Neurodevelopmental Impact of Copy Number Variants in Patients With Treatment-Resistant Schizophrenia.

Abstract

Copy number variations (CNVs) are a major contributor to the etiology and phenotypic variability in schizophrenia. CNVs are also independently associated with certain neurological, cognitive, and behavioral conditions, yet their role in early neurodevelopment in the context of treatment-resistant schizophrenia remain largely unexplored. This study aimed to investigate the contribution of neurodevelopmental CNVs to early development among individuals with treatment-resistant schizophrenia (TRS). We conducted a structured, systematic, retrospective record review within a case-control analytic framework. Our cases were the group of neurodevelopmental disorder (NDD) CNV carriers (N = 25) identified in the Pennsylvania State Hospital (PASH) cohort of individuals with treatment resistant psychotic symptoms; non-CNV controls were demographically matched individuals with treatment resistant psychotic symptoms (N = 24) from the PASH cohort. We examined the differences in early NDD phenotypes between cases and controls. CNV carriers had a higher total NDD burden score compared to non-CNV controls (z = 2.20, unadjusted p = 0.03, adjusted p = 0.08). Learning disabilities were significantly more prevalent among CNV carriers compared to non-CNV controls (χ² = 13.437, df = 1, unadjusted p = 0.0002, adjusted p = 0.0015), with 88% of CNV carriers having a history of learning disabilities relative to 38% of non-CNV controls. CNVs carriers with TRS had a higher prevalence of early NDDs compared to non-CNV controls, particularly in learning disabilities. Prospective studies are needed to elucidate the mechanisms linking CNVs, neurodevelopmental phenotypes, and disease progression in treatment resistant schizophrenia.