Blue Dreams

by Lauren Slater

  Whence the Magic

  Whatever its pros and cons, the invention and dissemination of Thorazine is ultimately as significant for what it did not do as for what it did. Yes, the drug reversed states of psychosis so severe they had trapped patients for years. Yes, by doing so, the drug helped to birth the deinstitutionalization movement and the corresponding rise of the community mental health center. And the drug finally put a dent in the deeply held American affinity for psychoanalysis, as even the clinicians most dedicated to “the talking cure” had to concede that this capsule could clear the mind more effectively and efficiently than could any leather couch and conversation. But the drug did not, at least initially, spur anyone to ask how or why it was working. No one had the slightest idea. It was simply enough for everyone that it was working. Clearly the capsule suggested that mental illness, at least in some respects, was a brain-based phenomenon, but beyond that, few had a clue.

  Indeed it would be years before any viable theories arose. The double-helix model of DNA was just being discovered, but its role in schizophrenia is only partially understood even today. English researcher Gregory Bateson developed, in the mid-1950s, what he called “the double-bind theory of schizophrenia,” a theory that suggests the disease arises when parents send conflicting messages to their child. A child might become schizophrenic if, for instance, he or she was praised with words but also frequently punished with actions. (This theory has been largely discarded as researchers have uncovered other, more persuasive possible etiologies that have to do with brain morphology, genetic predisposition, and, perhaps most important, the neurotransmitter dopamine, which we will come to.)

  Was it therefore irresponsible of physicians to be giving a drug about which they had no hypotheses, never mind theories, as to how and why it worked? It seems so, and yet think of the alternative—to withhold a drug that can restore a life because its mysteries have not been mapped. Thorazine reveals to us the sheer power of empiricism. In many ways it helped to set the stage for the other, more targeted psychotropic drugs that followed, about which, in truth, we still know much less than we’d like to. So much of psychopharmacology happens in the dark, which, one might say, is its premier weakness, or its defining strength, if you appreciate its willingness to persevere in shadow, propelled by faith and whatever facts can be unearthed along the way.

  Back in the 1920s, German researcher Otto Loewi, a professor of pharmacology at the University of Graz, had confirmed the function of the first neurotransmitter, no more, no less than a wet chemical, a part of the brain’s primordial soup that dwells in tracts within our neural tissue. Today scientists know that there are over forty different kinds of neurotransmitters in our brains, but Loewi knew of only one, discovering that the brain chemical acetylcholine mediated the transmission of nerve signaling from one cell to the next, a discovery for which he would eventually be awarded the Nobel Prize. In response to this newfound knowledge, psychiatrists in the 1930s had repeatedly tried giving acetylcholine to their schizophrenic patients in the hopes of achieving a remission, with no success. But between the discovery of acetylcholine in the 1920s and the phenomenon of psychiatry’s penicillin—Thorazine—in the 1950s, few other brain chemicals had been unearthed. In fact, back then, not all scientists even accepted that the brain operated via the chemical signaling of nerve cells; many suspected that any signaling going on was electrical rather than chemical in nature.

  Thus Thorazine was released into the world with no notion of what it was doing and no real way of finding out. After all, lobotomies notwithstanding, you cannot very well carve open the skull of a patient and start poking around in his head in the hopes of tracing the medicine’s path or impact. And while one can do some form of this to animals, by giving them the drug and then sacrificing them to study their brains, in the first half of the twentieth century, prior to the discovery of Thorazine, the field had no antipsychotics with which to make such a study. Beyond that, there is and was no way of creating an animal model of schizophrenia. It would take the discovery and introduction of a second antipsychotic, reserpine, to change this state of affairs.

