Lithium and the American dream

'My lifelong love affair with lithium began 65 years ago… I worked with some of the pioneers of lithium and, in particular, helped to make it a safer molecule to prescribe to patients. That initial wonder and excitement of a new treatment has never left me, and over the decades, I have seen countless people benefit from the effects of this seemingly magical element'. The phrase 'last in and first out', aptly describes the role that the United States (US) has played in developing and promoting the use of lithium, ever since John Cade discovered the wondrous properties of the element 75 years ago.1 But, whilst this phrase describes the overall role of the US, especially in the latter years of the 20th century, it does not do justice to the important earlier developments made by several researchers within the US and their contributions to the clinical application of lithium for the management of bipolar disorder.2 However, before addressing the clinical use of lithium, it is customary to make mention of the ongoing debate concerning who first identified its therapeutic effects. This is because the intellectual wrestling match between academics around the world as to who first noted and then reported the benefits of lithium in the treatment of mood disorders continues to date; extending the analogy, the 'disciples' of Mogens Schou and the 'Danish Diviners' Karl and Fritz Lange are in one corner and opposite them are the 'acolytes' of John Cade, the 'Australian Augur'. In this editorial, we do not decide this issue and instead have chosen to view the matter impartially (to the extent we are able) through the eyes of the referee. Alas, the match is perhaps tied, necessitating, as it does in physical competitive wrestling, extending the bout into overtime. Suffice to say, the two perspectives remain poles apart mirroring to some extent a core feature of the disease that lithium treats best, namely, its bipolarity. We concern ourselves with the controversy regarding its discovery because it is important to understand the prelude to what would later become a global effort to advance the uptake of lithium. The latter included proponents from Australia, Europe and North America, although it is fair to say that the US, arguably the most influential market for pharmaceutical treatments, was nearly the last to join the cause, but amongst the first to leave in favour of newer medications. Therefore, in this editorial, we review how this came about despite mounting evidence for its efficacy and overwhelming proof that it benefitted patients. As far back as the 19th century there were susurrations on both sides of the Atlantic that lithium was good for one's health. Alfred Garrod, a British doctor and Silas Weir Mitchell, a US physician, had independently noted in 1859 and 1870 respectively, that lithium enhanced 'general well-being'. A year later in 1871, William Alexander Hammond became the first physician to prescribe lithium for mania. Incidentally, in collaboration with Silas Weir Mitchell, he and several others founded the American Neurological Association in 1874. In his treatise on diseases of the Nervous System, published in 1871,3 Hammond notes under Insanity, in the chapter on diseases of the brain, 'I have used the bromide of lithium in cases of acute mania, and have more reason to be satisfied with it than with any other medicine calculated to diminish the amount of blood in the cerebral vessels, and to calm any nervous excitement that may be present'. Interestingly, Hammond also notes 'the rapidity with which its effects are produced renders it especially applicable in such cases' and he then goes on to describe how its dose should be titrated. Hammond also compared this formulation to potassium and sodium salts showing a preference for lithium because of its prompt action. The account by Hammond is important, not only because of its primacy and detail, but because he subscribed to a biological underpinning of the illness, stating 'the fact is daily becoming more evident and more generally admitted that insanity is to be treated as a material disease, and not as a metaphysical nonentity'. Unfortunately, Hammond's observations and comments lay dormant and had little long-term impact and at approximately the same time, on the other side of the Atlantic, the equally perspicacious observations of the Danish brothers Carl and Fritz Lange suffered the same fate. Thus, the fire seemed to have been extinguished even before it started, but in reality, it continued to smoulder within the folds of literary texts, which perhaps acted as embers, reigniting thoughts more than half a century later with renewed excitement. When in September of 1949 John Cade published his seminal paper in the Medical Journal of Australia, it caused a local buzz that caught the attention of a young Sam Gershon who, in the subsequent year, graduated from The University of Sydney. Sam then arrived in Melbourne in 1952 with the aim of specialising in psychiatry and investigating the effects of this element that he had heard so much about. However, after the initial deaths associated with the clinical use of lithium in psychiatric patients, Cade had banned its prescription in the local hospital. This meant Sam could not observe the molecule in clinical action and so acting on sage advice from the then head of physiology, Douglas Wright,ii he turned to Edward Trautner who Sam described as 'an elderly, wrinkled gentleman with a heavy German Accent'.iii Trautner was a doctor by training and a fiction writer and had spent time in internment both in England and then Australia before naturalising and changing his name from Eduard to Edward. By chance, Trautner