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

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.

Bipolar disorder is a chronic and debilitating psychiatric disorder with a lifetime prevalence of 1-3% with direct and indirect costs to the UK economy estimated to total £2 to 5 billion per year. Lithium remains the gold-standard in terms of efficacy for treating bipolar disorder yet it has a number of serious side-effects that have seen it replaced in the clinic by safer but less efficacious anticonvulsant and antidepressant mood stabilizers. In the search for novel, safer lithium mimetic drugs, inositol monophosphatase (IMPase) is an excellent candidate for the molecular target for lithium's action. Hence, IMPase, which dephosphorylates the inositol monophosphate substrates inositol 1-, 3- and 4-phosphate (collectively InsP1), is inhibited by therapeutically-relevant concentrations of lithium which in turn results in a reduction in the intracellular inositol available for recycling into the synthesis of phosphatidylinositol (the so-called inositol depletion hypothesis). As a consequence, the synthesis of phosphatidylinositol 4,5-bisphosphate (PIP2) is reduced and therefore less inositol 1,4,5 trisphosphate and diacylglycerol second messengers are produced following agonist-stimulated, phospholipase C-catalysed PIP2 hydrolysis.

Previous attempts to screen for novel inhibitors of IMPase were restricted due to the use of a relatively low throughput radiometric ion exchange assay (which necessitated the separation of [14C]-inositol from [14C]-inositol-1-phosphate) and/or relatively restricted chemical or natural product collections. Access to the AstraZeneca chemical collection coupled to a high-throughput phosphate-release assay greatly increases the probability of identifying novel chemical starting points for IMPase, which is excellent molecular target for developing lithium mimetic compounds that could revolutionise the treatment of bipolar disorder.

The chief direct beneficiaries of this research will be patients suffering from bipolar disorder in whom existing therapeutic options are limited either by significant side effects (lithium) or relative lack of efficacy (anticonvulsant and antipsychotic mood stabilisers). The much improved treatment of bipolar disorder by IMPase inhibitors offers the possibility that such patients might resume a relatively normal life and be able to sustain long term employment and meaningful relationships. Secondary beneficiaries, both emotionally and financially, would be the family and caregivers of such patients. Finally, society in general would be beneficiaries since there would be a reduction in direct and indirect costs (the latter including, for example, a reduction in costs to the judicial system) plus an increased financial contribution to society by a patient that is able to resume employment.