Investigating the relationships between risk factors and brain glutamate in schizophrenia

谷氨酸是一种关键的神经递质，与精神分裂症的神经生物学有关。在活体人脑内，可以使用基于核磁共振的质子磁共振波谱(1H-MRS)技术测量预先选择的大脑区域内的谷氨酸浓度。现在有80多项关于精神分裂症中谷氨酸的1H-MRS研究。这些单独的研究观察到了不同的结果，发现谷氨酸水平上升、下降或没有变化。在其他因素中，这可能与患者特征的差异、所调查的大脑区域以及在个别研究的相对较小样本量内测量变异性有关。知识可以通过检查更大的、具有良好特征的患者样本的研究来发展，或者通过应用巨型或元分析技术来结合来自个别研究的数据来发展。例如，由埃格顿教授的团队领导的最近的荟萃分析和大型分析表明，精神分裂症患者大脑中不同区域的谷氨酸含量升高(Merritt等人，2018年)，而且这种升高可能在精神病发作后不久最显著，或者是症状负担最高的患者(Merritt等人，2021年)。我们最新的荟萃分析(Merritt等人，正在准备中)表明，精神分裂症患者的谷氨酸水平比健康志愿者的谷氨酸水平变化更大。这种变异的原因和临床后果目前尚不清楚。了解这些过程可能具有翻译意义，因为它可以指出谷氨酸作用疗法可能对哪些患者亚组最有效，从而为分层医学方法提供信息。这一博士学位将从三个方面扩展这项工作。1.我们的小组和其他人还表明，对抗精神病药物治疗反应不佳的患者，前扣带皮质(ACC)中谷氨酸的升高更加明显(Egerton等人，2012、2018、2020；岩田等人，2018；Tarumi等人，2021)，尽管其他一些研究没有发现同样的发现(Goldstein等人，2015；Horne等人，2021)。PHD的第一项研究将包括荟萃分析和参与者水平的巨型分析，以确定当考虑到所有现有信息时，治疗无效的精神分裂症中谷氨酸是否会升高。其翻译含义是，这可能表明，降低谷氨酸的药物可能对那些对现有抗精神病药物反应不佳的人有效。2.目前尚不清楚谷氨酸异常对精神分裂症的特异性。谷氨酸是大脑中主要的兴奋性神经递质，因此错综复杂地参与健康认知的各个方面，因此谷氨酸的异常被认为存在于精神障碍中。除了我们小组(Merritt等人，2018年；Merritt等人，在PREP中)和其他人(Nakahara等人，2022年)在精神分裂症方面的荟萃分析外，荟萃分析显示，在严重抑郁障碍中，MFC谷氨酸减少(MOriguchi等人，2019年)，双相情感障碍大脑区域谷氨酸含量增加(Gigante等人，2012年)，在酒精使用障碍方面没有差异(Kirkland等人，2022年)。博士的第二项研究将使用荟萃分析方法来比较两种或两种以上精神疾病的大脑谷氨酸异常。这将为谷氨酸功能障碍在多大程度上代表一个共同或独特的机制，在跨诊断方法中提供初步的、新颖的信息。3.第三，几个环境和遗传风险因素与精神病和更严重的精神分裂症的发展有关，但生物学机制尚不清楚。我们的小组最近发现，涉及NMDA受体功能障碍的通路的多基因风险与ACC谷氨酸水平有关(Griffiths等人提交)。博士的第三项研究将调查是否存在其他危险因素，包括家族史，早期...

Glutamate is a key neurotransmitter implicated in the neurobiology of schizophrenia. Within the living human brain, the concentration of glutamate can be measured within pre-selected brain areas using the MRI-based technique of proton magnetic resonance spectroscopy (1H-MRS). There are now over 80 1H-MRS studies of glutamate in schizophrenia. These individual studies have observed various results, finding increases, decreases or no change in glutamate levels. Amongst other factors, this may relate to differences in patient characteristics, the brain regions investigated and measurement variability within the relatively small sample sizes of individual studies. Knowledge can be developed by studies examining larger, well-characterised patient samples or by applying mega- or meta- analytical techniques to combine data from individual studies. For example, recent meta and mega-analyses led by Prof Egerton's group have shown elevations in glutamate in schizophrenia in distinct brain regions (Merritt et al., 2018), and that elevations may be most marked shortly after onset of psychosis, or patients who have highest symptom burden (Merritt et al., 2021). Our most recent meta-analysis (Merritt et al., in preparation) shows that glutamate levels in schizophrenia are more variable than in healthy volunteers. The causes and clinical consequences of this variability are currently unclear. Understanding these processes may have translational implications, as it could indicate patient subgroups for whom glutamate-acting therapeutics may have greatest efficacy, and thus inform stratified medicine approaches. This PhD will extend this work in three ways. 1. Our group and others have also shown that elevations in glutamate in the anterior cingulate cortex (ACC) are more marked in patients who have not responded well to antipsychotic treatment (Egerton et al., 2012, 2018, 2020; Iwata et al., 2018; Tarumi et al., 2021), although some other studies have not detected the same finding (Goldstein et al., 2015; Horne et al., 2021). The first study of the PhD will consist of a meta-analysis and participant level mega-analysis, to determine whether glutamate is elevated in treatment-non-responsive schizophrenia when all the existing information is considered. The translational implication is that this could indicate that glutamate-lowering drugs may have efficacy in those who have not responded well to existing antipsychotics. 2. It is not clear how specific abnormalities in glutamate are to schizophrenia. Glutamate is the major excitatory neurotransmitter in the brain and is thus intricately involved in all aspects of heathy cognition, thus abnormalities in glutamate have been suggested across the psychiatric disorders. In addition to meta-analyses from our group (Merritt et al., 2018; Merritt et al., in prep) and others (Nakahara et al., 2022 ) in schizophrenia, meta-analysis have shown decreases in MFC glutamate in major depressive disorder (Moriguchi et al, 2019), increases in glutamate across brain regions in bipolar disorder (Gigante et al., 2012) and no difference in alcohol use disorder (Kirkland et al., 2022). The second study of the PhD will use meta-analytical approaches to compare brain glutamate abnormalities across two or more psychiatric disorders. This will provide initial, novel information on the extent to which glutamate dysfunction may represent a shared or distinct mechanism, in a transdiagnostic approach. 3. Third, several environmental and genetic risk factors have been associated with the development of psychosis and with more severe forms of schizophrenia, but the biological mechanisms are unclear. Our group has recently shown that polygenetic risk for pathways involving NMDA receptor dysfunction are associated with ACC glutamate levels (Griffiths et al., submitted). The third study of the PhD will investigate whether the presence of other risk factors, including family history, early...