Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 260-270 |
| Number of pages | 11 |
| Journal | Pharmacogenomics Journal |
| Volume | 20 |
| Issue number | 2 |
| DOIs | |
| State | Published - Apr 1 2020 |
Funding
Acknowledgements The authors would like to thank all the patients, healthy volunteers, and psychiatrists who intensively cooperated with us to recruit patients in this study. This work was supported by a grant awarded to HYM by Sunovion. Conflict of interest HYM is a stockholder in ACADIA. HYM receives grant support from ACADIA, Allergan, Aptinyx, Eli Lilly, Janssen, HTR1A auto-receptors in DRN may also cause an enhanced inhibition of dopaminergic neuron in VTA, resulting in better improvement in positive symptoms in SCZ. Ameliorating positive and negative symptoms further supports improvement in disorganization. Transcriptional factor(s) binding is important to regulate the gene expression of HTR1A. Using mfold, we simulated the 2nd structure of transcriptional factors binding site of the palindromic sequence formed by rs6295 G allele but absence in rs6295 C allele. Having C allele in HTR1A promoter region, the transcriptional suppressor has no palindrome structure to bind to, resulting in enhanced inhibition by increased expression of presynaptic HTR1A auto-receptors Lundbeck, Neurocrine, Sumitomo Dainippon, and Sunovion. Other authors declare that they have no conflict of interest.
ASJC Scopus subject areas
- Molecular Medicine
- Genetics
- Pharmacology