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Objective: An alternative metric for evaluating insulin resistance (IR) is the triglyceride glucose-body mass index (TyG-BMI). However, it is yet unclear how TyG-BMI and suicide attempts (SA) are related. The objective of this research was to explore the correlation between the TyG-BMI index and SA in individuals with untreated first-episode (UFE) major depressive disorder (MDD) in Shanxi Province., Methods: This cross-sectional study was conducted from September 2016 to December 2018 in the psychiatric outpatient clinic of Taiyuan General Hospital and included 1718 patients with UFE MDD, with a mean age of 34.9 ± 12.4 years. The relationship between TyG-BMI and SA was assessed using logistic regression modeling. We investigated threshold effects using a two-piecewise linear regression model., Results: Taking into consideration the potential influence of confounding variables, a comprehensive multivariate logistic regression analysis was conducted, which demonstrated the absence of a statistically significant association between the TyG-BMI index and the occurrence of SA, as evidenced by P-values that were all greater than 0.05. On the other hand, the visual analysis of the smoothed plots revealed a U-shaped relationship between the TyG-BMI index and the incidence of SA, with a notable inflection occurring at a TyG-BMI value of around 210. It was observed that the effect sizes flanking the inflection point, accompanied by their 95% confidence intervals, were 0.985 (95% CI: 0.972 to 0.999, P = 0.031) and 1.012 (95% CI: 1.003 to 1.047, P = 0.005), respectively., Conclusions: In UFE MDD patients, a U-shaped link was observed between TyG-BMI and SA, with the minimal SA incidence noted at a TyG-BMI level of 210, signifying that an augmented risk for SA might be connected to both diminished and augmented TyG-BMI levels., Competing Interests: Declarations Ethics approval and consent to participate The research involving human subjects received approval from the Institutional Review Board of the First Hospital, Shanxi Medical University (No. 2016-Y27). All studies were conducted in compliance with local laws and institutional guidelines. Participants provided their written informed consent to take part in the study. Additionally, written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article. Consent for publication Not application. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

High Mobility Group Box Protein-1 (HMGB1), which has proinflammatory properties, is known to be involved in psychiatric disorders as far as we know, there are only one clinical studies investigating the role of HMGB1 in major depressive disorder (MDD). In this study, we aimed to investigate the role of HMGB1 in the etiopathogenesis of MDD and whether HMGB1 can be used as a biomarker in MDD by measuring the serum HMGB1 levels of depressed patients in the episode and remission periods. This study included 30 patients diagnosed with MDD in episode, 30 patients in remission and 30 healthy controls. Each group comprised 20 female and 10 male participants. In this study, serum HMGB1 levels were found to be lower in the patient group in the episode compared to the patient group in the remission period and the healthy control group. There was no significant difference between the patient group in remission and the healthy control group in terms of serum HMGB1 levels. The fact that serum HMGB1 levels were lower in the patient group in the episode compared to the patient group in the remission period and the control group may be related to the neuroprotective effects of HMGB1. HMGB1 may be used as a biomarker for MDD., Competing Interests: Declaration of competing interest None. The financial expenses of this study were covered by the researchers., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Bilateral repetitive transcranial magnetic stimulation (B-rTMS) has been largely used in the treatment of major depressive disorder (MDD). Nonetheless, information on the acute treatment by B-rTMS combined with antidepressants (ADs) on the plasma fatty acids in MDD is limited. The present study focused on depressive symptoms; Plasma was obtained from 27 adult patients with MDD at baselinephase (MDD), after 2 weeks of treatment (MDD-2w), and 27 healthy controls (HC). Meanwhile, we evaluated the composition of short-chain fatty acids (SCFAs) and medium-and long-chain fatty acids (MLCFAs) in the plasma. Consequently, the levels of Isobutyric acid, Caproic acid, and Propionic acid were low both in the MDD and MDD-2w groups and negatively correlated with the scores of HAMD and HAMA. Besides, minimal changes were observed between the MDD and HC groups, whereas significant MLCFA levels were high in the MDD-2w group. Moreover, we developed combined panels that could effectively differentiate MDD from HCs (AUC=0.99), MDD-2w from HC (AUC=0.983), and MDD from MDD-2w (AUC=0.852). These findings may provide a reference for the use of B-rTMS combined with ADs against the acute phase of depressive episodes and shed light on the relationship between plasma FAs and MDD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The relationship