Chapter 6

Mother’s Little Helper: Medicine at Last

Mother needs something today to calm her down

And though she’s not really ill

There’s a little yellow pill

She goes running for the shelter of a mother’s little helper

—MICK JAGGER AND KEITH RICHARDS

It’s better to be lucky than smart.

—HENRY SPENCER

Chloral Simmerings in My Spine

These days, it’s difficult to imagine the practice of psychiatry without medication. You can hardly watch TV without seeing an ad for some mood-enhancing pill, usually featuring merry families frolicking on sandy beaches or joyous couples hiking through sun-dappled forests. Young people are far more likely to associate my profession with Prozac, Adderall, and Xanax than reclining on a couch week after week, divulging one’s dreams and sexual fantasies. Schools, colleges, and nursing homes in every state openly endorse the liberal use of psychoactive drugs to mollify their more disruptive charges. What is less well known is that psychiatry’s dramatic transformation from a profession of shrinks to a profession of pill-pushers came about through sheer serendipity.

When I was born, not a single therapeutically effective medication existed for any mental disorder. There were no antidepressants, no antipsychotics, no anti-anxiety drugs—at least, no sort of psychiatric drug that quelled your symptoms and enabled you to function effectively. The few existing treatments for the major categories of mental illness (mood disorders, schizophrenia, and anxiety disorders) were all invasive, risky, and burdened with appalling side effects, and these desperate measures were mostly used to control disruptive inmates in mental institutions. Similarly, the first psychiatric drugs were not intended to be curative or even therapeutic—they were blunt instruments for pacification. Their daunting side effects were only deemed acceptable because the alternatives—fever cures, coma therapy, induced convulsions—were even worse.

In the late nineteenth century, asylums used injections of morphine and other opiate-derived drugs to subdue recalcitrant inmates. While the patients may have ranked this among the most agreeable psychiatric treatments of the Victorian Era, the practice was discontinued once it became clear that opioids turned patients into hardcore addicts. The first behavior-altering drug commonly prescribed outside of asylums (psychotropic drug, in the argot of medicine) was chloral, a sleep-inducing non-opiate prescribed to relieve insomnia in anxious and depressed patients. Like morphine, chloral was not intended to treat a patient’s most salient symptoms—namely, the fearfulness in anxiety disorders or the feelings of sadness in depression—it was intended to knock the patient out cold. Chloral was preferable to morphine because it was reliable in strength from dose to dose and could be given orally, but patients disliked its awful taste and the distinctive odor it imparted to their breath, known as “alky-breath.”

Even though chloral was less addictive than morphine, it was still habit-forming. Women suffering from “nervous conditions” often self-administered the drug at home in order to avoid the embarrassment of institutionalization and frequently ended up as chloral addicts. The celebrated author Virginia Woolf, who suffered from manic-depressive illness and was repeatedly institutionalized, frequently swallowed chloral in the 1920s. From her boudoir, she wrote to her lover Vita Sackville-West about its effects: “Goodnight now, I am so sleepy with chloral simmering in my spine that I can’t write, nor yet stop writing—I feel like a moth, with heavy scarlet eyes and a soft cape of down—a moth about to settle in a sweet bush—would it were—ah, but that’s improper.”

Once its sleep-inducing properties became widely known, chloral quickly gained notoriety as perhaps the first drug employed to surreptitiously incapacitate a victim. Adding a few drops of chloral to someone’s drink gave rise to the expression “slip him a mickey.” (The term may have originally referred to a Chicago bartender, “Mickey” Finn, who added chloral to the drinks of customers he intended to rob.)

The simple act of putting a patient to sleep will inevitably reduce his symptoms. After all, when you lose consciousness, your anxieties, delusions, and manias subside, along with your nervous tics, ranting, and pacing. From this matter-of-fact observation, it was a short leap of imagination for psychiatrists to extrapolate the hypothesis that by prolonging their patients’ sleep, they might diminish their symptoms during waking hours as well. Around the turn of the nineteenth century, Scottish psychiatrist Neil Macleod experimented on a variety of mental illnesses with a powerful sedative known as sodium bromide. He claimed that by rendering patients unconscious for an extended period of time, he could produce a complete remission of their mental disorders, a remission that sometimes lasted for days or even weeks. He called his treatment “deep sleep therapy”—an appealing moniker, for who doesn’t feel rejuvenated after a restful slumber?

