Walter Brown: Lithium : A Doctor, A Drug, and a Breakthrough
Barry Blackwell’s comments
This pithy volume is only 256 pages and six chapters long, including an Epilogue, Index, Citations, End Notes and a Selected Bibliography. A press release heralds it as, “The untold story of a miracle drug, the forgotten pioneer who discovered it, and the fight to bring lithium to the masses.”
More realistically this is the third book published in the 21st century describing events that took place at the end of the first half of the 20th century, on the eve of a psychopharmacology revolution that produced almost all the modern drugs for the treatment of mental illness (1950-1980).
The author, Walter Brown, is a Professor at Brown University, Providence, RI, with a career-long interest in psychopharmacology. An American, he was preceded by the Australian authors of two other volumes eulogizing the discovery of lithium by their countryman John Cade (Schioldann 2009) and (de Moore and Westmore 2016).
The timing of this literary triumvirate is felicitous, a half century or more after the events themselves, at a time when the discipline of psychopharmacology is in the doldrums and the American College of Neuropsychopharmacology (ACNP) is considering a name change. Creativity and innovation have stalled abetted by corruption in the pharmaceutical industry aided by complicit members of our profession whose economic conflicts of interest go unchecked by their professional organizations and lax journal editors (Blackwell 2017).
Walter Brown’s upbeat story about a groundbreaking discovery of the first agent (a metallic ion) to stifle a major psychiatric disorder (acute mania) and the heroic figure who made the discovery (John Cade) has been categorized as “a fairy story.” It is told in elegant prose accessible to both lay and professional readers, including novel information and ideas not present in the volumes that preceded it.
This review provides a synopsis of each chapter (with the author’s opinions in quotation marks) followed by a Commentary with conclusions by this reviewer that take into account this volume and the two that preceded it.
Chapter 1: Manic-Depressive Illness, A Brief History describes the diagnosis in the DSM system now named bipolar disorder.
Interestingly Walter begins with Pope Urban VI, elected in 1378, whose “angry, violent and abusive behaviors” led to the eponym “The Mad Pope,” identified by John Cade (himself a Catholic), as an example of key leaders suffering from manic-depressive disorder whose illness changed the course of history, in this instance the Protestant Reformation.
Walter Brown continues with an impressive catalogue of the disappointing attempts to treat this disorder or to identify its biological or genetic etiology from Hippocratic times up to Cade’s discovery. This includes, bleeding, colonic purging, “moral” treatments, fever therapy, sedative and insulin induced comas, lobotomy, and perhaps most instructively, Henry Cotton’s surgical forays to remove a gamut of organs believed to house infection; teeth, testicles, colons, ovaries and gall bladders, all removed with “a vengeance bordering on the demonic from 1907 until 1930, all claiming an 85% cure rate.” Met with “world-wide accolades,” Walter suggests this illusion of benefit might be due to “spontaneous recovery at play… even without treatment patients in the throes of mania or depression usually recuperate within 3 to 6 months.” He concludes, “control groups are now an essential part of treatment research.”
The chapter ends with an accolade to Cade: “In 1948, an unassuming young psychiatrist from a small country town in Australia stepped into this medical morass. What he happened upon restored the lives of people with manic-depressive illness and brought psychiatry into the scientific age.”
Chapter 2: The Naturalist is a novel, perhaps unique account of Cade’s capability as a student of naturally occurring phenomena in human and subhuman species.
In a 1970 Presidential address to the Australian and New Zealand College of Psychiatrists (ANZCP), Cade catalogued his accomplishments. “My own research efforts have been sporadic over many years. Most have ended in blind alleys. Some have been successful. All have been fun. In the process I have learned a great deal about the habit of termites, the length of snake’s tails, the meaning of the Kookaburra’s raucous cry, the length of the vagus nerve in the sleeping lizard, the eccentricities of lightening, the dermatological metamorphoses of chameleons, the ecology of my own garden and, en passant, something of the causes and effective treatment of manic-depressive illness. I have taken a tremendous intellectual pride in all discoveries I have made, irrespective of their importance or whether the same fact had been ascertained by others.”
In the same Presidential address he exhorted his colleagues: “Almost everyone can and should do research… the intellectual discipline and training that it imposes is an essential pre-requisite to expertise in the professional field.” Unlike a majority of physicians he was not satisfied with graduation from medical school but, like some in Britain, he studied for and passed a postgraduate M.D. degree.
Cade began his medical career training in pediatrics but eventually changed to psychiatry, following in his father’s footsteps and in 1936 was appointed to Beechwood Mental Hospital where his father had worked when he was a child. His life as a psychiatrist was cut short by the outbreak of war against Germany and Japan in 1939 and after enrolling as a medical officer he served in that capacity until the war ended, including three years in a Japanese POW camp in Changi where he was responsible for a 12 bed inpatient unit housing the most serious mentally ill soldiers. “Cade was by all accounts an exemplary medical officer. The men who served with him admired – indeed treasured – him for his medical and psychiatric competence and for his equanimity, resilience and courage. His conviction that severe mental illness had a biological basis was cemented…’this fired my ambition to discover the etiology.’” On his way home he wrote a letter to his wife Jean: “The old brain is simmering with ideas. I believe this long period of waiting has allowed many of my notions in psychiatry to crystallize, and I’m just bursting to put them to the test. If they work out, they would represent a great advance in knowledge of manic-depressive disorder and primary dementia – sounds like my usual over-optimism, doesn’t it? Well there is only one way to find out – test it and see.”
Chapter 3: Lithium briefly outlines the discovery and use of lithium, worldwide up until Cade’s discovery.
Walter starts with the chemical structure of lithium as a naturally occurring basic metallic ion combined with salts as lithium chloride and lithium carbonate, its widespread distribution in nature and its identification as a discrete element in the early 19th century.
By mid-century it was introduced into medical practice based on the recognition that lithium joined with uric acid to form lithium urate that became a treatment for disorders, including gout in which uric acid might be a cause. “The uric acid diathesis brought with it a seemingly rational treatment in an era where there were few effective treatments for anything.”
