A functional HTR1A polymorphism, rs6295, predicts short-term response to lurasidone: confirmation with meta-analysis of other antipsychotic drugs

Stimulation of the serotonin (5-HT)1A receptor (HTR1A) has been shown to contribute to the mechanism of action of some atypical antipsychotic drugs (APDs), including clozapine and lurasidone. A meta-analysis of rs6295, a functional polymorphism located at the promoter region of HTR1A, showed association with clinical response in schizophrenic patients treated with atypical APD. We have now tested whether other SNPs related to rs6295 predict response to lurasidone. We first evaluated whether rs358532 and rs6449693, tag SNPs for rs6295, predicted response to lurasidone, using data from two clinical trials of acutely psychotic schizophrenia patients with European (EUR, n = 171) or African (AFR, n = 131) ancestry; we then determined if those findings could be replicated in a third trial of lurasidone of similar design. Weekly changes (up to 6 weeks) in the Positive and Negative Syndrome Scale (PANSS) Total score and its five subscales were used to assess response. In EUR, a significant association, or trends for association, were observed for PANSS Total (p = 0.035), positive (p = 0.039), negative (p = 0.004), and disorganization (p = 0.0087) subscales, at week 1–6. There was a trend for replication with PANNS Total (p = 0.036) in the third trial. No significant association was observed in AFR or the placebo group. Meta-analysis of five studies, including the three with lurasidone, showed that rs6295 was associated with improvement in positive (p = 0.023) and negative (p ≤ 0.0001) symptoms in EUR patients with schizophrenia. This is the first study to show a significant association between functional HTR1A polymorphisms and treatment response to lurasidone. The meta-analysis provides additional evidence that rs6295 could be a race-dependent biomarker for predicting treatment response to APDs in schizophrenic patients with European Ancestry.