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<p>Liafensine is a triple reuptake inhibitor targeting transporters for serotonin, norepinephrine, and dopamine for treatment-resistant depression (TRD). It did not exhibit efficacy in non-biomarker-selected TRD patients in two Phase 2b studies. We utilized the blood samples from the patients enrolled in these two studies and extracted genomic DNA to conduct a genome‑wide association study aiming to find a biomarker which can predict liafensine response. A single single-nucleotide polymorphism (SNP), rs12217173, at <i>ANK3</i> gene was identified as strongly associated with treatment response to liafensine (p = 6.61 × 10<sup>−8</sup>) in the discovery set (n = 186) and was further confirmed in the replication sample set (n = 47, p = 0.05, combined p = 1.27 × 10<sup>−8</sup>). In addition, this SNP was not associated with the efficacy of the duloxetine or escitalopram, suggesting it is a liafensine-specific biomarker. This finding was subsequently confirmed in a prospective clinical study. Thus, this study represents a novel approach to translating precision medicine into psychiatric diseases.</p>

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Discovery of a potential novel pharmacogenomic biomarker on ANK3 gene for liafensine, a triple reuptake inhibitor for treatment-resistant depression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月19日

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  • Wen Luo,
  • Gang Wang,
  • John W. Whitaker,
  • Zafrin Dhali,
  • Hong Sun,
  • Haiping Lu,
  • Xiaojun Li,
  • Tao Shi,
  • Jinkun Zhang

摘要

Liafensine is a triple reuptake inhibitor targeting transporters for serotonin, norepinephrine, and dopamine for treatment-resistant depression (TRD). It did not exhibit efficacy in non-biomarker-selected TRD patients in two Phase 2b studies. We utilized the blood samples from the patients enrolled in these two studies and extracted genomic DNA to conduct a genome‑wide association study aiming to find a biomarker which can predict liafensine response. A single single-nucleotide polymorphism (SNP), rs12217173, at ANK3 gene was identified as strongly associated with treatment response to liafensine (p = 6.61 × 10−8) in the discovery set (n = 186) and was further confirmed in the replication sample set (n = 47, p = 0.05, combined p = 1.27 × 10−8). In addition, this SNP was not associated with the efficacy of the duloxetine or escitalopram, suggesting it is a liafensine-specific biomarker. This finding was subsequently confirmed in a prospective clinical study. Thus, this study represents a novel approach to translating precision medicine into psychiatric diseases.