This was especially true for disorders that appeared to be co-morbid with gout. “One of the 19th century doctors who jumped on the uric acid bandwagon was the Danish psychiatrist Carl Lange who gave lithium to outpatients who suffered from recurrent depression using dosages comparable to those used today reporting success in acute treatment and recurrence.”
Walter describes how Carl Lange’s theory, confirmed by his brother Fritz (a psychiatrist), lacked support among the Danish medical profession and fell into disuse – “more than 60 years passed before John Cade rediscovered it.” But work with lithium “that most seems to directly shadow Cade’s discovery” came from William Hammond, a professor of nervous and mental disease at New York’s Bellevue Hospital. In 1871 he reported that he used lithium bromide to treat patients with mania and found that it swiftly and effectively calmed them. Hammond used exceptionally high doses and it’s not clear if it was the lithium or the bromine portion that produced the results. In later textbooks (1882-1890) he did not mention lithium.
Nevertheless popular belief in lithium and the uric acid diathesis persisted in lay remedies, patent medicines and spa waters despite the fact that “since lithium first surfaced as a medical treatment its toxic properties had been of concern. In doses not much higher than those given as a treatment, whether for gout or bipolar illness, lithium takes on the qualities of a poison. People taking too much can suffer dizziness, nausea, vomiting, tremors, drowsiness, and blurred vision. If lithium isn’t stopped these symptoms can proceed to seizures, coma and death. This toxic potential of lithium is why measurement of its blood levels became a necessary part of treatment in the 20th century.”
Sadly and paradoxically these fatal effects were not widely recognized until the “salt substitute fiasco in America positioned it in both the public’s mind and the medical profession as a potentially dangerous substance, best avoided. So John Cade’s original 1949 report of lithium’s benefit in mania could not have arrived at a less propitious time. But arrive it did, and in retrospect it is acknowledged as a revolutionary advance, one that ushered in the modern era of psychiatric treatment.”
Chapter 4: Breakthrough tells the story after Cade’s return to Australia from the POW camp in Changi, the details of his discovery of lithium for acute manic episodes and what became of the patients he treated with it.
When Cade emerged from his task of caring for his fellow soldiers at Changi his experiences “left him brimming with research ideas.” Like many of his civilian colleagues working in asylums he was convinced that psychotic disorders had a biological basis. So he abjured private practice and opted to become chief of Bundoora Mental Hospital an asylum with 200 patients many of whom were repatriated military veterans.
His first basic assumption about a potential biological cause grew out of an analogy with the role of the thyroid gland in creating the polar opposites of thyrotoxicosis and myxedema. Might manic-depressive illness reflect the existence of an unknown endogenous substance in excess or absence? Cade created a laboratory fashioned out of an unused pantry in one of the hospital wards, collected concentrated urine samples stored in the family refrigerator and injected it into guinea pigs and measured the amounts necessary to kill them. To determine the toxic agent “Cade embarked on a series of modest experiments that now have a mythic place in the history of psychiatry. These experiments did not follow an entirely logical or readily understood sequence, and Cade misinterpreted one of the critical results, but his effort to find the toxic substance led him, albeit by a circuitous and serendipitous route, to his groundbreaking discovery.” In efforts to find a substance that might enhance the toxicity of urea Cade set about the search. “I’ve read Cade’s description of his next steps that led to the discovery of lithium’s ability to relieve mania, more than a hundred times, and in a seminar I teach about discoveries in psychiatry I’ve gone over the steps with hundreds of students. Nevertheless the rationale continues to baffle us all.”
Cade decided he needed to look further at higher concentrations of uric acid but because it’s relatively insoluble in water he used the more soluble lithium urate. When he injected the lithium salt the guinea pigs appeared to be sedated and no longer displayed a startle response. This was the finding that led Cade to test lithium’s efficacy in mania after determining appropriate dosages by taking lithium himself over his wife’s objections. This conclusion was likely an error. “For now it seems clear that the lethargy of Cade’s animals was not a result of sedation but rather of lithium toxicity.”
Cade treated 10 patients overall with acute mania and six with schizophrenia. His paper describing the results was published in the Medical Journal of Australia on September 3, 1949, 10 years to the day after the outbreak of the Second World War, when Cade was 37-years-old. Interestingly the title was “Lithium salts in the treatment of psychotic excitement.” All the lithium patients’ mania subsided and 3 of those with schizophrenia were sedated but while the core symptoms of mania abated those in schizophrenia showed no improvement. Four patients with mania experienced lithium toxicity which in three abated with dose reduction.
Walter notes that “several patients whose vignettes in the published report ended with them doing well had a less happy outcome as time went on.” Cade’s first patient and poster child (WB) eventually fared worse with a rocky clinical course that ended two years later in death due to “lithium toxemia.”
At this juncture Walter comments on the “almost total absence of criticism directed to Cade or his methods.” For explanation he mentions Cade’s seemingly unassailable saint like status. He notes: “The vast majority who have spoken about Cade and his research, many of whom are fellow Australians, simply lavish him and his scientific approach with praise.” He concludes: “one reason for the reticence to criticize Cade comes from the fact that any hint that his conduct was less than exemplary is hard to square with the prevailing view of him as a man and scientist of impeccable integrity.” An obituary cites him as “An honorable, upright Christian gentleman, honest in all his dealings, and with a vast fund of kindly human feeling and consideration.” An additional aspect is his “status as a war hero.” Even Australian psychiatrist Johan Schioldann (author of a previous Cade biography) felt Cade knew of Lange’s previous work on lithium and disapproved of Cade’s egregious failure to cite it but, with tears in his eyes said, “there’s no way I’m going to criticize that guy. After what he went through at Changi he’s a war hero and I’m not going to say anything bad about him.”
In a remarkable volte-face Walter Brown states in the next paragraph, “Even before it was verified or extended by Schou and others, Cade’s research in 1948 and 1949 revolutionized the treatment of manic-depressive illness and the outlook for its victims. Cade is rightly credited for launching the ‘psychopharmacological revolution’ for showing that a drug can relieve mental symptoms.”
Chapter 5: Aftermath covers more than a decade between Cade’s discovery and the arrival of Schou on the scene in 1960.