was in the same physiology department as Victor Wynn who, using the flame photometer, had developed laboratory procedures for determining the plasma levels of electrolytes such as sodium and potassium. Adaptation of this technology made it possible to accurately measure the blood levels of lithium in patients with mania and so in collaboration with Charles Noack, a psychiatrist, Trautner found that the concentration needed to quell the illness was often close to that which could cause toxicity, but that the two effects were not necessarily related. Subsequently, the Trautner team, which now included Sam, embarked upon a series of studies throughout the 1950s that would prove to be essential to the clinical uptake of lithium (see Figure 1). In the words of Edward Shorter,4 Cade's paper ignited 'the modern revival of lithium'. The article outlines an elegant series of experiments through which Cade demonstrates both the therapeutic benefit of lithium in the treatment of mania (psychotic excitement) and its selectivity as it does not affect those with dementia praecox (schizophrenia) or melancholia. In nearly all 10 patients with mania (seven episodic and three chronic) lithium produced rapid and marked improvement. Unfortunately, the first patient that Cade treated died within a year of the paper being published because of lithium toxicity. This and other fatalities associated with the early use of lithium stunted its uptake and as mentioned earlier, John Cade himself shied away altogether from further prescribing the medication he had identified. Fortunately, again as pointed out earlier, clinical colleagues and those in the physiology department took up the cause and having identified a way of evaluating plasma levels, they used this technology to safely administer lithium. Noack and Trautner's paper was critical, as it was the first proper corroboration of Cade's findings and because it described in detail lithium's clinical effects. Having prescribed lithium to over 100 patients with 'various mental affections', the two authors had managed to study three times as many patients with mania as Cade and found improvement in up to 80%. They concluded that treatment with lithium was 'very beneficial in terminating and preventing the maniacal phase in cases of mania, hypomania and recurrent mania'. At the same time, the paper begins by addressing the issue that was on everyone's mind, stating that 'in recent years lithium salts have been widely used in the United States of America as a substitute for sodium chloride, especially in cardiac disease and hypertension. … [and although John Cade has] claimed great benefit from lithium medication in states of psychotic excitement, … its use has been discredited since several fatal cases of poisoning were reported in the United States …'. The paper then goes on to discuss dosing and lithium poisoning, but the authors clearly point out that 'in none of the patients treated by [them] has any serious condition of lithium intoxication been observed, and in none was sodium medication necessary'. This emphatic endorsement of lithium was important. However, lithium had acquired a 'bad name' and was therefore 'shunned in the USA',5 and so only a handful of US publications emerged in subsequent years. Much of lithium's clinical success came about because of the personal beliefs and steadfast efforts of key individuals; however, collaborations that allowed the exchange of knowledge also played an important role. In this context, the arrival of Sam in the US was significant (see Figure 2). Sam had secured a competitive scholarship to attend the University of Michigan, which was embarking on research projects into schizophrenia and psychopharmacology. Here he teamed up with Art Yuwiler, head of the biochemistry research division and together they published the first paper on lithium therapy for mania in the United States. Gershon and Yuwiler's paper was important because it ascribed the therapeutic specificity of lithium to its molecular properties and introduced the idea of a lithium-sensitive subtype, that was later characterised as the mania that is typically seen in classic manic-depressive illness. However, the primacy of publication in North America cannot be assigned solely to this article, as another paper was published concurrently. This article by Eddie Kingstone from Canada, described the findings of research he had conducted when he was Chief Resident at the Allan Memorial Institute of Psychiatry, at Royal Victoria Hospital in Montreal. Interestingly, when the article was eventually published, he was a Travelling Fellow at the Institute of Psychiatry, at Maudsley Hospital in London – suggesting that he would have shared his insights with UK psychiatrists. In its opening paragraph, the article claims that 'no report exists of lithium having been used in North America' and then proceeds to describe the treatment of 17 patients, most of whom recovered within 2 weeks; only one patient made no improvement at all. The article is noteworthy as it describes 'several patients … feeling internally curbed', which Kingstone clarified as '[although] these patient's moods and activity were returned to a normal state, the urge to remain elated and facilitated was still present'. He then infers that 'the feeling of internal curbing resulted from the inability of the patient to respond to this desire in thought, speech or act'. This sensation was also noted by patients in Joe Tupin's research programme at the University of Texas, the findings of which were presented at the 121st annual meeting of the American Psychiatric Association (APA), held in New York in May of 1965. Tupin noted that the effect of 'feeling