I was off the olanzapine completely within four days. I felt, well, despairing. I was still on my antidepressant, but on its own it wasn’t doing much to prop me up. I was scared that I’d get into a rut too deep to climb out of before the lithium could kick in, or that my brain would take a sudden swerve and I’d ascend higher and higher to the beautiful dirty place of warped angels and wrecked houses and off-key singing that is the signature of my mania. When I walked I did so slowly, deliberately, one foot in front of the other, keeping a tempo in my head, one two, one two, one two, trying to turn my confused brain into a metronome to steady my psyche. That night, as I stood in front of my mirror, surprised to see a hint of bone beneath my skin, my ribs having put in an appearance for the first time in who knows how long, I made a fist and curled my arm up. Some strength. It was a feeling that I hoped the lithium would help me hang on to.
Lithium as a Salt Substitute
Schou continued his studies in Denmark, amassing and interpreting data, trying to persuade Hartigan to write up and publish his own findings. Lithium, meanwhile, had already made its way to the United States, only it came to our side of the sea not as a psychiatric medicine but, rather, as a salt substitute for patients who needed a low-sodium diet because of hypertension, heart disease, kidney disease or oedema. Starting in 1948, four companies, having read that lithium has a naturally salty taste, produced this salt substitute – under the names Westal, Foodsal, Salti-salt and Milosal – and it didn’t take long before doctors were encouraging their patients to use it as a way of flavouring their food.
Patients (and doctors), unaware that lithium, in excess, could be poisonous, sprinkled it liberally over their meat and potatoes, and soon a number of people either became seriously sick or died. A. M. Waldron, a doctor in Ann Arbor, Michigan, wrote to the Journal of the American Medical Association (JAMA) that he had treated four patients who had consumed the lithium salt substitute and, as a result, presented with tremors, disturbed gait, general weakness, exhaustion and blurred vision, all of which are signs of a toxic lithium reaction. Waldron, probably unaware that toxic reactions to lithium can become lethal, did not suggest that the companies which made the salt substitute should cease doing so. He merely recommended that ‘practitioner[s] should be warned of its possible toxic reactions’. In the same issue of JAMA, however, another group of doctors reported the deaths of two patients who in both cases had been using Westal, while still another doctor described a patient severely poisoned by Westal. ‘Taken together’, according to historian F. Neil Johnson, ‘the four reports sounded a loud and very clear warning against the continued use of lithium-based salt substitutes.’
These deaths and poisonings, not isolated cases, were eventually reported in high-profile publications such as Time magazine, among others, and the result was what Johnson has called ‘the toxicity panic’. The FDA (the U.S. Food and Drug Administration) reacted swiftly, banning lithium from use in the United States in 1949. Once the FDA banned lithium, it became difficult to obtain legally in the country, although that didn’t stop some intrepid doctors from prescribing it in the years that followed. After all, the spectrophotometer, if used correctly, could in fact monitor blood levels, thereby preventing poisonings. There were US doctors who followed the publications coming from Denmark and Australia, and, through ingenuity, found ways to access the drug. Remember that most asylums still had huge canisters of lithium left over from the nineteenth century, and thus those psychiatrists, like R. M. Young in England, who happened to have read Cade’s paper often had a ready supply to try on their own flock of patients. Because manic or highly excitable patients are notoriously difficult to deal with, the temptation to administer the drug, despite the ban and despite the reports of deaths and toxicities, must still have been strong.
The toxicity panic was clearly a low point in the history of lithium but it had at least two positive impacts. First, it spurred researchers to develop ever more effective means of measuring blood levels of the drug in an effort to avoid lithium poisonings, and second, it raised the drug’s profile so that more and more doctors and psychiatrists became aware of it, took note of it, and began, presumably, to read the reports from Schou and Baastrup.
The Great Clash
Schou, meanwhile, already a believer in the therapeutic benefits of lithium, began to envision it as something of a wonder drug for a certain subset of patients – namely, those with manic-depressive disorder and those with recurrent depressive disorder. Throughout the 1950s and ’60s he was doing what he could to spread the word, speaking at symposia, publishing papers, collecting data, so immersed in his work that in all likelihood he was blindsided when, in 1968, an article appeared in The Lancet titled ‘Prophylactic Lithium: Another Therapeutic Myth?’
The paper, co-authored by British psychiatrists Barry Blackwell and Michael Shepherd of London’s Maudsley Hospital, was particularly fierce, critiquing Schou and Baastrup’s 1967 showing that lithium could effectively prevent periodic depressions from recurring. Shepherd and Blackwell had several criticisms, the most important one being that Schou and Baastrup had not done a double-blind, placebo-controlled study this time around and thus were vulnerable to all sorts of biases, primary among them observer bias – the contention that the results of their studies were compromised by their awareness of the goals, which influenced their observations and made it impossible for them to report impartially.