  An alkaloid from the rauwolfia plant that had been used in India to treat fever, vomiting, snakebite, insomnia, and insanity for thousands of years, reserpine was introduced in the United States at around the same time as Thorazine, but while Thorazine was used clinically, reserpine was used more experimentally. In 1955 Robert Bowman, a researcher at the National Institutes of Health, invented the spectrophotofluorometer, a machine that allowed scientists for the first time to detect other neurotransmitters in animal brains. Bowman’s fellow researcher Bernard Brodie investigated serotonin (the same neurotransmitter that Prozac would eventually seek to manipulate), using the new machine to discern whether the reserpine administered to rabbits that had been sedated with the alkaloid correlated with the serotonin levels in their brains. Brodie found that administering reserpine to rabbits decreased the amount of serotonin in their neural tissues. This in turn appeared to cause the rabbits to become lethargic, apathetic in just the same way that depressed people display these behaviors.

  The new technology was a significant moment in the fledging field of the neurosciences, and a solid step toward a more scientific psychiatry. With the invention of the spectrophoto- fluorometer—and the concomitant discovery that the administration of reserpine decreased serotonin in the brains of bunnies, making them seem slow and sad—researchers could now crack the capsule open, so to speak, and squeeze from Thorazine its chemical secrets and signatures in the hopes that, by understanding how it helped, they might discover something about the substrates of psychotic affliction.

  The Search for the Physical Substrates

  Given that in the early stages of Thorazine no one knew how it achieved its results, the drug did more than mend the minds of chronic schizophrenics; it also eventually pushed scientists to discover its hidden mechanisms and to try to reveal, in the process, the neural glitch that they had begun to believe schizophrenia must surely be. Thorazine set off a biological revolution in psychiatry. It made the discipline medical by allowing for a new language and structure of thought to emerge. A discipline that had its origins in the humors of Hippocrates was now governed by words like “neurotransmission” and “chemical signaling” and the logic that underlay them.

  The revolution that had started with the spectrophotofluorometer accelerated when, in 1957, Kathleen Montagu, a researcher at the Runwell Hospital, outside London, demonstrated the presence of dopamine in the human brain. Swedish neuropharmacologist (and eventual Nobel winner) Arvid Carlsson followed up on Montagu’s research by showing that dopamine, previously thought to have been just a precursor to norepinephrine, was a neurotransmitter in its own right. Curious to see what would happen to dopamine when mediated by Thorazine, scientists then gave the drug to mice and found that, under its influence, their dopamine levels decreased. These findings led to a spate of other dopamine experiments, and from these experiments emerged what is called the “dopamine hypothesis of schizophrenia.” The hypothesis at its most basic suggests that the schizophrenic brain is awash in dopamine; that excess dopamine is responsible for the voices and the visions; and that drugs which block or otherwise occupy D2 (dopamine) receptors in the brain are successful antipsychotics. The dopamine hypothesis was further supported by the fact that amphetamines, which increase dopamine production in the brain, make schizophrenia worse. The reason why Thorazine was working on psychotic patients, according to this hypothesis, was that it was lowering the level of dopamine in the schizophrenic brain.

  At the same time that psychopharmacology—motivated by the clinical success of Thorazine—was discovering endogenous chemicals and receptor sites in the brain, neuropathologists, inspired by the notion that the field of psychiatry could be made medical again, began looking for an anatomic explanation for mental illness. Some psychiatrists believe that schizophrenics at birth have often endured far more obstetrical trauma than had those subje
cts untroubled by the disease. But neuropathologists studying schizophrenia found that the problem had most likely occurred earlier, in the womb—an error in the way the fetal brain is wired. The dilemma was twofold. There were areas of the brain in schizophrenics where the neurons were jumbled, and even when properly arranged, the neurons weren’t uniformly sized, when compared to the brains of those unafflicted by schizophrenia. Scientists believe it’s highly improbable that these patterns could develop at any time other than during embryogenesis. By using PET scan and fMRI technology—neuroimaging procedures developed in the wake of the spectrophotofluorometer that are able to measure brain activity by detecting changes linked to blood flow—researchers were getting a look, for the first time, at the brains of schizophrenics versus those of controls. As a result, they were also able to demonstrate that schizophrenics have enlarged cerebral ventricles (the ventricles hold cerebral spinal fluid in the brain), and, more significant, that the degree of enlargement is proportional to the degree of impairment.

