Genetic Markers of Early Response to Lurasidone in Acute Schizophrenia

Abstract

Abstract Prediction of treatment response by genetic biomarkers has potential for clinical use and contributes to the understanding of pathophysiology and drug mechanism of action. The purpose of this study is to identify genetic biomarkers associated with response to lurasidone, an atypical antipsychotic drug, during the first four weeks of treatment. One-hundred and seventy-one acutely psychotic patients from two placebo-controlled clinical trials of lurasidone were included. Genetic associations with changes in Positive and Negative Syndrome Scale total score at weeks one, two, and four were examined. Genotyping was done with the Affymetrix 6.0 microarray and associations were computed using PLINK regression model. Although genome-wide significance was not reached because of the small sample size, the top associations were with genes important for brain function. The top week one marker, rs6459950 (p = 7.05 × 10-7), was close to the sonic hedgehog gene (SHH), involved in neuronal differentiation and neurogenesis. The top week two marker, rs7435958, was a SNP of GABRB1, encoding the GABA A Receptor β1. Notably, week four markers included a SNP within PTCH1, a specific receptor for SHH, possibly involved in the week one response. Pathway enrichment analysis further supported the involvement of neuron differentiation and neurogenesis. Tissue enrichment analysis suggested enrichment of these genes in anterior cingulate cortex relevant to GABAergic modulation of neuronal connectivity. This is the first study to identify genes possibly associated with very early response to lurasidone. Further replication study is warranted and needed to determine the functional effects of the genetic markers.