# Inflammation–neurotrophin synergy of Xiao-yao-san-type botanical drug formulations in depressive disorders: a qualitative synthesis of recent human studies with taxonomic and compositional characterisation

## TL;DR

Xiaoyao Formula, a traditional herbal treatment, may offer faster relief and fewer side effects for depression compared to SSRIs, based on recent human studies and mechanistic insights.

## Contribution

This study provides a qualitative synthesis of Xiaoyao Formula's efficacy and mechanisms in depression, supported by taxonomic and compositional analysis.

## Key findings

- Xiaoyao Formula may act faster than SSRIs with comparable or better remission rates and fewer side effects.
- Mechanistic studies suggest anti-inflammatory and neuroplasticity pathways involving IL-6, BDNF methylation, and PI3K-Akt activation.
- A three-dimensional Q-marker system identifies key metabolites like baicalin and ferulic acid linked to efficacy.

## Abstract

Depressive disorders represent a major contributor to the global burden of disease, with persistently rising prevalence rates posing significant challenges to individual quality of life and public health systems. Existing first-line medications such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) typically require 2–4 weeks to take effect, with complete remission rates below 60%. Approximately one-third of patients discontinue treatment within 90 days due to adverse reactions including gastrointestinal discomfort, weight changes, or sexual dysfunction. Consequently, exploring interventions with faster onset and improved tolerability holds significant clinical importance.

A systematic search of seven databases—PubMed, Embase, Web of Science, Cochrane CENTRAL, CNKI, AMED, and Scopus—identified randomised controlled trials (RCTs) and mechanism studies published between 2010 and 2025. A qualitative synthesis method analysed clinical efficacy and adverse reactions, integrating evidence from metabolomics, epigenetics, and network pharmacology. Botanical drug identification was performed in accordance with ConPhYMP guidelines, with all species names validated taxonomically against the Medicinal Plant Names Services (MPNS) and Plants of the World Online (POWO) databases.

Twenty-one RCTs (n = 2,766) and three mechanistic studies were included. Findings indicated that Xiaoyao Formula may exert earlier effects than SSRIs (descriptive trend: 1–2 weeks vs. 2–4 weeks), with comparable or preliminary evidence of superior remission rates and lower residual symptom incidence. Adverse reactions, particularly gastrointestinal discomfort and sleep disturbances, were significantly reduced. No serious adverse events, hepatotoxicity, or clinically significant drug interactions were reported across the evidence base, although systematic adverse event reporting was incomplete in earlier trials. Mechanistic studies suggest a hypothetical sequential pathway—‘inflammation precedes neuroplasticity recovery’—involving downregulation of IL-6 and NLRP3 inflammasome, reduced methylation of the BDNF promoter, and activation of the PI3K-Akt pathway. A three-dimensional Q-marker system (based on UPLC-HRMS) comprising baicalin, ferulic acid, and glycyrrhizic acid provides a preliminary framework for quantifying the metabolite-mechanism-efficacy relationship and may serve as a candidate criterion for cross-centre consistency testing.

Existing evidence preliminarily supports potential advantages of Xiaoyao Formula in treating depressive disorders, including possibly earlier onset of action, good tolerability, and potential additional benefits in female subgroups. However, given limitations such as small sample sizes, short intervention durations (6–12 weeks), and predominantly combination therapy rather than monotherapy comparisons, these conclusions should be regarded as suggestive or indicative findings rather than definitive efficacy. Long-term efficacy and generalisability across populations require further validation. Future studies should conduct multicentre, large-sample clinical trials with ≥24-week follow-up, incorporating wearable digital phenotyping technologies to confirm its application value in precision psychiatry.