Immune mechanisms of antipsychotic treatment response (360G-Wellcome-226779_Z_22_Z)

The first-line treatment for early psychosis is antipsychotic drugs. Antipsychotic drugs efficaciously reduce psychotic symptoms but have severe side effects. To advance interventions for early psychosis, it is crucial to understand the specific mechanisms mediating the therapeutic effects of antipsychotics so that they may be segregated from the mechanisms mediating adverse effects. Emerging evidence suggests that psychosis can be caused by immune responses targeting the brain, and that antipsychotic drugs favourably modulate this immune dysregulation. Here, we aim to elucidate whether and how immune processes contribute to antipsychotic treatment response. Drawing on our combined expertise in neuroscience, immunology, and psychiatry, we shall integrate investigations of blood and cerebrospinal fluid from individuals affected by psychosis with mechanistic investigations in mouse models. We shall use unbiased, high-throughput, high-resolution immunophenotyping alongside targeted immunological assays to delineate the immune processes most affected by antipsychotic treatment. Exploiting our mouse model for psychosis- like behaviour, we shall use causal interventions to validate these immune mechanisms underlying observed antipsychotic effects. Appropriate data-sharing pipelines will ensure that our findings provide a resource for future research. By systematically interrogating the immune system during antipsychotic treatment, we expect to gain mechanistic insights to guide future targeted immune-based interventions for early psychosis.