Baichuan Baile Formula, a Promising Herbal Dietary Supplement, Exerts Antidepressant‐Like Effects by Modulating the Serotoninergic System in Mouse Models

ABSTRACT Baichuan Baile (BCBL) is a novel formula that incorporates three herbs and a single food additive, all of which are widely used in ordinary or functional foods. It is a promising dietary supplement for the treatment of depression based on TCM principles and nutritional assessments. Our study was designed to explore BCBL's antidepressant‐like effects and elucidate its underlying mechanisms. First, the antidepressant‐like effects of BCBL were predicted through network pharmacology and validated using systematic depression models. Next, the 5‐HTP‐induced head‐twitch test, yohimbine‐induced death test, and reserpine‐induced ptosis, hypothermia, and akinesia test were conducted to assess BCBL's impact on monoaminergic function. Additionally, the effects of BCBL on monoamine neurotransmitters were measured using HPLC‐ECD and ELISA. As a result, an integrated analysis using the TCMSP and Genecards databases identified 37 active components sharing 192 targets associated with depression. Further construction of the PPI network, along with GO and KEGG enrichment analyses, revealed a comprehensive and synergistic interaction between BCBL and depression, also predicting that the serotoninergic system might partially mediate the antidepressant‐like effects of BCBL. Subsequent pharmacological tests indicated that BCBL demonstrated significant antidepressant‐like effects on behavioral despair mice, CRS and CNE‐induced depression‐like mice, and chronic reserpine‐induced depression‐like mice. The DDI tests, HPLC‐ECD, and ELISA analyses validated that BCBL's antidepressant‐like effects were mediated through upregulation of the serotoninergic system. Our findings provided a safe and effective candidate for the amelioration of depression that deserves further investigations and explorations.