Predicting antipsychotics response in an animal model investigating neuroimmune-dopamine interactions and its translation into a schizophrenia patient cohort

迄今为止，从精神分裂症动物模型中的分子发现到精神分裂症患者的转化的成功是有限的，这就提出了关于转化研究在精神病学中的价值的问题。治疗抵抗是精神分裂症的一个严重问题，许多患者对一线抗精神病药物没有反应。该项目显示了一种摆脱转化精神病学困难的方法，以加深对神经免疫-多巴胺相互作用的了解，确定精神分裂症子集的特定免疫生物型，以及能够预测精神分裂症患者对抗精神病药物治疗反应的血液测试。我们以前开发了一种散发性精神分裂症的转基因大鼠模型，其错误组装的DISC 1蛋白的信号传导受损，具有精神分裂症相关的神经解剖学特征，与异常多巴胺稳态相关的神经化学和行为表型。我们在这种动物模型中鉴定了能够以高特异性预测精神分裂症患者子集的血液生物标志物。这两个，过度的氯氮平使用在这个子集中，以及减少NudE样1酶活性在这个动物模型中，类似于难治性精神分裂症，支持的假设，动物模型可能是第一个模型难治性精神分裂症，以及相关的，可翻译的免疫生物型可能表明抗精神病药物的治疗反应。氨磺必利或氯氮平的药物治疗是否不同地挽救动物模型的关键行为表型，是否可以使用行为、神经解剖学和神经炎症读数来定义该动物模型中的治疗抗性表型，以及是否可以通过血液生物标志物来预测治疗反应。2.将修改现有的动物模型，以建立行为障碍的两次打击模型，其中将母体免疫激活添加到已经受损的信号传导通路中。来自实验1和2的外周血的RNAseq生成的免疫特征将被翻译到可用的COMBINE群组的精神分裂症患者中，在对照抗精神病药物治疗之前，血液可从所述COMBINE群组获得。联合收割机队列研究是一个独立的、已完成的BMBF项目，旨在前瞻性地检测氨磺必利/奥氮平联合治疗与单药治疗的临床疗效，在该项目结束时，将获得对DISC 1蛋白介导的与多巴胺稳态、行为、免疫生物型和抗精神病药物治疗反应相关的信号转导网络的基本见解。此外，还将鉴定出外周血中明显的免疫生物型，其与预测抗精神病药物治疗的临床应答可能高度相关。

The success of translation from molecular discoveries in animal models of schizophrenia to schizophrenia patients has so far been modest and this has raised questions on the value of translational research in psychiatry in general. Treatment resistance is a serious problem in schizophrenia where many patients do not respond to first line antipsychotics. This project shows a way out of the difficulties of translational psychiatry towards deepening insight into neuroimmune-dopamine interactions, identifying a specific immune biotype for a schizophrenia subset, and a blood test able to predict treatment response to antipsychotics in schizophrenia patients.We previously developed a transgenic rat model for sporadic schizophrenia with impaired signaling of the misassembled DISC1 protein featuring schizophrenia-relevant neuroanatomica, neurochemical and behavioral phenotypes related to aberrant dopamine homeostasis. We identified blood biomarkers in this animal model that were able to predict a subset of schizophrenia patients with high specificity. Both, overrepresentation of clozapine use in this subset, as well as decreased NudE-like 1 anzyme activity in this animal model, similar to treatment-resistant schizophrenia, support the hypothesis that animal model may be the first to model treatment-resistant schizophrenia, and that the associated, translatable immune biotype may indicate treatment response to antipsychotics.In this proposal, it will be tested 1. whether pharmacotherapy with amisulpride or clozapine differentially rescues key behavioral phenotypes of the animal model, whether a phenotype of treatment resistance in this animal model can be defined using behavioral, neuroanatomical and neuroinflammatory readouts, and whether the therapy response can be predicted by blood biomarkers. 2. The existing animal model will be modified to establish a two-hit model of a behavioral disorder where maternal immune activation is added to the already impaired signaling pathways. RNAseq-generated immune signatures from peripheral blood of experiments 1 and 2 will be translated into schizophrenia patients of the available COMBINE cohort from which blood prior to controled antipsychotics therapy is available. The COMBINE cohort is an existing independent and completed BMBF project aiming to prospectively test the clinical therapy response a amisulpride / olanzapine combination therapy over monotherapy of each antipsychotic.At the end of this project, fundamental insights into the interaction network of DISC1 protein-mediated signaling relevant for dopamine homeostasis, behavior, immune biotypes and response to antipsychotic treatment will be been gained. In addition, an immune biotype apparent in peripheral blood will have been identified that is potentially highly relevant for predicting clinical response for antipsychotic treatment.