The Drugs That Changed Our Minds

by Lauren Slater

  I had hit a girl, or so it seemed, but she was nowhere on the road; she had disappeared into droplets and risen up. I kept going. Now the girl was following my car on a carpet that flew and she was singing a song so mournful and accusatory that my heart burbled and seemed to claw at my chest. After some time, her song turned to tears and then the night was over and the sun climbed a vine high in the sky. I heard that girl all that day and all the next day and then the days turned to weeks and still she wept in my ear.

  My psychiatrist, meanwhile, was writing me prescriptions: ziprasidone, aripiprazole, risperidone. I was desperate enough to try anything. And then one day my doctor suggested a drug called Zyprexa (olanzapine), the name of which sounded to me like a musical instrument, an accordion from which you could gently squeeze a song. Zyprexa, a prescription I filled. I took the first tablet in the evening, the second tablet the following morning, and within a mere three days something clicked inside me and suddenly I was back in balance again. I remembered everything that had happened, the mania of stones, the grief and the girl’s high cry, but primarily I was grateful, as I always am, whenever I come through a psychiatric event – or let’s call it what it is: a breakdown. I’ve had many in my life, and one of their side effects, so to speak, is gratitude, because there is nothing so sweet after a breakdown as returning to the normal world and tasting curry or asparagus or buttered corn on the cob. In the case of olanzapine, the drug increases your appetite while simultaneously slowing down your metabolism, so in short order I got fat, but this seemed a small price to pay for my sanity. Then I got diabetes, another potential side effect of olanzapine, but even this seemed a price worth paying.

  I don’t want to go back. I know, however, that sooner or later I will. My adulthood has been marked – marred – by periodic depressions preceded by stupid, inane manias. This is who I am, like it or not.

  An Element Becomes a Twentieth-Century Drug

  Cade’s patients were worse than I am but only by degrees. The reason I have not been hospitalised in over thirty years is that I have learned how to have breakdowns in the comfort of my own home. Many of Cade’s patients, by contrast, were long-term residents of the asylum, and these chronic cases were the ones that most interested him for lithium experimentation, because he believed that ‘in them spontaneous remission is far less likely to occur’.

  It remains unclear whether Cade was familiar with any of the published reports from doctors like the Lange brothers of Denmark and Sir Alfred Garrod, all of whom had used lithium to treat madness with some success in the previous century. His notes suggest that he was, and that he also had awareness of the potential deleterious effects of the drug and of the dosing instructions in the literature of the nineteenth and early twentieth centuries. Nevertheless, ‘How to proceed?’ Cade wrote in his notebook. ‘Primum non nocere. The older pharmacopoeias did not describe any toxic effects of lithium salts but was that good enough? There is always the number one experimental animal, oneself.’ That conclusion didn’t really please Cade’s family. As one of his sons recalled, ‘Our kitchen refrigerator usually had jars of manic patients’ urine and racks of blood samples in it, always on the top shelf and much to my mother’s consternation. Her greatest distress was when Dad started taking lithium carbonate himself for a few weeks before giving it to patients.’

  We can consider it a great relief that Cade felt no ill effects whatsoever from the lithium, because if he had, the history of psychiatry and the fate of millions of men and women would likely have been completely altered, and for the worse. Instead, having deemed the drug safe, he brought it to his patients, deciding the dose on the basis not of prior medical evidence but of his own experience. In total he treated nineteen patients, ten with mania. Of those ten, three had chronic mania and seven had recurrent mania. He also dosed several schizophrenic patients and three patients with deep depressions.

  W. B. was possibly the patient who meant the most to Cade. His was a chronic case of severe and unremitting mania that rendered the patient, long regarded as ‘the most troublesome in the ward’, utterly disabled and confused. W. B. was fifty-one years old at the time Cade gave him his first dose of lithium and had been ‘in a state of typical manic excitement for five years, restless, dirty, destructive, mischievous, and interfering’. Cade started W. B. on lithium on 29 March 1948, and watched the metamorphosis unfold as this pest, this dirty and dishevelled man who had ‘enjoyed preeminent nuisance value in a back ward for all those years and bid fair to remain there for the rest of his life’, slowly settled down. Ever the cautious scientist, Cade was not sure he could credit the change to lithium, wondering if W. B.’s convalescence was due to Cade’s own ‘expectant imagination’, noting three days after treatment had begun that it was April Fools’ Day.