Walter begins this chapter with a statement that appears to rescind the closing sentiment of the previous chapter. He notes that despite the praise heaped on Cade by himself and others the use of lithium did not increase in the familiar manner by which a new treatment for a significant disorder usually takes off. “It took a full 20 years before psychiatrists accepted and routinely prescribed lithium.”
He correctly attributes this to a number of facts. First, lithium is not a drug but a naturally occurring substance that cannot be patented so there are no pharmaceutical companies marketing it with extravagant claims expecting to yield healthy profits. Secondly, the industry was churning out rival, so-called mood stabilizers colorfully advertised and endorsed by well-paid psychiatry key opinion leaders (KOL’s). “These drugs became the rage, and in doing so drew attention away from lithium.” Cade’s more personal observation was because, “his discovery was made by an unknown psychiatrist, working alone in a small chronic hospital with no research training, primitive techniques and negligible equipment; hardly likely to be a compellingly persuasive especially in the United States.”
Walter points out that “notwithstanding all of the above the major impediment was its potential toxicity.” This was true and Cade’s self-deprecating statement could not detract from it or from his own role in the toxicity issue. That lithium was a toxic substance was well documented in “the 100 years before Cade’s work.” To make matters worse directly preceding Cade’s publication of his findings was a crisis involving lithium in America where it was being marketed as a salt substitute in the low salt diet management of hypertension. In February 1949 four reports in the Journal of the American Medical Association (JAMA) totaled 14 patients with lithium toxicity of whom three were fatal. An outpouring of warnings in the newspapers and on the radio revealed further cases and on February 18 the FDA “ordered lithium salt manufacturers to take their products off the market.” The news reached Australia and was published in the July 10 issue of the Medical Journal of Australia (MJA) just 5 weeks before Cade’s research was published in the same journal. Cade did not cite the American prohibition although his paper cautioned against and discussed the toxic effects of lithium. A month later in the 1949 issue of the Australasian Association quarterly newsletter Cade made a personal plea to be informed of any cases of lithium toxicity. A further fatality due to lithium appeared in MJA in August 1950. Soon afterwards, “The reported instances of lithium-induced illness and death, combined with his own encounters with lithium toxicity, convinced Cade that lithium’s potential for harm outweighed its benefit, and he stopped using it.”
Cade’s reputation had advanced to the point he became Superintendent of Melbourne’s prestigious Royal Park Mental Hospital in 1952 and on doing so “he banned the use of lithium at the institution.” The year before, in August 1951 the MJA carried a report of a study carried out by Edward Trautner, a research worker in the Physiology Department at the University of Melbourne and Charles Noack, a psychiatrist at Melbourne’s Mont Park Psychiatric Hospital. Using a new instrument, a flame spectrophotometer, they developed a method for measuring the plasma levels of lithium, had confirmed Cade’s clinical findings and had safely treated more than 100 patients none of whom developed serious toxicity. Meanwhile, a young psychiatrist named Sam Gershon, a Jewish refugee from Poland, had started his residency training in psychiatry and landed at Park Royal hoping to work under Cade on lithium; he got short shrift from someone who wanted no more to do with the troublesome treatment and was dispatched to obtain supervision elsewhere. On graduating Sam would become a trainee, colleague and friend of Trautner before migrating to America to begin a distinguished career with a major interest and research on lithium and advocacy for its use.
Cade showed no interest in Trautner’s work and it did not influence his decision to ban the use of lithium, now rendered potentially safe. Cade’s aversion to Trautner and failure to endorse or employ his results remain speculative. Trautner, of German descent, served in the First World War for Germany, then graduated as a physician but left Germany for Spain and then England to escape Hitler. In Britain he was falsely identified as a potential spy and shipped to Australia in 1940 for internment in a prison camp before being rescued by the Professor of Physiology in Melbourne who knew of his research. Raised a Catholic he was “a devout atheist, a maverick but also a scientific polymath who had his fingers in all sorts of research.”
Although scorned by Cade, Noak and Trautner’s work gained the attention of Danish psychiatrist Mogens Schou. His father, Hans Jacob Schou, was director of two psychiatric hospitals, particularly interested in manic-depressive illness. “Convinced of its biological basis he ran a research unit to study chemical and physiological changes in psychiatric disorders.”
Inspired by his father’s example Mogens Schou “decided to study medicine with a specific view to do research on manic-depressive illness.” After graduating from medical school in 1944 he studied biochemical research for two years and then set up his research at Risskov Psychiatric Hospital where the head of the hospital acquainted him with Noak and Trautner’s research as well as Cade’s own paper that had aroused their interest in developing the measurement of lithium plasma levels that would make the treatment safe.
Schou decided to do the first randomized controlled trial (RCT) of lithium in mania. “Following Trautner and Noak’s lead Schou measured serum lithium levels.” Walter notes, “Small, untidy and rudimentary as it was this study that put lithium’s unique benefit as a treatment on solid ground. Yet more than a decade passed before the psychiatric community took much notice.” Published in 1944 it was first rejected by a prestigious journal and published in a lesser “out of the way one; few psychiatrists read it, and the response was a rather deafening silence.”
By the mid 1950s lithium was languishing in the wake of new psychiatric drugs.” The new neuroleptic drugs, first the phenothiazines, then the butyrophenones were not specific for acute mania and unlike lithium they were sedating but they worked more quickly and adequately stifled manic behaviors.
But Schou continued to study lithium. “Through the latter half of the 1950s Schou wrote a dozen papers reporting the results of animal studies and the outcome of additional patients treated with lithium.” In 1958 Schou attended the First International Congress of the CINP. The proceedings ran to 720 pages including papers on the new antidepressants, tranquilizers and ant-psychotics. Lithium does not appear in the title of any paper. “In a cry of despair and defiance” Schou made the following comment during a general discussion at the end of the conference:
“On the chemotherapeutic firmament lithium is one of the smaller stars, and until now it may not even have been noticed by all psychiatrists. But its light appears unmistakable, and it may turn out to be steadier than that of several other of the celestial bodies which now burn so brightly.”
