The Drugs That Changed Our Minds

by Lauren Slater

  In any event, once the efficacy of G22355 as an antidepressant was established, Kuhn went on to publish his findings in a Swiss medical journal, in August 1957. The following month he attended the Second World Congress of Psychiatry, held that year in Zurich, where he reported his results during a session in which there were just twelve or thirteen people in the audience. The biology of depression and the treatment of mood disorders were very much out of vogue.

  Vital Depression

  Kuhn, however, was undeterred. By 1958 he had treated more than five hundred depressed patients with G22355, taking the initial input from the Geigy scientists and then extending the research broadly. Here is where the role of Geigy – of Broadhurst and Schmidlin and the other scientists – fades into the background while Kuhn steps forward as an essential protagonist in this story of the early antidepressants. Despite being somewhat disliked by his colleagues, Kuhn was sensitive and attentive to his patients, both empathic and observant, so much so that he was able to ascertain what types of depression would most likely respond to G22355 and to describe to Geigy the drug’s effects in a nuanced fashion, explaining that, while it was an antidepressant, it was not a euphoriant, a critical distinction for the field in particular and for the public in general.

  Euphoriants – cocaine, for instance – are not drugs that treat a discrete disease, while an antidepressant, according to Kuhn, would be able to do that. Moreover, in Kuhn’s view, an antidepressant would work only on someone suffering from a particular kind of despair, one that he called a ‘vital depression’, a state marked by reduced appetite, psychomotor retardation, a worsening of mood in the morning with some relief granted as the day went on. Those with vital depression tended to sleep poorly, were gripped by guilt and hopelessness, and either wept copiously or stared dry-eyed out into a world without colour. These were the patients who responded best to G22355. Patients without vital depression tended to experience no effect or a negative effect. Kuhn explained in the papers he published that it was possible those suffering from vital depression might not show any overt sadness at all. The depression might, he claimed, instead take on the guise of a phobia or an obsession. Thus he used G22355 on patients with phobias and obsessions as well, and got good results.

  Meanwhile, as Kuhn was conducting his trials of G22355 between 1954 and 1957, Geigy knew they had a useful compound on their hands, but the firm was slow to bring it to market. It wasn’t that there was no other interest. The Canadian doctor Heinz Lehmann – one of the first, you’ll recall, to prescribe chlorpromazine in North America – had been at the Second World Congress of Psychiatry, where Kuhn gave his poorly attended talk. Lehmann read Kuhn’s lecture on his flight back to Montreal and, intrigued, contacted the Geigy offices in Canada once he was home to ask for some samples. The Canadian branch of Geigy had never even heard of G22355. Nevertheless, Lehmann managed to get his hands on some samples and immediately started a trial at his own asylum, using the drug on eighty-four depressed patients and reporting, in 1958, that two-thirds of them responded positively. But despite its stellar success in treating a devastating condition, still G22355 did not catch on.

  Is There a Market?

  For fretful Geigy, the overarching question was whether there would ever really be a market for the drug. In a post-fluoxetine era this concern seems astounding. A market for an effective antidepressant, and safe to boot? Of course. Without a doubt. But this was well before fluoxetine had made depression into a superstar syndrome. By emphasising for Geigy that G22355 was not a stimulant, Kuhn forced company executives to tussle with a paradoxical phenomenon – a compound that eradicated the creep and crawl of severe depression, a compound that allowed its users to feel joy, vitality, energy, but that was not a stimulant or a euphoriant? Then what was it? Kuhn couldn’t say but he was quite sure the drug would be most useful for patients who were appropriate candidates for electroconvulsive therapy; in other words, for seriously ill patients, which, from Geigy’s point of view, made for a very small market indeed.

  Studies by the World Health Organization to determine the range and reach of depression indicate that, on any given day, up to 350 million people worldwide are suffering from the disorder. Had Geigy been able to see into a future in which fluoxetine would one day so saturate our culture that it has literally leaked into our waterways, they might not have dallied in marketing their new product. But they were operating in a cultural milieu in which ‘depression’ was not yet a household word, not by a long shot. In their milieu, one suffered in silence, and often got treatment only if or when the depression became so severe that the ability to function was lost.

  By late 1958, more than a year after Kuhn’s presentation at the Second World Congress of Psychiatry, Geigy did finally throw its weight behind G22355, but not because the company came to a clearer understanding of how or why it worked, or of what class of drug it was precisely, or, indeed, of whether there was really a market for it. What happened is this: the wife of one of the company’s top shareholders, Robert Böhringer, had become depressed. In a move that echoes Mogens Schou’s concern for his brother, Böhringer, who was made aware of Geigy’s work on G22355 by Kuhn, asked for some samples, brought them home and within a week his wife recovered. After that Böhringer became insistent, and since he was one of the owners of Geigy, his vote counted.

  But there was more. The previous year another antidepressant, iproniazid, had been announced on the front page of the New York Times. Now there was competition. Geigy shot forward. Given the name imipramine, G22355 was brought to market first in Switzerland, and then in other European countries under the name Tofranil, by which it was also known in the United States, when it was finally released here, in 1959, a full eight years after Geigy had first patented the drug.

