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健康状况。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念、思维混乱、对日常活动失去兴趣或逃避社交接触。抗精神病药物可以有效减轻精神分裂症的症状，但不幸的是，大约三分之一的人的症状无法改善。当使用两种不同的抗精神病药物进行充分治疗后症状没有改善时，这可以称为治疗抵抗性精神分裂症。此外，虽然某些症状通常对药物反应良好，但包括认知障碍（例如记忆力差）在内的其他症状可能会持续存在并对日常生活产生负面影响。非常需要治疗精神分裂症的新药。精神分裂症的病因尚不清楚，可能涉及不止一种因素。主要理论之一是，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。还有早期证据表明，谷氨酸的变化对于那些经历更严重症状和治疗抵抗的人来说可能特别重要。因此，科学界对开发作用于谷氨酸系统的新药物产生了兴趣，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供应葡萄糖来满足的，葡萄糖是大脑的主要能量来源。当能量需求高时，乳酸可以提供补充能量来源。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，对于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利用有很好的科学认识，但谷氨酸、葡萄糖利用和乳酸产生之间的关系以前从未在活人大脑中测量过。我们将通过对患有和不患有精神分裂症的人进行两种类型的脑部扫描（称为 MRI 和 PET）来实现这一目标。我们认为，在精神分裂症中，谷氨酸的变化与大脑难以满足的额外能量需求有关，这在患有难治性疾病的患者中最为明显。我们希望这些知识可能有助于确定旨在开发精神分裂症新药的新研究途径。