internally curbed' emerged soon after clinical improvement and that patients found it difficult to pin down the subjective experience and therefore, when describing the phenomenon, they resorted to comparisons with 'being unable to talk, think or move as fast as they would like'. However, 'none objected greatly to this sensation, and all preferred it to the drugged feeling that is so frequent with large doses of phenothiazines'. Perhaps most importantly though, 'these feelings persisted for varying lengths of time … [and] always disappeared or became negligible after about six weeks'. Further, akin to Cade's findings 'all patients returned to their usual business, family, or housekeeping activities without difficulty' with most patients being 'released from the hospital within three weeks after beginning lithium'. These were significant and promising findings, but the legacy of early deaths with lithium lingered and so the uptake of lithium in the US remained frustratingly slow. Intriguingly, Schou may also have facilitated US interest in lithium, having established links during the time he worked (1949–1950) at The New York State Psychiatric Institute (NYSPI) under the aegis of the National Institute of Mental Health. However, it was his collaborative efforts in Europe that led to major lithium studies being undertaken, as well as the promotion of lithium both by the French in the 1950s and then the British in the 1960s, that heralded the importance of this new therapy (see Figure 1). Thus, in the US, by the mid-60s, the perception of lithium was becoming more positive as exemplified by Joe Tupin and Jerome Jacobson presenting their research findings at the 1965 APA meeting in New York. Based on observations of patients under his care from 1935 to 1964, Jacobson saw an opportunity for a natural experiment in which patients treated for mania, prior to the advent of lithium therapy, could be compared with those treated once it became available. The latter group comprised those who were treated with lithium and they were further subdivided into nine patients who were entered into a programme of monitoring that Jacobson had devised and eight patients who continued with management as usual. In comparison, the control group comprised 42 patients, all of whom had been 'treated for at least one attack of hypomania' and everyone in this group, bar one, received ECT. The early intervention that Jacobson had devised was called the 'manic alert' programme. It involved identifying a 'pathognomic tell-tale sign in each patient which heralds the onset of an attack' – an early warning sign. It also involved what we now term psychoeducation and regular supervision and follow-up with allied mental health staff, as well as prompt intervention with lithium therapy 'at the first sign of a hypomanic attack'. The programme that Jacobson proposed was remarkable in terms of design and impact and apart from benefitting mental wellbeing, Jacobson foresaw that this package of care would 'provide a financial saving for the patient'. Thus, it was truly prescient—and he was possibly the first to introduce the ideas and concepts of early intervention, psychoeducation and community follow-up for the management of mood disorders. In the following year, 1966, at the APA conference in Atlantic City, Ronald Fieve presented findings on 19 patients he had treated with lithium. The full paper was published that same year together with Ralph Wharton and it reported their experience of lithium use at the NYSPI. Of the 19 patients they described, three-quarters had experienced more than one episode of mania and the majority of these prior episodes had been treated unsuccessfully with chlorpromazine. The study involved two weeks of active treatment with lithium carbonate following a 10-day placebo lead-in. Of the manic episodes treated with lithium, 68% responded (duration of mania shortened), but in many of these cases, there was inadequate documentation and a reliable comparison with previous outcomes could not be made. However, in 44% of episodes of mania, the response was unequivocal and their duration was clearly shorter. Overall, in 'patients who had good responses all did so within two weeks of lithium carbonate treatment' and the authors concluded that 'there is no question that lithium is a potent drug in its capacity to alter mood' and that it 'may be the drug of choice' in the treatment of mania, especially where other medications such as antipsychotics (phenothiazines) have failed. Subsequent interest by the National Institute of Mental Health (NIMH) led to the establishment of large-scale projects designed to examine the therapeutic potential of lithium. Studies were constructed to compare lithium's effects against those of phenothiazines in the treatment of mania and tricyclics in the prevention of mood episodes. In these studies, lithium established its efficacy for all facets of the illness and across a variety of contexts, although it also became apparent that not everyone had a robust response to lithium therapy. Further, lithium was found to be limited in its capacity to promptly contain behavioural disturbance and concerns regarding its tolerability still persisted. Nevertheless, it was also evident that fears regarding severe toxicity and death were unfounded, provided lithium levels were monitored. With greater clinical experience these concerns gradually subsided and enthusiasm for lithium grew amongst both clinicians and researchers, all of whom were keen to trial lithium. As such, in 1964, Tupin became the first clinician in the US to obtain an individual new drug (IND) licence for lithium and only 4 years later, more than 200 psychiatrists had applied for the