Altered in vivo early neurogenesis traits in patients with depression: Evidence from neuron-derived extracellular vesicles and electroconvulsive therapy

Background: The neurogenesis hypothesis is a promising candidate etiologic hypothesis for depression, and it is associated with electroconvulsive therapy (ECT). However, human in vivo molecular-level evidence is lacking.Objective: We used neuron-derived extracellular vesicles (NDEVs) as a "window to the neurons" to explore the in vivo neurogenesis status associated with ECT in patients with treatment-resistant depression (TRD).Methods: In this study, we enrolled 40 patients with TRD and 35 healthy controls (HCs). We isolated NDEVs from the plasma of each participant to test the levels of doublecortin (DCX), a marker of neurogenesis, and cluster of differentiation (CD) 81, a marker of EVs. We also assessed the plasma levels of brain-derived neurotrophic factor (BDNF), a protein that is known to be associated with ECT and neuroplastic processes.Results: Our findings indicated that both the levels of DCX in NDEVs and BDNF in plasma were significantly lower in TRD patients compared to HCs at baseline, but increased following ECTs. Conversely, levels of CD81 in NDEVs were found higher in TRD patients at baseline, but did not change after the ECT treatments. Exploratory analyses revealed that lower levels of BDNF in plasma and DCX in NDEVs, along with higher CD81 levels in NDEVs, were associated with more severe depressive symptoms and reduced cognitive function at baseline. Furthermore, higher baseline CD81 concentrations in NDEVs were correlated with greater decreases in depression symptoms.Conclusions: We first present human in vivo evidence of early neurogenesis using DCX through NDEVs: decreased in TRD patients, increased after ECTs.