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

超越精神分裂症中的多巴胺受体 - 使用 PET 成像评估磷酸二酯酶 10A 在疾病和治疗中的作用。

• 批准号: MR/L022176/1
• 负责人: Oliver Howes
• 金额: $ 89.82万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL022176%2F1
• 关键词: Beyond; dopamine; receptors; Schizophrenia; evaluating

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.

我们面临的挑战是什么：精神分裂症是一种严重的致残性精神疾病。它袭击了近1/100的人，通常在他们的成年早期，通常表现为一系列症状-妄想，偏执，幻觉沿着失去兴趣和动力以及注意力和记忆力的困难。毫不奇怪，只有不到十分之一的精神分裂症患者找到工作，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）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（现在有近20种这样的药物在积极使用）阻断大脑的多巴胺系统。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。即使在他们平静的妄想和幻觉的患者中，目前的药物也无法帮助失去驱动力或记忆/集中困难。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PDE 10A，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家公司有积极的计划。然而，这些程序都是基于试管和动物模型中的数据，没有人研究过精神分裂症中的PDE 10A系统。这是困难的，因为没有成像方法（脑扫描）可以帮助测量PDE 10A信号。我们已经克服了这个困难。使用一种特殊的大脑扫描，称为PET成像，我们已经开发出一种方法[使用一种名为IMA 107的化学物质]，可以在治疗前后准确测量患者的PDE 10A系统。我们现在想做的是：我们现在有第一次机会测量患者的PDE 10A水平。我们已经证明，这种方法可以用于健康志愿者，它是安全的，并给出了一个很好的读数。我们现在想招募20名精神分裂症患者和20名健康对照者，看看患者的PDE 10A水平是否发生变化。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PDE 10A产生继发性影响。我们也将通过在患者接受任何治疗前进行检查来测试这一点，然后在他们接受治疗几周后再次进行检查。这样做的好处是什么：这项研究将是第一次直接测量患者的PDE 10A。这将产生三个潜在影响。首先，不管结果如何，这项研究将回答一个关于精神分裂症大脑化学的基本问题。其次，如果精神分裂症中的PDE 10A发生了变化，这将为处于早期开发阶段的药物提供明确的理论依据。最后，我们开发的成像方法也可用于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。

项目成果

The effects of voice content on stress reactivity: A simulation paradigm of auditory verbal hallucinations.

• DOI: 10.1016/j.schres.2019.07.019
• 发表时间: 2022-05
• 期刊: SCHIZOPHRENIA RESEARCH
• 影响因子: 4.5
• 作者: Baumeister, David;Peters, Emmanuelle;Pruessner, Jens;Howes, Oliver;Chadwick, Paul
• 通讯作者: Chadwick, Paul

41.2 THE EFFECTS OF DEVELOPMENTAL STRESS AND TRAUMA ON THE DOPAMINE SYSTEM

41.2 发育应激和创伤对多巴胺系统的影响

• DOI: 10.1093/schbul/sbz022.170
• 发表时间: 2019
• 期刊: Schizophrenia Bulletin
• 影响因子: 6.6
• 作者: Bloomfield M

Prevalence of serum N-methyl-d-aspartate receptor autoantibodies in refractory psychosis - ADDENDUM.

难治性精神病中血清 N-甲基-d-天冬氨酸受体自身抗体的患病率 - 附录。

• DOI: 10.1192/bjp.2019.141
• 发表时间: 2019
• 期刊: the journal of mental science
• 作者: Beck K