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A functional HTR1A polymorphism, rs6295, predicts short-term response to lurasidone: confirmation with meta-analysis of other antipsychotic drugs.
The Pharmacogenomics Journal ( IF 2.8 ) Pub Date : 2019-10-21 , DOI: 10.1038/s41397-019-0101-5
Akane Yoshikawa 1, 2 , Jiang Li 1 , Herbert Y Meltzer 1
Affiliation  

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.



中文翻译:

功能性HTR1A多态性rs6295预测对卢拉西酮的短期反应:通过对其他抗精神病药物的荟萃分析确认。

血清素(5-HT)1A受体(HTR1A)的刺激已被证明有助于某些非典型抗精神病药物(APD)的作用机理,包括氯氮平和卢拉西酮。对rs6295(位于HTR1A启动子区域的功能性多态性)进行的荟萃分析显示,在接受非典型APD治疗的精神分裂症患者中,其与临床反应相关。现在,我们已经测试了与rs6295相关的其他SNP是否可以预测对卢拉西酮的反应。我们首先使用来自欧洲(EUR,n  = 171)或非洲(AFR,n = 131)血统;然后,我们确定这些发现是否可以在类似设计的卢拉西酮的第三次试验中重复使用。阳性和阴性综合征量表(PANSS)的总评分及其五个子量表的每周变化(最多6周)用于评估反应。在欧元中,在 1周,观察到PANSS Total(p = 0.035),正(p  = 0.039),负(p  = 0.004)和混乱(p  = 0.0087)子量表的显着关联或关联趋势。6,PANNS Total(p = 0.036)。在AFR或安慰剂组中未观察到明显的关联。五项研究,包括三带鲁拉西,表明rs6295在正(与改善相关的Meta分析p  = 0.023)和阴性(p  ≤0.0001)症状EUR精神分裂症患者。这是第一项显示功能性HTR1A多态性与对卢拉西酮的治疗反应之间显着相关性的研究。荟萃分析提供了其他证据,表明rs6295可能是种族依赖性生物标志物,可用于预测欧洲祖先精神分裂症患者对APD的治疗反应。

更新日期:2020-01-16
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