Background Astrocyte-derived extracellular vesicles (ADEVs) have emerged as a novel research tool in the field of central nervous system disorders. However, significant differences in yield and purity exist among extracellular vesicles (EVs) isolated by different methods, leading to considerable heterogeneity in clinical study outcomes. Therefore, establishing appropriate normalization strategies to enhance comparability across results is a key prerequisite for their clinical translation. Methods This study included 15 patients with major depressive disorder (MDD) and 15 healthy controls (HCs). ADEVs were isolated from plasma using ultracentrifugation combined with immunoaffinity capture. Subsequently, the levels of brain-derived neurotrophic factor (BDNF), five EV biomarkers (CD9, CD63, CD81, Alix, and TSG101), and particle counts in ADEVs were quantified. In addition, plasma lipoprotein levels were measured. Results Our results demonstrated a lack of significant correlation between particle counts and the levels of five EV biomarkers in plasma ADEVs, whereas strong correlations were observed among the five biomarkers themselves. Normalization of BDNF levels to CD81 or CD9 revealed a significant decrease in the MDD group, whereas normalization to EV particle counts or other EV biomarkers did not show such differences. Notably, plasma levels of apolipoprotein B (APOB), low-density lipoprotein (LDL), and total cholesterol (TC) significantly interfered with the measurement of particle counts. Conclusions In summary, under conventional EV isolation and detection conditions, our findings support the use of EV biomarker levels rather than particle counts as a normalization method for quantifying target proteins of ADEVs in plasma.

For young patients with depression, electroconvulsive therapy (ECT) is highly effective but causes acute cognitive side effects. We designed a new individualized hybrid electroconvulsive therapy (i-HECT) combines ECT with low-charge electrotherapy (LCE) and individual symptom monitoring to reduce cognitive impairments. i-HECT comprised two treatments: ECT and LCE. ECT utilized an energy set of 1.5 times the seizure threshold (ST), while LCE was set at 0.5 ST. The initial session employed standard bilateral ECT. Subsequent sessions involved ECT or LCE, depending on whether meeting the ECT-LCE transition criteria (Montgomery-Åsberg Depression Rating Scale (MADRS) total score < 22 or ≥ 50

Abstract Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis involves dynamic changes in glutamatergic signalling. Magnetic resonance spectroscopy can monitor these changes but lacks temporal resolution and cell-type specificity. We investigated whether urinary astrocyte-derived extracellular vesicles (ADEVs) could serve as a non-invasive proxy for brain receptor dynamics. We prospectively collected longitudinal urine and cerebrospinal fluid (CSF) samples from a 30–35-year-old female patient during 34 days of treatment. We isolated ADEVs using a specific protocol and measured GluN1 protein levels. A 30–35-year-old healthy female provided control samples. Wavelet transform analysis of the patient’s GluN1 time series revealed two distinct patterns. First, a low-frequency trend showed declining GluN1 levels over the treatment period, which mirrored the reduction in CSF GluN1 concentrations. Second, a high-frequency oscillation appeared to be coupled with methotrexate infusions, with GluN1 peaks occurring approximately 48 hours after each dose. This secondary increase may reflect drug-induced p53 activation, which promotes the exosomal release of internalised receptors. These findings suggest that urinary ADEVs provide a feasible and informative method to monitor real-time molecular fluxes in the brain.

Background Vascular endothelial growth factor (VEGF) is a candidate mediator of blood-brain barrier (BBB) disruption in depression. However, previous studies have mainly focused on peripheral blood VEGF levels, and the results are heterogeneous. Here we use astrocyte-derived extracellular vesicles (ADEVs) isolated from plasma to explore the in vivo changes of VEGF levels in patients with major depressive disorder (MDD). Methods Thirty-five unmedicated patients with MDD and 35 healthy controls (HCs) were enrolled, and plasma ADEVs were isolated from each participant. VEGF levels in ADEVs and glial fibrillary acidic protein (GFAP) in plasma were measured. Additionally, Alix and CD81, two established extracellular vesicle markers, were quantified in ADEVs. Results At baseline, MDD patients exhibited significantly increased levels of VEGF in ADEVs and GFAP in plasma. Following four weeks of selective serotonin reuptake inhibitor treatment, these target protein levels did not significantly change. ROC curve analysis revealed an AUC of 0.711 for VEGF in ADEVs. In exploratory analysis, VEGF levels in ADEVs were positively correlated with Alix and CD81. Limitations Multiple factors regulate BBB permeability. This study focused solely on VEGF and the sample size for longitudinal analysis was relatively small. Conclusion Our study is the first to confirm increased ADEV-derived VEGF levels in patients with MDD, thereby providing preliminary evidence supporting the hypothesis that the BBB is disrupted in depression.

