Neurobiology of response to clozapine in treatment resistant schizophrenia

难治性精神分裂症对氯氮平反应的神经生物学

• 批准号: MR/L003988/1
• 负责人: Alice Egerton
• 金额: $ 88.21万
• 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%2FL003988%2F1
• 关键词: Neurobiology; response; clozapine; treatment; resistant

The aim of this research is to understand how Clozapine, a drug used to treat schizophrenia, produces its therapeutic effects. Clozapine is normally only used in very unwell patients, who have already tried other medications which have not worked. This is because, although clozapine is the most effective treatment for schizophrenia, it can also cause serious side effects. Patients taking clozapine are therefore closely monitored, including having regular blood tests. Unfortunately clozapine is only effective in reducing symptoms in about half of patients who try it, and there are very few treatment options left for patients who do not do well on clozapine. For these reasons, many doctors and patients put-off trying clozapine, only using it as a last resort. During this delay, patients are often treated instead with high doses of other medications or several medications in combination, which is not proven to be a good strategy and may also be harmful. At the moment, it is unknown how clozapine produces its therapeutic effects and why it works better in some people than in others. In this project, we will try and understand the biology behind the therapeutic effects of clozapine. We hope that understanding the biology will help scientists develop new medications as alternatives to clozapine, which could be used in patients who do not get better with clozapine or who experience bad side effects. We also hope that understanding the biology behind the effects of clozapine will help us to develop tests to predict in advance whether or not an individual patient is likely to get better with clozapine treatment. Such a test would mean that clozapine might be given earlier to patients who are likely to do well on it, while it could be avoided in patients who are unlikely to benefit. We think that the therapeutic effects of clozapine might be due to its ability to improve chemical signalling in the brain. On the basis of previous research, we are particularly interested in the effects of clozapine on two closely related chemicals which are vital for normal brain functioning - glutamate and GABA (gamma-amino-butyric-acid). We also think that the response to clozapine will be associated with specific patterns of blood flow in the brain. Using magnetic resonance imaging (MRI) brain scans, we are able to measure the amounts of glutamate and GABA and blood flow non-invasively in patients. In this project, we will use MRI scans to measure brain glutamate, GABA and perfusion in patients with schizophrenia before they start clozapine treatment and after they have been taking clozapine for 12 weeks, as part of their normal clinical care. We will assess each patients' symptoms before and after 12 weeks of clozapine to see how well their symptoms have improved. By looking at the changes in glutamate, GABA and blood flow in the brain which occur with clozapine treatment in relation to change in symptoms, we will better understand how clozapine produces its therapeutic effects. We will also be able to determine whether the level of glutamate, GABA and pattern of blood flow in the brain before starting clozapine can predict whether or not clozapine will improve symptoms in a particular patient.We hope that this information will then be useful to developing new drugs for schizophrenia, for example drugs with greater effects on brain glutamate, GABA and blood flow. We also hope that this research could lead to tests, where MRI scans measuring glutamate, GABA and blood flow could help doctors decide whether or not clozapine might be effective in their individual patient, where a positive result would encourage them to try it earlier. In these ways, this research could improve the health of patients with schizophrenic illness.