  At the present time no one really knows what the relationship is between the dopamine hypothesis of schizophrenia, which posits that excess dopamine is at the root of the disease, and the observations of the disorganized neurons and the enlarged cerebral ventricles found in many (although not all) schizophrenic brains. Does excess dopamine somehow scramble the neurons or cause the enlargement of cerebral ventricles? Or are these phenomena merely two distinct symptoms of what is a multifaceted syndrome? Some people with the illness, for instance, become catatonic; others become paranoid. We know of several strains of schizophrenia, and there may be still subtler variations of the illness, perhaps dozens, in which case it may also be that just as healthy brains are vastly different, so are sick ones, which means that a unified theory of schizophrenia, while appealing, may be misleading.

  The New Antipsychotics

  All of this neurological research has been the guiding force behind efforts at refining our antipsychotics over the past sixty years. At the present time we have a wide array at our disposal, some of them similar in their pharmacological action to Thorazine, while others, the newest antipsychotics—Abilify, Geodon, Zyprexa, and Seroquel, for example—act on entirely different brain chemicals, such as serotonin and norepinephrine. The new antipsychotics are now a multibillion-dollar industry in this country, and by 2011 they had surpassed statins—cholesterol-lowering agents such as Lipitor and Zocor—as the best-selling category of drugs in the United States, a truly mind-boggling fact when one considers how rare psychosis is in the population. Schizophrenia in particular and psychosis in general affect no more than 1 percent of the population, around 3 million people in the United States, but far more than 1 percent of the population is imbibing some sort of antipsychotic drug. For instance, by 2011, the total number of annual prescriptions written for the group of drugs known as atypical antipsychotics (which includes Abilify and Seroquel) rose to 54 million from 28 million in 2001, almost doubling in the space of a decade, meaning that psychiatrists and psychopharmacologists are likely prescribing the new antipsychotics for off-label conditions not approved by the FDA. The astounding rise in the number of prescriptions for the newer antipsychotic drugs may be due to psychopharmacologists’ belief that, when added to a depressive’s diet, so to speak, an antipsychotic boosts the action of the antidepressant and more effectively irradiates the iron grip of despair than does an antidepressant alone.

  As for Thorazine, the loudly touted penicillin for psychiatry, the drug responsible for initiating pharmacological and neuropathological inquiries into the human head, it has fallen by the wayside, outshone by the newer offshoots that emerged in its wake, drugs that boast a supposedly safer side effect profile and a more efficacious antipsychotic action, which may not be at all true. Thorazine’s reputation was done in primarily by its link to tardive dyskinesia, combined with the rampant antipsychiatry movement that started in the 1960s—initiated in part by books like Thomas Szasz’s Myth of Mental Illness and in part by the rise of the civil rights movement and feminism, both of which employed a rhetoric later adapted by the antipsychiatry movement to insist that mental patients were another oppressed minority, “their psyches manipulated by therapists.” Thus the drug once hailed for saving the minds of many madmen and -women the world over is rarely prescribed anymore, so out of fashion has it fallen. Indeed, with some exceptions, the drug has been relegated to the veterinary world, where it goes by the name acepromazine and is given to circus elephants with pre-performance jitters and high-strung horses whose owners are hoping to bring home a blue ribbon.

  For a drug that so effectively and completely, if temporarily, cleaned up the chaos of entrenched psychotic conditions to be relegated to the dustbin of the back ward, so to speak, seems odd, but it reveals how susceptible psychiatry is to fashion and fad, how hard a time psychiatry has holding on to the very science it seeks, too often falling prey to the new and the nifty. Psychiatrists, of course, will not admit that their preference for newer antipsychotic drugs has anything to do with trend, and will insist instead that it has everything to do with research and patient safety, but the fact is that the new antipsychotics on the market carry their own significant risks, some of them far more severe than the motor dysfunction that Thorazine, in excessive doses, can cause. It is well documented that some of the new antipsychotics can cause enormous weight gain, leading to metabolic disturbance, which in turn can develop into type 2 diabetes. “When it comes to antipsychotics,” says McLean Hospital’s psychopharmacologist Alexander Vuckovic, also a Harvard professor, “you have to pick your poisons. Which would you rather be in two years—a circus freak or a diabetic?”