The oral microbiota is associated with neuro-psychiatric disorders. However, there is presently inadequate comprehension regarding the correlation between schizophrenia and the oral microbiota. Moreover, patients with schizophrenia frequently exhibit poor oral health, potentially influencing research outcomes. Therefore, this study aims to investigate changes in the oral microbiota and oral health status in drug-free schizophrenia patients. Oral microbiota samples were collected from 50 drug-free patients with schizophrenia and 50 healthy controls (HCs). The downstream microbiota analysis was based on Illumina sequencing of the V3-V4 hypervariable region of the 16 S rRNA gene. The alpha diversity of SCZ group is increased, such as the Shannon index (p < 0.001) and Simpson index (p = 0.004), while the community structure also displays variance compared to the HC group (p < 0.001). Key discriminative taxa were found in LEfSe analysis, including the phyla Fusobacteriota, Firmicutes, and Actinobacteriota. The differential taxa and microbial functions showed a strong correlation with clinical oral conditions. Further analysis demonstrated that models based on the entire oral microbiota effectively distinguished SCZ patients from HC (AUC = 0.97). The significant changes in the microbiota of Drug-free SCZ patients appear to be closely associated with the poor oral environment. Sample: 50 HCs 50 drug-free SCZ patients recruited to reduce medication impact. Employed comprehensive oral assessments and microbiota sequencing. SCZ patients showed poorer oral health and altered oral microbiota. Oral microbiota changes correlated with oral health in SCZ patients.

We present an extension of the Time-Varying Vector Autoregressive (TV-VAR) model by incorporating static variables and Type I error controlling, to expand its utility to time series data involving multiple individuals and to decrease the number of spurious interactions. A simulation study with 324 scenarios varying sample sizes, number of time points, correlation coefficients, the probability of cross-lagged effects, and number of time-varying variables is presented. The correlation between estimated and data generating parameters, the sensitivity and the specificity were used to assess model performance. The extension model was applied to empirical data to detect the dynamic changes in depressive symptoms during the period of electroconvulsive therapy in patients with depression. Results show consistent improvements over the TV-VAR model, with higher correlation and specificity, except for slightly lower sensitivity. Notably, enhancements shine in larger samples (>= 250) and larger time points (>= 12), while a decline occurs with higher interaction probabilities (e.g., 0.85). Empirical analysis shows that depressive symptoms were generally predicted by themselves and the relationship between depressive symptoms became weaker over time. The extension of the TV-VAR model presents a valuable tool for studying mental health dynamics, particularly in scenarios with appropriate sample size and time points.

The involvement of lipids in the mechanism of depression has triggered extensive discussions. Earlier studies have identified diminished levels of lysophosphatidic acid (LPA) and autotaxin (ATX) in individuals experiencing depression. However, the exact significance of this phenomenon in relation to depression remains inconclusive. This study seeks to explore the deeper implications of these observations. We assessed alterations in ATX and LPA in both the control group and the chronic unpredictable mild stress (CUMS) model group. Additionally, the impact of ATX adeno-associated virus (AAV-ATX) injection into the hippocampus was validated through behavioral tests in CUMS-exposed mice. Furthermore, we probed the effects of LPA on synapse -associated proteins both in HT22 cells and within the mouse hippocampus. The mechanisms underpinning the LPA-triggered shifts in protein expression were further scrutinized. Hippocampal tissues were augmented with ATX to assess its potential to alleviate depression -like behavior by modulating synaptic -related proteins. Our findings suggest that the decrement in ATX and LPA levels alters the expression of proteins associated with synaptic plasticity in vitro and in vivo, such as synapsin-I (SYN), synaptophysin (SYP), and brain -derived neurotrophic factor (BDNF). Moreover, we discerned a role for the ERK/CREB signaling pathway in mediating the effects of ATX and LPA. Importantly, strategic supplementation of ATX effectively mitigated depression -like behaviors. This study indicates that the ATX-LPA pathway may influence depression -like behaviors by modulating synaptic plasticity in the brains of CUMS-exposed mice. These insights augment our understanding of depression's potential pathogenic mechanism in the context of lipid metabolism and propose promising therapeutic strategies for ameliorating the disease.

