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

双相情感障碍是一种慢性衰弱性精神障碍，终生患病率为1-3%。据估计，它每年给英国经济造成的损失在20亿至50亿英镑之间，其中约3.5亿英镑是NHS的直接成本，其余部分包括社会关怀、刑事司法服务、家庭成员的非正式照顾以及与失业相关的成本。治疗双相情感障碍的黄金标准是锂，它在各种可用的治疗方案中是独一无二的，因为它不仅具有抗躁狂和抗抑郁的特性，而且还降低了患者自杀的风险。然而，锂的处方继续减少，因为与它如何影响大脑功能无关的严重副作用的数量。最值得注意的是，如果血液浓度仅达到治疗浓度的2-3倍，锂就会导致死亡。因此，血液中的锂浓度需要持续监测，因此锂已被各种更安全但效果较差的情绪稳定药物取代，成为双相情感障碍的一线治疗方法。很明显，有必要找出既能保留锂的有益作用，又没有严重副作用的药物。在这方面，有相当多的证据表明，锂通过降低一种叫做肌醇单磷酸酶（IMPase）的蛋白质的活性来发挥其对大脑的有益作用。结果，锂抑制了神经细胞的活动，而在双相情感障碍中，神经细胞被认为比正常情况下更活跃。理论上，一种只抑制IMPase而没有锂所具有的多种其他作用（这些作用是锂的副作用的原因）的药物应该保留锂的显著有益作用，但更安全。这种药物有可能彻底改变双相情感障碍的治疗方法，这样做不仅可以降低经济和社会成本，还可以帮助患者过上正常、有意义的生活。筛选阿斯利康的化学文库是一个独特的机会，沿着确定这种潜在的变革性药物的路径开始。

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.