Shepherd was convinced that Schou was actively avoiding the rigours of a double-blind, placebo-controlled trial. It was an impression stemming from a meeting both men had attended in Göttingen, Germany, during which Shepherd had discussed the importance of double-blind trials and later claimed that he had tried to ‘point out politely’ to Schou the need for further research, while Schou insisted that his evidence was compelling enough to suggest that there might be new avenues and interventions when it came to curing manic depression. Schou, in an effort to underscore how powerful lithium prophylaxis could be, told Shepherd the story of his younger brother’s miraculous recovery, completely unaware that in Shepherd’s eyes this was still further proof of researcher bias, an emotional overinvestment in what should be a strictly scientific question, and therefore a subjective stance that would surely stain whatever results Schou obtained in his work. According to Schou, Shepherd ‘clearly felt that when I showed gratification with my findings that I must necessarily be a “believer”, an enthusiast, naive and not to be trusted.’ And indeed, in their 1968 paper, Shepherd and Blackwell did accuse Schou and Baastrup of using ‘an “open” method to evaluate a therapy for which they have been enthusiastic advocates for several years’.
The Lancet paper, and the attack contained within it, caused quite a stir in psychiatric circles, in both Europe and the United States, as doctors divided on the question of whether lithium was an effective prophylactic against recurrent depressive disorder, perhaps losing sight of Shepherd and Blackwell’s core argument, which was not so much about the drug’s efficacy as it was about the researchers’ methodology. Schou and Baastrup responded to the attack one month later, but what they could not do, Schou felt, and felt passionately, was continue to implement a double-blind, placebo-controlled study to test the question because to do so presented Schou with a terrible ethical dilemma. Although Schou had conducted, with lithium, a double-blind, placebo-controlled study in the past, he had not known then about how effective lithium could be in treating mania and depression.
Now, however, he did know, and doing a double-blind study would mean assigning some manic-depressive patients to a placebo when there was a proven treatment for their condition. Such patients, on a placebo, would be left to the terrible turmoil of their own minds and, in a manic state, might spend away their savings or do other damage, while, in a depressive state, might go so far as to commit suicide. The fact that Schou’s brother had not had a single depressive episode since starting on lithium only intensified the quandary for Schou. ‘How’, he asked, ‘could I put him, or othe
rs like him, in a clinical trial where he would face the possibility of lithium being withdrawn?’ Indeed, he went on to say, in more forceful language: ‘Could we . . . expose a random sample of our patients to a placebo . . . to painful relapses and possibly suicide in order to obtain evidence for the benefit of patients in England and the United States? To do so would presumably be against the Helsinki Declaration, which clearly states that patients must not be exposed to risk through experiments unless these are of potential benefit to themselves.’
Shepherd and Blackwell, however, appeared to see no ethical problems in doing a double-blind, placebo-controlled study. But the debate was not relegated to the strictly scientific. Blackwell and Shepherd continually questioned Schou’s motives, hinting, if not outright stating, that as a scientist he was emotionally over-involved in the subject and therefore not qualified to draw meaningful conclusions from his data. In later interviews, Shepherd went so far as to be condescending about Schou’s bearing and attire:
He was a genial man . . . He wears a blazer; he speaks perfect English; he has considerable charm; he’s got this Danish humour . . . I realised that I was in the presence of a believer – somebody who knew . . . He told me that a relative had been ill and that he was taking it and that really there ought to be a national policy in which everybody could get lithium. Because he had this jovial manner I wasn’t altogether certain he was serious but then I realised he was . . . Quite inadvertently we sparked off a nightmare which went on for years . . . I had to restrain Blackwell; otherwise there would have been further trouble.
With the stakes so high (that is, the possibility, in their view, that patients from whom lithium was withheld might commit suicide), and with the accusations seemingly laced with personal judgement, Schou and Baastrup struggled to defend themselves. It is ironic that Shepherd and Blackwell accused Schou in particular of being overly involved with his study and thus unqualified to come to conclusions when in fact it appears that they were the ones who were personalising the debate, yanking it from the realm of science into something much more subjective by psychologising Schou, by questioning not his data but his underlying motives, his putative ‘over-involvement’. It was not the criticism per se to which Schou objected. ‘Critical debate is what science thrives on and should at all times be welcomed,’ he stated. ‘But one does not appreciate having one’s data . . . and ethics rejected totally and unfairly. Conjectures about other scientists’ motives are irrelevant in and should be kept out of scientific discussions.’ Blackwell countered that Schou’s entire professional life had been ‘dominated by lithium’, and that ‘his persistent refusal to attempt double-blind methodology is partly determined by his strong personal convictions about the drug’.
Knowing they needed to respond to the criticism in some fashion, Schou and Baastrup decided, in the end, to do a modified double-blind, placebo-controlled study as a way of attenuating the critiques cast their way. Eighty-four patients who had been taking lithium for a year or more were involved in this study. Some of these patients continued with their lithium treatment, while others were given a placebo, but if the patients on the placebo relapsed, then the blind was broken and they were restarted on the lithium. At the end of six months, the findings, according to Schou, were ‘unequivocal’. ‘More than half of the patients given the placebo had relapsed,’ he wrote. ‘None of the lithium patients had done so. In the view of the authors of the report, the prophylactic efficacy of lithium had been conclusively demonstrated.’