  Within a mere three weeks, however, W. B.’s trajectory towards mental health became obvious to everyone. He ceased making life so difficult for others on the ward. He was polite and to the point. That W. B.’s brain was still intact was noteworthy, as his illness had been so long and so persistent that he might have been a candidate for lobotomy. Once Cade was sure of lithium’s efficacy, he pointed out that the drug could and should be used in place of that severing scalpel.

  A calmer, more reasoned W. B. eventually moved from the chronic ward to the convalescent ward, where he took in the new surroundings and tried to accustom himself to the slower tempo. ‘He had been ill for so long’, wrote Cade, that ‘he found normal surroundings and liberty of movement strange at first’. But on 9 July 1948, a little over three months after treatment had begun, this apparently hopeless case was well enough to be released from the asylum with instructions to take five grains of lithium twice a day. Cade considered the transformation ‘highly gratifying’. W. B. was now back at his old job and settling into a steady life – so steady, in fact, that over time he became lax about his lithium, at first just skipping a dose here and there and then, over a period of time, letting days slide by without the drug, until he finally ceased taking it altogether. Thus, on 30 January 1949, W. B. was readmitted to the asylum. In his private notes Cade wrote that it was with ‘the most abject disappointment that I readmitted him to the hospital six months later as manic as ever’. W. B. was dirty and chattering and completely erratic, just as before. Once again he was started on a lithium regime and, once again, the illness receded and the person emerged from behind a set of scrambled symptoms, a little like a photograph in fluid, with the span of obliterating white slowly giving way to shape and form and detail.

  Cade’s original paper in which he reports on the effects of lithium on his cadre of patients is, in total, four pages long. It was titled simply ‘Lithium Salts in the Treatment of Psychotic Excitement’, and was published unassumingly, in September 1949, in the Medical Journal of Australia. Cade’s writing is spare and decidedly undramatic, consistent with the man’s modesty and his attachment to the scientific argot. Psychiatrist Barry Blackwell wrote, ‘Cade’s research . . . is remarkable because it is the very first scientific evidence of a biological cause leading to drug treatment for a major psychiatric disorder, made almost three years before the discovery of chlorpromazine for schizophrenia.’

  Cade’s paper gives only hints of the thrill and the sense of mystery he must have felt as he watched patient after patient emerge from a manic twilight. Of his second subject, Cade wrote:

  E. A., a male, aged forty-six years, had been in a chronic manic state for five years. He commenced taking lithium citrate, 20 grains three times a day, on May 5, 1948. In a fortnight he had settled down, was transferred to the convalescent ward in another week, and a month later, having continued well, was permitted to go on indefinite trial leave whilst taking lithium citrate 10 grains three times a day. This was reduced in one month to 10 grains twice a day, and two months later to 10 grains once a day. Seen on February 13, 1949, he remained well and had been in full employment for three months.

  All of the published case studies in Cade’s first lit
hium paper read as above, bare-boned and almost, if not entirely, emotionless. But while the paper reads like a book report, the case notes make it clear that Cade was an empathie clinician as well as an objective scientist. His case notes give glints of his character, his heart, his hopes. After all, while grounded in reality always, he was also the man who had spent years in captivity, a man with a muscular mind that had built hypotheses which allowed him to survive the incarceration and torture that many others did not.