Unfortunately, there’s quite a bit of difference between natural deep sleep and the sleep produced by a chemical strong enough to knock out an elephant. Deep sleep therapy can elicit a cauldron of scary side effects, including coma, cardiovascular collapse, and respiratory arrest; one of Macleod’s own patients died during his experiments. It was also difficult to judge the right dose, and sometimes patients slept for a day or two longer than intended. Most problematic was the fact that bromide is a toxin that builds up in the liver, becoming more harmful with each use.

At first, bromide compounds spread rapidly through public asylums because they were cheaper and easier to manufacture than chloral, while producing more potent effects. The “bromide sleep cure” was briefly taken up by other physicians, too, before being abandoned as too dangerous.

Even though morphine, chloral, and bromide were all crude and addictive sedatives with harmful side effects, the notion that drug-induced sleep was therapeutic became firmly established by the start of World War II. (Except, of course, among the psychoanalysts, who dismissed sleeping pills out of hand, insisting they did nothing to resolve the unconscious conflicts that were the true mainspring of all mental illness.) Even so, no psychiatrist, psychoanalyst or otherwise, believed that there would ever be a drug that targeted the symptoms of mental illness or empowered a patient to lead a normal life—at least, not until 1950, the year the first psychopharmaceutical drug was born, a drug providing true therapeutic benefits for a troubled mind.

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, more 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; needless 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.

The next step, Cade reasoned, was to find a compound that would neutralize uric acid, the putative mania-producing toxin. Since uric acid is not soluble in water (this is why it accumulates in gout victims), he decided to add a chemical to the manic-derived urine that would dissolve the uric acid and help the guinea pigs (and, presumably, manic patients) excrete it more easily, thereby reducing the guinea pigs’ mania.

Now, let’s pause just a moment to put Cade’s experiment into perspective. Henri Laborit, recall, was pursuing a (largely incorrect) theory of surgical shock when he stumbled upon the first antipsychotic drug entirely by accident. Roland Kuhn, for no logical reason, decided to find out if a psychosis-fighting compound might be better suited for lifting the spirits of the despondent, leading to the first antidepressant. From these examples it is clear that the process that led to such momentous discoveries was not a rational one, but rather, more guided by intuition and serendipity. And now, since metabolic toxins have absolutely nothing to do with mania, John Cade was pursuing the totally spurious hypothesis that mania could be eliminated by finding the right solvent to dissolve uric acid.

The solvent Cade selected was lithium carbonate, a compound known to dissolve uric acid. Cade first injected his guinea pigs with “manic urine,” then injected them with lithium carbonate. To his delight, the previously “manic” guinea pigs soon became calm. Cade took this as further confirmation of his toxin theory—after all, weren’t the guinea pigs quieting down because they were successfully excreting uric acid? Unfortunately for Cade, when he tested other uric acid solvents on the animals, they failed to produce any calming effects. Gradually, he realized that the guinea pigs’ placated behavior was not because uric acid was getting dissolved—there was something special about the lithium itself.

To his credit as a scientist, Cade abandoned his toxin theory of mania, which his data simply didn’t support. Instead, he threw himself wholeheartedly behind the development of lithium carbonate as a treatment for mental illness, without having any clue why it pacified hyperactive animals. In 1949, Cade conducted a small-scale trial of lithium on patients diagnosed with mania, psychosis, and melancholia. The effect on the frenzied behavior of the manic patients was nothing short of extraordinary. The calming effect was so robust that Cade came up with a new hypothesis: mania was caused by a physiological deficiency of lithium.

While Cade’s second theory turned out to be as short-lived as his first, his treatment was not. Lithium proved to be a godsend, and today lithium is used around the world as a first-line drug to treat bipolar disorder. Left untreated—and before the discovery of lithium, bipolar disorder always went untreated—the illness is highly destructive to the brain and can sometimes be fatal, as illustrated by the untimely death of Philippe Pinel’s friend. Another casualty of bipolar disorder was Philip Graham, the celebrated publisher of the Washington Post. On August 3, 1963, while on a brief leave from the Chestnut Lodge psychiatric hospital, where he was receiving psychoanalytic treatment for his manic-depressive illness, he went to his country home and killed himself with one of his hunting rifles. His widow, Katherine Graham, never forgave the psychiatric profession for failing him. Sadly, lithium was already available at the time of his death, though it was not approved for use in the U.S. until 1970.

When given in the proper dosage, lithium levels out the wild mood swings of bipolar disorder, permitting those suffering from the illness to live normal lives. To this day, lithium remains the most effective mood stabilizer (the name given to the class of medication for treating bipolar disorder), though alternative mood stabilizing drugs are now available.