between neurotransmitters and oxidative stress in Major Depressive Disorder (MDD) patients, considering HPA axis activity and psychological and cognitive states, is unclear. This study examines changes in neurotransmitters (GABA, Glx) and antioxidants (GSH) in the dorsal anterior cingulate cortex (dACC) of MDD patients under varying levels of ACTH, and their relationship with psychological and cognitive conditions., Methods: Forty-five MDD patients were divided into high-ACTH (>65 pg/mL; n = 16) and normal-ACTH (7-65 pg/mL; n = 29) groups based on blood ACTH levels, along with 12 healthy controls (HC). All participants underwent HAM-D, HAM-A assessments, and most completed MMSE and MoCA tests. GABA+, Glx, and GSH levels in the dACC were measured using the MEGA-PRESS sequence. Intergroup differences and correlations between clinical factors, HPA axis activity, and metabolites were analyzed., Results: Compared to HC, the normal ACTH group showed higher Glx and lower GSH levels. Glx and GSH were negatively correlated with MDD severity. In the high-ACTH MDD group, Glx positively correlated with delayed memory, and GSH positively correlated with abstraction. Factors influencing GABA included ACTH levels, depression duration, and negative events. Predictive factors for HAM-D scores were GSH and GABA., Limitations: The sample size is small., Conclusion: MDD patients exhibit neurochemical differences in the brain related to HPA axis levels, MDD severity, and cognitive function. Clinical factors, neurotransmitters, and neuroendocrine levels significantly influence depression severity., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Previous studies demonstrated thyroid stimulating hormone (TSH) plays an important role in regulating lipid metabolism, but the relationship between the two is controversial. Meanwhile, it has not been reported in a population with major depressive disorder (MDD)., Methods: We divided 1718 first-episode and drug naïve patients with MDD into a TSH abnormal group (TSH-AB) and a TSH normal group (TSH-NOR). The participants in the two groups were assessed by the Hamilton Depression Rating Scale (HAMD), Hamilton Anxiety Rating Scale (HAMA) and the positive subscale of Positive and Negative Syndrome Scale. The patients' blood was tested for TSH, free T3, free T4, fasting blood glucose, lipid indexes and body mass index was recorded., Results: The participants in the TSH-AB group had significantly higher HAMD scores, HAMA scores and total scores of positive symptoms, as well as higher incidence of suicide attempts than those in the TSH-NOR group, accompanied by significantly higher thyroglobulin antibodies, thyroid peroxidase antibodies, fasting blood glucose values, total cholesterol (TC), triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C) levels compared with those of TSH-NOR patients. However, the high-density lipoprotein cholesterol (HDL-C) of TSH-AB patients was lower than those of TSH-NOR patients. TSH values were positively correlated with TC, TG, and LDL-C values, and negatively correlated with HDL-C value., Conclusion: TSH was highly correlated with abnormal lipid metabolism in patients with MDD. The specific molecular mechanism of the relationship between TSH, lipid metabolism and the development of depression needs to be further in-depth investigation., (© 2024. The Author(s).)

Background: Inflammatory bowel disease (IBD) is a chronic, inflammatory, and autoimmune disorder, and its incidence of comorbid with major depressive disorder (MDD) is significantly higher than the general population. However, many patients lack proper recognition and necessary psychological health treatments. We aimed to identify potential biomarkers and mechanisms involved in the development of IBD comorbid with MDD (IBD-MDD)., Methods: We utilized IBD and MDD-related datasets from the GEO database for differential gene expression analysis, protein-protein interaction (PPI) and pathway enrichment analysis, random forest algorithm, LASSO regression analysis, and construction of a disease prediction model. We assessed the accuracy of the model using ROC curve, explored potential mechanisms through immune infiltration analysis, and validated candidate biomarkers using peripheral blood samples from patients in our center's cohort., Results: We identified 484 IBD-related secreted proteins and 142 key module genes associated with MDD. PPI analysis revealed two crucial modules primarily involved in inflammation and immune regulation. We identified four diagnostic genes (HGF, SPARC, ADAM12, and MMP8) from the 21 shared genes between IBD-related secreted proteins and MDD key module genes, constructed a nomogram model and confirmed its accuracy using ROC curve from an external independent dataset. Immune infiltration analysis revealed significant associations between the four diagnostic genes, and cellular immune dysregulation in MDD. Finally, we validated the expression patterns of the four diagnostic genes in our cohort., Conclusions: Our study discovered four candidate biomarkers for IBD-MDD, providing new insights for the diagnosis and therapeutic intervention of serum-based IBD comorbid with MDD., (© 2024. The Author(s).)

