Integrated methods for drug discovery and repurposing in psychiatry: genomics, iPSC modelling, and pharmacogenetics (360G-Wellcome-337247_Z_25_Z)

A major challenge in current psychiatric practice is that standard therapies fail for a subset of patients, with approximately 30% in both depression and schizophrenia. One symptom that stands out in these treatment-resistant cases is Anhedonia. Anhedonia (the reduced capacity to experience pleasure or pursue meaningful rewards) is a core, transdiagnostic symptom that appears across multiple psychiatric disorders including major depression, schizophrenia, and bipolar disorder. Its mechanisms remain unclear, and current medications only partly relieve anhedonic symptoms. Drug repurposing, guided by genetic evidence, enables identification of existing medications already approved for other conditions that may target relevant biological pathways in psychiatric disorders. However, no drug has been specifically developed for anhedonia. To address this unmet clinical need, our project will leverage GWAS and molecular QTL data to identify and prioritise druggable targets for anhedonia using cis- Mendelian randomisation and pharmacological annotation. Promising candidates will then be tested in human striatal-midbrain assembloids derived from induced pluripotent stem cells carrying schizophrenia-associated structural genetic variants, enabling mechanistic validation. Finally, our findings will be extended into patient populations using Triangulation WIthin a STudy framework that leverages multiple complementary causal inference methods to UK Biobank, assessing how genetic variation moderates patient response to antidepressants and antipsychotics.