Shrinks

by Jeffrey A. Lieberman

  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 co
untercultural 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 tr
anquilizer 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.