  Rocket Fuel

  Meanwhile, back in the United States, a charismatic figure named Nathan Kline, who was the research director at Rockland State Hospital, an asylum in New York on the western bank of the Hudson River, had his hands on the competition, a class of drugs called monoamine oxidase inhibitors (MAO inhibitors, or MAOIs, for short). A monoamine oxidase is an enzyme that interacts with neurotransmitters such as serotonin, dopamine, and noradrenaline, removing them from the brain. Scientists had begun to wonder if an MAO imbalance in a person – too little or especially too much of the stuff – could cause schizophrenia or depression. Perhaps the MAO inhibitor could restore the balance of monoamine neurotransmitters in the brain by preventing the enzyme from removing them, thereby making them more available for use.

  Unlike tricyclics such as imipramine, a three-ringed chemical structure, the MAOIs were made of much different stuff, specifically hydrazine, a toxic liquid better known as rocket fuel – the same fuel, in fact, that the Germans had used during the Second World War to launch their V-2 missiles. Once the war was over, Germany found itself in possession of excess hydrazine, useless with the imposition of the new military limitations. With no need for hydrazine any longer, the country passed it off cheaply to different chemical companies keen to experiment with it.

  Both of our two earliest antidepressants, then, have lyrical links. The first, like chlorpromazine, our original antipsychotic, has its roots in the dye industry, springing from summer blue, treating the blues with the blues. The second, birthed from the fuel that propelled rockets into the sky, was rediscovered for the purpose of propelling people, launching them upwards and forwards to a place from which they could shed their misery. The MAO inhibitors were as celebrated as imipramine was ignored, at least initially, and they caused a major hubbub in the United States, with pictures in the press and great claims made and prizes awarded. Would there be a market? Geigy had asked. The answer was an emphatic yes.

  Hydrazine. Rocket fuel. In 1951 scientists discovered that it had anti-tubercular effects. The following year one of the compounds cooked up from hydrazine, iproniazid, turned out to do something else in addition to being effective against tuberculosis. Scientists noted that patients tr
eated with it manifested not only an improvement in their primary disease but also a greater vitality overall, a sense of extreme well-being along with a marked increase in social activity. An Associated Press photograph from the time, taken at Sea View, a hospital on Staten Island for tubercular patients, shows the patients in a party mood. The caption reads, A few months ago the only sound here was the sound of victims of tuberculosis, coughing up their lives. In another photo, patients waltz in the dayroom above the caption Dancing in the halls tho’ there were holes in their lungs. Well before iproniazid became a bona fide antidepressant, then, its euphoriant effects were noted. The road it travelled, from a tuberculosis drug that put a smile on sufferers’ faces to an approved ‘psychic energiser’ for the treatment of depression, is long and twisty, with a number of years between the first observations of its mood effects and its proper packaging as an antidepressant.

  But how did Nathan Kline become the primary discoverer of the MAOIs? The 1950s and ’60s, sometimes called the ‘golden era of psychopharmacology’, were a time when it seemed the doors to understanding human suffering, previously sealed, were being flung open, as the brain yielded up its harvest of secrets and paths, and new neurotransmitters were discovered one after the other. Noradrenaline. Serotonin. Dopamine. If you listened closely you could almost hear the click of axons and dendrites, the stutter of cognitive sparks, the sound of neurons nicking one another as they jostled inside the circle of the skull.

  This was the world in which Nathan Kline moved and worked, circling the New York psychiatry circuit lit with enthusiasm and spark. He seemed to know everyone who was anyone. And if Roland Kuhn, his contemporary, was slow, steady, strict and regimented, then Kline, who a decade later would appear on the cover of Fortune magazine as one of the ten best-known men in America, was his polar opposite: flashy, magnetic, keen and malleable, easily adopting new ideas. Kline was ambitious, too, and had every intention of discovering a drug. Interest in iproniazid was beginning to develop, and he wondered what would happen if it was systematically dispensed to depressed patients. But before he tried doing that, he appeared before Congress in July 1955 to discuss the new drugs just cresting the horizon and the need for proper evaluation tools. Because of Kline’s passionate and convincing presentation, Congress awarded $2 million for the study of the new mental health drugs, a vast sum at that time, so much money, Healy wrote, ‘that those charged with administering it found it difficult to give it away’.

  Part of the reason why Kline could get such significant backing is that he was already well known for a 1953 study that demonstrated the effects of reserpine, an alkaloid, on 710 psychiatric patients, finding that it was an efficacious antipsychotic. (For this he was later awarded the first of his two Lasker prizes, sometimes called the ‘American Nobel’, sharing it with Henri Laborit, Heinz Lehmann, Pierre Deniker and Robert H. Noce for the contributions that each had made to the treatment of schizophrenia.) Reserpine did not cause the big bang that chlorpromazine did, in part because it tended not to cause the same kind of dramatic awakenings that Delay and Deniker witnessed in Paris. And eventually Kline abandoned it entirely, once he realised that although it managed his most troubled patients’ psychoses, it had the unintended side effect of sometimes inducing depression.