By 1960—after a century and a half of groping in the darkness—psychiatry possessed reliable treatments for all three types of severe mental illness. What made chlorpromazine, imipramine, and lithium so different from the sedatives and tranquilizers that came before was that they directly targeted psychiatric symptoms in a kind of lock-and-key relationship. Sedatives and tranquilizers produced the same broad mental changes in everyone, whether or not a person suffered from a mental disorder, whereas antipsychotics, antidepressants, and mood stabilizers reduced the symptoms of illness without producing much of an effect on healthy people. Even better, the new drugs were not addictive and did not produce euphoria, like barbiturates or opiates. This meant the drugs were not particularly appealing to the worried well and did not become habit-forming in those suffering from mental illness.

Unfortunately, the fact that these new classes of drugs were not habit-forming meant that many patients did not feel compelled to continue taking them once their symptoms subsided, especially since chlorpromazine, imipramine, and lithium each had various unpleasant side effects, particularly if the doses were not carefully regulated. But for most patients (and their families), the side effects of psychopharmaceuticals were far outweighed by the near-miraculous relief from chronic, distressing symptoms.

I have experienced firsthand the unique effects of each class of psychopharmaceuticals. During my pharmacology class in medical school, my instructor assigned us to imbibe a series of medications during the semester, one dose each week. Every Friday we were given a small cup of liquid to swallow. Our assignment was to describe the effects we experienced over the following hour and then guess which drug it was. While we knew the possible choices—which included alcohol, amphetamine, the sedative Seconal, Valium, Thorazine, the antidepressant Tofranil, and a placebo—the identity of each drug was not revealed until we had completed the entire series. The results shocked me. I had guessed wrong on every single drug except for Thorazine; the antipsychotic had made my mind feel fatigued and dull, thinking demanded painful effort, and I felt indifferent to everything around me. Later, as a resident, I sampled lithium but didn’t feel much of anything other than increased thirst and the paradoxical need to urinate.

The mind-boggling effectiveness of psychiatric drugs began to transform the fundamental nature of psychiatry—and elevate its professional status. The black sheep of medicine could rejoin the flock because it finally had medicine. President Kennedy, in his address to Congress in 1963, acknowledged the changing landscape of mental health: “The new drugs acquired and developed in recent years make it possible for most of the mentally ill to be successfully and quickly treated in their own communities and returned to a useful place in society. Such breakthroughs have rendered obsolete a prolonged or permanent confinement in huge, unhappy mental hospitals.”

Needless to say, the transformation of psychiatry also transformed the psychiatrist.

The Pioneers of Psychopharmacology

At various moments during my undergraduate years at Miami University in Oxford, Ohio, I imagined myself as a surgeon, obstetrician, cardiologist, radiologist, neurologist, and, on occasion, as a psychiatrist. The writings of Sigmund Freud first introduced me to the medicine of the mind and the possibility of fathoming the most beguiling organ of the human body through thoughtful analysis. But a very different sort of encounter introduced me to the possibility of understanding the brain through biology, chemistry, and neural circuitry. While working on this book, I discovered that Bob Spitzer and I shared a common experience in our professional development—a youthful experiment with LSD.

Though taking mind-expanding drugs was something of a rite of passage for those coming of age in the ’60s, I suspect that my own approach to dropping acid was rather atypical. In 1968, my junior year—the same year the Beatles released their psychedelic movie Yellow Submarine and a year before the Woodstock Festival in Bethel, New York—I decided to try psychedelic drugs. I didn’t rush out to join the latest hippie “happening.” Cautious by nature, I systematically considered the recreational drugs that were in popular use—marijuana, uppers, downers, hallucinogens—and weighed the pros and cons of each, the way most people might approach buying a new car. I decided that my (perhaps overambitious) goal was to expand my understanding of the world and illuminate the mystery that was myself. After reading several exciting countercultural books detailing the wild mind-expanding journeys evoked by hallucinogens, such as The Varieties of Religious Experience, The Doors of Perception, and The Teachings of Don Juan, I thought I had finally found the drug I was looking for—the sultan of psychedelics, lysergic acid diethylamide.

I decided to trip with my girlfriend Nancy and, characteristically, I fastidiously planned out every detail of the big event in advance. The LSD came in squares of absorbent paper, called blotter acid, and Nancy and I each swallowed two small squares (about 100 micrograms), then headed out onto campus on a warm spring afternoon. Within fifteen minutes, I felt a tingling sensation throughout my body, beginning in my abdomen and then welling up throughout my body. Soon, my visual, auditory, and tactile perceptions began to fluctuate and intensify. The grass and trees appeared brighter, the green almost spectacular in its vividness. My hands became objects of wonder, radiating kaleidoscopic patterns that oscillated in and out of focus. The ambient noise of the field we were crossing twisted through bewitching arpeggios of sound.