Schou followed up with a brief report of his findings about lithium and its safety before noting, “A handful of psychiatrists in Australia, France and England started prescribing lithium.” Most yielded positive and encouraging results. In Australia two psychiatrists published papers and one, Bernard Glesinger, who treated 104 patients with positive results also declared, “There is no necessity to measure or control lithium excretion by complicated chemical methods or to determine plasma content. This refinement can be reserved for institutions with appropriate facilities.” A sentiment perhaps shared by Cade, confident and proud of his clinical skills but adamantly rejected by Schou.
The Second CINP international conference in 1960 once again, “Included no papers at all about lithium” but when in 1962 a symposium appeared called “Ten years of psychopharmacology: critical assessment of the present and future,” Schou felt compelled to speak, “This morning’s discussion seems to be about to create the false history that 1962 is the tenth anniversary of the psychopharmacological era. This however is neither true nor fair, because in 1949 the Australian, Cade discovered the therapeutic efficacy of lithium salts against manic phases of manic- depressive psychosis.”
Schou continues to identify a cause for this oversight: “But the main reason for the neglect of lithium may be quite simply that lithium salts are so inexpensive that no commercial interests are involved. This drug has therefore completely lacked the publicity which is invariably given to drugs of higher money-earning capacity.” He also adds a further reason. “…that lithium is chemically unrelated to any of the other drugs used in psychiatry” and does not fit into conventional classificatory schemes.
Note, however, that Schou does not mention lithium’s toxicity problems, Cade’s ban on lithium or his failure to endorse Trautner and Noak’s work ensuring its safety.
This chapter ends with Walter’s own thoughts on the failure of lithium to flourish. “The fact is that had treating mania remained lithium’s only use it would have never gotten off the ground. Chlorpromazine, which came on the scene in 1952, quickly surpassed lithium not only because it was promoted by drug companies, but also because in important ways it was a better treatment for mania. It usually takes about a week for lithium to reduce the symptoms of mania, whereas chlorpromazine, as well as the related drugs that came in its wake, improve these symptoms in hours.”
Walter then gives the reason why “lithium did get off the ground. …In the early 1960s, at the same time that lithium seemed stalled as a treatment for mania, Schou began to spearhead an effort that ended up revealing an effect of lithium that dwarfed its use in acute mania and that, more than any treatment before or since, allowed people with manic-depressive illness to lead normal lives. Finally, the medical establishment would begin to give lithium the serious study that it deserved.”
What Martin fails to add is that Schou’s success included the recognition that lithium’s serious and lethal toxicity could be dealt with not by banning its use as Cade did but by rendering it safe using Trautner and Noak’s findings which Cade chose to ignore.
Chapter 6: Prophylaxis Rex tells the story of Schou’s definitive work discovering and defining the concept of “prophylaxis” and the efficacy of using lithium to safely treat and prevent manic and depressive episodes of bipolar disorder.
The concept began to emerge in the early 1960’s with observations by two psychiatrists familiar with Schou’s work on lithium, Hartigan in England and Baastrup in Denmark. Each communicated to Schou their independent but unique clinical finding that continuous use of lithium following an acute episode prevented future episodes. Neither psychiatrist had published their findings or had undertaken research to confirm it until encouraged by Schou them to do so; Hartigan was first in 1963, followed by Baastrup the following year.
Schou and Baastrup lived in different parts of Denmark but had kept in touch since 1960. So, together they joined forces on a study of prophylaxis. Baastrup recruited, treated and observed the patients while Schou analyzed the data and wrote their joint paper (Baastrup and Schou 1967).
Trouble with its reception began to brew in 1966 at a small psychiatric meeting in Gottingen, Germany. Shepherd from the Maudsley Hospital in London (where I began my residency training in 1962) gave a talk about the principles of clinical evaluation and the importance of using rigorous trial methods, “all of which were familiar to Schou from his earlier RCT on lithium.” Schou followed with a preliminary presentation of the data he and Baastrup were preparing for publication. A member of the audience passed a note to Shepherd, “This man just contradicted everything you were saying.” In relating this tale to Walter, Shepherd “had no trouble remembering his consternation and hoped not to be asked to comment … but of course I was asked as a guest … I tried to be tactful but nevertheless proceeded to state in no uncertain terms that the evidence Schou had put forward was not good enough to support the conclusion.”
This upset Schou and his wife took Shepherd aside to say this hurt him very much by implying more evidence was needed. Schou joined the couple and catching the tone of their dialogue launched into defending his position, then informing Shepherd that one of the patients had been a relative and that there “really ought to be a national policy that everybody could get lithium.” Presumably Denmark, like America, had banned the use of lithium for anything other than research. Shepherd however concluded he was “in the presence of a true believer.” Walter correctly notes, “Shepherd didn’t suffer fools gladly and it didn’t take much to evoke his scorn.”
Shepherd returned to the Maudsley and the following year Baastrup and Schou’s study was published in a leading British Journal (Baastrup and Schou 1967). Feeling obligated to make his feelings public Shepherd determined to publish a rebuttal. By then I had graduated from the residency program and Shepherd had recruited me to be his research assistant in analyzing the data and preparing a publication for the Lancet. He never communicated to me the details of the 1966 meeting that laid the foundation of his disdain although his critical approach towards research in general was always readily apparent.
The results of our analysis (which included a small study showing comparable effects due to imipramine that is never discussed) was “Prophylactic Lithium; Another Therapeutic Myth?”, published in the Lancet (Blackwell and Shepherd 1968).
This story had a happy ending when Schou used his considerable skill to design another and convincing study (Baastrup, Poulsen, Schou et al. 1970). A quarter of a century later INHN revisited this controversy (Blackwell 2015) eliciting the comments of many leading lithium researchers, now available in a collated document (reference).
This chapter also includes an account of the fate of lithium in the United States, including the two-decade embargo on its use imposed by the FDA in 1949. Sam Gershon is given pre-eminent status as someone who “got the ball rolling.” After his work in Melbourne with Trautner he visited the U.S in 1959 on a Pfizer scholarship at the University of Michigan. In addition to his year-long work in a schizophrenia research program he gave lectures about lithium at the National Institute of Health and elsewhere, treated over 20 patients with lithium and with a colleague published the first article on lithium in an American journal. (Yuwiler and Gershon, 1960).
