Blue Dreams

by Lauren Slater

  As we have seen with virtually all psychotropic medications, when it comes to drugs and the complex chemical soup of the brain, the only shred of certainty is this: there was, and still is, no real understanding of how and why our drugs work. The public continues to clamor for them, imbibing them in continually increasing doses, eager to believe the pharmaceutical companies’ simplistic pictorial explanations, which tend to show a synaptic cleft drained of its serotonin along with the ever-present phrase “chemical imbalance.” The roots of this understanding, or misunderstanding, are planted firmly in Kuhn and Kline, or, more fairly, in the pharmaceutical factories that manufactured not only the two men’s drugs but also the necessary “explanations” that would sell these drugs to the public. There is a sense in which one becomes converted to the antidepressant narrative spun by pharmaceutical firms. It may not be psychologically possible for some people to take a substance that alters their psyche at its most precious points and at the same time admit to themselves that the substance is mired in contradictory evidence that effectively cancels out the possibility of certainty. Thus, when one agrees to take an antidepressant, one may also be agreeing, to some extent, to adhere to a certain story about how the drug works.

  Side Effects

  It should not be surprising to us, given what we know about Thorazine and lithium, that the side effects of the tricyclics and the MAOIs turned out to be not insignificant. Imipramine, for example, can leave the mouth so dry that the teeth start to rot, deprived of saliva’s sealants. One also gets groggy on the tricyclics, and emerging from slumber can be like coming up from under a pool of sludge with your eyes tarred shut. As for the MAOIs, they cannot be mixed with any food substance, such as cheese and red wine, that contains the compound tyramine. In the event that an MAOI is combined with tyramine, the patient risks dangerously high blood pressure, hemorrhaging, and other possibly toxic events.

  Novelist and essayist David Foster Wallace has been one of our more famous public figures to take an MAOI. Wallace lived with the side effects of his MAOI, Nardil, for many years before finally deciding to go off the drug. His decision was spurred by a dining episode. One night, after eating at a Persian restaurant he frequented, Wallace became seriously ill. It wasn’t food poisoning but rather an interaction of his Nardil with tyramine, which, unbeknownst to Wallace, had been in his food. Wallace experienced heart palpitations and was felled by terrible stomach pains that laid him low for days. After he recovered he decided he wanted off, he wanted out; he had been on the drug for more than two decades and it was time to see if he could transition to an antidepressant without the MAOI side effect profile. His psychiatrist agreed.

  They did a slow taper that took months, and for a time, at his own insistence, Wallace even tried to go without medication entirely. It didn’t work, and he was hospitalized for severe depression. After his release, he cycled through many different antidepressants, not always staying on them long enough for them to take effect, and each time his dark mood returned, coming in as a series of gray days that eventually darkened dangerously, sapping him of strength and vigor. His depression was deep, and had teeth. According to his biographer D. T. Max, in the spring of 2008, almost a year after the initial event, “a new combination of antidepressants seemed to stabilize Wallace.” But the reprieve turned out to be short-lived, and in June of that year he made a suicide attempt.

  Following that episode, Wallace underwent twelve rounds of ECT, and returned to his old standby, the MAOI Nardil, which had worked so well for him before. Surely it would work again, as it was the same drug and he was the same man. He had hope. He took the Nardil pills. But now, for reasons neither he nor anyone else in his circle could really understand, it no longer worked for him. Days turned to weeks turned to months. Something was terribly, cruelly wrong. He was getting no relief this time. No one knows why a drug that once worked well ceases to have any effect at all after a patient tries it again, but this is a documented phenomenon that makes relinquishing a well-working drug very risky. That his psychopharmacologist could not explain to Wallace why the Nardil was so spectacularly ineffective this time around when before it had held him aloft for over two decades must have made his suffering that much worse.