Background: For young patients with depression, electroconvulsive therapy (ECT) is highly effective but causes acute cognitive side effects. We designed a new i-HECT therapy combines ECT with low-charge electrotherapy (LCE) and individual symptom monitoring to reduce cognitive impairments. Methods: i-HECT comprised two treatments: ECT and LCE. ECT utilized an energy set of 1.5 times the seizure threshold (ST), while LCE was set at 0.5 ST. The initial session employed ECT. Subsequent sessions involved ECT or LCE, depending on whether meeting the ECT-LCE transition criteria (MADRS total score < 22 or ≥ 50% reduction), assessed after each session. Results: The intention-to-treat analysis revealed an 80.4% response rate and a 58.7% remission rate (Hedges' g = 3.29). Notably, both subjective and objective cognitive functions significantly improved post-i-HECT treatments and during the 3-month follow-up periods. Conclusion: The i-HECT protocol may provide a rapid antidepressant treatment option with cognitive benefits for young depression patients. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial ChiCTR2100045682 ### Funding Statement This work was supported by grant from the Science and Technology Program of Huizhou (Grant No. 2021SC010311001 (Baijian Tan) and 2022CQ010013 (Lun Zeng)) and the Guangdong Medical Research Foundation (Grant No.A2022333 (Lun Zeng)). This work has not received funding/assistance from any commercial organizations. The funding source had no roles in the design of this study and will not have any roles during the execution, analyses, interpretation of the data, or decision to submit results. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This single-arm trial employed a Simon's optimal two-stage design with a 3-month follow-up duration, conducted at the Second People's Hospital of Huizhou in accordance with the Declaration of Helsinki. The Human Ethics Committee of the Hospital approved the protocol. Patients and their legal guardians can withdraw at any time for any reason. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data that support the findings of this study are available from the corresponding author, upon reasonable request.

Many central nervous system diseases are closely related to nerve damage caused by dysregulation of the endogenous neurotransmitter glutamate. Exosomes derived from bone marrow mesenchymal stem cells (BMSC-Exos) play an important role in improving injury and regeneration functions. However, its mechanism remains unknown. Therefore, the aim of this study is to investigate whether and how BMSC-Exos improve neurotoxicity caused by glutamate and to fill the gap in the literature. In this study, glutamate-treated HT22 cells were first exposed to mouse-derived BMSC-Exos at different concentrations to observe their effects on HT22 apoptosis. Next, we treated glutamate-treated HT22 cells with mouse-derived BMSC-Exos. We then inhibited the PI3K/Akt/mTOR signaling pathways using the PI3K/Akt inhibitor and the mTOR inhibitor, respectively, and observed the protective effect of mouse-derived BMSC-Exos on HT22 cells treated with glutamate. Our results show that BMSC-Exos reduced apoptosis triggered by glutamate stimulation, increased cell vitality, and decreased the levels of proapoptotic proteins while increasing the levels of anti-apoptotic proteins. The protective effect of BMSC-Exos was weakened when PI3K/Akt inhibitor and mTOR inhibitor were added. To sum up, we draw the following conclusions: BMSC-Exos can reduce neuronal apoptosis and apoptosis-related protein expression after glutamate stimulation by regulating the PI3K/Akt/mTOR signaling pathway.