Gershon emigrated to America in 1963 and in 1965 became Director of Neuropsychopharmacology at New York University and set up a lithium research clinic. “Gershon had a major impact on lithium’s acceptance in the United States. His energy and infectious enthusiasm, along with his scientific acumen, made him an influential advocate for lithium. He served on the APA’s Task Force on Lithium which advised the FDA on the efficacy and safety of lithium. Gershon was the editor in chief of the journal Bipolar Disorders and one of a handful of colleagues who lobbied the NIMH, excoriated the FDA for its ban on lithium and spoke to anyone who would listen to get lithium available for general use.” These efforts were rewarded in 1970 when during the same month Cade made his first visit to the United States to receive the Taylor Manor Award for his discovery of Lithium the FDA lifted the ban on its use in acute mania. Sam has chosen never to speak or explain his experience as a resident psychiatrist when Cade discouraged his interest in lithium. Since retiring at the age of 86 Sam has served as a founding member of the INHN and its network.
Schou died at the same age in 2005: “Over the decades he aided an untold number of patients with bipolar disorder, convinced lithium was an important treatment he never stopped conducting research related to it and strove to educate both professionals and the lay public about its value.”
Epilogue is a 35-page synopsis that paints a picture of Cade, his character, his accomplishments and the fate of lithium, the substance on which his reputation largely hinges.
It begins by noting, “After his landmark study Cade did no further research on lithium. From today’s perspective this is perplexing.” Indeed Cade’s expressed interest in the topic evaporated for almost two decades until it was revived when Schou contacted him and their relationship blossomed into a friendship. The reasons for this hiatus are clear. He knew the results of his study “were valid and I simply cast my bread upon the waters. Fortunately it was turned into cake, pre-eminently by Schou and his co-workers.”
In fact, he was busily occupied after 1952. He was appointed Superintendent of Melbourne’s esteemed Royal Park Psychiatric Hospital and Dean of its clinical school for residents and medical students. Energetic and compulsive by nature he took up time consuming “administrative, teaching and clinical responsibilities.”
“Cade’s talent for educated speculation, for weaving disparate facts into a more or less plausible hypothesis, was a particular strength; it far out-weighed the sophistication of his research methods or his interest in and aptitude for subjecting a hypothesis to a rigorous test.” Schou, who admired Cade and became very fond of him, characterized him as “an artistic scientist as opposed to a scientific one. So, although Cade was never short of ideas - some more plausible than others - neither those ideas nor his later research left a mark.”
Some of these ideas were odd, even eccentric. He experimented on himself and sometimes on patients looking for “abnormalities in chemicals the brain cells depend on, sodium, potassium and magnesium among them.” He surveyed the urban and regional of admissions for schizophrenia. The rural areas with a low incidence had an abundance of fruit trees and Cade “hypothesized that fruit contained a “protective factor.” Two years later he speculated that Down’s Syndrome was due to a lack of manganese in the diet of pregnant women. In a letter to the MJA he hypothesized that chondrodystrophy in chick embryos due to manganese deficiency was analogous to similar changes in the bone and cartilage of Down’s Syndrome. “These women were saved from this fate when, a year after Cade’s letter appeared, French researchers traced the cause to an extra chromosome.”
Cade became one of Australia’s foremost teachers of psychiatry, teaching psychopathology at Saturday morning lectures to medical students at Royal Park, Barney Carroll was among them. His message was Kraepelinian and his style dramatic “in a very Edwardian manner.” Bringing patients on stage, announcing their diagnosis to the “ladies and gentlemen” in the audience and relating symptoms and signs to outcome in the style of Sherlock Holmes. “His style was very autocratic and old fashioned but in many ways effective.”
Cade took “an active role in psychiatric organizations” including a Mental Health Officers Association (MHAOA) that advocated research in mental hospitals and public education about mental health treatments. In 1946 he was a founding member of the Australian Association of Psychiatrists that later morphed into the Royal Australian and New Zealand College of Psychiatrists (RANZCP). Cade was among the few to be selected as Fellows and he became President in 1969.
Cade had “an encyclopedic knowledge of the history, treatments and theories in psychiatry but held strong idiosyncratic opinions… Although he had a sophisticated understanding of psychoanalytic theory he believed Freudian psychology cast a blight upon the minds of men that will last another fifty years.” He complained of its “esoteric jargon and fascinating phantasmagoria” and identified psychoanalysis as “the art of defining the commonplace in terms of the incomprehensible.”
Although these attitudes “got him a frosty reception” among some psychiatrists they won appeal in the Catholic Church to which he was a firm adherent, “a refreshing antidote to the Godless and altogether repugnant psychoanalytic concepts.” Cade wrote a column on mental health matters for a Jesuit magazine and “proffered advice on everything from child rearing to insomnia.”
While Cade inveighed against both psychoanalysis and “modern secular psychology” he was not above using their precepts and strategies on occasion. In 1955 when the Democratic Labor Party (DLP) split from the Australian Labor Party Cade and many other Catholics joined and who were “stridently anti-communist and socially conservative, opposing homosexuality and other sorts of permissiveness.” Cade became the groups “go-to psychiatrist.” In 1972 he gave a talk to the RANZCP titled, “Masturbational Madness: An Historical Annotation. It is salutary in this amoral and licentious age to again draw attention to the disastrous consequences of this disgusting practice.” He included mental illness. Yet, the very next year he read a paper at a symposium titled, “An Eclectic Psychiatrist Looks at Homosexuality” in which his theme was “remarkably liberal.” I regard it as highly irrelevant and always mischievous to make moral judgment on patient’s problems and attitudes.
From 1963 and for the next 15 years Cade and Schou “corresponded regularly and visited twice; they expressed both publicly and privately their gratitude to each other.” In 1970 Schou introduced Cade to an audience in Risskov gathered to hear him speak. “I do not have it in my power to endow knighthoods or honorary degrees but permit me to express quite simply to you, John Cade, the gratitude of all the psychiatrists and scientists for whom your work has been an inspiration and stimulus.”
