability to function independently. And, as with the cognitive deficiencies that mark the disorder, the new drugs left these deficits largely untouched. These were uncomfortable realities that psychiatrists preferred to ignore, emphasizing instead, to themselves as well as to outsiders, the gains that the antipsychotics brought in their train.
As usual, science journalists provided the public with enthusiastic accounts of the latest scientific breakthroughs. At least as important in persuading people that mental troubles could be dissolved by taking a pill was the marketing, in 1955, of Miltown and Equanil (both the identical chemical meprobamate). If Thorazine was a drug for the serious forms of mental illness, these “minor tranquilizers,” as they were soon called, were chemical balm for the ordinary troubles of daily life. Within a year, one in twenty Americans had tried them, and by 1957, they accounted for a third of all the prescriptions written in the United States. The following year, 500 tons of them were manufactured, and in its first decade on the market, the Carter-Wallace drug company sold 14 billion tablets of Miltown, filling 500 million prescriptions for the drug.29
Milton Berle, the first major star of the new television era, started calling himself “Uncle Miltown” and heavily promoted the drug. Later joined by benzodiazepines (the first ones were trademarked as Valium and Librium), it accustomed a whole generation to the idea of medicating away their troubles.30 Though these were drugs that fostered dependence, and brought a host of other troubles in their wake (memorably captured for a mass audience by the Rolling Stones’ song “Mother’s Little Helper”), they were immensely profitable and played a vital role in ushering in the psychopharmacological revolution. Librium and Valium’s sales exceeded those of Equanil and Miltown by the mid-1960s. By 1971, these two drugs alone accounted for $200 million of Hoffmann-Laroche’s $280 million in US sales. They were soon joined by copycat benzodiazepines (the most successful of these was Upjohn’s Xanax, launched in 1981), as competing pharmaceutical houses rushed to share in the bonanza. By 1977, 8,000 tons of these drugs were consumed in the United States alone.
The massive commercial success of the tranquilizers was no accident. Arthur Sackler, the doyen of the Sackler family who would subsequently become enormously wealthy from marketing Oxycontin, one of the major sources of America’s opioid addiction crisis, played a vital role in marketing both drugs. Alongside his career as a pharmaceutical executive, Sackler had pioneered ways of marketing pharmaceuticals directly to physicians. He correctly perceived that by clever marketing in medical journals and via promotional literature distributed directly to doctors’ offices, he could have a massive effect on drug sales. The advertisements looked like serious clinical information provided by one doctor to another, and they were enormously effective as a result. Alongside these direct forms of advertising, he began publishing a biweekly newspaper, the Medical Tribune, which eventually reached some 600,000 physicians. Here was another way of persuading physicians to adopt certain products, in stories that were ostensibly noncommercial. The advertising campaigns for Librium and Valium were perhaps his greatest marketing triumph and brought him a fortune.31
Psychoanalysts had reacted with relative equanimity to the advent of Thorazine and its competing drugs. Few analysts, after all, ventured to treat the psychotic. But many of those who did comment on drug treatment were dismissive, calling the drugs a placebo, a Band-Aid, or, worse, actively harmful. “Drug therapy,” these analysts argued, “impaired the patient’s progress by increasing his magical reliance upon medical treatment, fostering his dependency upon the physician and blunting his capacity for insight.”32 Others adopted a less confrontational position, claiming the drugs were a useful adjunct, diminishing florid symptomatology so that the real work of analysis could proceed.
As long as the phenothiazines were seen as tranquilizers, drugs that calmed patients and reduced violent and disruptive behaviors, such ideas enjoyed some purchase. Increasingly, however, as the enthusiasm for the drugs grew, some psychiatrists began to conceive of them in more ambitious terms: they were no longer “major tranquilizers” but rather “antipsychotics,” disease-specific treatments for schizophrenia and the major psychoses.33 It was a subtle but important shift of perspective, one that was both welcomed and encouraged by the pharmaceutical industry. It implied that rather than simply suppressing or masking mental distress, the new drugs were somehow acting on the disease process itself. To the extent that this belief spread, biology rather than psychodynamics became not only the place one needed to look to in order to treat mental illness but also the sole and singular cause of mental illness.
Provided that heretical notion remained confined to what the psychoanalysts regarded as the second-class psychiatrists who manned the back wards of the nation’s mental hospitals, they could complacently assure themselves that their hegemony would persist largely untouched. But the drug treatments insidiously captured the public imagination, with a large assist from the “educational” efforts of the pharmaceutical industry. In 1964, the Archives of General Psychiatry published a collaborative study funded by the National Institute of Mental Health, which claimed to demonstrate that Thorazine and two rival phenothiazines had disease-specific effects when given to schizophrenic patients. Its conclusions that “the phenothiazines should be considered to be ‘anti-schizophrenic’ in the broad sense” and that “it is questionable whether the term ‘tranquilizer’ should be retained” was prophetic of a coming seismic shift in American psychiatry.34 Within two decades, biology and Big Pharma would essentially complete their capture of the psychiatric profession.