BACKGROUND: Many metabolomics studies of depression have been performed, but these have been limited by their scale. A comprehensive in silico analysis of global metabolite levels in large populations could provide robust insights into the pathological mechanisms underlying depression and candidate clinical biomarkers. METHODS: Depression-associated metabolomics was studied in 2 datasets from the UK Biobank database: participants with lifetime depression (N = 123,459) and participants with current depression (N = 94,921). The Whitehall II cohort (N = 4744) was used for external validation. CatBoost machine learning was used for modeling, and Shapley additive explanations were used to interpret the model. Fivefold cross-validation was used to validate model performance, training the model on 3 of the 5 sets with the remaining 2 sets for validation and testing, respectively. Diagnostic performance was assessed using the area under the receiver operating characteristic curve. RESULTS: In the lifetime depression and current depression datasets and sex-specific analyses, 24 significantly associated metabolic biomarkers were identified, 12 of which overlapped in the 2 datasets. The addition of metabolic features slightly improved the performance of a diagnostic model using traditional (nonmetabolomics) risk factors alone (lifetime depression: area under the curve 0.655 vs. 0.658 with metabolomics; current depression: area under the curve 0.711 vs. 0.716 with metabolomics). CONCLUSIONS: The machine learning model identified 24 metabolic biomarkers associated with depression. If validated, metabolic biomarkers may have future clinical applications as supplementary information to guide early and population-based depression detection.

Purpose:To investigate the neuroplasticity hypothesis of depression by measuring brain-derived neurotrophic factor (BDNF) levels in plasma astrocyte-derived extracellular vesicles (ADEVs) and to evaluate their potential as biomarkers for depression compared with plasma BDNF levels. Patients and Methods:Thirty-five patients with major depressive disorder (MDD) and 35 matched healthy controls (HCs) were enrolled. Plasma ADEVs were isolated using a combination of ultracentrifugation and immunoaffinity capture. Isolated ADEVs were validated using transmission electron microscopy, nanoparticle tracking analysis, and Western blotting. BDNF levels were quantified in both ADEVs and plasma. ALG-2-interacting protein X (Alix) and cluster of differentiation 81 (CD81) levels, two established extracellular vesicle markers, were measured in ADEVs. Results:After false discovery rate correction, patients with MDD exhibited higher CD81 levels (P FDR = 0.040) and lower BDNF levels (P FDR = 0.043) in ADEVs than HCs at baseline. BDNF levels in ADEVs normalized to CD81 (P FDR = 0.002) and Alix (P FDR = 0.040) remained consistent with this finding. Following four weeks of selective serotonin reuptake inhibitor treatment (n=10), CD81 levels in ADEVs decreased (P FDR = 0.046), while BDNF levels normalized to CD81 increased (P FDR = 0.022). BDNF levels in ADEVs were more stable than in plasma. Exploratory analysis revealed no correlation between BDNF levels in ADEVs and plasma (ρ=0.117, P = 0.334). Conclusion:This study provides human in vivo evidence supporting the neuroplasticity hypothesis of depression by demonstrating altered BDNF levels in ADEVs. ADEVs may be more suitable for developing biomarkers of depression than plasma-derived biomarkers.

The identification of particularly individual-level biomarkers, for certain central nervous system (CNS) diseases remains challenging. A recent approach involving the enrichment of brain-derived extracellular vesicles (BDEVs) from peripheral blood has emerged as a promising method to obtain direct in vivo CNS data, bypassing the blood-brain barrier. However, for rapidly evolving CNS diseases (e.g., weeks or even days), the Nyquist-Shannon sampling theorem dictates the need for a high-frequency sampling rate. Obviously, daily collection of blood or cerebrospinal fluid from human subjects is impractical. Thus, we innovated a novel method to isolate astrocyte-derived EVs from urine (uADEVs). It involves three main steps: 1) concentrating urine samples, 2) isolating total EVs from urine (uTEVs) using ultracentrifugation, and 3) using an anti-glutamate/aspartate transporter (GLAST) antibody to isolate GLAST+EVs from uTEVs. Subsequently, we confirmed the identity of these GLAST+EVs as uADEVs using transmission electron microscopy, nanoparticle tracking analysis, western blotting, and the measurement of astrocyte-related neurotrophins. Furthermore, we applied the uADEVs protocol to depict the detailed trajectory of the N-methyl-d-aspartic acid receptor (NMDAR) subunit zeta-1 (GluN1) in an anti-NMDAR encephalitis patient, demonstrated the potential of this method for capturing intricate trajectories of CNS-specific molecular in vivo signals at the individual level. This non-invasive approach enables frequent sampling, up to daily or even half-daily, analogous to capturing molecular "movies" of the brain, coupled with appropriate signal processing algorithms, holds promise for identifying novel biomarkers or illuminating the etiology of rapidly evolving CNS diseases by tracking the precise trajectories of target molecules.### Competing Interest StatementThe authors have declared no competing interest.### Funding StatementThis work was supported by grant from the National Natural Science Foundation of China (grant number: U21A20364). This work has not received funding/assistance from any commercial organizations. The funding source had no roles in the design of this study and will not have any roles during the execution, analyses, interpretation of the data, or decision to submit results.### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The study protocol was approved by both the Human Ethics Committee of Renmin Hospital of Wuhan University and Wuhan First Hospital.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesAll data were presented in the Supplementary Material.