In return Cade referred to Schou’s work on prophylaxis in metaphorical terms, “I feel rather like a woman who had an illegitimate child and adopted it out. Now, twenty years later, I am visiting the adoptive parents and finding out what a fine big boy he has grown into but knowing far less about him than his adoptive parents.”
In addition to Cade and Schou’s mutual admiration “by the late 1960’s [sic] lithium therapy became widely used, Cade was credited with its discovery and the accolades started coming.”
1970 was a banner year. Cade received the Taylor Manor Award in America, coupled with the Pope’s blessing and award, as well as becoming a Distinguished Fellow of the American Psychiatric Association. In 1974 Cade and Schou shared a $25,000 Kittay Scientific Foundation Award, the world’s foremost and largest prize. “Reserved, unpretentious and self-deprecating though he was, Cade fully enjoyed these tributes.”
In 1976 Queen Elizabeth II announced the “scrapping of the knighthood and other British honors for citizens of Australia and their replacement with the Order of Australia (OA).” Cade was among the first recipients and expressed his consternation at “having missed a knighthood” to his friend and author of a book eulogizing Cade (Johnson 1978). “He would have much preferred to be known as Sir John Cade rather than the dull OA. To have missed out on a knighthood by little more than a year struck him hard luck of the worst kind.” Johnson reluctantly noted, “John Cade was not immune entirely from social approbation.”
John Cade died a tragic death from esophageal cancer in November 1980 and requested he be buried next to his parent in the “simplest box.”
While the synopsis is entirely from Walter Brown’s recent book this commentary is reflective of all four books about Cade, three of which I have reviewed previously (Johnson 1984; Schioldann 2009; de Moore and Westmore 2016).
History, Truth, Sophistry and Profits.
In my review of Schioldann’s mammoth history of lithium’s use throughout history and Cade’s contribution I quote from the introduction to his book written by German Berrios, Chair of the History of Epistemology in Psychiatry at Cambridge University (My alma mater from whom I received my undergraduate and graduate degrees in Medicine):
“Priority issues often raise concern of a nationalistic nature: the Lange brothers and Schou in Denmark fulfill the same function as Cade does in Australia. All that a good historian can (and should) do is try and understand why it is so important for countries to have heroes and why some official stories, however mythological they may be, cannot be changed or replaced.”
But surely the literature about scientific discoveries and those who make them has to operate at two levels: a critical level of the facts equal to that which science demands of itself and a more subjective level regarding the behavior of the protagonists. To any extent which it deviates from the first requirement it enters the realm of sophistry (OED: A fallacious presentation).
At times the tale of lithium has been likened to “a fairy story.” Of the four books the oldest by Johnson is the most romantic and he energetically eulogizes Cade. The next two books by Australian authors understandably err on the side of national pride at times. While Walter Brown sticks closest to the facts he does not appear to have the courage of his convictions in the final analysis about Cade’s historical place. Here another component enters the picture. The publisher of the book goes further than its author: “The untold story of a miracle drug, the forgotten pioneer who discovered it, and the fight to bring lithium to the masses.”
Previously told three times, not a drug but a toxic natural substance, for a specific indication, not the masses. Of course publishers always hope for a “bestseller” so money enters the picture. But without profit there would be no books and no authors.
Components of the Fairy Tale
My review of all four books left an impression that the story of lithium was impervious, almost Teflon coated, to critical analysis. Lithium, metaphorically Cinderella, a simple ion, unworthy of a patent, lacking a wealthy pharmaceutical sponsor is rescued by a Prince, Cade, endowed with noble motives, finds a shoe that fits. As a fairy tale these metaphors repel criticism like a vigilant but invisible guardian angel.
A dystopic analysis
Perhaps the only appropriate and effective rebuttal to this fairy tale is a blunt no-holds-barred critical commentary, a residue of my Maudsley training.
In 1949 there were no specific drug treatments for any major psychiatric disorder. Crude ECT, cruel lobotomy, dangerous insulin coma and expensive ineffective psychoanalysis nibbled at the edges but the asylums were chock full of psychotic patients. Psychiatry, an orphan in the family of medicine, was devoid of coherent research beyond descriptive labels based on nosology and natural history.
Along came a genuine post war hero from a Japanese POW camp with a firm conviction of the biological causation for manic-depressive disorder and a specific hypothesis of a potential endocrine cause or remedy akin to an under or overactive thyroid gland. Without research training and with only primitive facilities and no support he embarked on a bungled series of animal experiments that nobody has been able to explain, even his admirers. A combination of persistence and luck led to lithium in acute mania, the first of several more important discoveries made by others within a few years by the same process of serendipity - a term Cade hated and felt was disparaging.
So far, Cade deserved and received ample credit but look closer. Acute mania was a rare condition and while lithium was a specific remedy (to Cade’s credit) it was also toxic and kept its pre-eminence for only three years with no impact on crowded asylums in Australia or elsewhere until along came chlorpromazine, more rapidly acting, far safer to use and so effective that was capable of emptying out asylums into communities worldwide.
Chlorpromazine and the drugs that soon followed in America sparked the development of the NIMH and vast infusions of Federal and industry funds for research, initially in the VA and State hospitals but then in the Early Clinical Drug Evaluation Units (ECDEU) throughout North America and Canada, reaching into academic departments and weakening the hegemony of psychoanalysis.
No similar renaissance took place for psychiatry in Australia which was in the doldrums. In 1952 Cade was sent by his ex-patriate British supervisor to England to visit the Maudsley and neighboring hospitals in the London area and bring back ideas for improvement of the mental health system. This trip aside Cade never joined or participated in the European CINP and no Australian psychiatrist belonged until the early 1960s when Brian Davies left the Maudsley to become the first Professor Psychiatry at Melbourne University.
The lithium limbo
In 1952, based on his reputation, Cade was appointed Superintendent of the Park Royal Hospital, the largest in Melbourne where he remained until his retirement in 1977. During much of this time lithium would remain in limbo. Banned by the FDA in America for cardiac toxicity, virtually at the same time Cade reported its discovery, it was little used worldwide, even in Australia where Cade banned its use in his own hospital even after Trautner at Melbourne University measured and described its metabolism making it safe to use, information Cade spurned. The FDA did not rescind its ban until 1970, largely due to Sam Gershon’s efforts.