Background: Despite the well-documented efficacy of antidepressant agents for the treatment of major depressive disorder (MDD), initial treatment nonresponse rates are high. Recent years have seen an increase in research into predictive biomarkers toward improving diagnosis and individualized treatment. Among those, epigenetic mechanisms such as DNA methylation constitute promising candidate markers in predicting antidepressant treatment response in MDD. The present study sought to address epigenome-wide DNA methylation as a predictor of antidepressant treatment response in the largest sample to date of patients with MDD., Methods: Epigenome-wide DNA methylation was analyzed using the Infinium MethylationEPIC BeadChip in peripheral blood of n = 230 Caucasian patients with MDD receiving 6-week antidepressant treatment in a naturalistic in-patient setting as well as in a subsample of n = 107 patients primarily receiving continuous treatment with serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors. Treatment response was assessed by means of the Hamilton Depression Scale., Results: No genome-wide significant hits were observed. Suggestive (P < 1E-5) epigenome-wide evidence was discerned for altered DNA methylation at 6 CpG sites (LOC102724467, LOC100506023, RSPO2, SAG, IL16, PRKCI) to predict response to naturalistic antidepressant treatment. In patients treated with serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors, differential DNA methylation at 11 CpGs, for example, mapping to the TIMP2, VDAC1, or SORL1 genes, was suggestively associated with treatment response., Conclusions: The present results provide preliminary evidence for altered DNA methylation patterns to be associated with antidepressant treatment response in MDD. Provided significant replication in independent and larger samples, the present findings might in the future aid in clinical decision-making toward more individualized and thus more efficacious treatments of MDD., (© The Author(s) 2024. Published by Oxford University Press on behalf of CINP.)

Background: Major Depressive Disorder (MDD) is a heterogenous and etiologically complex disease often presenting with divergent appetitive phenotypes including Hyperphagic MDD (characterized by an increased appetite) and Hypophagic MDD (characterized by a decrease in appetite) which are closely related to comorbidities, including cardiometabolic disorders. Hyperphagia is associated with atypical depression, decreased stress-hormone signaling, a pro-inflammatory status, hypersomnia, and poorer clinical outcomes. Yet, our understanding of associated biological correlates of Hyperphagic and Hypophagic MDD remain fragmented., Methods: We performed an exploratory study on peripheral blood RNA profiling using bulk RNAseq in unmedicated individuals with Hyperphagic and Hypophagic MDD (n = 7 and n = 13, respectively)., Results: At baseline, we discovered an increased expression of TADA2B in hyperphagic MDD with the significant enrichment of 72 gene ontology pathways mainly related to inflammation. In addition, we used the Maastricht Acute Stress Task to uncover stress-related transcriptomic profiles in Hyper- and Hypophagic MDD and discovered the upregulation of CCDC196 and the downregulation of SPATA33 in hyperphagic MDD. Gene ontology enrichment analysis after stress exposure showed pathways related to ribosomal activity., Limitations: The present findings are tempered primarily by the limited sample size, which requires independent replication of this exploratory study. However, stringent methods controlling for false positive findings mitigate the risk associated with sample size limitations., Discussion: Limitations notwithstanding, findings suggest that hyper- and hypophagic MDD is associated with divergent RNA expression profiles in peripheral blood that are amplified by exposure to a controlled stress test. Our findings in a well-controlled study provide evidence for peripheral markers of a relevant endophenotype of MDD., Competing Interests: Declaration of competing interest The authors do not declare any relevant conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Aim: Prenatal maternal depression is known to affect the neurodevelopment of offspring. This study aimed to investigate the profile of umbilical cord serum in mothers with major depressive disorder (MDD)., Methods: Liquid chromatography-tandem mass spectrometry (LC-MS) was conducted using umbilical cord serum from mothers with MDD (n = 5) and controls (control, n = 5). The levels of several differentially expressed proteins in umbilical cord serum were compared between the MDD (n = 10) and control groups (n = 10) by enzyme-linked immunosorbent assay., Results: The proteomic profiles in the umbilical cord serum were different between the MDD and control groups, including the pathways of regulation of plasma lipoprotein particle levels, and synapse organization. Only apolipoprotein A4 (APOA4) was significantly higher in the cord blood of MDD group. APOA4 levels in maternal serum were also significantly higher in the MDD group than those in the control group. The APOA4 levels in the umbilical cord serum were higher than that in the maternal serum., Conclusions: The levels of APOA4, a biomarker of depression, in the umbilical cord serum at birth were elevated in the neonates of MDD mothers. It is, therefore, likely that fetuses of MDD mothers were exposed to higher APOA4 levels in utero and this could have developmental and mental health implications for the offspring., (© 2024 The Author(s). Journal of Obstetrics and Gynaecology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Obstetrics and Gynecology.)

