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

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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.