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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by grants from the National Natural Science Foundation of China (U21A20364). No funding was received from commercial organizations. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Human Ethics Committee of Renmin Hospital of Wuhan University approved the study protocol. Patients or their legal guardians provided informed consents. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.

AIMS:To investigate the antidepressant role of oligodendrocyte-derived exosomes (ODEXs)-containing sirtuin 2 (SIRT2) and the underlying mechanism both in vivo and in vitro.METHODS:Oligodendrocyte-derived exosomes isolated from mouse serum were administered to mice with chronic unpredictable mild stress (CUMS)-induced depression via the tail vein. The antidepressant effects of ODEXs were assessed through behavioral tests and quantification of alterations in hippocampal neuroplasticity. The role of SIRT2 was confirmed using the selective inhibitor AK-7. Neural stem/progenitor cells (NSPCs) were used to further validate the impact of overexpressed SIRT2 and ODEXs on neurogenesis and synapse formation in vitro.RESULTS:Oligodendrocyte-derived exosome treatment alleviated depressive-like behaviors and restored neurogenesis and synaptic plasticity in CUMS mice. SIRT2 was enriched in ODEXs, and blocking SIRT2 with AK-7 reversed the antidepressant effects of ODEXs. SIRT2 overexpression was sufficient to enhance neurogenesis and synaptic protein expression. Mechanistically, ODEXs mediated transcellular delivery of SIRT2, targeting AKT deacetylation and AKT/GSK-3β signaling to regulate neuroplasticity.CONCLUSION:This study establishes how ODEXs improve depressive-like behaviors and hippocampal neuroplasticity and might provide a promising therapeutic approach for depression.

Depression and sleep disturbances are highly prevalent health problems that have been suggested to be associated with vitamin D deficiency. This study investigated whether sleep disturbances affect the association between vitamin D and depressive symptoms. A total of 425 patients with depression were included in this study. Spearman correlation coefficients were chosen to assess the relation between vitamin D concentrations and depressive symptomatology (according to the PHQ-9 and HAMD-17 scores). The GLM Mediation Model in the Medmod module for data analysis in Jamovi 2.2.5 was used to analyze the mediation models for sleep disturbances. Vitamin D concentrations were significantly correlated with PHQ-9 and HAMD-17 scale scores. In addition, item 3 was suggested to have a mediating effect between vitamin D and depressive symptoms in the mediating model of PHQ-9, and item 4 was suggested to have a mediating effect between vitamin D and depressive symptoms in the mediating model of HAMD-17. Sleep disturbances (especially difficulty falling asleep) are mediators between vitamin D and depressive symptoms, suggesting that increasing vitamin D levels at the right time to regulate sleep disturbances may improve depression symptoms, yet further research is necessary.