Increasing evidence demonstrates that brain-derived neurotrophic factor (BDNF) can be regarded as a biomarker for major depression. Our previous work found that the ratio of mature BDNF (mBDNF) to precursor-BDNF (proBDNF) was a pivotal factor in the pathogenesis of major depressive disorder (MDD). But the mechanism behind the ratio is still obscure. Tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) both play essential roles in depression by regulating the ratio of BDNF/proBDNF. In present study, we analyzed BDNF, proBDNF, tPA and PAI-1 in the peripheral blood in 57 MDD patients pre- and post-treatment and in 57 healthy controls. We verified that BDNF and tPA levels were significantly decreased, whereas proBDNF and PAI-1 levels elevated obviously in MDD group pre-treatment. And after 4 weeks SSRIs treatment, the BDNF and tPA levels increased while the proBDNF and PAI-1 levels reduced. The MDD pre-treatment group had the lowest ratio of BDNF to proBDNF compared to MDD post-treatment group and control group. Though the ratio of tPA/PAI-1 in MDD pre-treatment had not reached the significance, it was still the lowest one among the three groups. The combination of tPA + PAI + BDNF showed the best diagnostic value for MDD. In summary, our data suggested that the interaction between tPA and PAI-1 implicated to the MDD and the antidepressant treatment which might through regulating the BDNF/proBDNF ratio. The combination of tPA, PAI-1 and BDNF might offer a helpful way for MDD diagnosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Major depressive disorder (MDD) is a complex mental disorder, potentially linked to the gut-microbiota-brain axis. Probiotics like Lactobacillus plantarum PS128 (PS128) may improve depressive symptoms by modulating the gut microbiota based on our previous open trial. We conducted an 8-week double-blind, placebo-controlled trial to investigate the impact of PS128 on depression severity, markers of inflammation and gut permeability, and the gut microbiota composition in 32 patients with MDD with stable antidepressant treatment but moderate symptom severity. Following the 8-week intervention, both the Hamilton Depression Rating Scale-17 score (HAMD), and Depression and Somatic Symptoms Scale (DSSS) showed a significant decrease in both groups (p<0.001). However, there was no significant difference in the change of depression severity between groups (p=0.203). Moreover, alterations in serum levels of high sensitivity C-reactive protein, interleukin-6, tumor necrosis factor-α, and intestinal fatty acid binding protein, as well as changes in the gut microbiota composition, did not exhibit significant differences before and after intervention or between the groups. In comparison to the placebo group, our study did not find significant effects of PS128 on depressive symptoms, biomarkers of inflammation and gut permeability, and the overall gut microbiota composition. Nonetheless, we observed a potential impact of PS128 on the symbiosis of specific taxa. To comprehensively understand the psychophysiological effects of PS128 in patients with MDD, further research with a larger sample size is imperative., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Neuropsychiatric disorders such as major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ) are considered a public health problem since it interferes in personal relationships and at work. The pathophysiological mechanisms of these mental disorders are still not completely understood. The variety and heterogeneity of symptoms, as well as the absence of biomarkers, make the diagnosis, prognosis, and treatment of these disorders difficult. However, oxidative stress appears to play a role in the pathophysiology of these diseases. In this context, advanced oxidation protein products (AOPPs) are considered a biomarker of protein oxidative damage and have been associated with neuroinflammatory diseases. In patients with neuropsychiatric disorders, increased levels of AOPPs were associated with the severity of symptoms and decreased quality of life. Thus, the objective of this integrative review is to investigate and discuss the relationship between AOPPs levels and MDD, BD, and SZ. Different databases were consulted and approximately 112 scientific articles were found relating AOPPs and psychiatric disorders. In the majority of studies, the blood levels of AOPPs were increased in MDD, BD, and SZ and associated with the severity of the disorders. Although the association of this marker with the risk of developing one of these mental disorders is more uncertain, some studies have suggested this relationship. Of the twenty-four