A multi-omics comparison unveils convergent and divergent antidepressant mechanisms of fluoxetine and St. John's wort extract.

Fluoxetine (Flx), a selective serotonin reuptake inhibitor, and St. John's Wort extract (SJW), a herbal remedy, are common treatments for depression. However, a comprehensive comparison of their molecular mechanisms remains elusive. This study aimed to systematically elucidate and compare their therapeutic actions using an integrated proteomics and metabolomics approach. Behavioral and pharmacological effects of both treatments were assessed through behavioral tests. Proteomics and metabolomics analyses were performed on cortical tissue to identify differentially expressed proteins and metabolites. Furthermore, Mass Spectrometry Imaging (MSI) was employed to visualize the spatial distribution of key metabolites within the cortex. Bioinformatic analysis and integrated multi-omics analysis were used to map the signaling pathways and key molecular targets. Both Flx and SJW induced behavioral changes in locomotor activity as observed through behavioral tests. Multi-omics analysis revealed that both treatments share common regulatory patterns involving neuroplasticity-related pathways and Nicotinate and nicotinamide metabolism. Flx showed a more focused effect on synaptic plasticity. In contrast, SJW exhibited a broader modulation involving inflammatory pathways and amino acid metabolism. MSI analysis confirmed the localized accumulation of key differential metabolites, such as N-Acetyl-l-aspartate, ADP and l-Glutamine. Integrated analysis identified Rhoa, Scn1a, and Camk2a as key shared hub proteins. SIGNIFICANCE: Flx and SJW are widely used antidepressants in clinical practice. This multi-omics study deciphers the convergent and divergent molecular modulations of Flx and SJW, providing insight into their potential mechanisms relevant to depression treatment. While both promote neuroplasticity, Flx's action is more centered on synaptic remodeling, whereas SJW possesses additional strong anti-inflammatory and amino acid metabolism-modulating properties. These findings provide a detailed molecular basis for their clinical efficacy and suggest distinct therapeutic strengths.