Background: This study aimed to examine the neurotrophic factors secreted from astrocytes in depression by analyzing astrocyte-derived extracellular vesicles (ADEVs) isolated from plasma, and to explore the causal relationship between the expression of neurotrophic factors in the brain and depression. Methods: A total of 40 patients with treatment-resistant depression (TRD) and 35 matched healthy controls (HCs) were recruited at baseline, and 34 TRD patients completed the post-electroconvulsive therapy (ECT) visits. The concentrations of five neurotrophic factors in ADEVs were measured. A correlation analysis was performed between neurotrophic factors in ADEVs and our previously published data on the neurogenesis marker doublecortin (DCX) in neuron-derived extracellular vesicles (NDEVs). Subsequently, Mendelian randomization (MR) study and cell experiments were conducted. Results: Our findings revealed a decrease in the level of epidermal growth factor (EGF) in ADEVs among TRD patients compared to controls, with an increase observed post-ECT. MR suggested that decreased expression levels of the EGF gene in the cortex constitute a risk factor for depression. We observed a positive correlation between the levels of EGF in ADEVs and DCX in NDEVs. Subsequently, cell experiments suggested that EGF can activate EGF receptor (EGFR) to trigger the PI3K-Akt pathway, participating in the promotion of DCX. Conclusions: This study provides the in vivo evidences supporting that a reduction in EGF levels in the central nervous system could potentially contribute to depression and serve as a biomarker for it. Additionally, the EGF/EGFR signaling pathway may be involved in regulating early neurogenesis traits in depression.

The authors have declared no competing interest.

This work was supported by grants from the National Natural Science Foundation of China (U21A20364). No funding was received from commercial organizations.

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The Human Ethics Committee of Renmin Hospital of Wuhan University approved the study protocol. Patients or their legal guardians provided informed consents.

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