  The Dark Side of Lithium

  It was the scientist in Cade, however, who noted which patients lithium did and did not help. The schizophrenic patients, for instance, responded to lithium, but much differently than did the manic patients. While the manic patients who took the lithium got better, and got better fast, the schizophrenic patients who took lithium ceased their uproar but were as mad as ever, their hallucinations and delusions continuing unabated. This suggests something highly significant: unlike chlorpromazine (then unknown), which wiped out psychosis but acted, at the same time, as a major tranquilliser, making it unclear whether the drug was treating a specific set of symptoms or was simply subduing those who took it, lithium seemed much more selective in its actions. It appeared, therefore, that the drug targeted specific neural networks rather than blanketing the whole brain. Cade hypothesised that in manic patients there might be a deficiency of lithium ions which the drug was now restoring, allowing those so afflicted to return at long last to normalcy.

  The one group of people who were not helped by lithium were Cade’s depressed patients, and subsequent studies by other researchers confirmed that outcome. R. M. Young, deputy medical superintendent of Parkside Hospital in Macclesfield, England, near Manchester, actually found, in 1949, that lithium salts could aggravate ‘endogenous depressive states’, but like Cade, he also found that the effects on patients suffering from mania were stellar.

  In time, however, some of lithium’s darker, dangerous aspects were revealed. W. B., for instance, experienced severe nausea while being treated with lithium, and after his second release his side effects became so severe he had to be readmitted to the hospital with a frank case of lithium poisoning: dyspepsia, fever, nocturnal vomiting, diarrhoea and bradycardia, an abnormal slowing of the heart rate. After the bradycardia persisted for a month, his dosage was lowered, and then he was taken off lithium altogether. Two months later, Cade wrote, W. B. was ‘back to his old form again – restless, dirty, mischievous, destructive and thoroughly pleased with himself’. According to historian F. Neil Johnson, ‘he remained in this state for just over a week, becoming emaciated and developing infected self-inflicted sores’. Hence, once again, W. B. was started back on his lithium regime and, once again, he calmed down considerably. But as it turned out, he would tolerate the lithium treatment for only one more week, at the end of which his body started to seize as he faded into semiconsciousness. Once more the lithium was withdrawn, but this time too late. On 22 May 1950, Cade reported that W. B.’s skin was ‘breaking down everywhere’; he was ‘in extremis’, with ‘continuous myoclonic twitching’. The following day, Cade wrote in his case notes that W. B. had died from ‘toxaemia due to lithium salts therapeutically administered’. Thus his first lithium patient – the one who had responded to the drug with such stunning success, emerging from a five-year mania to become in all respects a solid citizen, holding down a job and engaging appropriately with family and friends – was killed by the very drug that had given him back his life.

  No One Listened

  Cade did not discuss the dangerous side of lithium in his 1949 paper. After all, despite the fact that lithium could be toxic, it was also, clearly, a kind of miracle drug, yanking insane people back into the quotidian world and doing so quickly, eradicating the seething and spectacular fantasies of those made mad by their manias. Cade hoped the world would recognise what he had discovered. A four-page compendium of miniature biographies in which one ordinary citizen after another was saved the same way – by salt from a stone – was without doubt a revolutionary treatise. And yet, at least in the beginning, the paper stirred little interest.

  The oversight was massive, considering that Cade’s work clearly suggested that there could very well be a cure for a crippling psychological disorder. Beyond that, even when lithium failed to cure completely – with depressives, for instance – it nevertheless seemed capable of targeting specific symptoms in a way no other medication could. In the 1940s and ’50s, psychiatrists had at their disposal very few chemical options. The barbiturates, discovered in 1903, broadly sedated people, as did morphine and, eventually, chlorpromazine. But these were broad-brush drugs, blanketing the entire brain in syrupy side effects, whereas lithium, it appeared, went straight to the site of ‘excitement’ and dampened it, leaving other neural functions and their behavioural sequelae relatively untouched. Lithium, therefore, was the first ‘magic bullet’, a site-specific drug, or at least a symptom-specific drug, auguring what would follow decades down the line: the selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and sertraline, hailed because they could – supposedly – work on a single neurotransmitter system without involving the entire brain, unlike the ‘dirty’ drugs that had preceded them. Lithium, it could be argued, was psychiatry’s first clean drug, modifying a discrete set of symptoms without spread or stain.

