Personalised medicine in psychosis treatment

​Currently, the clinical diagnosis of schizophrenia (SCZ) relies heavily on psychosis symptoms. Antipsychotic (AP) drugs remain the only effective pharmacological intervention and benefit a majority of people with SCZ (i.e., first-line AP responsive SCZ, FRS). However, around one-third of SCZ cases, known as treatment-resistant SCZ (TRS), are resistant to common first-line AP treatments. People with TRS often benefit from clozapine, a third-line AP with  special properties, however, the administration of clozapine is often delayed for several years due to the lack of clinical tools or biomarkers to predict TRS, resulting in a strong negative impact on overall clinical outcomes. Preliminary clinical evidence suggests that TRS may be heritable and a categorically distinct disorder from FRS, with different underlying biology; however, the differences between and within these clinical populations are not understood in molecular terms. In particular, although individual response to medication has a clear genetic basis, it is unknown which genetic networks underlie the phenotypic signatures of each SCZ subset. As TRS remains an area of significant unmet medical need, identifying biological differences between the two forms of SCZ will accelerate efforts to develop clinical tools for the stratification of SCZ cases at an early stage of the disease, based on initial response to APs. 

 

Therefore, the overall aim of the project is to uncover functionally important genetic and cellular pathways underlying TRS and FRS that contribute to inter-individual differences in treatment response. Here, we propose an interdisciplinary approach drawing from diverse fields, from clinical psychiatry to molecular biology. We will employ a combination of several state-of-the-art methods, including access to large and well-characterised patient cohorts from longitudinal clinical trials, patient-derived human induced pluripotent stem cells (hiPSCs), single-cell transcriptomics, and high-throughput screening. 

 

Our short-term goal is to determine the cell-type-specific cellular and genetic signatures that underlie abnormalities in neurotransmitter pathways that contribute to the distinct neurobiology of TRS. Our long-term goal is to improve diagnostics, predict clinical trajectories and develop novel therapeutic interventions.