studies highlighted, only four did not find significant differences in AOPPs levels in patients with the disorders mentioned. In summary, it may be suggested that the assessment of AOPPs levels can be a useful tool in the evaluation of neuropsychiatric disorders, at least for prognostic evaluation. However, the role of this biomarker in the pathophysiology of mental disorders is still unclear, as well as whether reducing its levels represents a potential therapeutic strategy., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Biological risk factors for cardiovascular disease may relate to poor treatment responsiveness in major depressive disorder (MDD). These factors encompass low-grade inflammation and autonomic dysregulation, as indexed by decreased heart rate variability (HRV) and increased heart rate (HR). This secondary analysis examined whether higher levels of inflammatory markers or autonomic alterations relate to lower responsiveness to cognitive behavioral therapy (CBT) among individuals with MDD., Methods: Eighty antidepressant-free patients with MDD were randomly assigned to 14 weeks of CBT or waitlist (WL). Potential biological moderators at study entry included HR and HRV (24-h, daytime, nighttime) and inflammatory markers such as C-reactive protein (CRP), interleukin (IL)-6, and tumor necrosis factor (TNF)-α. Forty non-clinical controls were involved to verify biological alterations in MDD at study entry. Depressive symptoms were assessed at baseline and at the end of treatment., Results: Individuals with MDD exhibited reduced total 24-h HRV (i.e., triangular index) and daytime HRV (i.e., triangular index, HF-HRV, LF-HRV, RMSSD), as well as increased levels of inflammatory markers. Patients who received CBT exhibited stronger reductions in self- and clinician-rated depressive symptoms, compared to WL. False discovery rate-adjusted moderation analyses did not show overall moderating effects of biological measures on treatment responsiveness. However, higher CRP levels were specifically associated with poorer improvement in somatic depressive symptoms., Conclusions: There was no overall evidence for a moderating role of inflammation or autonomic features in CBT responsiveness in MDD. Higher levels of CRP might, however, specifically be associated with less improvement in somatic depressive symptoms during CBT., Competing Interests: Declaration of competing interest The authors declare no specific conflict of interest that could have influenced treatment results or the content of this paper., (Copyright © 2024. Published by Elsevier Inc.)

Our aim was to evaluate whether alcohol use is associated with changes in the circulating metabolite profile similar to those present in persons with depression. If so, these findings could partially explain the link between alcohol use and depression. We applied a targeted liquid chromatography mass spectrometry method to evaluate correlates between concentrations of 86 circulating metabolites and self-reported alcohol use in a cohort of the non-depressed general population (GP) (n = 247) and a cohort of individuals with major depressive disorder (MDD) (n = 99). Alcohol use was associated with alterations in circulating concentrations of metabolites in both cohorts. Our main finding was that self-reported alcohol use was negatively correlated with serum concentrations of hippuric acid in the GP cohort. In the GP cohort, consumption of six or more doses per week was associated with low hippuric acid concentrations, similar to those observed in the MDD cohort, but in these individuals it was regardless of their level of alcohol use. Reduced serum concentrations of hippuric acid suggest that already-moderate alcohol use is associated with depression-like changes in the serum levels of metabolites associated with gut microbiota and liver function; this may be one possible molecular level link between alcohol use and depression., Competing Interests: Declaration of competing interest OK is a co-founder of Afekta Technologies Ltd., a company providing metabolomics analysis services (not used in the present study). All other authors have no conflicts of interest to declare., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Mild cognitive impairment (MCI) is a prodromal stage in aging to possible progression to Alzheimer's disease and related dementia (ADRD), where co-occurrence of major depressive disorder (MDD) accelerates the progression. Metabolic and mitochondrial abnormalities in ADRD and other neurodegenerative disorders have been widely suggested, while possible mitochondrial dysfunction has been associated with etiopathology of both MCI and