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Peer-reviewedCC BY 4.0Frontiers in Pharmacology

Effects and potential mechanisms of si-ni-san on animal models of depression: a preclinical systematic review and meta-analysis

  • Yuzhi Wang1
  • Qun Wang2,3
  • Hui Xie1
  • Xiaozhu Liu1
  • Yuhuan Ju1
  • Xifeng Liu1
  • Shiguang Sun1,4
4 affiliations
  1. 1College of Pharmacy, Shandong University of Traditional Chinese Medicine
  2. 2College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine
  3. 3Department of Vertigo, Jinan Shizhong People’s Hospital
  4. 4Department of Pharmacy, Second Affiliated Hospital, Shandong Provincial Hospital of Integrative Medicine, Shandong University of Traditional Chinese Medicine
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Abstract

Context: In Traditional Chinese Medicine depressive disorders are commonly associated with liver qi stagnation syndrome. Si-ni-san (SNS), a classic formula for soothing the liver and relieving qi stagnation, is widely used for its potential antidepressant-like effects.

Objective: This preclinical systematic review and meta-analysis aimed to evaluate the pharmacological effects of SNS on depression-related behavioral outcomes in animal models and to summarize its mechanisms of action.

Methods: We conducted a systematic search of seven databases (including PubMed) for records published up to December 2025. Risk of bias was assessed using SYRCLE’s tool. Meta-analyses were performed using STATA 15.0 and RevMan 5.4. Subgroup and leave-one-out sensitivity analyses were conducted to test the robustness of the findings. Publication bias was assessed using funnel plots and Egger’s test. Trim-and-fill analysis was performed to adjust for potential publication bias. The certainty of evidence was evaluated using a modified GRADE approach for preclinical studies.

Results: A total of 28 studies were included, involving 384 animals and three behavioral tests: sucrose preference test (SPT), forced swim test (FST), and tail suspension test (TST). SNS treatment was associated with increased sucrose preference in the SPT (SMD = 3.18, 95% CI = [2.44, 3.93]), and reduced immobility time in both the FST (SMD = −2.17, 95% CI = [-2.86, −1.49]) and TST (SMD = −2.55, 95% CI = [-3.31, −1.78]). Mechanistically, SNS treatment was associated with increased monoamine neurotransmitters (MNTs), reduced hypothalamic-pituitary-adrenal (HPA) axis hormones, and decreased pro-inflammatory cytokines.

Conclusion: These findings suggest that SNS is associated with antidepressant-like pharmacological effects in rodent models, with changes in MNTs, HPA axis hormones, and inflammatory markers. However, due to substantial heterogeneity, risk of bias, and inadequate phytochemical characterization, these results should be considered hypothesis-generating and interpreted with caution.

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Cite

BibTeXRIS
BibTeX
@article{wang2026effects,
  title = {{Effects and potential mechanisms of si-ni-san on animal models of depression: a preclinical systematic review and meta-analysis}},
  author = {Yuzhi Wang and Qun Wang and Hui Xie and Xiaozhu Liu and Yuhuan Ju and Xifeng Liu and Shiguang Sun},
  journal = {Frontiers in Pharmacology},
  year = {2026},
  month = oct,
  doi = {10.3389/fphar.2026.1818197},
  url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1818197/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Effects and potential mechanisms of si-ni-san on animal models of depression: a preclinical systematic review and meta-analysis
AU  - Yuzhi Wang
AU  - Qun Wang
AU  - Hui Xie
AU  - Xiaozhu Liu
AU  - Yuhuan Ju
AU  - Xifeng Liu
AU  - Shiguang Sun
PY  - 2026
DA  - 2026/10/08
JO  - Frontiers in Pharmacology
DO  - 10.3389/fphar.2026.1818197
UR  - https://www.frontiersin.org/articles/10.3389/fphar.2026.1818197/full
AB  - Context: In Traditional Chinese Medicine depressive disorders are commonly associated with liver qi stagnation syndrome. Si-ni-san (SNS), a classic formula for soothing the liver and relieving qi stagnation, is widely used for its potential antidepressant-like effects.  Objective: This preclinical systematic review and meta-analysis aimed to evaluate the pharmacological effects of SNS on depression-related behavioral outcomes in animal models and to summarize its mechanisms of action.  Methods: We conducted a systematic search of seven databases (including PubMed) for records published up to December 2025. Risk of bias was assessed using SYRCLE’s tool. Meta-analyses were performed using STATA 15.0 and RevMan 5.4. Subgroup and leave-one-out sensitivity analyses were conducted to test the robustness of the findings. Publication bias was assessed using funnel plots and Egger’s test. Trim-and-fill analysis was performed to adjust for potential publication bias. The certainty of evidence was evaluated using a modified GRADE approach for preclinical studies.  Results: A total of 28 studies were included, involving 384 animals and three behavioral tests: sucrose preference test (SPT), forced swim test (FST), and tail suspension test (TST). SNS treatment was associated with increased sucrose preference in the SPT (SMD = 3.18, 95% CI = [2.44, 3.93]), and reduced immobility time in both the FST (SMD = −2.17, 95% CI = [-2.86, −1.49]) and TST (SMD = −2.55, 95% CI = [-3.31, −1.78]). Mechanistically, SNS treatment was associated with increased monoamine neurotransmitters (MNTs), reduced hypothalamic-pituitary-adrenal (HPA) axis hormones, and decreased pro-inflammatory cytokines.  Conclusion: These findings suggest that SNS is associated with antidepressant-like pharmacological effects in rodent models, with changes in MNTs, HPA axis hormones, and inflammatory markers. However, due to substantial heterogeneity, risk of bias, and inadequate phytochemical characterization, these results should be considered hypothesis-generating and interpreted with caution.
SN  - 1663-9812
ER  -