Beyond dopamine receptors in Schizophrenia - evaluating the role of Phosphodiesterase 10A in disease and treatment using PET imaging.

我们正在应对的挑战是什么：精神分裂症是一种严重的致残精神疾病。几乎每100人中就有1人患此病，通常发生在成年早期，通常表现为一系列症状——妄想、偏执、幻觉，同时失去兴趣和动力，注意力不集中，记忆力差。不足为奇的是，不到十分之一的精神分裂症患者找到了工作，很少有人结婚或成家。目前的治疗包括药物（称为抗精神病药物）和各种形式的治疗。目前的抗精神病药物起源于近50年前的发现，它们都阻断了大脑的多巴胺系统（目前有近20种此类药物在积极使用）。虽然这对大约三分之二的患者有效，但这些方法并不适用于所有患者。即使是那些用药物平息妄想和幻觉的病人，目前的药物也无法帮助他们失去动力或记忆/注意力集中困难。因此，人们必须找到一种替代多巴胺系统治疗的方法。我们的方法是什么：基础科学研究和动物研究表明，另一种帮助精神分裂症患者的方法是阻断另一种化学物质PDE10A，因为它在多巴胺系统的下游起作用。这种方法正在被制药公司采用，其中近20家公司已经申请了专利，其中5家公司有活跃的项目。然而，这些项目都是基于试管和动物模型的数据，没有人研究过精神分裂症中的PDE10A系统。这很困难，因为没有成像方法（脑部扫描）可以帮助测量PDE10A信号。我们已经克服了这个困难。使用一种特殊的脑部扫描，称为PET成像，我们开发了一种方法（使用一种名为IMA107的化学物质），可以准确测量患者在治疗前后的PDE10A系统。我们现在想做什么：我们现在有了第一个机会来测量患者体内PDE10A的水平。我们已经证明这种方法可以用在健康的志愿者身上，它是安全的，而且读数很好。我们现在想招募20名精神分裂症患者和20名健康对照者，看看PDE10A的水平在患者中是否发生了变化。其次，动物研究表明，目前用于治疗精神分裂症的药物也可能对PDE10A产生继发性影响。我们也会在病人接受任何治疗前对他们进行检查，然后在他们接受治疗几周后再进行检查。这项研究的好处是：这项研究将是第一次直接测量患者的PDE10A。这将有三个潜在的影响。首先，不管结果如何，这项研究将回答一个关于精神分裂症的大脑化学的基本问题。其次，如果精神分裂症患者的PDE10A发生变化，它将为处于早期开发阶段的药物提供明确的依据。最后，我们开发的成像方法也可以用来测量新药对大脑的影响——这可能使开发这些药物的科学家能够选择适当的剂量和给药频率，以获得最佳效果。

What is the challenge we are addressing:Schizophrenia is a serious and disabling mental illness. It strikes nearly 1 in 100 people, usually in their early adulthood, and is usually manifested with a range of symptoms - delusions, paranoia, hallucinations along with loss of interest and drive and difficulties with concentration and memory. Not surprisingly, less than 1 in 10 people with schizophrenia find work, and few marry or have families. The current treatment involves medications (called antipsychotics) and various forms of therapies. The current antipsychotics have their origins in discoveries nearly 50 years ago, and they all (nearly 20 such drugs are actively used now) block the dopamine system of the brain. While this works for about two-thirds of the patients - these approaches do not work for all patients. Even in the patients in whom they calm the delusions and hallucinations, the current drugs to not help with loss of drive or memory/concentration difficulties. Thus, one has to find an alternative to the dopamine-system treatments.What is our approach:Basic science research and research in animals suggests that another way to help patients with Schizophrenia would be to block another chemical PDE10A, as it works downstream from the dopamine system. This approach is being adopted by drug companies, nearly 20 of them have filed patents, and five of them have active programs. However, these programs are based on data in test-tubes and animal models and no one has looked at the PDE10A system in Schizophrenia. This has been difficult as there was no imaging method (brain scan) that could help measure the PDE10A signal. We have overcome this difficulty. Using a particular kind of brain scanning, called PET imaging, we have developed a method [using a chemical called IMA107] which can give us an accurate measure of PDE10A system in patients before and after treatment. What would we like to do now:We now have the first opportunity to measure the levels of PDE10A in patients. We have already shown that this method can be used in healthy volunteers, it is safe, and gives a good readout. We would now like to enroll 20 patients with schizophrenia and 20 healthy controls and see if the levels of PDE10A are changed in patients. Secondly, there are indications from animal studies that the drugs currently used to treat schizophrenia, may also secondarily have an effect on PDE10A. We will test for that too by examining patients before they have any treatment, and then again after they have been treated for a few weeks.What are the benefits of this:This research will be the first direct measurement of PDE10A in patients. This will have three potential implications. First, regardless of the outcome, the study will answer a fundamental question about the brain chemistry of schizophrenia. Second, if there is a change in PDE10A in schizophrenia, it will provide a clear rationale for the drugs that are in the early stages of development. Finally, the imaging method that we have developed can also be used to measure the effect of the new drugs on the brain - this may allow the scientists developing those drugs to choose the appropriate dose and frequency of administration for best effects.