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Background <p>Breast cancer is a leading malignancy and a significant cause of mortality in women. The coexistence of depression has been associated with a more aggressive breast cancer progression. Si–Ni–San (SNS), a Traditional Chinese medicine (TCM) formula, has been traditionally used for the treatment of depression. This clinical trial aimed to evaluate the effectiveness and safety of SNS in relieving depression in breast cancer patients, and explore its molecular mechanism.</p> Methods <p>A randomized, double-blind, placebo-controlled crossover trial was conducted in breast cancer patients with mild to moderate depression (MMD). Patients were asked to participate over a four-week SNS treatment and a four-week placebo intervention in randomized order, with a two-week washout period. The primary endpoint was the change of Hamilton Depression Scale-24 (HAMD-24) score. Secondary endpoints were the changes of Functional Assessment of Cancer Therapy—Breast (FACT-B) and syndrome score of Traditional Chinese medicine (TCMSS). Liver function test (LFT) and mental status examination (MSE) were conducted to ensure the safety. Gut microbiota, serum metabolomics, cytokine profiling and T lymphocyte subsets were tested to explore the molecular mechanisms.</p> Results <p>A total of 53 patients completed the trial. Compared to placebo intervention, SNS treatment significantly reduced HAMD-24 score (4.46 ± 4.403 (95% CI −&#xa0;5.69, −&#xa0;3.24) <i>vs.</i> 0.66 ± 4.463 (95% CI −&#xa0;1.89, 0.57), <i>P</i> &lt; 0.001), accompanied by the improved FACT-B scores (7.22 ± 13.77 (95% CI 3.66, 10.77) <i>vs.</i> − 0.78 ± 15.32 (95% CI −&#xa0;4.74, 3.17), <i>P</i> = 0.09) and TCMSS scores (−&#xa0;12.71 ± 12.88 (95% CI −&#xa0;16.30, −&#xa0;9.13) <i>vs.</i> −&#xa0;5.60 ± 4.69 (95% CI −&#xa0;9.42, −&#xa0;1.79), <i>P</i> = 0.01). No obvious risk in LFT, MSE and fewer adverse events were observed. Exploratory multi-omics analyses revealed three key phenomenon including specific reduction in <i>Lactobacillus</i> abundance, decreased serum indole levels, and increased CD8<sup>+</sup> T cell proportions, suggesting their potential involvement in breast cancer-related depression.</p> Conclusions <p>SNS is efficacious for relieving depression in breast cancer patients with high safety, and <i>Lactobacillus</i>-Indole-CD8<sup>+</sup> T signaling may be involved in its pharmacological mechanisms. Further research is required to refine study designs and substantiate the speculated mechanism.</p> <p><i>Trial registration</i>: ChiCTR, ChiCTR2200065009. Registered 25 October 2022.</p> Graphical Abstract <p></p>

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Clinical efficacy and multi-omics analysis of Si–Ni–San for depression treatment in breast cancer patients: a randomized, double-blind, placebo-controlled, crossover trial

  • 期刊论文

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  • 发表日期：

    2026年1月6日

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  • Shicui Hong,
  • Miao Yu,
  • Yifeng Zheng,
  • Shengqi Wang,
  • Juping Zhang,
  • Bo Pan,
  • Honglin Situ,
  • Li Guo,
  • Shaowen Zhong,
  • Ying Chen,
  • Yunxi Li,
  • Lingling Yang,
  • Yan Li,
  • Zhiyu Wang

摘要

Background

Breast cancer is a leading malignancy and a significant cause of mortality in women. The coexistence of depression has been associated with a more aggressive breast cancer progression. Si–Ni–San (SNS), a Traditional Chinese medicine (TCM) formula, has been traditionally used for the treatment of depression. This clinical trial aimed to evaluate the effectiveness and safety of SNS in relieving depression in breast cancer patients, and explore its molecular mechanism.

Methods

A randomized, double-blind, placebo-controlled crossover trial was conducted in breast cancer patients with mild to moderate depression (MMD). Patients were asked to participate over a four-week SNS treatment and a four-week placebo intervention in randomized order, with a two-week washout period. The primary endpoint was the change of Hamilton Depression Scale-24 (HAMD-24) score. Secondary endpoints were the changes of Functional Assessment of Cancer Therapy—Breast (FACT-B) and syndrome score of Traditional Chinese medicine (TCMSS). Liver function test (LFT) and mental status examination (MSE) were conducted to ensure the safety. Gut microbiota, serum metabolomics, cytokine profiling and T lymphocyte subsets were tested to explore the molecular mechanisms.

Results

A total of 53 patients completed the trial. Compared to placebo intervention, SNS treatment significantly reduced HAMD-24 score (4.46 ± 4.403 (95% CI − 5.69, − 3.24) vs. 0.66 ± 4.463 (95% CI − 1.89, 0.57), P < 0.001), accompanied by the improved FACT-B scores (7.22 ± 13.77 (95% CI 3.66, 10.77) vs. − 0.78 ± 15.32 (95% CI − 4.74, 3.17), P = 0.09) and TCMSS scores (− 12.71 ± 12.88 (95% CI − 16.30, − 9.13) vs. − 5.60 ± 4.69 (95% CI − 9.42, − 1.79), P = 0.01). No obvious risk in LFT, MSE and fewer adverse events were observed. Exploratory multi-omics analyses revealed three key phenomenon including specific reduction in Lactobacillus abundance, decreased serum indole levels, and increased CD8+ T cell proportions, suggesting their potential involvement in breast cancer-related depression.

Conclusions

SNS is efficacious for relieving depression in breast cancer patients with high safety, and Lactobacillus-Indole-CD8+ T signaling may be involved in its pharmacological mechanisms. Further research is required to refine study designs and substantiate the speculated mechanism.

Trial registration: ChiCTR, ChiCTR2200065009. Registered 25 October 2022.

Graphical Abstract