  Of course, if you are not afflicted with schizophrenia or another psychosis, you can cull a third choice from Vuckovic’s comment and say “neither,” but if you happen to be a person in need of an antipsychotic in order to see straight, a person who is persecuted by voices or sees filmy beings flying before your eyes, a person who can rarely speak a sane sentence, then “neither” is not an option. Such a person is faced with unfortunate choices indeed. The very starkness of the choices suggests that, while psychiatry has come far, it still has a long way to go. The bare basic facts reveal a profession still stuttering, with at best a slippery grasp on the science behind its pills and potions, a legion of medical men and women who can help you in one way but hurt you in another. The misgivings and doubts that many people feel about this inherent risk are in part what gave rise to the antipsychiatry movement.

  The Antipsychiatry Movement

  In 1961, after a year spent working as an orderly in a mental institution, a Stanford student by the name of Ken Kesey began to write a book. What emerged from his experience is One Flew Over the Cuckoo’s Nest, which eventually inducted millions of readers into the putative world of the ward. Kesey’s cuckoo’s nest featured traumatic shock treatments, forced medication, a nurse named Ratched who would have whipped her charges were it legal, such was her dislike. One Flew Over the Cuckoo’s Nest portrayed the mental hospital as a dark and demeaning place where people were regularly stripped of their humanity and shocked again and again on a cold steel slab until they were empty-eyed and crippled, while orderlies without care or concern held down the doughy bodies of people imprisoned in pitiless wards for years, with no end in sight.

  Kesey’s fictional account, along with works by intellectuals like Thomas Szasz, Michel Foucault, and Erving Goffman, to name a few, ignited the fledgling antipsychiatry movement of the 1960s, which began to flourish here and abroad. Suddenly mental illness was a myth designed to punish what was in fact just another variation of creativity, and the wards were really prisons, places whose purpose was to repress the wayward tendencies of those who lived on and mined the margins of society, gifted people whose voices and visions should be celebrated rather than treated or in any way tamped down. The drug that had freed, the drug that had redeemed the seemingly hopeless mentally ill, became the chemical straitjacket, and now the juggler, the bar
ber, and all the other patients brought back to reality by Thorazine did not have, and never had had, anything wrong with them in a strictly medical sense, because madness was just a social construct used to suppress and repress. The celebrated silence of the wards now became proof of oppression.

  In 1969, prominent antipsychiatrists such as Szasz and R. D. Laing visited Tokyo University, inspiring students there to revolt, which they did, occupying the department of psychiatry and tossing out Hiroshi Utena, a professor of psychiatry who had done biological work in the 1950s. For a full decade the department remained occupied by students, and all inquiry there screeched to a halt. All across Europe, similar scenarios played out. In France, fired by the ideology of the antipsychiatrists, students stormed the venerable Sainte-Anne asylum and assaulted Delay’s office. One imagines college kids upending his handsome desk, tossing his gilded pens out windows, emptying his drawers, and shredding his papers. In an instant, it seemed, this giant of psychiatry and the huge institution he ran were ransacked and a whole new kind of madness now swirled around Delay, one for which he had neither clue nor cure.

  HELP

  But it seems wrong to end the story of Thorazine here. Without a doubt, schizophrenia is a dreadful illness, perhaps the most dreadful of all the psychiatric conditions, and so even if we don’t have all the answers we need, we should be grateful for the story of Thorazine, the fact of Thorazine, which started a ball of knowledge rolling that has not stopped. Perhaps, then, this story should end where it started, with methylene blue, that brilliant transparent dye the color of the Caribbean Sea, out of which sprang promethazine, which then gave way to Thorazine, which turned the world of psychiatry on its tender head.