Genetic markers of early response to lurasidone in acute schizophrenia

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 detect genetic biomarkers possibly associated with response to lurasidone, 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 with a limited sample size, signals of potential interest for further studies were with genes important for neurogenesis. Possible week one marker, rs6459950 (p = 7.05 × 10^-7), was close to the sonic hedgehog gene (SHH), involved in neuronal differentiation and neurogenesis. Possible week two marker, rs7435958, was a SNP of GABRB1, encoding the GABA_A Receptor β1. Notably, possible week four signals included a SNP within PTCH1, a specific receptor for the SHH, the possible week one marker. Pathway analysis supported the possibility that neurogenesis might be involved in early antipsychotic response. Tissue enrichment analysis suggested that potential signals were enriched in anterior cingulate cortex, reported to be relevant in antipsychotic action. This is the first study to examine genes possibly associated with very early response to lurasidone. Further replication studies in larger sample size should be required.