Pathways to cardiac dysfunction in psychosis: building a cross-platform understanding (360G-Wellcome-313979_Z_24_Z)

People with psychotic disorders such as schizophrenia die 15-years prematurely, mainly due to cardiac disease. Converging lines of evidence point towards a genetic overlap between psychosis, cardiac inflammation, and heart failure, with immune pathways implicated. However, there is also evidence for cardiac inflammatory effects of antipsychotics, the main treatment for people with psychosis. The relative contributions of these pathways to cardiac dysfunction in psychosis are unknown. Characterising these roles will further our pathophysiological understanding of psychosis and its shortened life expectancy, and identity novel therapeutic targets. To test the relative contributions of psychosis and antipsychotic-treatment, I will conduct a cohort study using cardiac MRI to test if there is myocardial inflammation in antipsychotic-naïve people with first-episode psychosis compared to controls. I will then examine cardiac changes following 1-year of antipsychotic- treatment. To explore the contribution of immune and other biochemical pathways implicated in cardiac dysfunction in psychosis, I will measure circulating cytokines and metabolites and test their relationship with cardiac changes. To further explore antipsychotic cardiotoxic effects, I will analyse cardiac MRI data from the large-scale UK Biobank resource. I will compare myocardial inflammatory measures in antipsychotic-treated versus antipsychotic-naïve participants and examine if variations in antipsychotic pharmacology predict cardiac alterations.