Dissecting the molecular bases of treatment resistant schizophrenia

• Applicant: Professor Dr. Michael J. Ziller
• Subject Area: Biological Psychiatry
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 567116946

Treatment of schizophrenia (SCZ) traditionally relies on first- and second-generation antipsychotics that predominantly target the dopaminergic system. This treatment strategy is partially successful in 60-70% of SCZ. However, a large fraction of patients remains affected by residual symptoms, particularly in the cognitive domain. Moreover, 20-30% of patients do not show substantial improvement in any symptom class and are considered treatment resistant (TRS). Together with other lines of evidence from neuroimaging and animal studies, these observations suggest the existence of other pathomechanisms beyond dopamine. These mechanisms likely contribute to SCZ to varying extent across patients, driving clinical heterogeneity and specifically affect TRS patients as one clinical subgroup. Here, we hypothesize that the de-regulation of the glutamate system is a distinct molecular mechanism contributing to SCZ emergence and progression that is exacerbated in the TRS patients and contributes to neurocognitive impairment. However, at present, neither the molecular genetic basis underlying alterations in the glutamate system nor the molecular and neurobiological basis of TRS is known. To address these questions, we (i) will establish a molecular roadmap of differences between TRS and non-TRS patients on the cellular level. To this end, we will utilize a large cohort of induced pluripotent stem cells (iPSCs) from healthy controls, non-TRS and TRS patients (n=60) and perform multi-modal deep molecular and cellular phenotyping on iPSC derived neurons and complex neuronal networks. Association of these results with deep-clinical phenotyping data will then empower the identification of relevant intermediate phenotypes on the patient level that are linked to specific molecular and cellular alterations, connecting phenotypic changes in TRS to neurobiological mechanisms. Subsequently, we will (ii) determine the molecular hallmarks underlying differential response to antipsychotics in TRS, comparing cellular and circuit level changes of iPSC derived neurons from all three study groups to the first line antipsychotic aripriprazole and the second line antipsychotic clozapine. These experiments will reveal genes, pathways and physiological parameters that are differentially modulated by distinct antipsychotics in TRS compared to non-TRS and healthy controls. Lastly, we will functionally validate key genes mediating response to clozapine in TRS patient derived neurons using gain- and loss-of-function experiments. Jointly, this research program will pinpoint the molecular genetic basis contributing to treatment resistance in SCZ, specifically testing the glutamate hypothesis as one independent mechanisms contributing. These results and the generated high dimensional dataset will constitute a valuable resource for the field and identify new pharmacological entry points beyond direct modulation of glutamate receptors.

• DFG Programme: Research Grants