Glutamate-Energetics In Schizophrenia And Treatment Resistance

精神分裂症中的谷氨酸能量学和治疗抵抗

• 批准号: MR/X021696/1
• 负责人: Alice Egerton
• 金额: $ 160.43万
• 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: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX021696%2F1
• 关键词: Glutamate; Energetics; Schizophrenia; Treatment; Resistance

Schizophrenia is severe mental health condition. Symptoms vary from person to person, but can include hallucinations, having unusual thoughts or beliefs that are not based on reality, muddled thinking, loss of interest in everyday activities or avoiding social contact. Antipsychotic medication is effective in reducing the symptoms of schizophrenia, but unfortunately in around a third of people symptoms will fail to improve. When symptoms do not improve following adequate treatment with two different antipsychotic medications, this can be termed treatment resistant schizophrenia. Furthermore, while some symptoms generally respond well to medication, other symptoms including cognitive impairments (such as poor memory) may persist and negatively impact on everyday life. There is a substantial need for new medicines to treat schizophrenia. The causes of schizophrenia are unknown and are likely to involve more than one factor. One of the leading theories is that schizophrenia is related to changes in glutamate, which is the main excitatory neurotransmitter in the brain. There is also early evidence that changes in glutamate could be particularly important in those who experience more severe symptoms and treatment resistance. There is therefore scientific interest in developing new medicines that work on the glutamate system, although these have not yet been successful. Regulation of glutamate neurotransmission is by far the most energy demanding process in the brain. These energy demands are met through supply of glucose, which is the brain's main source of energy. When energy demands are high, lactate may provide a supplementary energy source. This ability to meet energy demands and regulate glutamate neurotransmission is a fundamental biological process, vital for healthy brain functioning and cognition. Our theory is that this process is not working optimally in schizophrenia. Although there is good scientific understanding of glutamate and energy use, the relationships between glutamate, glucose utilisation and lactate production have not been measured in the living human brain before. We will do this by acquiring two types of brain scans (called MRI and PET) in people with and without schizophrenia. We propose that in schizophrenia, changes in glutamate are associated with an additional energy demand which the brain struggles to meet, and that this is most apparent in those with treatment resistant illness. We hope that this knowledge may help to identify new avenues for research aimed at developing novel medicines for schizophrenia.

精神分裂症是一种严重的精神疾病。症状因人而异，但可能包括幻觉、有不基于现实的不寻常想法或信仰、思维混乱、对日常活动失去兴趣或避免社交。抗精神病药物在减轻精神分裂症症状方面是有效的，但不幸的是，大约三分之一的人的症状无法改善。当两种不同的抗精神病药物治疗后症状没有改善时，可称为治疗难治性精神分裂症。此外，虽然一些症状通常对药物反应良好，但包括认知障碍（如记忆力差）在内的其他症状可能持续存在，并对日常生活产生负面影响。治疗精神分裂症的新药有很大的需求。精神分裂症的病因尚不清楚，可能涉及不止一种因素。其中一个主要理论是，精神分裂症与谷氨酸的变化有关，谷氨酸是大脑中主要的兴奋性神经递质。也有早期证据表明，谷氨酸的变化可能对那些经历更严重症状和治疗耐药性的人特别重要。因此，开发对谷氨酸系统起作用的新药引起了科学界的兴趣，尽管这些药物尚未取得成功。谷氨酸神经传递的调节是迄今为止大脑中最需要能量的过程。这些能量需求是通过葡萄糖的供应来满足的，葡萄糖是大脑的主要能量来源。当能量需求高时，乳酸盐可以提供补充能量。这种满足能量需求和调节谷氨酸神经传递的能力是一个基本的生物过程，对健康的大脑功能和认知至关重要。我们的理论是，这个过程在精神分裂症中并没有发挥最佳作用。尽管对谷氨酸和能量使用有很好的科学理解，但在人类大脑中，谷氨酸、葡萄糖利用和乳酸生成之间的关系还没有被测量过。我们将通过对精神分裂症患者和非精神分裂症患者进行两种类型的脑部扫描（称为MRI和PET）来做到这一点。我们认为，在精神分裂症患者中，谷氨酸的变化与大脑难以满足的额外能量需求有关，这在患有治疗抵抗性疾病的患者中最为明显。我们希望这些知识可以帮助我们找到新的研究途径，以开发治疗精神分裂症的新药。