Eventually, as part of my planned itinerary, we arrived at a church near the campus and sat together in a pew. I marveled at the dazzling stained glass and the staggering beauty of the altar. Until then, the effects of the LSD had been mostly perceptual. Now a new experience emerged that was far more intense and mind-bending—in fact, I often recall this portion of my trip when I work with psychotic patients. As I gazed upon the religious accouterments of the church, I was filled with an overwhelming spiritual awareness, as if God was communicating His secret and divine meaning to me. A cascade of insights tumbled through my consciousness, seeming to touch my soul and thrilling me with their profundity. And then in the midst of this revelatory reverie, a disembodied voice whispered, “And no one will ever know,” which seemed to signify to me that this was where the real truths lie, in these secret interstices of consciousness which most human beings never accessed—or if they did, they were unable to retain these precious encounters in their memory. I looked over at Nancy, assuming that she was immersed in the same transcendent, exalting experience as I was. “We must start coming to services here to maintain this spiritual connection!” I exclaimed. She looked at me querulously and barked, “But you’re Jewish!”

We later realized that our individual experiences were entirely separate and often absurdly different. As my mind soared through metaphysical realms of empyrean knowledge, she spent most of her trip reflecting on her relationship with her father, an Episcopalian WASP whose ancestors came over on the Mayflower, ruminating fearfully on what he would say about her having a Jewish boyfriend.

But the most deflating moment came when I pulled out my written notes. During the trip, I had jotted down descriptions of my revelations, expecting to revisit these profound pearls of cosmic wisdom once the drug wore off. Now, as I scanned my chaotic scribbles, I found them either boringly mundane—“love is the essence”—or ludicrously nonsensical—“leaves are green clouds.” Later, whenever I encountered Szasz or Laing or any other antipsychiatrist talking about the “journey of the schizophrenic,” I recalled my private log of Great Thoughts. Just because a person believes he is having a cosmic encounter—whether because of drugs or mental illness—it doesn’t mean he is.

My trip did produce one lasting insight, though—one that I remain grateful for to this day. Though my LSD-fueled reverie dissipated with the light of the morning, I marveled at the fact that such an incredibly minute amount of a chemical—50 to 100 micrograms, a fraction of a grain of salt—could so profoundly affect my perceptions and emotions. It struck me that if LSD could so dramatically alter my cognition, the chemistry of the brain must be susceptible to pharmacologic manipulation in other ways, including ways that could be therapeutic. During an era when Freud still held dominion over American psychiatry, my psychedelic experiment opened me up to an alternative way of thinking about mental pathologies beyond psychodynamics—as something concrete and biochemical in the cellular coils of the brain.

Before chlorpromazine, imipramine, and lithium, severe mental illness was almost always a life sentence of misery and a source of great shame to the families of the afflicted. Making matters worse, the prevailing psychiatric theories blamed the parents for the way they raised their child, or the patients themselves for their “resistance to treatment.” But the success of the psychopharmaceuticals challenged head-on the fundamental tenets of psychoanalysis. If depression was due to parental anger turned inward, if psychosis was due to demanding and confusing mothers, if mania was due to unresolved infantile grandiosity, then how could gulping down a small tablet make these symptoms fade away?

Psychiatric medication not only challenged everything psychoanalysts had ever been taught about mental illness—it threatened their very livelihood. Those psychoanalysts who did deign to prescribe the new drugs considered them to be a treatment of last resort, to be used only when psychotherapy had been tried and had failed. But along with many other psychiatrists from my generation—many of whom also experimented with psychedelic drugs—I became receptive to the unexpected new role of psychiatrists as psychopharmacologists, as empathic prescribers of medication.

The very first generation of psychopharmacologists had all been indoctrinated into the psychoanalytic tradition during their training but often harbored doubts about Freudian dogma. Not surprisingly, it was the youngest psychiatrists who most readily embraced the new psychiatric drugs. Starting in psychiatry departments in the 1960s, the pressure to use the new medications often came from residents who were still in training. Gradually, medications began to permeate clinical psychiatry, and practitioners who buoyantly advocated drug therapy became increasingly common.