MDD. Hence, investigation of mitochondrial markers in MCI, MDD, and presence of both conditions is warranted. In total, 332 older adult participants were included: 168 with MCI, 108 with MCI plus remitted MDD (rMDD), and 56 with rMDD but without MCI. We measured plasma circulating mitochondrial DNA (ccf-mtDNA), lactate, and extracted nuclear mitochondrial encoded (NMt) single-nucleotide variants (SNVs) (n = 312). Non-parametric statistical tests on ccf-mtDNA and lactate levels were performed on the diagnosis, clinical and cardiometabolic variables. Binary sequence kernel association test (SKAT-O) and burden test were performed on NMt-SNV, adjusted for age, race, gender, type II diabetes, and APOE genotype. Lower level of lactate was observed in MCI (KW χ 2  = 14.8, P = 0.0024), more specifically, significant differences of lower plasma lactate between MCI only and rMDD, but not between MCI+rMDD and MCI were found, suggesting potential roles in MCI driving lactate lower levels. While higher levels of ccf-mtDNA were observed in APOE-ε4 carrier (χ 2  = 5.04, P = 0.05). This relationship was present only in MCI (P = 0.043) and MCI+rMDD groups (P = 0.023). No significant nuclear-encoded mitochondrial gene associations were observed with MCI or MDD. The results suggest decreased level of plasma lactate in individuals with MCI and MCI+rMDD, with inverse correlation with ccf-mtDNA, in addition to effect of APOE-ε4 in further increasing ccf-mtDNA specifically in participants with cognitive impairment. These findings contribute to a deeper understanding of the mitochondrial markers in MCI and MDD, warranting further research to explore the precise roles of mitochondrial abnormalities in the development and progression of MCI., (© 2024. The Author(s).)

Objective: The objective of the present study was to examine the effect of calorie restricted diet (CRD) plus inulin supplementation on serum levels of tryptophan (Trp), kynurenine (Kyn) and Trp/Kyn ratio in obese women with major depressive disorder (MDD)., Results: In this double-blind placebo-controlled randomized clinical trial, 51 obese women (BMI = 30-40 kg/m 2 ) with mild MDD were assessed for depression level using Hamilton depression rating scale (HDRS). The patients were randomly allocated into either "Prebiotic group" (received 10 g/day inulin) or "Placebo group" (received 10 g/day maltodextrin). All participants also received individualized CRD. Fasting serum levels of Trp, Kyn, and Trp/Kyn ratio were assessed at baseline and after 8 weeks. Results showed slightly greater increases in serum levels of Trp and Trp/Kyn ratio as well as reductions in serum level of Kyn and HDRS score in prebiotic group than placebo group. However, between group differences in these parameters as well as HDRS score were not statistically significant after adjusting for baseline variables at the end of the trial. Results indicates that CRD accompanied by inulin supplementation (10 g/day) did not influence serum levels of Trp, Kyn and Trp/Kyn ratio as well as HDRS score after 8 weeks., Trial Registration: The trial was registered in the Iranian registry of clinical trials at 2018-08-02 ( https://www.irct.ir/ ; registration number: IRCT20100209003320N15)., (© 2024. The Author(s).)

In patients with major depressive disorder, various functional areas are impaired, negatively impacting the quality of life. Remission can restore pre-depression functions; however, some patients may still have residual impairments. Distinguishing between near-normal recovery and residual impairment helps identify those at a high risk of relapse risk and helps tailor treatment. Accordingly, we aimed to discover and validate biomarkers that distinguish between near-normal recovery and residual impairment in remission states through serum proteome analysis. Pooled serum and individual serum samples from three groups (depression status, remission status with residual impairment, and remission status with normal recovery) were analyzed using liquid chromatography-tandem mass spectrometry. The combination of four proteins-antithrombin-III, serum amyloid A4 protein, C1q subcomponent subunit B, and serum amyloid P-component-was selected as a candidate biomarker. The trend of protein changes suggests complement C1q subcomponent subunit B and serum amyloid P-component as potential biomarkers for distinguishing remission from residual impairment. Changes in complement C1q subcomponent subunit B and serum amyloid P-component suggest that the complement system and inflammation-related immune mechanisms are associated with residual impairment in remittent major depressive disorder., (© 2024. The Author(s).)

