A DeCade of science

A period of excitement

Answerable only to his own conscience, unhindered by ethical and advisory committees and unimpeded by the bureaucratic red tape that inexorably constricts exciting research of today, John Cade embarked upon his seminal, uncontrolled open trial of lithium in patients in Bundoora Hospital in Victoria, Australia on 29 March 1948 aged 36 years. Cade had already noted the calming effects of lithium in animal studies and had even trialled single and repeated doses of lithium carbonate on himself, fortunately without any discernable ill effects. He therefore decided, most likely with some degree of apprehension and excitement, to test lithium salts in the treatment of mania or, as it was called then, ‘excitement’.

By today’s standards, the trial itself was middling at best as it lacked phenotypic homogeneity in an already small sample without any control or placebo, but Cade’s real accomplishment was to envisage and extrapolate so far as to take such a bold step in the first place.

The trial, published in 1949, included 10 patients with mania (three chronic and seven recurrent), along with six patients with schizophrenia and three with melancholia (Cade, 1949). All were administered either lithium carbonate or lithium citrate. Remarkably, every patient with mania improved in a matter of days or weeks and, in instances where lithium was either stopped or withdrawn, the symptoms of mania recurred. Selectivity was revealed by the fact that the patients with schizophrenia showed no significant improvement, even though they became less ‘excited’ and were described as being ‘quieter and more amenable’. Again quite significantly, the patients with melancholia neither worsened nor improved.

Based on these observations, Cade noted in his paper ‘there is no doubt that in mania patients improvement has closely paralleled treatment …’. Gradually Cade linked the actions of lithium to the biochemistry of manic-depressive illness.

In a later paper (Cade, 1962), Cade noted that the effectiveness of lithium in ‘vanishing manic excitement showed clearly that at least manic states were biochemically determined’. Importantly, he further extrapolated that the same would apply to the opposite pole of the illness, namely, psychotic depression, and perhaps also to schizophrenia. His prescient thinking and ability to theorise and build on his observations are perhaps equally noteworthy as the findings from his enterprising experiment.

It is important to add that fortune favoured Cade and that the manic patients he treated most likely had a classic pattern of manic-depressive illness with periods of inter-episode remission, the so-called typical bipolar patients that have been shown to have the best responses to lithium (Gershon et al., 2009; Grof et al., 1993).

Sir Cadian rhythm

Although a pioneer, Cade was not alone, and he was not the only person to have investigated lithium. Many of his insights may well have been guided by the observations and inferences of others (Schioldan, 2009), but it is because he dared to pursue better treatments for his patients and took risks in conducting research that he succeeded in achieving a breakthrough. In the History of the Introduction of Lithium into Medicine and Psychiatry (Schioldan, 2009), Johan Schioldan provides an intriguing account of the discovery and rediscovery of lithium, and discusses in detail the nuances of this story. Cade was clearly in tune with the zeitgeist of the day and was able to add his own melody to the rhythm provided by those before him.

Much has been written about Cade’s initial discovery and to what extent he was aware of others, such as Alfred Garrod and Carl and Frederick Lange, who had travelled before him along similar intellectual forays towards divining lithium’s therapeutic effects. Suffice to say, as conceded by Cade himself much later in his career, he was certainly aware of lithium’s early history and the contributions of early researchers.

The Lange brothers were probably the first to use lithium therapy purposefully in the treatment of mood disorders, although the exclusive use of lithium in treating mania was first reported by William Hammond of Bellevue Hospital, New York, in 1871 (Yeragani and Gershon, 1986). But their understanding was somewhat limited by the prevailing 19th century model, which centred on the ‘uric acid diathesis’. Interestingly, and perhaps partly because of this, Kraepelin disregarded their views in his own formulations and, because his influence was so important at the time, the potential benefits of lithium lay dormant for many decades (Malhi and Gershon, 2009). However, the contribution of the Lange brothers was indeed significant and should not be forgotten; maybe they should be accorded the title ‘Founding Fathers of Lithium Therapy’ (Schioldan, 2009).

The importance of lithium extends beyond manic-depressive illness and present-day bipolar disorder (Malhi et al., 2012). Its discovery and introduction into practice forced psychiatry to focus on serious mental illness and to consider treating psychiatric disorders within the medical model. As a consequence, lithium use also rekindled interest in diagnosis and the importance of phenotypic specificity, and brought into sharp relief the importance of long-term observation in understanding the course of illness and treatment outcome.

