Decoding Mechanisms of Early Antipsychotic Response in First-Episode Psychosis: A Multimodal Approach

Psychotic disorders affect more than 3% of the global population and rank among the most disabling health conditions worldwide. Over 40% of individuals with first-episode psychosis (FEP) do not respond to first-line antipsychotic therapy; however, the neurobiological basis for early-treatment non-response remains poorly understood. Converging evidence points to differences between responders and non-responders across multiple brain systems—including dopaminergic, glutamatergic, and large-scale neural networks—however, integrative studies at illness onset are lacking. This project will use a multimodal approach to understand the disease mechanisms underlying early-treatment non-response in FEP. Participants will undergo neuromelanin-sensitive MRI (to probe dopamine system integrity), magnetic resonance spectroscopy (to quantify glutamate levels in the anterior cingulate cortex), resting-state fMRI (to examine large-scale network dynamics), alongside neurocognitive assessment. Structured clinical assessments will determine treatment response at six weeks, with plasma antipsychotic levels to confirm adherence. Healthy controls will provide normative reference data. The study will generate preliminary effect sizes, evaluate feasibility, and identify candidate markers for future mechanistic models. An international placement at a centre of excellence will support training in multimodal data integration and explainable machine learning. This work will lay the foundation for a more personalised and mechanistically informed approach to psychiatric care.