Objective: Coronary artery calcification (CAC) is a well-established independent predictor of coronary heart disease, and patients with schizophrenia have significantly higher rates compared to the general population. We performed this study to examine the population-specific risk factors associated with CAC in patients with schizophrenia.Methods: In this cross-sectional study, patients with schizophrenia who underwent low-dose chest CT scans be-tween January 2020 and December 2021 were analyzed. Ordinary CAC scores and results of routine blood tests were obtained. Logistic regression was used to calculate the odds ratio (OR) for potential risk factors in patients with and without CAC, while the negative binomial additive model was used to explore the dose-response relationship between risk factors and CAC score.Results: Of the 916 patients, 233 (25.4 %) had CAC, while 683 (74.6 %) did not. After adjusting for confounding factors, higher triglyceride levels (OR = 1.20, 95 % confidence interval (CI): 1.04 to 1.38, p = 0.013) and low triiodothyronine levels (OR = 0.50, 95 % CI: 0.29 to 0.84; p = 0.010) were identified as risk factors for CAC. Both triglycerides (p = 0.021) and triiodothyronine (p = 0.010) were also found to have significant dose-response relationships with CAC scores according to the negative binomial additive model in the exploratory analysis.Conclusions: This study highlights elevated serum triglycerides and decreased triiodothyronine levels as population-specific risk factors for CAC in patients with schizophrenia, suggest the need for close monitoring of CAC in patients with schizophrenia and further prospective trials to provide additional evidence on this topic.

Background: There is a high correlation between the risk of major depressive disorder (MDD) and adverse childhood experiences (ACEs) such as adverse parenting (AP). While there appears to be an association between ACEs and changes in brain structure and function, there have yet to be multimodal neuroimaging studies of associations between parenting style and brain developmental changes in MDD patients. To explore the effect of AP on brain structure and function. Methods: In this cross-sectional study, 125 MDD outpatients were included in the study and divided into the AP group and the optimal parenting (OP) group. Participants completed self-rating scales to assess depressive severity, symptoms, and their parents' styles. They also completed magnetic resonance imaging within one week of filling out the instruments. The differences between groups of gender, educational level, and medications were analyzed using the chi-squared test and those of age, duration of illness, and scores on scales using the independent samples t-test. Differences in gray matter volume (GMV) and resting-state functional connectivity (RS-FC) were assessed between groups. Results: AP was associated with a significant increase in GMV in the right superior parietal lobule (SPL) and FC between the right SPL and the bilateral medial superior frontal cortex in MDD patients. Limitations: The cross-cultural characteristics of AP will result in the lack of generalizability of the findings. Conclusions: The results support the hypothesis that AP during childhood may imprint the brain and affect depressive symptoms in adulthood. Parents should pay attention to the parenting style and avoid a style that lacks warmth.

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.

Anxious depression is a common subtype of major depressive disorder (MDD) associated with adverse outcomes and severely impaired social function. It is important to clarify the underlying neurobiology of anxious depression to refine the diagnosis and stratify patients for therapy. Here we explored associations between anxiety and brain structure/function in MDD patients. A total of 260 MDD patients and 127 healthy controls underwent three-dimensional T1-weighted structural scanning and resting-state functional magnetic resonance imaging. Demographic data were collected from all participants. Differences in gray matter volume (GMV), (fractional) amplitude of low-frequency fluctuation ((f)ALFF), regional homogeneity (ReHo), and seed point-based functional connectivity were compared between anxious MDD patients, non-anxious MDD patients, and healthy controls. A random forest model was used to predict anxiety in MDD patients using neuroimaging features. Anxious MDD patients showed significant differences in GMV in the left middle temporal gyrus and ReHo in the right superior parietal gyrus and the left precuneus than HCs. Compared with non-anxious MDD patients, patients with anxious MDD showed significantly different GMV in the left inferior temporal gyrus, left superior temporal gyrus, left superior frontal gyrus (orbital part), and left dorsolateral superior frontal gyrus; fALFF in the left middle temporal gyrus; ReHo in the inferior temporal gyrus and the superior frontal gyrus (orbital part); and functional connectivity between the left superior temporal gyrus(temporal pole) and left medial superior frontal gyrus. A diagnostic predictive random forest model built using imaging features and validated by 10-fold cross-validation distinguished anxious from non-anxious MDD with an AUC of 0.802. Patients with anxious depression exhibit dysregulation of brain regions associated with emotion regulation, cognition, and decision-making, and our diagnostic model paves the way for more accurate, objective clinical diagnosis of anxious depression.