Predictive Biomarkers for Antipsychotic Treatment Response in Early Phase of Schizophrenia: Multi-Omic Measures Linking Subcortical Covariant Network, Transcriptomic Signatures, and Peripheral Epigenetics.

Background: Volumetric alterations of subcortical structures as predictors of antipsychotic treatment response have been previously corroborated, but less is known about whether their morphological covariance relates to treatment outcome and is driven by gene expression and epigenetic modifications. Methods: Subcortical volumetric covariance was analyzed by using baseline T1-weighted magnetic resonance imaging (MRI) in 38 healthy controls and 38 drug-naïve first-episode schizophrenia patients. Patients were treated with 8-week risperidone monotherapy and divided into responder and non-responder groups according to the Remission in Schizophrenia Working Group (RSWG). We utilized partial least squares (PLS) regression to examine the spatial associations between gene expression of subcortical structures from a publicly available transcriptomic dataset and between-group variances of structural covariance. The peripheral DNA methylation (DNAm) status of a gene of interest (GOI), overlapping between genes detected in the PLS and 108 schizophrenia candidate gene loci previously reported, was examined in parallel with MRI scanning. Results: In the psychotic symptom dimension, non-responders had a higher baseline structural covariance in the putamen-hippocampus-pallidum-accumbens pathway compared with responders. For disorganized symptoms, significant differences in baseline structural covariant connections were found in the putamen-hippocampus-pallidum-thalamus circuit between the two subgroups. The imaging variances related to psychotic symptom response were spatially related to the expression of genes enriched in neurobiological processes and dopaminergic pathways. The DNAm of GOI demonstrated significant associations with patients' improvement of psychotic symptoms. Conclusion: Baseline subcortical structural covariance and peripheral DNAm may relate to antipsychotic treatment response. Phenotypic variations in subcortical connectome related to psychotic symptom response may be transcriptomically and epigenetically underlaid. This study defines a roadmap for future studies investigating multimodal imaging epigenetic biomarkers for treatment response in schizophrenia.