EVEN BEFORE RHÔNE-POULENC had been alerted to the potential psychiatric value of the phenothiazines, another compound had been serendipitously discovered to have a therapeutic impact on another major form of mental illness, mania. In 1949, an obscure Australian physician, John Cade, who ran a small mental hospital for chronic patients in a Melbourne suburb and had, as he later confessed, “no research training, primitive techniques and negligible equipment,” announced in a weekly medical journal largely ignored outside his own country that he had discovered a sovereign remedy for this debilitating and often fatal disorder: lithium.35
The metal lithium had been discovered in 1817, and its salts had become a common element in many patent medicines later in the nineteenth century, especially for the treatment of gout and a variety of “nervous” complaints. Silas Weir Mitchell and William Alexander Hammond, both prominent late nineteenth-century neurologists, had used lithium salts to treat their patients.36 But lithium salts are toxic. In excess, they produce tremors, nausea, seizures, damage to the kidneys, and, in cases of serious overdose, death. Even at therapeutic levels, they can cause kidney and thyroid damage. Accumulating evidence of these problems eventually caused lithium to be banned from sale in the United States in 1949.
Cade guessed—and it was simply an unfounded guess—that mania might be caused by some toxic substance produced in the body and excreted in the urine. He attempted to prove this hypothesis by injecting the urine of manic patients into guinea pigs. The guinea pigs promptly died. Undeterred, Cade sought to break down the various components of urine to see if one of them would prove his speculation. Uric acid, however, had to be made soluble to make it injectable, and Cade chose lithium salts to accomplish the task.37 On a whim, he decided to inject some guinea pigs with lithium carbonate alone, and the excitable animals at once became tranquil. As we’ve seen, the obstacles to moving immediately to trials on mental patients were nonexistent, and Cade claimed that once he did so, trying it out on an array of schizophrenic, depressed, and manic patients, the effects on one subset of these verged on the miraculous: manic patients calmed down dramatically.38
The medical world shrugged. Cade’s claims were ignored for several years, before a Danish psychiatrist, Mogens Schou, happened upon Cade’s paper. Many of Schou’s relatives had symptoms of manic depression (later relabeled bipolar disorder), so he was motivated to try the treatment, subjecting it to one of the first controlled trials in psychiatry. He proclaimed the trial a success and lithium a valuable prophylactic, diminishing the risk of manic episodes. That alone did not suffice to create a market for the drug, in part because, as a natural substance, it was unpatentable, giving no drug company an incentive to market it. Perhaps, had it not been for an explosive and long-running dispute with another prominent pioneer of controlled trials in psychiatry—Michael Shepherd of London’s Institute of Psychiatry—the drug might have fallen by the wayside. But the dispute was lasting and vituperative. It attracted the attention of others, and further controlled trials showed that lithium indeed was somewhat useful in the treatment of mania.39
It was not until 1970, however, that the FDA licensed its use in the United States, and it took even longer before it began to be prescribed on a routine basis to patients with bipolar disorder. It has significant side effects, including increased urination, tremors, diarrhea and vomiting, and, if the therapeutic dose is exceeded (and the therapeutic / toxic ratio is narrow), hypothyroidism and kidney damage. Consequently, it requires careful monitoring of levels in the blood.
The discovery of the therapeutic effects of lithium was pure happenstance. Its ability to reduce the chances of relapse or suicide is obviously important, and it can head off much misery for those patients for whom it works. Just as Thorazine and its analogues unquestionably acted in many patients to relieve some of the more disturbing features of schizophrenia (those that psychiatrists label, oddly, its positive symptoms, most notably delusions and hallucinations), so, too, lithium has positive effects. It diminishes the rate of suicide and reduces the chances of recurrence of what is generally a relapsing disorder. But it remains a partial and imperfect treatment, and episodes of mania and depression often recur even among those taking the drug.40 It is curious, though, given its usefulness, that a recent study of drug-prescribing patterns shows that prescriptions for lithium and other mood stabilizers have fallen dramatically in the twenty-first century. Prescribed in 62.3 percent of outpatient visits from 1997 to 2000, they were prescribed in only 26.4 percent of cases from 2013 to 2016.41
Two decades ago, David Healy, a psychiatrist who is also one of the leading historians of the psychopharmacological revolution, made a bold prediction. He noted that “there was then and still is now no theoretical basis for lithium’s use, no rationale that could then or can now be used to sell it. As a result, the use of lithium will almost certainly end when Schou dies. Another agent, probably of lesser efficacy, will displace it by virtue of a marketing strategy that depends on offering a ‘biological rationale.’ ”42 Mogens Schou died on September 29, 2005. Healy’s comments increasingly seem prophetic.