  Reserpine, however, did become an indispensable research tool, perhaps the most significant research tool of that era. Remember those reserpine rabbits? In Bernard Brodie’s laboratory at the US’s National Institutes of Health, researchers demonstrated that reserpine caused a lowering of serotonin in rabbits’ brains while simultaneously making the animals lethargic, thereby providing researchers with their first animal model of depression, along with its neurochemical signature – low serotonin. Interestingly, rabbits pretreated with either imipramine or an MAOI were protected from ‘the reserpine effect’. And when the pretreated rabbits’ brains were sliced and studied, their synapses were found to be loaded with serotonin, suggesting, for the first time, that depression, and its cure, were closely allied with this neurotransmitter.

  Kline knew about the animal studies done using iproniazid and reserpine, and he needed to make only the littlest leap to conceive of using the MAOIs for depression in his own patients. In November 1956 Kline began to test his hypothesis, treating seventeen inpatients with iproniazid while also giving the drug to some of his melancholic outpatients as well. Two-thirds of the patients showed marked improvement.

  The pharmaceutical firm Roche produced iproniazid. Kline alerted company executives to his findings only to discover that Roche did not much care. Nevertheless, iproniazid was already on the market as a tuberculosis drug, so Kline’s hurdle was not that high. As a means of swaying Roche executives, and because of his general love of publicity, Kline reported his study results to the New York Times and various articles were written about this new old drug that could produce ‘remarkable mood improvement’. The public took note, and thanks in large part to Kline’s expert public relation efforts, the drug took off. Within the first year 400,000 people were treated with iproniazid, usually with positive results.

  A Psychic Energiser

  Kline, for his part, did not call the drug an antidepressant. He preferred the term ‘psychic energiser’, a concocted category which feels very different from the term ‘antidepressant’. A psychic energiser has a whiff of magic to it. It feels more closely allied to a vitamin than to a drug. It calls to mind the ephemeral, immeasurable psyche, with a little fizz now added, as opposed to the plodding and stern term ‘antidepressant’. Would iproniazid have caught on so widely had Kline labelled it an antidepressant? After all, who can’t use a little psychic energy?

  In the end, however, despite Kline’s efforts, the serious and stodgy won out. The term ‘psychic energiser’ faded away, and MAOIs are now called antidepressants. But let’s consider what would have happened if we had gone Klineian instead of Kuhnian; if we had decided to call the new drugs psychic energisers rather than antidepressants; if when you went to see your psychopharmacologist, he agreed to write you a prescription for a psychic energiser; if you said to friends that you were on a psychic energiser. Would we have been as quick to pathologise depression if the tablets to treat it didn’t suggest sickness? A psychic energiser is Everyman’s medication, while an antidepressant seems destined for the sickest of souls. One can only conjecture, of course, but the question underscores the weight of the labels we give and how, in our quest to define things, the things we name in turn name us.

  The public popularity of the MAOIs with the thousands upon thousands of people who were getting psychically energised foreshadowed the offshoot drug that was still decades away: fluoxetine, that green-and-ivory orb hailed as a breakthrough. The story of the MAOIs first revealed to us that we have long been clamouring for a cure, that we want to be believers, and that we are quick to embrace and be swayed by the offerings of pharmaceutical companies. Our belief can seem astounding when one considers the facts, which, depending on your perspective, were either nil or simultaneously abundant and contradictory. As with the drugs that had presaged them, no one really had any idea how imipramine worked, or how the MAOIs worked, only that for many people they did. True, when it came to the MAOIs, we had some inchoate theories about the level of neurotransmitters. And yes, the research of Bernard Brodie’s NIH laboratory on reserpine had shed significant light on the link between levels of brain serotonin and depression, suggesting that low serotonin leads to low mood. That light vanishes, however, when we face yet another fact: reserpine itself, which lowers serotonin, supposedly the opposite of what we want for a depressed person, has been shown in other studies to be an effective antidepressant. So the facts tell us this: reserpine causes and cures depression, a statement that cancels out understanding in one swift swipe.

  We know that reserpine causes lethargy in animals and that when the reserpine rabbits’ brains were analysed they showed a depletion of serotonin, leading one to think that low serotonin is a culprit in depression
and that the new antidepressants must have been somehow ‘raising’ levels of this neurotransmitter, especially because when the rabbits were pretreated with either imipramine or an MAOI, they did not show lethargy after imbibing reserpine. The same is true for rats. Rats treated with reserpine and then fed a tricyclic, in this case desipramine, a close cousin of imipramine, not only shrugged off the reserpine cloud but also became more active. The brains of these can-do rats were swimming in serotonin. The only explanation, then, was that their zeal and zest had to be a by-product of the antidepressants they were on. And yet – and in this story of drugs and neurotransmitters there is almost always an ‘and yet’ – when researchers have measured serotonin levels in actual depressed human beings and compared them to controls, they have found that some depressed people have low serotonin, some have normal levels of serotonin and some have high levels of serotonin, a statement that makes you swing your head dizzily around, or better yet duck so as to miss the facts flying every which way.

  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 clamour for them, imbibing them in continually increasing doses, keen 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.