Lithium: The defining element?

A defining moment

Enthusiasm for lithium has been growing ever since commemorations took place in 1999 to mark Cade’s rediscovery of this simple element. A defining moment in this renaissance was the publication of BALANCE in 2010 (The BALANCE investigators and collaborators, 2010). Compelling new data was needed to rekindle interest in the actions of lithium, and publication in The Lancet of impressive real-world clinical trial findings achieved this. The study firmly positioned lithium as an effective prophylactic agent in the maintenance treatment of bipolar disorder – without doubt the most critical phase of the illness. Equally importantly, successful implementation and completion of the trial provided proof that meaningful questions concerning therapeutic effectiveness, no matter how ambitious, can be addressed, even in the most challenging of clinical environments, by ensuring methodological rigour and employing sophisticated analyses. The outcomes of the study (The BALANCE investigators and collaborators, 2010) confirmed widespread clinical experience and underscored lithium’s pole position amongst pharmacological treatments for bipolar disorder. However, disappointingly, the resurgence of interest in lithium remains largely confined to academia, with little impact thus far on clinical practice. Even amongst researchers, the initiation of strategic efforts to advance our understanding of this element has been slow. In part, this is because lithium is not new and it lacks the financial backing of big Pharma. Nevertheless, lithium is certainly shiny and holds immense potential. The real question is whether its brilliance can shine through the diagnostic clouds that eclipse its effects (Malhi, 2013), and the smog of publicity generated by heavily marketed alternative compounds. In making such comparisons between lithium and other putative mood stabilizers, it is important to emphasize lithium’s unique additional qualities, in particular its neuroprotective, neurotrophic and antisuicidal actions (Malhi et al., 2012).

Diagnostic quagmire

The inadequacies of current psychiatric taxonomy have recently been brought into sharp relief by the publication of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), in which ‘disorders’ have seemingly been created by arbitrarily grouping symptoms into syndromes, which in turn have then been partitioned into ‘subtypes’ using rather blunt instruments. This is particularly evident in the classification of mood disorders, in which the subtyping of bipolar disorder lacks clinical validity and the introduction of a ‘mixed features specifier’ has created a diagnostic quagmire with potentially dire consequences.

In this climate, fresh ideas to better conceptualize and clinically define mood disorders have all but evaporated. And just as depression now has myriad connotations depending on context, so too bipolar disorder has developed an ever-expanding lexicon with different meanings nuanced by milieu. It is in this atmosphere of confusion and flux that reframing and reinventing psychiatric disorders using the Research Domain Criteria (RDoC) proposed by the National Institute of Mental Health (NIMH) may provide some opportunities for improving our understanding of mood disorders.

Elementary mechanisms

A heuristic focus on neurocircuitry and the adoption of a mechanistic approach to the neurobiology of psychiatric phenomena to create a framework for understanding clinical syndromes may assist in advancing our taxonomy of mood disorders and facilitate the identification of medications that achieve a significant benefit over placebo. In this respect, lithium appears to provide an important key, in that, given time, it is effective in alleviating the symptoms of both acute mania and depression, and, more importantly, it confers mood stability by reducing perturbations of mood. This prophylactic effect and ability to stabilize emotional circuitry distinguish it as a true ‘mood stabilizer’.

Despite being a simple element, lithium affects many complex biological systems and, although it remains unclear which of these actions lead to its mood stabilizing properties, this clearly warrants determined investigation and the precise molecular targets need to be identified (Malhi et al., 2012). Clinically, the profiling of lithium response has identified ‘responders’ as those who experience recurrent episodes of illness (depression/mania) and who have complete remission in between (Gershon et al., 2009). Furthermore, they usually remain well for extended periods of time, provided they maintain adequate plasma lithium levels. The significance of this ‘phenotype’ is that the biological basis of lithium responsiveness may provide a means of defining a subset of mood disorder patients. Apart from providing a profile of those patients likely to benefit clinically from lithium, identifying these patients as a phenotype automatically ‘defines’ remaining patients as lithium non-responders. It is quite likely that the latter have different pathophysiological mechanisms driving their symptoms, and will therefore respond to alternative treatments. Segregating mood disorder patients in this manner could provide a means of enriching samples in randomized controlled trials that are either lithium responsive or not. These samples could then be used to study the effects of novel medications, which could either be attempting to mimic the actions of lithium or endeavouring to act via separate mechanisms. Such lines of research could introduce new molecules into clinical practice that achieve better and more specific outcomes. However, in assessing outcome in responders and non-responders to lithium, it will be important to include both a clinical and a functional evaluation of the euthymic period; another aspect that has been understudied. The question here would be, does lithium effectuate ‘restitutio ad integrum’ or only a subsyndromal phase?

The momentum of lithium

After more than 60 years, lithium reigns supreme. Newer medications have repeatedly threatened to supplant its use with claims of being equally effective, if not better. However, lithium has survived these repeated challenges; the main reason that it has not been relegated to history is because its clinical benefits are self-evident and undeniable. It is therefore imperative that its pharmacology is subjected to scrupulous examination. Genetic studies, neuroimaging investigations and molecular research are likely to provide the necessary insights (Duffy et al., 2014), but, contemporaneously, where possible and where indicated, lithium should be trialled in clinical practice in patients with mood disorders. Clinical improvement, or a lack of it, will assist in defining the clinical response and inform future treatment. This clinical paradigm should then be superimposed upon basic science investigations in order to understand the specific biological mechanisms of action of lithium that result in mood stability. In this manner, the clinical application of lithium is capable of providing much-needed diagnostic clarity.

Back to basics

It is noteworthy, but also somewhat disheartening, to acknowledge that, despite many decades of research and enormous financial investment, one of the very first elements to have been identified as having benefit in the treatment of mood disorders remains our best, and perhaps only, prospect for deciphering the pathophysiology of mood disorders and developing better treatments. Investigations into the mechanisms of action of lithium, coupled with clinical and neurocognitive studies of emotion processing and regulation, are likely to position lithium as the defining element in mood disorders research in the coming decade. All that is needed now is renewed vigour and application.