  Depression is a disorder of desire in which the world, stripped of its meaning, becomes absurd. The naked trees look like upright forks spearing the skin of the sky. A smile is a split in the skin, a red rip, each tooth a tiny tombstone. Your dreams are drenched in dark, all the figures faceless, blurred by an inky sludge. How long can a person survive in this mindset? Wallace made it more than a year, which is, when one really thinks about it, a heroic achievement. At last, however, with the Nardil no longer working, and with Wallace’s profound depression remaining unyielding to any other pharmaceutical intervention, he ran out of hope. One evening his wife left him alone for just a little while, to set up an art show at her gallery nearby, and when she came back home he was hanging from his belt, which he’d nailed into a rafter on their patio, the lawn chair he’d used kicked over beneath him.

  The suicide of Wallace underscores the seriousness of depression, the lethality of it, and why its steady rise—the increase in diagnoses—is a phenomenon we need to understand from as many angles as are available to us. As said, psychiatrists have little understanding of why a drug that once worked well for a person ceases to have any effect. All we know, in the case of David Foster Wallace and hundreds of thousands of others, is that the MAOIs have provided steppingstones out of terrible depressions. But the MAOIs, despite their efficaciousness, have all but disappeared from the current antidepressant landscape. Given how potent they are, why are they so rarely prescribed anymore? Is it because we do not want to be psychically energized? Is it because we have realized that researchers know really nothing about what the drug does once it’s absorbed into our bloodstream and circulated to our inner and outer extremities, ferried on the backs of cells into the sacred chamber of the brain, where it…where it…and here words run dry. We can fall back on hypotheses for depression—the catecholamine hypothesis, for instance, which states that depression is due to a deficiency of norepinephrine, or the serotonin hypothesis—but a hypothesis doesn’t do us much good when we’re talking about putting pills into the vault of our one and only body. We’d like to know. We should know. And yet, even so, the lack of knowledge does not explain why MAOIs went from being homecoming queen to beggar under a bridge, in what seems like a snap.

  It had something to do with cheese. Cheese? Yes, yellow cheese, white cheese, stringy cheese, aged cheese. At first, everything appeared to be delightful for the several hundred thousand people who went on the drug. Previously mad or morose people were suddenly social and socializing, as the world took on a positive tint. For some, however, that tint became jaundiced. In 1957, there were 127 cases of jaundice reported in those taking iproniazid. It was hard to know for sure whether the MAOI was causing the jaundice; it could have merely been a correlation. Perhaps people prone to depression were also prone to jaundice. And 127 cases represented just 0.03 percent of the people who had been prescribed the drug. If it had been one hundred, just twenty-seven fewer, it would have been the same amount that occurs in the normal population. Kline shrugged his shoulders and waved away the whiff of something wrong. Roche, however, withdrew the drug.

  That could have been the end of the whole story, but by this time other pharmaceutical houses had developed their own MAOIs, which were now on the market. In 1961 The Lancet reported on a patient who died from a sudden hemorrhage while taking the MAOI tranylcypromine, which went by the brand name Parnate. Between 1961 and 1963 there were, all told, six more cases reported of people on MAOIs spontaneously hemorrhaging. The problem was that because these patients were all on other medications as well, you couldn’t point the finger at the MAOIs. Perhaps the problem had been due to one of those other medications, or perhaps simply to chance. But that possibility seemed less and less likely when primary care physicians began to report
occurrences of headaches in patients taking an MAOI. Some of these patients, it turned out, also had elevated blood pressure, which can contribute to spontaneous hemorrhaging. Still, no one was sure.

  The first inkling of understanding came through a hospital pharmacist from Nottingham who wrote to researcher and physician Barry Blackwell (one of the famous antagonists of Mogens Schou in the battle over lithium) that his wife, while taking an MAOI, had experienced headaches and hypertension after eating cheese. Could cheese be the culprit? the pharmacist wondered. Blackwell and associates laughed that off. Cheese! Everyone loved cheese. Just to show that people taking an MAOI could safely and serenely eat their cheese, Blackwell and a colleague ingested an MAOI for one whole week, after which they ate cheese. Nothing happened.

