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

• Applicant: Professor Dr. Carsten Korth
• Subject Area: Biological Psychiatry
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 457534312

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.

• DFG Programme: Research Grants