same. As described by Shorter, 'by the late 1960s, a kind of lithium underground had formed in the United States, many physicians prescribing it without bothering to seek INDs, or a permit to use an investigational new drug from the FDA' and studies into the clinical effects of lithium were being conducted by researchers across the US (e.g., studies in Los Angeles, Buffalo, Portland and New York were being carried out by Eugene Ziskind, Stanley Platman, Paul Blachly and Nathan Kline, respectively). At the same time, two major federal agencies (NIMH and Veterans Administration) began planning studies that also engaged researchers from all corners of the country. These organisations and other professional bodies, along with groups such as the Lithium Task Force of America, which included Sam Gershon, Robert Prien, Ronald Fieve, Joseph Tupin, Jonathan Cole, Irvin Cohen and William Bunney, repeatedly lobbied the FDA to formally approve lithium's use. Finally, in 1970, in the face of overwhelming pressure, the FDA relented and lithium carbonate was approved for use in the United States, but only for 'the control of manic episodes of manic-depressive psychosis'. Throughout its history, lithium has been discovered and rediscovered. This is because, in addition to its mood-stabilising properties, which entail countering the acute symptoms of mania and depression and providing long-term prophylaxis, lithium has several additional qualities that have only come to light relatively recently. For instance, by modulating various homeostatic mechanisms within the brain, lithium has been shown to be neuroprotective; it also protects against suicide – over and above its improvement of mood and given these benefits, it is puzzling why its use has declined. It seems that several factors have contributed to its diminishing use in clinical practice. Firstly, lithium is viewed as an old drug, which it most definitely is and because of this, it is seen as being difficult to prescribe, as it needs regular blood monitoring. Secondly, as compared to newer medications lithium is more likely to develop tolerability issues, both acute and long term. These practical limitations have certainly hindered its use, but another important factor is that it has lacked the promotion of a big pharmaceutical company. As such, following its discovery, the US was late to adopt lithium and even after lithium had proven its efficacy in local studies, it never fully established itself in the way it had done in Europe. Indeed, the US was one of the first countries to lose interest in lithium and move on to other medications – spurred to some extent by the arrival of novel molecules. Hence, in the US, lithium's place in the management of bipolar disorder has never been as secure as it is in most other parts of the world and its use has dropped despite its prominent positioning in contemporary treatment guidelines. However, lithium has not completely disappeared, indeed far from it and even in the US it is still prescribed. Lithium's resilience is easily explained, as it is the only agent that 'selectively curbs' manic thinking without unnecessary sedation. It also prevents patients from sinking into depression or taking off into mania. In other words, it is one of the few agents that has both acute and prophylactic effects and this is because it is a genuine mood stabiliser and arguably the only one. American enthusiasm for the use of lithium in the treatment of mood disorders only began in earnest in the latter half of the twentieth century, once the molecule had well and truly 'arrived' so to speak. Uptake was facilitated by research studies conducted in both Australia and Europe along with a growing body of home-grown research that helped reassure American academics and clinicians that the element could be safely prescribed and that clinically it had potential and purpose. Convincing US physicians and legislative bodies was no mean feat and a key proponent in this venture was Samuel Gershon, the founding editor of this journal, Bipolar Disorders. However, as we have shown no one person can be credited for the discovery of lithium or indeed its implementation in the treatment of bipolar disorder. Instead, the story of lithium is perhaps best recounted as a tale of excitement, that captured the imagination of many, who then devoted their working lives to bringing lithium to life. Over the past 75 years, with this injection of intellectual vitality, the element has endured and saved the lives of countless people. For this alone, both lithium and its many champions warrant our admiration and recognition. Hence, in some ways, lithium is the American Dream. G.M. and E.B. both contributed to the initial research, drafting and editing of this manuscript. E.B. developed the figures. All authors have read and approved of the final manuscript. The author(s) received no financial support for the research, authorship and/or publication of this article. G.S.M. has received grant or research support from the National Health and Medical Research Council, Australian Rotary Health, NSW Health, American Foundation for Suicide Prevention, Ramsay Research and Teaching Fund, Elsevier, AstraZeneca, Janssen-Cilag, Lundbeck, Otsuka and Servier and has been a consultant for AstraZeneca, Janssen-Cilag, Lundbeck, Otsuka and Servier. He is the recipient of an investigator-initiated grant from Janssen-Cilag (PoET Study), joint grant funding from the University of Sydney and National Taiwan University (Ignition Grant) and grant funding from The North Foundation. E.B. has received joint grant funding from the University of Sydney and National Taiwan University (Ignition Grant) and grant funding from The North Foundation.