  But all this – the specificity, the lives lost and then regained, the implications for treatment, the tale of how it had all happened with guinea pigs in the garden and one man and his hypothesis built bit by bit in a POW camp – fell mostly on deaf ears. If lithium had been a synthetic drug that a chemical company could have competed for, Cade might have found himself instantly famous and potentially quite rich, but this was not the case. The drug was a simple salt. It came from a stone; it could be found by the seaside. These facts made it all but prosaic. It didn’t cost a ten pence piece. It wasn’t made in a lab by spinning complex molecular constellations together. And because there was no way to patent the drug, no great profit motive existed.

  There were a relatively small number of studies following up on Cade’s work, including four in Australia and ten in France. And among the few who did take note was the aforementioned English doctor R. M. Young. Upon reading a summary of Cade’s paper in 1949, Young ‘found a supply of effervescent lithium citrate on the back shelf of the dispensary’. He wrote that, after giving the lithium citrate to his patients in a double dose, as instructed by the Australian article, he ‘was immediately converted by the dramatic way in which the manic symptoms were switched off in a few days’. Otherwise Cade’s paper seemed largely to disappear.

  A Champion in Europe

  In 1952, however, three years after Cade published his findings, Danish psychiatrist Erik Strömgren, head of Aarhus University’s psychiatric clinic in Risskov, came across Cade’s case histories and then turned them over to Mogens Schou, a junior psychiatrist, suggesting to Schou that here was a topic he might want to investigate. Mogens Schou claimed he had ‘caught’ psychiatry from his father, who practised throughout Schou’s childhood at a provincial mental hospital which housed psychiatric and epileptic patients. Schou recalled how his father built what he termed a ‘nervesanatorium’, the purpose of which was to treat neurotic patients. It ministered mostly to those with ‘light psychoses’ and ‘mild depressions’. Schou, immersed from his youngest days in the despair of other people, clearly remembered the ‘drooping attitudes’ and the ‘disconsolate faces’ of the men and women who wandered in a park surrounding the hospital as the trees cast their shadows on to the verdant grounds.

  Schou was struck – both as a youngster and, later, as a psychiatrist himself – by the absence of effective treatment for psychological illness. Thus when he read in Cade’s paper not only about W. B.’s emergence from madness but also about the eight other patients who were cured, many of them living outside the asylum and holding down regular jobs, his interest was more than piqued. Here, finally, was a compound that m
ight be more effective than the barbiturates, which simply put patients to sleep, or opium drops, which relieved despair but replaced it with either addiction or somnolence. As Schou would say several decades later, he was convinced from the beginning that ‘Cade’s paper would soon have become known, and it unavoidably struck the clinical by its vivid descriptions of the patients and their responses to the treatment.’

  After reading Cade’s study, Schou, along with several other colleagues in the hospital where he worked, set up a clinical trial aiming to test the anti-manic action of lithium. Their methodology was quite different from Cade’s and notable for its complex design. The patients with more prolonged manias participated in a double-blind design that shifted between lithium and a placebo, while those with more frequent manic episodes were treated with lithium continually. In total thirty-eight patients were treated. Schou’s study was, in fact, the first placebo-controlled trial ever to occur in psychopharmacology.

  In 1954 he published his findings, which were largely consistent with Cade’s. Lithium had a therapeutic and specifically an anti-manic effect in patients with bipolar disorder. When the manic patients in the study were switched from lithium to the placebo, they relapsed. One patient died during the study, but Schou claimed that the death was due not to lithium toxicity but to a pre-existing heart condition. Schou’s paper and his study differed from Cade’s in at least two significant ways, one being the double-blind, placebo-controlled design, the second being the use of a recently invented device called a flame spectrophotometer, which allowed the Danish research team to monitor the serum blood levels of lithium in their study participants, and to correlate those levels with possible toxic side effects.