Uncle Sam and his allies

Just as important as the contributions made by Cade’s predecessors are the vital contributions of his colleagues, contemporaries and successors, who collectively facilitated the further investigation and safe implementation of lithium for the treatment of mood disorders from 1950 onwards.

Samuel Gershon, described as one of the pioneers of modern lithium ‘therapy’, overlapped with Cade when he embarked upon his career in psychiatry whilst still in Australia. Having worked as a resident in psychiatry at the Royal Park Hospital in Melbourne, where Cade was superintendent, and then alongside Edward Trautner investigating the clinical effects of lithium on mania, Gershon was very much aware of Cade and his clinical observations, even though he had no direct scientific relationship with him. Gershon describes Cade’s re-discovery as ‘serendipitous’ and, along with many others, notes that, in addition to good fortune, Cade must be credited for his systematic investigations and incisive intellect. Trautner’s work, with that of Gershon and others, led to the development of reliable means by which the level of lithium in the blood could be assayed. This immediately made lithium much safer to use. Others replicated the effects of lithium in manic-depressive illness using more rigorous methodology and disseminated knowledge of how it could be applied clinically. In this regard, the contributions of Mogens Schou, Erik Strömgren and Poul Baastrup proved to be invaluable (Schioldan, 2009).

Alas it decayed

The element that began the psychopharmacology revolution almost became a martyr. Lithium research had already experienced a long period of quiescence at the beginning of the 20th century prior to its dramatic resurrection by Cade. However, its second demise was orchestrated rather than occurring by chance and circumstance. Whereas in the 19th century the discovery of the effects of lithium was perhaps ahead of its time, in the last quarter of the 20th century newer but less effective alternatives were aggressively marketed, and their promotion actively undermined the benefits of the element. Gradually the pool of lithium knowledge was depleted and its potential uses became known to relatively few. Its prescription in clinical practice became increasingly specialised and eventually it was viewed as a complicated medication to administer, and one that was often associated with considerable risks. Hence, as the 20th century came to a close so did the enthusiasm for lithium and, having lost its champions long ago, its reputation as the archetypal mood stabiliser began to decay.

The element of surprise

Throughout the first decade of the 21st century the future of lithium in the treatment of bipolar disorder continued to hang in the balance, without any sign of a reprieve. Until finally, in 2010, a seminal multi-site European study lead by Oxford University researchers in the UK revealed that lithium had demonstrable mood-stabilising properties (BALANCE investigators and collaborators, 2010) and that its use is much safer than previously thought (McKnight et al., 2012). Once again, Cade’s stalwart treatment was in its element and regained its throne (Malhi, 2010).

Buy polar research

In 2011, recognising the importance of discovery and hoping no doubt to build on the spirit of Cade’s achievements, the National Health Medical Research Council allocated approximately AU$26,000,000 to capacity building and investment in mental health research. The devotion of such a substantive amount acknowledged the impact of mental illness and the relative paucity of funding devoted to mental health research. Within this funding initiative, the NHMRC created two specific fellowships for senior researchers to facilitate the growth and expansion of their research. In celebration of the achievements of John Cade, they were named the John Cade Fellowships. The focus of these fellowships is transformative research, but they are also intended to build capacity in mental health science. A special call for applicants resulted in applications from many leading researchers, of whom fewer than a dozen were short-listed for interview. Finally, two outstanding researchers were awarded the fellowships, each of which provides 5 years of funding which, viewed together, will promote a decade of science.

The dual Cade Fellowships provide balance and a sense of completeness, given that Cade was also trying to tackle a two-headed dragon. Whilst Cade’s knight in shining armour was lithium, the modern-day equivalents for these fellowships are the vitamins of life and technological innovation. Much is written and said about translational research in medicine, in which lessons from the bench-top are applied at the bedside and basic research is informed by clinical experience. The two arenas often seem poles apart and require effortful integration with both top-down and bottom-up endeavours. Perhaps this is why the NHMRC has also adopted a bi-directional approach and supported both acceleration of the discovery of effective treatments and development of their efficient delivery (Christensen, 2014; McGrath, 2014).

It’s been okayed

Whatever the rationale, funding is important both for lubricating the wheels of research and for the development of capacity to conduct meaningful research; therefore these fellowships are to be applauded. But, as Cade’s discovery clearly illustrates, ingenuity and insight are of critical importance. In other words, it is ideas that matter and this is what distinguished Cade and his colleagues. Undoubtedly it is this quality that the NHMRC has recognised in the recipients of the fellowships. Cade would certainly have approved.