The growing contingent of psychopharmacologists increased the number of biological psychiatrists to its largest since the heyday of Wilhelm Griesinger. To their medical colleagues in other specialties, the psychopharmacologists were a breath of fresh air; finally, there were medically minded psychiatrists to whom they could relate and confidently refer mental patients. But from the point of view of their psychoanalytic colleagues, these maverick psychopharmacologists were regarded as heretics and worse—the pitiable products of failed analyses, individuals who could not overcome their own conflicts, conflicts that made them defy Freud’s masterful teachings and neurotically cling to the delusion that chemicals could cure patients.

Brash and outspoken, the psychopharmacologists didn’t just voice a new and radical philosophy about mental illness; they behaved in forbidden ways. They refused to affect the deliberate manner of a proper analyst, who spoke in stilted and omniscient tones or quietly listened in a detached manner. Instead, they engaged their patients with lively and probative back-and-forth discussions and strove to be empathetic and even reassuring. Sometimes they saw patients for 30, 20, or even 15 minutes rather than the requisite 45-or 50-minute hour. Occasionally, in order to take someone’s pulse or blood pressure, examine side effects, or just greet a patient with a handshake, they even committed the cardinal sin of touching their patients. These early heretics/pioneers included Jonathan Cole of Harvard, Frank Ayd of the University of Maryland, Sam Gershon of New York University, Donald Klein of Columbia, and—the most notorious apostate of them all—Nathan Kline.

Perhaps better than any other, the story of Kline’s career illustrates the greatest triumphs of the first generation of psychopharmacologists—as well as their most egregious shortcomings. When Nathan Kline graduated from the NYU School of Medicine in 1943, psychiatry was a scientific wasteland parched by psychoanalytic theory. But Kline was too intellectually restless to engage in what he felt was a scientific charade, and early in his career he began searching for pharmaceutical treatments. At first, the only compounds available to a would-be psychopharmacologist were the various sedatives and tranquilizers, which he dutifully investigated. Frustrated by the lack of effective drugs, he expanded his search to other spheres of medicine. Intrigued by the use of the snakeroot plant (Rauvolfia serpentina) as a tranquilizer in India (Gandhi famously used it), he used a snakeroot extract called reserpine experimentally on schizophrenics in the early 1950s. Although his initial results were promising, they were abruptly eclipsed by the emergence of chlorpromazine.

Kline began investigating other novel psychoactive compounds. Eventually, in 1959, he published a groundbreaking series of studies of iproniazid, a drug used to treat tuberculosis, demonstrating its effectiveness as an antidepressant. Kline’s studies established an entirely new class of antidepressants with a pharmacology distinct from imipramine called monoamine oxidase inhibitors (this time, scientists understood how the drug worked in the brain). This discovery launched Kline into the scientific stratosphere. His research accorded him the unique distinction of being the only scientist to ever win the prestigious Lasker Award twice.

As a flood of new psychiatric drugs began to be approved by the FDA in the late ’50s and ’60s, Kline eagerly tried out each one in his clinical practice in New York. Whereas most Manhattan psychiatrists of the era focused on endless sessions of Freudian talk therapy, Kline aggressively prescribed the very latest drugs, often in creative combinations, and dramatically reduced the length, number, and frequency of talk therapy sessions.

In 1960, Life magazine called Kline “a pioneer of the new drug therapies for mental illness.” He was celebrated throughout medicine and elected to the most elite scientific societies. Perhaps more than any other single person, Nathan Kline was also responsible for the deinstitutionalization of patients from mental hospitals in New York State: Buoyed by the dramatic results of his ongoing psychopharmacologic research, Kline supplied Governor Nelson Rockefeller with a vision of medication-driven community mental health care, an effort that dovetailed with President Kennedy’s introduction of the Community Mental Health Act in 1963. Kline was sought out by celebrities and politicians for treatment and frequently lauded in the press. His meteoric rise demonstrated the transformative effects that drugs were having on psychiatry and mental health care—but it would also reveal the hazards that accompanied the rapid pharmaceuticalization of psychiatry.

Nathan Kline was at the height of his career when I first met him in 1977 at a psychopharmacology meeting sponsored by the National Institute of Mental Health in Florida. I was in my second year of residency training in psychiatry and had been dispatched to the Sonesta Hotel on Key Biscayne by my mentor to present the results of our investigation of a new antipsychotic drug.