Blackwell and Shepherd remained unconvinced, claiming that the study still had methodological flaws. Perhaps, they suggested, the placebo-treated patients might have been aware that their medication had been withdrawn, given the sudden absence of lithium-induced side effects, and this knowledge could in and of itself have caused a relapse. But despite the misgivings of Blackwell and Shepherd, Schou and Baastrup’s second study appeared to settle the prophylaxis argument in their favour within the majority of the psychiatric community. The victory came at quite a cost to Schou, however, both personally and professionally. The public debate – so full of vitriol and so time-consuming – and the unending criticism, at once pointed and personal, took a toll. Even as the kerfuffle raised the profile of lithium still higher, David Healy claims, so that now it was a well-known drug in every first world country, the entire debacle, with papers flying back and forth in The Lancet and other publications – complete with attacks, rebuttals, refusals and the like – cast a shadow over Schou’s career. The controversy had been that loud and long.
And despite the fact that Schou and Baastrup prevailed in the end, even years later Shepherd was unpersuaded, eventually suggesting that, with the pharmaceutical companies not pursuing lithium development, Schou had been partially motivated by an economic incentive. ‘They saw a killing here,’ Shepherd claimed.
The industry had ignored lithium because it’s an element, it’s cheap and suddenly they saw money . . . We got involved as a sort of scapegoat in all this because we’d had the effrontery to raise the questions. Well, at least it did force them to do a more scientific study. I didn’t think that the evidence from the trial justified the conclusions . . . but it was never an important matter to me, whereas it was a very important matter to Schou because it challenged an article of faith and of course his reputation was built on this.
Lithium’s Rising Reputation
Schou’s reputation aside, the notoriety that lithium gained from the long and painful controversy surrounding it meant that more and more psychiatrists in the United States were beginning to petition the FDA to lift the ban that had followed in the wake of the great toxicity panic two decades earlier. One such enthusiast was Ronald Fieve, a psychiatrist in New York who began using lithium on his manic-depressive patients in the 1960s, touting the drug with considerable vigour. Comfortable in the public eye, perhaps even somewhat of a show-off, Fieve, who would later write the bestselling book Moodswing, helped lithium make headway in the American public consciousness, in part by persuading one of his famous patients – Joshua Logan, producer and director of the Broadway musicals South Pacific and Camelot, whose manic depression had been successfully treated with the salts – to appear with him on multiple national television networks in the 1970s, giving candid interviews about both the drug and the disorder it treated. Even respected textbooks such as The Pharmacological Basis of Therapeutics stated that ‘the lithium ion has no known therapeutic applications’. But Fieve and other US psychiatrists hoped to change the drug’s official status on this side of the sea, and to get the lithium ban lifted.
With the efforts of these psychiatrists to spread the word in the United States, and with the drug’s profile having been raised by the charged arguments between Blackwell and Shepherd on one side and Schou and Baastrup on the other, more and more clinicians in the United States began applying to the FDA for permission to use lithium on their patients, both those with manic depression and those with periodic or recurrent depressions. Eventually the FDA became so overrun that ‘many of the FDA staff were eager to grant approval simply to avoid having to process further applications’.
At the same time, Smith, Kline & French – famous for chlorpromazine – and Rowell Laboratories, perhaps at last sensing a financial opportunity, submitted new drug applications for lithium carbonate to the FDA. The pressure from the pharmaceutical companies, combined with the clamour from individual psychiatrists, went a long way towards persuading the FDA to lift its ban, which it finally did, on 6 April 1970, more than two decades after it had first outlawed the drug. Lithium was approved in the United States for the treatment of manic-depressive disorder. This, however, was the sole indication granted. Despite the research of Schou and Baastrup, the FDA did not approve lithium – and to this day has not approved lithium – for prophylactic use in the treatment of recurrent depression.
On Lithium
Still I dreamt of depression. A sheet fell over me, trapping my body beneath. A shadow, swollen, crept a
cross a wall.
The pharmacy was overbright, with festive red notebooks, spotted headbands, lipsticks in coloured casings, false eyelashes mounted inside plastic boxes. I waited in a line of people, all with their own square script, a single piece of paper that had compressed within it a long unscrolling story. My prescription was written in a hurried, arterial scrawl, with various flourishes, the letters loopy and linked together in an idiosyncratic cursive. This turned out to be a problem.
When it was my turn I presented my prescription to a white-coated woman whose lipstick was siren red, her earrings tiny pearl points, her shirt buttoned all the way up the slender stalk of her neck so that her head appeared to hover, detached. Her hair was pulled back and coiled into a bun that perched primly on top of her head, glazed and shiny, like a pastry. Extending her hand, with its long and glossy fingernails, she picked up the script between thumb and forefinger, as though it, not me, had the disease. She scanned the prescription, her lips pursed, and gave me a long look, then very deliberately smoothed the prescription with one hand, pressing it into the counter, erasing any wrinkles, after which she picked up the prescription and held it up to the light. The people in the line behind me shifted, shuffled. In one of the aisles a child started to cry.
The Drugs That Changed Our Minds Page 11