During this time Cade did no further research or work on lithium but his reputation in Australia flourished due to his undisputed talents and attractive persona. He was a respected clinician, a competent if somewhat rigid administrator and an instructive and entertaining teacher of psychiatric residents and medical students.
His relentless curiosity at the human and animal level based on deductive reasoning was appealing but led to unconfirmed or improbable hypotheses due to limited inductive capability. Cade wrote for and talked to approving audiences, including Catholic and conservative citizens who admired his upright righteous manner and morals.
Perhaps, most of all, Cade portrayed a disarming, self-disparaging persona that was also somewhat disingenuous at times. He clearly liked approbation but was also proud and thin skinned at criticism.
His disinterest in lithium came to an abrupt end when Schou reached out to him and their mutual admiration blossomed into friendship during the early 1960s.
Cade and Schou, an odd couple
Walter Brown explains how Schou reached out to Cade, extolled the virtues of his 1949 work and anointed him first discoverer of lithium’s therapeutic effect. Schou’s discovery of prophylaxis greatly increased the extent of lithium’s use and Schou had proselyted that worldwide through presentations at the CINP and elsewhere.
Unlike Cade, Schou had incorporated Trautner’s work as an integral necessity for a safe and effective remedy, not just for acute mania but for manic and depressive recurrence in bipolar disorder, an indication that improved the lives of patients beyond anything Cade’s use of lithium in acute mania foretold.
The boost to Cade’s stature and reputation as a result of Cade’s endorsement as well as the tangible awards was immediate and immense. Overnight Cade went from being a footnote to a headline in the history of psychopharmacology.
Why Schou chose to anoint Cade in this manner is one of the remaining mysteries in the lithium saga. Solving it requires we return to Schioldann’s book with a willingness to engage in Oedipal speculation.
Both Cade and Schou were the sons of psychiatrists. Cade’s father was disabled by the trauma of serving during the trench warfare of the First World War, yielding not a powerful role model but someone who still expected his son to become the best psychiatrist in Australia, which Cade undoubtedly did.
Schou’s father was a strong prominent figure in Danish psychiatry; the owner of two psychiatric hospitals with a major interest in manic-depressive disorder and a laboratory committed to biological research and its etiology. In 1927 he wrote a “vehement defence” of Carl Lange’s contributions to the use of lithium in “periodical depression” describing it as “one of the most beautiful descriptions, absolutely classical, which can still instruct readers at this time” (Schou 1927).
Mogens Schou would later deny that his father was the source of any knowledge of lithium’s potential therapeutic activity and denied ever having heard his father speak of it (Schou 2005).
Schioldann, based on his vast knowledge of lithium’s history and committed to the histiographic method believed that both Schou and Cade would have known about the Lange brothers’ research on lithium in recurrent depressive disorder during the 19th century. That Cade denied this and gave no evidence for it in either his writing or his talks is understandable. That Schou also denied this knowledge is contested by evidence and lacks credibility.
One credible conclusion is that it served Schou’s purpose to deflect interest in a Danish psychiatrist’s primacy by giving all the credit to Cade, living on the other side of the world, someone innocent of the Lange story and happy to be accorded the honor.
Cade’s status as a pioneer in the field of psychopharmacology
All four books claim that Cade’s discovery initiated the field of psychopharmacology; in fact it was a small star in a large firmament; a myth that only began to arise in the 1970s as use of lithium prophylaxis spread around the globe and late-in-the game researcher’s sought historical validation.
This is a matter in which I have a personal stake. In 1970 I had finished two years working as the Psychotropic Drug Research Director for the pharmaceutical company that had marketed thalidomide as a safe hypnotic for pregnant women (prior to my joining them), causing phocomelia and leading to the Harris-Kefauver legislation empowering the FDA to require that all future drugs be scientifically shown to be “safe and effective.”
During my tenure and just before I returned to academia I met Frank Ayd, an expert on psychotropic drugs and ethical issues pioneer. He was founding member of ACNP who had just returned from a sabbatical in Rome as a consultant to the Pope and Vatican Radio.
I had just begun to teach psychopharmacology to medical students and residents in psychiatry at the University of Cincinnati when I became a friend and colleague of Frank, also a teacher to both lay and psychiatric audiences. In conversation we shared an awareness that the scientists and psychiatrists who had discovered all of the new drugs between 1949 and 1970 were still alive, all known personally to Frank. Together we planned a national conference to be hosted by the Taylor Manor Hospital in Baltimore where Frank did his inpatient work.
The conference, titled “Discoveries in Biological Psychiatry,” took place in April 1970 and was published later that year (Ayd and Blackwell 1970). There were 18 speakers, us and the 16 pioneers we had invited: Joel Elkes (First Director of the NIMH Research Center at St. Elizabeth’s Hospital in Washington DC); Irvine Page (Emeritus Professor Cleveland Clinic), discoverer and namer of serotonin; Lothar Kalinowsky (Professor of Psychiatry at New York Medical College), on Biological Psychiatric Treatments Preceding Pharmacotherapy, Fever therapy, ECT and insulin coma; Chauney Leake (Senior Lecturer, University of California at San Francisco), opioids, addiction and amphetamines; Tracy Putnam (Harvard Neurology), Epilepsy and Dilantin; Albert Hofman (Director of Research, Sandoz Ltd. Basel), LSD and hallucinogens; John Krantz (Director Pharmacologic Research, Maryland Psychiatric Research Center), Fluorinated anesthetics; Frank Berger (Director of Research, Wallace Laboratories), Minor tranquilizers and meprobamate; Irvin Cohen (Associate Professor of Psychiatry, Baylor College of Medicine), Benzodiazepines; Hugo Bein (Director of Biological Research, Ciba Ltd.), Reserpine; Pierre Deniker (Professor agrege, Clinique des Maladies et de L’Encephale, Paris), Chlorpromazine and Neuroleptics; Paul Janssen (Director Janssen Pharmaceutics, Beerse, Belgium), Butyrophenones and haloperidol; Jorgen Ravn (Head of the Mental Hospital in Middlefart, Denmark), Thioxanthines and navane; Nathan Kline ((Director, Research Center, Rockland State Hospital, NY), Monoamine Inhibitors; Roland Kuhn (Cantonal Psychiatric Clinic Munsterlingen, Switzerland), Imipramine; and John Cade (President Australian and New Zealand College of Psychiatrists), Lithium.