  That should have shut down the whole issue but it didn’t. Hundreds of thousands of people in the United States, and thousands more in Europe, were now launched on MAOIs, and some subset of them seemed to be getting sick in dangerous ways. Soon after Blackwell had demonstrated the innocence of cheese, in fact, he noted that a patient who hemorrhaged had eaten a cheese flan for supper, an incident that was shortly followed by Blackwell being called out to see a woman who was on an MAOI and had developed a crushing headache and high blood pressure after eating a cheese sandwich.

  It is unclear exactly how many people died from the MAOIs, although Blackwell claimed that forty deaths attributable to this particular side effect of hypertension were recorded in the first eight years of the drug’s existence. Eventually scientists figured out that cheese—along with other foods, such as beans, and beverages such as wine and beer—contains a substance called tyramine, which the MAOIs were increasing, an uptick that resulted in escalating blood pressure and headaches and hemorrhaging. It became apparent that certain foods had to be avoided if a person was on the drug. Chocolate, for example. Olives, too. Pickles and cured meats. All of them contain tyramine and must be renounced if a person is taking an MAOI. These revelations are what ultimately sounded the death knell for what had heretofore been a very potent and useful antidepressant. The drug’s usage was vastly curtailed not because no one knew how it worked or what it did once it entered our bodies—not, in other words, because patients realized they were swallowing a mystery—but because of the dietary restrictions patients would have to follow lest they lose their lives.

  Despite the fatalities, the drug was not actually taken off the market. Instead, MAOIs were repackaged with black box warnings. To many psychiatrists, then, the tricyclics emanating from imipramine seemed so much simpler and certainly safer to prescribe. After all, could a physician trust his patient to follow the food guidelines? One small slip and a burst of blood. At the same time, there was the fortuitous appearance of a prominent study from Britain which concluded that the tricyclics were the new gold standard in the treatment of depression. Gradually doctors began prescribing MAOIs less and less frequently, until finally they became what they are today—last-ditch drugs that you try when there’s nothing else left. By the time Dr. Mazor suggested I try a psychotropic medication, imipramine and other tricyclics had survived the intervening decades, while the MAOIs largely had not.

  Thought Leaders

  The MAOIs are a mini-drama showing the rise and fall of a superstar drug in a compressed fashion. When we watch the mini-drama, we come to understand how it is that drugs gain popularity and how it is that they lose it. Behind the tricyclics stood stodgy Roland Kuhn. Behind the MAOIs stood the dynamic Nathan Kline, who literally called the New York Times to report his study results, who culled from Congress $2 million, riding the crest of his charm and cheer.

  We have probably all heard stories of the aggressive marketing strategies of pharmaceutical firms, which pay charismatic “thought leaders” to tout their newest concoction, and we fret over the handouts, the gifts, the lavish lunches, and wonder how the process can possibly be impartial and accurate. Drugs, we like to think, are the product of science and, as such, rotate in pure spheres, but this is hardly the case. Charisma, the preen and polish of the thought leader who lends his or her light to whatever the product is, plays a huge role in drug development and dissemination. While this behavior is perhaps more extreme now than it was then, we can see that back in the 1950s Nathan Kline all but fed rocket fuel from the palm of his gilded hand to hundreds of thousands of Americans. Beyond that, every drug is mired in a marketing campaign that colors the way we understand them. In the case of the MAOIs, they were advertised as peppy pills in the New York Times, and as energizers by Nathan Kline, who sang a better song than Kuhn could ever hope to.

  When the MAOIs disappeared from view, they did so not because they were ineffective but because one had to follow certain dietary restrictions. Not eating cheese or even chocolate seems a small price to pay for the recession of a debilitating depression. And yet the cheese, the olives, the peanuts—together they put a taint on the MAOIs, a sort of scarlet letter, something that, in the end, burned brighter than anything even the charming Kline could say or do to counteract it, and the public rejected a potent antidepressant in favor of the deli and the candy counter. How does one make sense of that? As much as drugs define us, capturing us—our moods, our minds—in their chemical complexities, we also define drugs, deciding which capsule we’ll endorse, and doing our crucial part to create the currents by which drugs move in and out of culture.