The roughly three hundred attendees were a mix of academic researchers and National Institute of Health scientists, along with representatives from pharmaceutical companies. On the evening of the first day’s sessions, a cocktail reception was held on the terrace adjacent to the pool overlooking the beach. I approached the crowd and was struck by a memorable sight. On one side of the terrace was a rowdy group of conference-goers gabbling away in shorts, bathing suits, and T-shirts. On the other side, reclining on a chaise longue overlooking the ocean, was Nathan Kline, looking regal in an immaculate white tropical leisure suit, and surrounded by a coterie of attendants. He held a tropical drink in one hand as he directed his minions with the other, like a monarch granting an audience to his subjects.

Shortly before the conference I had read a report in the Archives of General Psychiatry about Kline’s research with a new compound called beta-endorphin, which he had administered to schizophrenia patients with dramatic results. This was an astonishing finding, as the only known antipsychotics were all chemical variants of chlorpromazine, whereas beta-endorphin was a naturally occurring peptide that was produced by the body, a completely different kind of compound. After discovering an entirely new class of antidepressants (the MAO-inhibitors), it appeared that Kline had now discovered an entirely new class of antipsychotics.

I nervously walked over and introduced myself. I asked him several questions about his study, as much to impress him with my knowledge as to deepen my understanding of his. At first he greeted me warily, but after realizing that I was a genuine admirer he warmed up and responded enthusiastically. He concluded by thanking me magisterially for my questions.

Only later did I learn that despite his fame, Kline had become something of a pariah in scientific circles. In modern parlance, he had “jumped the shark.” It should have been apparent to me at the Florida conference that his pompous behavior would be alienating to his colleagues, but as a young resident I was naïve and starstruck. I would soon learn firsthand his sins against the medical codes of conduct.

As I continued my residency at St. Vincent’s Hospital in Manhattan, I began to encounter what many psychiatrists in New York dubbed the “Kline experience.” Patients of Dr. Kline began to drift into the emergency room and the outpatient clinic, and as new admissions to the psychiatric inpatient unit. All were victims of Kline’s risky and sometimes heedless practice. They suffered from severe adverse reactions caused by elaborate cocktails of psychotropic medications—or from the effects of their abrupt withdrawal. Whereas most psychiatrists treated depression, bipolar disorder, schizophrenia, or anxiety disorders by prescribing one or two medications, possibly three on a rare occasion, Dr. Kline frequently prescribed extravagant combinations of five or more medications in their most potent forms, often at high doses. It got to the point where I was able to guess whether a patient was one of Kline’s simply by glancing at the list of medications on his chart. No one else had the confidence—or recklessness—to prescribe such witches’ brews of mind-altering cocktails.

Nathan Kline (1916–83), a flamboyant pioneer of psychopharmacology. (Portrait of Dr. Kline by David Laska, courtesy of Dr. Eugene Laska and the Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY; photograph courtesy of Koon-Sea Hui, MPhil, PhD)

In the end, it was not the death of a patient or a massive malpractice suit that prompted Kline’s downfall, though that was surely a possibility. It was the very study that had inspired me to timidly seek an audience with him in Florida. Kline had failed to submit the protocol for his study to an Institutional Review Board for approval, an ethical and legal requirement when conducting medical research on human subjects. Not only that, he hadn’t bothered to get the proper informed consent from the patients to whom he was administering experimental psychoactive compounds. Apparently, in his eagerness to achieve another stunning scientific success (and perhaps win a Nobel), he had rushed to be the very first researcher to publish on a potential new class of psychopharmaceutical.

The FDA investigated Kline, and in 1982 he was compelled to sign a federal consent decree swearing to never conduct research on drugs again. Psychoactive drugs had launched Kline’s career—and they ended it in ignominy. A year later, he died on an operating table from complications arising from an aortic aneurysm.

Despite Kline’s excesses, the advent of psychopharmacology had irrevocably changed the field of psychiatry for the better. Those suffering from severe mental illness now could hope for relief and genuine recovery. But it also created tensions in a field struggling to redefine itself. This quandary was not lost on the media, which laid bare the emerging ideological fault lines. In 1955, in the wake of chlorpromazine’s redesign of the mental health landscape, Time magazine reported, “The ivory-tower critics (mainly psychoanalysts) argue that the red-brick pragmatists—state hospitals—are not getting to the patients’ ‘underlying psychopathology’ and so there can be no cure. These doctors want to know whether he withdrew from the world because of unconscious conflict over incestuous urges or stealing from his brother’s piggy bank at the age of five. In the world of red-bricks, this is like arguing about the number of angels on the point of a pin.”

But before the psychopharmacologists could permanently tip the balance away from the ivory-tower psychoanalysts, one final revolution was still necessary.