What lithium can tell us about bipolar disorder

AT least 40% of Australians will experience a mental illness at some time in their lives, with almost 20% having a major difficulty in any 12-month period. Mental illnesses are the leading cause of non-fatal burden of disease worldwide, accounting for almost a quarter of all years lived with disability. Further, those living with persistent mental illness have a 10–15-year lower life expectancy than the general population.

For patients who live with the most severe mood disorders, such as bipolar disorder, there are major limitations in our current therapeutics. Treatment of acute mania still relies heavily on antipsychotic and anticonvulsant medications, both of which impose significant side effects. More than 60 years after Australian psychiatrist John Cade’s discovery, lithium is still a first-line choice for prophylaxis in bipolar disorder. It also remains one of our most effective antimanic, mood-stabilising and putative antisuicidal agents.

First-person accounts of patients living with bipolar disorder emphasise the extent to which the depressive phase is often more prolonged and debilitating than the “high” periods. The depressive phase is not just “low mood”, but more like prolonged and severe “jet lag”, with a profound loss of energy and physical wellbeing, alongside observable motor slowing and major cognitive difficulties. Both the manic and depressive phases can also be accompanied by psychotic phenomena, agitation or intense suicidal thoughts or behaviour.

At this time, there is no consensus internationally as to the most effective treatments for the depressive phase of bipolar disorder. While an emphasis on antidepressant therapies remains common in Europe, North American guidelines place emphasis on the use of other mood-stabilising agents. Standard antidepressant therapies are often ineffective and may be associated with worsening of some aspects of the experience, including agitation, suicidal ideation or possible switching to a manic phase. By contrast, newer anticonvulsant agents, or other antipsychotic agents, may have very limited antidepressant effects and their own range of side effects (eg, sedation, weight gain, parkinsonism).

Real advances in therapeutic options require new approaches that focus directly on characterisation of the underlying pathophysiological mechanisms. Substantial response to lithium carbonate may well be a signpost that we can now exploit more usefully to unravel some of these more fundamental pathways.

For example, it is clear that underlying circadian mechanisms are perturbed in many people with bipolar disorder, switching from oversleep, low energy to no-sleep, activation with changes in phase of illness. These “switch” phenomena are present during the earliest phases of illness onset or recurrence. Conceptually, this places bipolar disorder in the category of a disorder of “activation” rather than “mood” (and here).

Lithium has a clear impact on activation and also has a therapeutic effect on circadian cycles. It results in less day-to-day variations in these 24-hour sleep–wake cycles. It may prevent switching between the manic and depressive phases of illness, which often accompany key seasonal (autumn and spring) changes.

It is highly likely that individual responses to lithium, and perturbations in the circadian system, are both genetically determined. To date, however, genetic studies have not shown a clear association between these two factors in people living with bipolar disorder. Successes of the international Psychiatric Genomics Consortium (PGC), in recent years, have demonstrated that such negative findings are, however, often a function of small sample sizes.

In 2012, the PGC published an impassioned plea for support for larger genome-wide association studies (GWAS) of psychiatric conditions as the best way of uncovering causal pathways and new therapeutic opportunities. Subsequently, the PGC has fostered remarkable large-scale collaborations between global research teams to achieve this common purpose. For example, the most recent GWAS analyses for bipolar disorder, which included data from 20 352 cases and 31 358 controls, have identified 30 genome-wide significant loci.

One of the most productive additional strategies now being pursued is medication-based recruitment. We have been greatly impressed recently by Australians’ willingness to participate in such studies. For our related Australian Genetics of Depression Study, more than 20 000 Australians taking antidepressant medications have already volunteered. For bipolar disorder, response to lithium carbonate is the most obvious target, and it is now the inspiration for the Australian Genetics of Bipolar Disorder Study.

In addition to directly contributing to the international effort to identify new risk factors, these data will contribute to pharmacogenetic studies of efficacy and side effects of lithium treatment. Two GWAS for lithium response have recently been published with sample sizes of about 2500 individuals (here and here). While it is clear that both analyses show evidence of genetic effects, the two studies identified different genome-wide significant loci and show little replication between them.

Therefore, there is a pressing need to increase the power of these studies, and the samples collected in the Australian Genetics of Bipolar Disorder Study will make a substantial contribution. More immediately, those Australians who participate will be providing vital data on the lived experience of the benefits and pitfalls of current practice. In the shorter term, our clear aim is to develop much better genetic and clinical predictors of who is most likely to respond, with minimal side effects, to our available therapeutics.

Professor Ian Hickie, AM, is co-director (Health and Policy) of the University of Sydney’s Brain and Mind Centre, and is one of Australia’s first National Mental Health Commissioners. You can find him on Twitter @ian_hickie

Volunteers for the Australian Genetics of Bipolar Disorder Study can head to www.geneticsofbipolar.org.au, email gbp@qimrberghofer.edu.au or call 1800 257 179.

The statements or opinions expressed in this article reflect the views of the authors and do not represent the official policy of the AMA, the MJA or MJA InSight unless that is so stated.