Glutamate-Energetics In Schizophrenia And Treatment Resistance

精神分裂症是一种严重的精神健康问题。症状因人而异，但可能包括幻觉、有不寻常的想法或不符合现实的信念、思维混乱、对日常活动失去兴趣或逃避社交。抗精神病药物在减少精神分裂症的症状方面是有效的，但不幸的是，大约三分之一的人的症状无法改善。当使用两种不同的抗精神病药物进行适当的治疗后症状没有改善时，这可以被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会持续存在，并对日常生活产生负面影响。对治疗精神分裂症的新药有很大的需求。精神分裂症的原因尚不清楚，很可能涉及多个因素。最主要的理论之一是，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。也有早期证据表明，谷氨酸的变化可能对那些经历更严重的症状和治疗耐药性的人特别重要。因此，科学上对开发作用于谷氨酸系统的新药很感兴趣，尽管这些药物尚未成功。到目前为止，谷氨酸神经传递的调节是大脑中最需要能量的过程。这些能量需求通过葡萄糖的供应来满足，葡萄糖是大脑的主要能量来源。当能量需求较高时，乳酸可作为补充能源。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不是最好的。尽管对谷氨酸和能量的利用有很好的科学理解，但在活的人脑中，谷氨酸、葡萄糖的利用和乳酸产生之间的关系以前还没有被测量过。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扫描(称为核磁共振和正电子发射计算机断层扫描)来做到这一点。我们认为，在精神分裂症中，谷氨酸的变化与大脑努力满足的额外能量需求有关，这在那些患有治疗耐药疾病的人中最为明显。我们希望，这些知识可能有助于确定新的研究途径，旨在开发治疗精神分裂症的新药。

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.