Objective To overcome the clinical limitations of selective serotonin reuptake inhibitors (SSRIs), address the inadequate understanding of individual differences and pathological mechanisms in the antidepressant combination of Xiaoyao Powders with SSRIs, achieve precise combination medication, and promote the transformation of depression treatment toward a “data intelligence-driven” model. Methods A systematic search was conducted in CNKI, VIP, and Wanfang databases using combined subject terms: “Xiaoyaosan + Paroxetine” “Xiaoyaosan + Escitalopram/Citalopram” “Xiaoyaosan + Fluoxetine” “Xiaoyaosan + Sertraline” and “Xiaoyaosan + Fluvoxamine”. The search period spanned from the establishment of each database to May 10, 2025. Literatures were screened based on inclusion and exclusion criteria, and key data were extracted. A database titled “Xiaoyao Powders combined with SSRIs for treating depression” was constructed after verification and cleaning. The Apriori algorithm was applied to mine the association rules between “administration regimens and adverse reactions”, with lift used to quantify the association strength. A hypernetwork of “administration regimens-depression types” was built on the basis of hypergraphs, and the PageRank algorithm was integrated to calculate node weights. A comprehensive efficacy factor was introduced to optimize hyperedge weights, enabling precise matching between depression types and optimal traditional Chinese medicine combination regimens. Results A total of 78 literature was valid and included, with the most study on Xiaoyao Powders with Fluoxetine (33) whereas the least study on Xiaoyao Powders with Fluvoxamine (1). When depression subtypes are not differentiated, the combination of Xiaoyao Powders with Fluoxetine exhibits the highest utilization frequency. Jiawei Xiaoyao Powders was the most used among the applicaitons of Xiaoyao Powders with SSRIs (21). Apriori algorithm analysis showed that the combination of Xiaoyao Powders with Paroxetine was associated with a wide range of adverse reactions but weak single-type associations. Strong associations were observed between the combination with Escitalopram/Citalopram and dry mouth or gastrointestinal reactions, as well as between the combination with Sertraline and diarrhea or nausea. Hypergraph analysis revealed that the “Xiaoyao Powders with Fluoxetine” node had the highest hyperdegree, treating seven depression subtypes; the “depression” node also had the highest hyperdegree, matching five combination regimens; the ranking of hyperedge weights clarified the optimal regimens for different depression types. For example, the “Xiaoyao Powders with Escitalopram/Citalopram” combination was prioritized for senile depression patients, while the “Xiaoyao Powders with Fluoxetine” regimen was preferred for postpartum depression patients. Conclusion The Apriori algorithm can accurately analyze the association characteristics between “combination regimens and adverse reactions”, while hypergraphs can effectively achieve high-order matching between “administration regimens and depression types”. The combination of the two methodologies provides a quantitative basis for the precision medication strategy of depression integrating “disease-symptom-medicine”, and lays a foundation for establishing a new evidence-based, quantitative, and predictable paradigm for the combinations of traditional Chinese and Western medicines.

depression  /  Xiaoyao Powders analogs  /  selective serotonin reuptake inhibitors  /  integrated traditional Chinese and Western medicine  /  Apriori algorithm  /  hypergraph  /  precision medication