This cadre of all the true pioneers in psychopharmacology reflected the breadth of Frank Ayd’s international connections in academia and industry. His relationship with Cade was also cemented by their Catholic Faith and joint involvement in both clinical and ethical matters.
Frank and I provided bookends to the conference; I gave a talk at the beginning on “The Process of Discovery” and Frank gave a closing talk on “The Impact of Biological Psychiatry.” There was a friendly sense of collegiality among the participants, a shared awareness of being part of a group of pioneers in the field. Lithium was one compound among many and no speaker was singled out for special credit or leadership in psychopharmacology. Every participant received the same Taylor Manor Award for excellence in the field.
My talk on discovery combined my own experience concerning cheese and the MAOI with a review of the world literature that included the considerable contributions of sociologist Robert Merton on the behavior of scientists in assigning priority and the well documented tendency to overlook the contributions of others. He discussed the ambivalence created by the dilemma of claiming credit and remaining modest and gave examples including Freud. Merton cites Ernest Jones erroneous statement that “Freud was never interested in questions of priority” by dissecting out 150 examples from Freud’s work. Merton coined the term “cryptomnesia” to describe one possible explanation for how scientists recalled their own contributions but selectively forgot those of others. I gave an example of my own. Three years after I discovered and described the “cheese reaction” I was confronted by the SKF representative about my failure to mention several helpful suggestions he had made about cheese and its possible composition. To make amends we published a joint article with his name as first author (Samuels and Blackwell 1968) We celebrated its publication with dinner at my home when he presented me with a cheese board that had a small plaque that said – “Everyone eats cheese” – one reason why the interaction went un-noticed for several years after the introduction of Parnate the SKF MAOI that Samuels detailed. This story has an unhappy ending. More than a decade later Samuels repeated the same angry recriminations in a letter to the British Journal of Psychiatry without the journal notifying me. (In America I no longer received it! I decided to say nothing.)
This tale may have no relevance to Cade but having heard me relate it he went ahead in his talk with no mention of Trautner or Gershon and once again gave an account of his first patient, claiming he remained well and making no mention of the fatal outcome. “Selective forgetting” or mild early dementia (which I don’t recall considering) may be too timid and kindly explanations for that behavior.
John Cade is well remembered by his country and the field of psychopharmacology he contributed to. These accolades are:
· In 1980 the CINP created a John Cade Memorial Lecture
· In 2004 Film Australia produced a documentary: ‘Troubled Minds” that received the International Vega Award for Excellence
· The Royal Melbourne Hospital has a John Cade Adult Acute Inpatient Unit
· The RANZCP awards a John Cade Memorial Medal each year to a first-year Victorian medical student clinical examinee
· The Faculty of Medicine at the University of Melbourne awards an Annual John Cade Memorial Prize
· In 2013 the National Health and Medical Research Council endowed two $750,000 annual scholarships in Mental Health Research.
In September 2014, JAMA published an article by Hampton, Daubresse, Chang et al “Emergency department visits by adults for psychiatric medication adverse events.” A statistical analysis of 10,000 ER visits it reported that one of the most common were the 16.4% due to lithium toxicity of which over half (53.6%) were admitted to hospital for management. Like so many large-scale statistical studies there was little additional information. How many were prescribed by psychiatrists, primary care doctors or other subspecialists? What were the specific errors in management leading up to ER referral? What type or severity of side effects merited admission?
Worse still, a commentary by a person not the author concluded: “The high frequency and clinical severity of adverse events associated with lithium should be considered amid calls to expand lithium treatment for bipolar disorder.” The credentials of this individual to offer such advice were not apparent.
I wrote a letter to the Editor in response; within the 400-word allowed limit and including the five supporting references. I received a “Decision letter” from a scribe of junior editors stating, “Considering the opinion of the editorial staff we determined your letter did not receive a high enough priority rating.” I was invited to “contact the author of the article but we cannot guarantee a response.” This exchange is posted on the INHN website (Blackwell 2017).
Sad to relate that although lithium in America experienced a renaissance after the FDA lifted its ban on the treatment of acute mania in 1970 it competes less well with three anti-epileptic drugs and four antipsychotics as mood stabilizers in the management of bipolar disorder approved by the FDA which does not require comparison with lithium for approval and, unlike lithium, all of which are probably expensively advertised and eulogized in the pages of JAMA.
One must also question how adequately the safe use of lithium is taught not only in psychiatric residency training but also to medical students, primary care doctors and subspecialists, something the authors and editors at JAMA failed to ask.
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Blackwell B. The Process of Discovery. In: Ayd FJ, Blackwell B, editors. Discoveries in Biological Psychiatry. Philadelphia, Lippincott 1970, 11-29
Blackwell B. Barry Blackwell: Risk and Relevance to Lithium Usage. Unpublished Letter to the Editor of JAMA. Collated by Olaf Fjetland. inhn.org.collated. July 20, 2017.
Blackwell B. Corporate Corruption in the Psychopharmaceutical Industry (Revised). inhn.org.controversies. March 16, 2017.
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Hampton LM, Daubresse M, Chang HY, Alexander GC, Budnitz DS. Emergency department visits by adults for psychiatric medication adverse events. JAMA Psychiatry. 2014;71(9):1006-14
Johnson FN. The History of Lithium Therapy. Palgrave Macmillan UK. 1984.
Schioldann J. History of the introduction of lithium into medicine and psychiatry: birth of modern psychopharmacology 1949. Adelaide AU, Adelaide Academic Press; 2009
Schou HJ. La depression psychique. Quelques remarques historiques et pathogeniques. Acta Psychiatr. Neurol. 1927: 345-53.
Schou M. Min rejse med lithium. Selvbiografiske noter [My journey with lithium]. Bibliotek for Læger. 2005;3:217–28. In Danish, with English abstract. English version in Schioldann J. 2009.
January 23, 2020