  The Shape of a Swan

  Imipramine never worked for me. I gave it a good go, staying on it for several years. I had every side effect noted, or so it seems: a continuously tacky tongue, a dry mouth that eventually caused massive cavities, a tendency to perspire profusely even when sitting still. The drug also caused my heart to stutter—arrhythmia—and gave me enormous dreams that clung to me like mud each morning. On imipramine I dreamt of golden loons and screaming monkeys hunched on parapets, parrots of every conceivable color repeating nonsense words in a green and gleaming jungle, a river thick with bones and bodies strewn along its bank in torn translucent garments. In my dreams I was washed away again and again, sometimes in the river full of ribs, other times in the ocean, as the tides pulled me out to the satin scar of the horizon while tiny unreachable houses perched on rocky promontories in the distance. In the beginning, every month or so my doctor upped my dose, hoping for a response, and each time she did I dreamt in the daylight. The drug gave me hallucinations such that sounds became colors—a scream like a red siren—and scents became visible in the air like tendrils of filmy smoke.

  Although imipramine is an antidepressant, it had an opposite effect on me, at least for the first few weeks after a dosage adjustment, when I’d weep and weep—skinned, it felt like; without defense. All my griefs came calling, all my losses, some small and some severe, each one honed to a piercing point. I cried for rabbits and books and broken eggs; for the scarf I’d loved and accidentally left behind on a train trip years earlier; for my mother and the mask she wore; for our faces, every one of which, it seemed to me, was full of holes. I don’t know why Dr. Mazor chose to keep me on the drug when all it did was make me weep and sweat, but this was the early 1980s and there were not many alternatives, certainly not the cornucopia of antidepressants we have now. It’s reasonable to ask why, other than out of a deference to authority, I myself didn’t quit when the prescription didn’t help me at all. I can only say that after a while, although the drug offered no relief, I worried that if I went off it I’d get even worse.

  At one point, likely at her wits’ end, Dr. Mazor sent me for a consultation with a colleague at Mass Mental, a Dr. Carl Salzman, who offered me an MAOI to try instead. But first, he said, if I was interested, there was actually a new drug just come around the corner and he thought it might be even more helpful to me. Prozac, he said. Prozac? The name to me sounded dull, dead, and on that basis alone I doubted it would help me, but given the severity of my mood and the ineffectuality of imipramine, I was game to try.

  I didn’t know then that this new drug, this Prozac, w
ould lift my symptoms off me as if they were mere mist, and that I would stay on a serotonin booster not for six years, and not for sixteen years, but for almost thirty years, swallowing it down each night with a tall glass of water while around me debates raged about the safety of the medication, especially for long-term use, with some critics saying it causes irreversible damage to the brain. Still I stayed on it because, for me, I didn’t see any other option. Without the drug I could not properly function. Prior to Prozac in particular, and the SSRIs/SNRIs in general, I had been hospitalized five times and many mornings could not make it out of bed. Prozac made of me a functioning individual on the one hand, while it also turned me into something of an addict on the other hand. Psychiatrists are quick to distinguish their drugs from “street drugs,” but in fact I see very little difference between the legal pills that prop me up and the illegal pills you can buy in that dead-end alley somewhere in the city. Just like an opiate addict I have experienced tolerance (needing to raise my dose over and over again to get the same effect), dependence, and withdrawal effects if I try to cease taking the medication. I identify myself as a highly functioning addict and I tell myself that, God knows, there are worse things I could be. Yet on many days I wish it were not so.

  Bottom line: psychiatry has sickened me even as it has saved me. I know the bind I’m in is not unique to me. Think of all those patients awakened to the world by Thorazine, a deeply restorative drug that then turned around and bit back hard, causing tardive dyskinesia. Psychiatry has yet to find a drug that does not exact a physical price. Everything in the psychopharmacological arsenal gives and takes. Sometimes the price is uncertainty itself, because no one knows what chronic use of any of these medicines really does to the brain. There are scant studies of the brains of people who have been chronically exposed to imipramine, the MAOIs, Prozac, or Thorazine, in part because few long-term users give their brains to science upon their death, preferring to go to the grave intact.