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.

Human in vivo evidence of reduced astrocyte activation and neuroinflammation in patients with treatment-resistant depression following electroconvulsive therapy.

AIM: The current study aimed to investigate the neuroinflammatory hypothesis of depression and the potential anti-inflammatory effect of electroconvulsive therapy (ECT) in vivo, utilizing astrocyte-derived extracellular vesicles (ADEVs) isolated from plasma. METHODS: A total of 40 patients with treatment-resistant depression (TRD) and 35 matched healthy controls were recruited at baseline, and 34 patients with TRD completed the post-ECT visits. Blood samples were collected at baseline and post-ECT. Plasma ADEVs were isolated and confirmed, and the concentrations of two astrocyte markers (glial fibrillary acidic protein [GFAP] and S100ß), an extracellular vesicle marker cluster of differentiation 81 (CD81), and nine inflammatory markers in ADEVs were measured as main analyses. In addition, correlation analysis was conducted between clinical features and ADEV protein levels as exploratory analysis. RESULTS: At baseline, the TRD group exhibited significantly higher levels of two astrocyte markers GFAP and S100ß, as well as CD81 compared with the healthy controls. Inflammatory markers interferon γ (IFN-γ), interleukin (IL) 1ß, IL-4, IL-6, tumor necrosis factor α, IL-10, and IL-17A were also significantly higher in the TRD group. After ECT, there was a significant reduction in the levels of GFAP, S100ß, and CD81, along with a significant decrease in the levels of IFN-γ and IL-4. Furthermore, higher levels of GFAP, S100ß, CD81, and inflammatory cytokines were associated with more severe depressive symptoms and poorer cognitive function. CONCLUSION: This study provides direct insight supporting the astrocyte activation and neuroinflammatory hypothesis of depression using ADEVs. ECT may exert an anti-inflammatory effect through inhibition of such activation of astrocytes.

Young Adults with Major Depression Show Altered Microbiome.

There is growing basic and clinical evidence that major depressive disorder (MDD) is associated with gut microbiome alterations, but clinical studies have tended not to adjust for confounding factors. And few studies on the gut microbiome focused on young adults with MDD. Here we performed a pilot study to compare the gut microbiome of young adults with MDD with healthy controls. Shotgun metagenomic sequencing was performed on stool samples obtained from 40 young adults with MDD and 42 healthy controls. After controlling for confounding factors including sex, age, BMI, alcohol or cigarette consumption, bowel movement quality, exercise or defecation frequency, we compared microbiome diversity between groups, identified differentially abundant taxa, and further compared functional differences through gut-brain and gut-metabolic module analysis. There were no significant differences in overall gut microbiome structure and function in young adults with MDD compared with controls. Abundance of Sutterellaceae and species belonging to Clostridium, Eubacterium, and Ruminococcus were significantly different between groups. The cysteine degradation I pathway was increased in MDD. After controlling for most confounding factors, this pilot study provides new evidence on the specific, often subtle gut dysbiosis affecting young adults with depression.

Hyper-inflammation of astrocytes in patients of major depressive disorder: Evidence from serum astrocyte-derived extracellular vesicles.

Astrocyte-derived extracellular vesicles (ADEs) allow the in vivo probing of the inflammatory status of astrocytes practical. Serum sample and ADEs were used to test the inflammatory hypothesis in 70 patients with major depressive disorder (MDD) and 70 matched healthy controls (HCs). In serum, tumor necrosis factor α (TNF-α) and interleukin (IL)-17A were significantly increased, where as IL-12p70 was significantly reduced in the MDD patients compared with HCs. In ADEs, all inflammatory markers (Interferon-γ, IL-12p70, IL-1ß, IL-2, IL-4, IL-6, TNF-α, and IL-17A) except IL-10 were significantly increased in the MDD patients, the Hedge's g values of elevated inflammatory markers varied from 0.48 to 1.07. However, there were no differences of all inflammatory markers whether in serum or ADEs between MDD-drug free and medicated subgroups. The association of inflammatory biomarkers between ADEs and serum did not reach statistically significance after multi-comparison correction neither in the HCs nor MDD patients. The spearman coefficients between inflammatory factors and clinical characteristics in the MDD patients, such as onset age, disease course, current episode duration, and severity of depression, were nonsignificant after multi-comparison correction. In the receiver operating characteristic curves analysis, the corrected partial area under the curve (pAUC) of each inflammatory markers in ADEs ranged from 0.522 to 0.696, and the combination of these inflammatory factors achieved a high pAUC (>0.9). Our findings support the inflammatory glial hypothesis of depression, and suggests that in human ADEs could be a useful tool to probe the in vivo astrocyte status.

The relationship between vitamin D levels in seasonal variations and Chinese patients with first-episode drug-naive depression.

BACKGROUND: Vitamin D deficiency is highly prevalent worldwide and is associated with various diseases, including depression. Previous studies on vitamin D and depression have different conclusions. OBJECTIVES: Our study aimed to examine the association between vitamin D levels in seasonal variation and depression. METHODS: A total of 324 patients with first-episode depression aged 18-50 years were recruited for our study. Vitamin D levels were recorded, and PHQ-9 scale evaluation was performed in different seasons. Seasonal variations in vitamin D levels and depressive symptoms were examined. RESULTS: The cohort comprised 77 males and 247 females. 98.1% of patients had insufficient or deficient vitamin D levels. The median vitamin D level was 12 ng/mL; 14.5 ng/mL in summer and 13 ng/mL in autumn, which was significantly higher than 9 ng/mL in spring, and the correlation between vitamin D level and PHQ-9 score was more significant in spring but not in summer and autumn. LIMITATIONS: Our study used cross-sectional data and could not examine the causal relationship of the vitamin D level and depressive symptoms. There are also some possible influencing factors, such as the dietary habits, outdoor sports, and the use of sunscreen were not investigated. CONCLUSION: Observational data showed that the vitamin D level of depression is lower than the normal (30 ng/mL), and it is closely related to depressive symptoms in spring. The seasonal variations in vitamin D levels might play a critical role in Chinese patients with first-episode depression.