Neurobiology of the Major Psychoses – Transdiagnostic and longitudinal characterisation of schizophrenia and affective disorders

不仅是精神分裂症，所有主要精神病（重度抑郁症，MDD；双相情感障碍，BD；精神分裂症，SZ和分裂情感障碍，SZA）的病因学研究进展都受到大多数研究的明显缺陷的阻碍，主要是由于实际实施。这些局限性在包含生物学（如遗传学、免疫学、微生物组）和/或环境或行为因素（如环境风险、临床变量）的MR脑成像研究中最为明显。大多数研究仅限于小样本量，并且在调查中显示出巨大的异质性，并且几乎没有使用相同方法的直接重复。此外，精神分裂症的纵向磁共振成像研究很少，缺乏跨诊断方法。因此，需要新一代的研究，采用a)大规模样本，b)纵向设计，c)多模式（结构和功能）成像方法，d)定义明确，深入表型的患者和对照样本，e)用最新的遗传和表观遗传方法进行分析，f)创新的多组学分子方法。为了真正推动该领域超越目前的水平，g)基于h)来自这些患者组的多模态（成像）数据的多变量分析和i)独立复制的多个患者组的跨诊断方法将是必要的下一步。目前的建议的目标是在两个时间点调查300名SZ和SZA患者，间隔2年，应用深度表型方法，包括多模态MRI， GWAS，细胞因子，微生物组分析，环境以及其他生命风险，神经心理学，个性和多个临床/社会人口变量。将采用与DFG FOR2107相同的方案，其中共纳入n=2577例患者（MDD， BD，以及n=180例SA/SZA患者，后者自费表型）和健康对照受试者（截至2019年5月）。目前的拨款将用于招募和分析剩余的120例基线时SZ/SZA患者和144例2年后随访、数据分析和发表的费用（见前言）。它将以多种方式以高成本效益大大增加现有的FOR2107数据集。该项目将为SZ和SZA患者提供一个庞大而独特的队列，为研究GxE在多个（外）遗传和（内）表型水平上的相互作用提供新的机会。它将描述具有共同神经生物学基础的新病理生理实体，并将为了解SZ的病因学铺平道路，并与DFG FOR2107数据相结合，为了解主要精神病铺平道路，可能导致其预防，个体疾病病程预测和未来的新疗法。

Progress in etiological research not only in schizophrenia, but all major psychoses (major depression, MDD; bipolar disorder, BD; schizophrenia, SZ and schizoaffective disorder, SZA), is hampered by obvious shortcomings in the majority of studies, mainly due to practical implementation. These limitations are most evident in MR brain imaging studies nested with biological (e.g. genetics, immunology, microbiome) and/or environmental or behavioural factors (e.g. environmental risks, clinical variables). Most studies are limited to small sample sizes and show massive heterogeneities across investigations, and almost no direct replications with identical methods. Furthermore, longitudinal MR imaging studies in schizophrenia are scarce, and are lacking for transdiagnostic approaches. Thus, there is a need for a novel generation of studies employing a) large-scale samples, b) longitudinal designs, c) multimodal (structural and functional) imaging approaches in d) well-defined, deeply phenotyped patients and control samples which are e) analysed with latest genetic and epigenetic methods and f) innovative multi-omics molecular approaches. To truly advance the field beyond the state of the art, g) a transdiagnostic approach with several patient groups based on h) multivariate analyses of multimodal (imaging) data from these patient groups and i) independent replications will be a necessary next step.The objective of the current proposal is to investigate 300 patients with SZ and SZA at two time points, 2 years apart, applying a deep phenotyping approach with multimodal MRI, GWAS, cytokines, microbiome analyses, environmental and, among others, life time risks, neuropsychology, personality and multiple clinical/sociodemographic variables. The identical protocol of the DFG FOR2107 will be applied, by which a total n=2577 patients (MDD, BD, as well as n=180 patients with SA/SZA, the latter phenotyped at own costs) and healthy control subjects have already been included (as of 5/2019). The present grant would cover the costs for recruitment and analysis of the remaining 120 patients with SZ/SZA at baseline and 144 after 2 years follow up, data analysis, and publications (see preamble). It would significantly augment the existing FOR2107 data set in multiple ways with high cost-effectiveness. The project will provide a large and unique cohort of SZ and SZA patients, with novel opportunities to study GxE interactions on multiple (epi-)genetic and (endo-) phenotypic levels across time. It will delineate new pathophysiological entities with common neurobiological underpinnings and will pave the way for an etiologic understanding of SZ and, in combination with the DFG FOR2107 data, of the major psychoses, potentially leading to their prevention, the prediction of individual disease courses, and novel therapies in the future.