Cade's lithium: an extraordinary experiment with a not-so-ordinary element

Lithium research continues to yield benefits for treatment of bipolar disorder

To those familiar with the properties of lithium, it was no surprise that John Cade's seminal article1 was, in 2004, the most cited in the history of the Journal, and was aptly described as a jewel in the crown.2 After all, lithium has long had royal status in clinical practice guidelines and is very much in its element in blue blood.3 Hence, the fact that another decade later Cade's groundbreaking study has retained regal standing in the archives of the Journal is to be expected. But perhaps what is truly remarkable is the fact that lithium has recently strengthened its clinical profile in the pharmacological armamentarium presently used to treat bipolar disorder.4 This resurgence of interest reflects lithium's enduring efficacy — put bluntly, it works. Lithium is arguably the best agent for the most critical phase of bipolar disorder, long-term prophylaxis, and as such it is the only true mood stabiliser.5 Boosting its profile further, lithium is both antisuicidal6 and neuroprotective.4

Unfortunately, lithium can be toxic, acutely so at high doses, but also at low doses when administered chronically, although the true risks have been somewhat exaggerated.7 As the only antimanic agent, it would be useful to understand its mechanism of action, so as to target those patients most likely to respond and to develop mimetics that can replicate lithium's specific actions without reproducing its tolerability problems. Recent studies have identified genetic variations associated with lithium response,8 and potential lithium-like molecules are undergoing development.9 These ambitious endeavours aim to advance the treatment of bipolar disorder and, in doing so, will provide more robust means for defining the illness and equating diagnoses to disease. A lithium-responsive and lithium-defined subtype of bipolar disorder representing a biologically anchored phenotype could be called Cade's disease.10 Alas, although this would be a tremendous acknowledgement, perhaps the eponym would be better suited to describing the remedy that he discovered.