本研究的目的是了解用于治疗精神分裂症的药物氯氮平是如何产生疗效的。氯氮平通常只用于非常不适的患者，他们已经尝试过其他药物，但没有工作。这是因为，虽然氯氮平是治疗精神分裂症最有效的药物，但它也会引起严重的副作用。因此，服用氯氮平的患者受到密切监测，包括定期验血。不幸的是，氯氮平只能有效地减轻大约一半尝试过的患者的症状，并且对于氯氮平效果不佳的患者来说，治疗选择很少。由于这些原因，许多医生和病人推迟尝试氯氮平，只是把它作为最后的手段。在这种延迟期间，患者通常用高剂量的其他药物或几种药物联合治疗，这并不是一个好的策略，也可能是有害的。目前，尚不清楚氯氮平如何产生治疗效果，以及为什么它对某些人的效果比对其他人更好。在这个项目中，我们将试图了解氯氮平治疗效果背后的生物学。我们希望了解生物学将有助于科学家开发新的药物作为氯氮平的替代品，可以用于氯氮平没有好转或出现不良副作用的患者。我们还希望，了解氯氮平作用背后的生物学机制将有助于我们开发测试，以提前预测个体患者是否可能通过氯氮平治疗好转。这样的测试意味着氯氮平可能会更早地给那些可能会有良好效果的患者，而对于那些不太可能受益的患者则可以避免。我们认为，氯氮平的治疗效果可能是由于它能够改善大脑中的化学信号。在以前研究的基础上，我们特别感兴趣的是氯氮平对两种密切相关的化学物质的影响，这两种化学物质对正常的大脑功能至关重要-谷氨酸和GABA（γ-氨基丁酸）。我们还认为，对氯氮平的反应将与大脑中特定的血流模式有关。使用磁共振成像（MRI）脑部扫描，我们能够无创地测量患者体内谷氨酸和GABA的含量以及血流。在这个项目中，我们将使用MRI扫描来测量精神分裂症患者在开始氯氮平治疗之前和服用氯氮平12周之后的脑谷氨酸，GABA和灌注，作为他们正常临床护理的一部分。我们将评估每位患者在服用氯氮平12周前后的症状，以了解他们的症状改善情况。通过观察与氯氮平治疗有关的谷氨酸、GABA和脑血流量的变化，我们将更好地了解氯氮平如何产生治疗效果。我们还将能够确定在开始服用氯氮平之前，谷氨酸、GABA的水平和脑血流的模式是否可以预测氯氮平是否会改善特定患者的症状，我们希望这些信息将有助于开发治疗精神分裂症的新药，例如对脑谷氨酸、GABA和血流有更大影响的药物。我们还希望这项研究可以导致测试，其中测量谷氨酸，GABA和血流的MRI扫描可以帮助医生决定氯氮平是否对他们的个体患者有效，积极的结果将鼓励他们更早地尝试。通过这些方式，这项研究可以改善精神分裂症患者的健康状况。

项目成果

Changes in Brain Glutamate on Switching to Clozapine in Treatment-Resistant Schizophrenia.

• DOI: 10.1093/schbul/sbaa156
• 发表时间: 2021-04-29
• 期刊: Schizophrenia bulletin
• 影响因子: 6.6
• 作者: McQueen G;Sendt KV;Gillespie A;Avila A;Lally J;Vallianatou K;Chang N;Ferreira D;Borgan F;Howes OD;Barker GJ;Lythgoe DJ;Stone JM;McGuire P;MacCabe JH;Egerton A
• 通讯作者: Egerton A

Is treatment-resistant schizophrenia categorically distinct from treatment-responsive schizophrenia? a systematic review.

• DOI: 10.1186/s12888-016-1177-y
• 发表时间: 2017-01-13
• 期刊: BMC psychiatry
• 影响因子: 4.4
• 作者: Gillespie AL;Samanaite R;Mill J;Egerton A;MacCabe JH
• 通讯作者: MacCabe JH

Additional file 2: of Is treatment-resistant schizophrenia categorically distinct from treatment-responsive schizophrenia? a systematic review

附加文件 2：难治性精神分裂症与治疗反应性精神分裂症有明显区别吗？

• DOI: 10.6084/m9.figshare.c.3665929_d1
• 发表时间: 2017
• 作者: Gillespie A

Subcortical volume reduction and cortical thinning 3 months after switching to clozapine in treatment resistant schizophrenia.

• DOI: 10.1038/s41537-022-00230-2
• 发表时间: 2022-03-02
• 期刊: Schizophrenia (Heidelberg, Germany)
• 作者: Krajner F;Hadaya L;McQueen G;Sendt KV;Gillespie A;Avila A;Lally J;Hedges EP;Diederen K;Howes OD;Barker GJ;Lythgoe DJ;Kempton MJ;McGuire P;MacCabe JH;Egerton A
• 通讯作者: Egerton A

Additional file 1: of Is treatment-resistant schizophrenia categorically distinct from treatment-responsive schizophrenia? a systematic review

附加文件 1：难治性精神分裂症与治疗反应性精神分裂症有明显区别吗？

• DOI: 10.6084/m9.figshare.c.3665929_d2
• 发表时间: 2017
• 作者: Gillespie A