Incremental Predictive Value of Genetic Risk and Functional Brain Connectivity in Determining Antipsychotic Response in Schizophrenia

Abstract

We aimed to assess the incremental value of schizophrenia polygenic risk score (PgRS) and resting-state functional brain connectivity (rsFC) when added to clinical data in predicting the six-week response to oral risperidone in schizophrenia. Fifty-seven, 54, and 43 individuals in a group of never-before-treated first-episode schizophrenia had good quality whole-genome sequencing (10x), rsFC, and both genomic and rsFC data, respectively, at baseline. Symptom severity ratings were obtained at baseline and six-weeks of oral risperidone treatment. The primary outcome was the percentage change in the Positive and Negative Syndrome Scale Total scores after risperidone treatment. Clinical, PgRS, and rsFC determinants of treatment response were first evaluated independently. Subsequently, three blocks of hierarchical multiple regression analyses with leave-one-out cross-validation (n=43), were implemented to study clinical, clinical + PgRS and clinical + PgRS + rsFC determinants of treatment response. While the combined clinical variables did not show a statistically significant prediction of treatment response, adding PgRS (9% R2 change) and rsFC (26% R2 change) in hierarchical steps, significantly improved the overall proportion of variance explained in treatment response. This proof-of-concept investigation underscores the incremental benefits offered by genetic and neuroimaging metrics over clinical measures in determining prospectively-ascertained short-term treatment response in first-episode schizophrenia.