MICA: Inhibitors of inositol monophosphatase for the treatment of bipolar disorder

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Bipolar disorder is a chronic and debilitating psychiatric disorder that with a lifetime prevalence of 1-3%. It has at a cost to the UK economy estimated to be in the region of £2 to 5 billion per year, of which around £350m are direct costs to the NHS with the remainder including social care, criminal justice services, informal care from family members and costs associated with lost employment. The gold-standard treatment for bipolar disorder is lithium, which is unique among the various treatment options available in that it not only has anti-manic and anti-depression properties but also reduces the risk of suicide in patients. However, the prescribing of lithium continues to decline due to the number of serious side effects that are unrelated to how it affects brain function. Most notably, lithium can cause death if blood concentrations reach only 2-3-fold higher than therapeutic concentrations. Consequently, lithium concentrations in the blood need continual monitoring and as a result lithium has been replaced as the first-line treatment of bipolar disorder by a variety of safer but less effective mood stabilising drugs.There is clearly a need to identify drugs that retain the beneficial effects of lithium yet are devoid of the serious side effects. In this regard, there is considerable evidence to suggest that lithium exerts its beneficial effects in the brain by reducing the activity of a protein called inositol monophosphatase (IMPase). As a result, lithium dampens down the activity of nerve cells that are presumed to be more active than normal in bipolar disorder. In theory, a drug that only inhibits IMPase and is devoid of the multiple other effects that lithium possesses - and which are the responsible for lithium's side effects - should retain the remarkable beneficial effects of lithium yet be much safer. Such a drug has the potential to revolutionise the treatment of bipolar disorder and in doing so, not only reduce the financial and social costs but also assist patients in achieving normal, productive lives. Screening of the AstraZeneca's chemical library is a unique opportunity to start along the path of identifying such a potentially transformative drug.