Depressive disorder is a significant public health problem worldwide, which adversely affects children and adolescents' health. Impaired fasting blood glucose (IFG) is more common in depressive disorder, which becomes a clinical problem that needs to be focused on. The study purposed to determine the prevalence and related factors of IFG in Chinese children and adolescents with depressive disorder and the relationship between triglyceride and high-density lipoprotein cholesterol (TG/HDL-C) ratio and IFG. This research encompassed 756 individuals aged 8 to 18 with major depressive disorders, all diagnosed under DSM-5 criteria at the Third People's Hospital of Fuyang from January 2020 to December 2021. We detected fasting blood glucose (FBG) and lipid levels and assessed the suicidal behaviors and depressive symptoms severity of each participant. The sociodemographic and included study variables were collected and analyzed. Our study employed multiple logistic regression to discern independent factors affecting IFG in conjunction with depressive disorders among children and adolescents. The prevalence of IFG was 6.5% (49/756). IFG was positively correlated with FBG, BMI, TG, TG/HDL-C, and was negatively correlated with gender and the type of antidepressant drug taken. Binary logistic analysis showed that male (OR = 2.57, 95% CI: 1.43-4.63, P = 0.002) and higher levels of TG (OR = 1.63, 95% CI: 1.11-2.38, P = 0.013) were independently associated with IFG in children and adolescents with depressive disorder. The incidence of IFG in children and adolescents with depressive disorder was high and was positively related to the TG/HDL-C ratio. The evaluation and management of IFG in pediatric depression should extend beyond pharmacological interventions. Comprehensive strategies in both assessment and management of IFG are essential to address this condition effectively in young patients facing depressive disorders., (© 2024. The Author(s).)

Background: Major depression is a public health problem facing the world. This study aimed to identify the risk factors for major depression and clarify their causal effects., Methods: Data from the National Health and Nutrition Examination Survey (NHANES). Multifactorial logistic regression analysis was used to calculate the effect of each variable on major depression. Subgroup analyses and interaction tests were conducted to observe the stability of the association between them. Nonlinear correlations were explored using restricted cubic spline plots. The causal effects of serum Klotho on major depression were assessed using Mendelian randomization (MR) analysis., Results: A total of 8359 participated in the study. After adjusting for all covariates, the risk of having major depression was 1.47 times higher for each unit rise in serum Klotho (OR = 1.47, 95 % CI = 1.07-2.02; P = 0.0183). MR analysis showed no causal relationship between serum Klotho levels and risk of major depression (OR = 1.09, 95 % CI = 0.91-1.30; P = 0.4120). Sensitivity analysis verified the reliability of the results., Conclusions: Serum Klotho is positively associated with an increased risk of major depression in the U.S. population, but MR analyses did not show genetic causality between Klotho and major depression in individuals of European ancestry. Based on the results of the current study, no indication maintaining high levels of Klotho may increase the risk of major depression., Limitations: The main limitation of this study is the inconsistency of the cross-sectional study and the MR population., Competing Interests: Declaration of competing interest The authors have declared no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Background: Previous studies have shown a lower hemodynamic response in patients with major depressive disorder (MDD) during cognitive tasks. However, the mechanism underlying impaired hemodynamic and neural responses to cognitive tasks in MDD patients remains unclear. Succinate dehydrogenase (SDH) is a key biomarker of mitochondrial energy generation, and it can affect the hemodynamic response via the neurovascular coupling effect. In the current study, cerebral hemodynamic responses were detected during verbal fluency tasks (VFTs) via functional near-infrared spectroscopy (fNIRS) and SDH protein levels were examined in serum from MDD patients to quickly identify whether these hemodynamic alterations were related to mitochondrial energy metabolism., Methods: Fifty patients with first-episode drug-naïve MDD and 42 healthy controls (HCs) were recruited according to inclusion and exclusion criteria. The 17-item Hamilton Depression Rating Scale (17-HDRS), Hamilton Anxiety Rating Scale (HAMA) and Inventory of Depressive Symptomatology-Self Report (IDS-SR) were used to assess the clinical symptoms of the patients. All participants underwent fNIRS measurements to evaluate cerebral hemodynamic responses in the frontal and temporal cortex during VFTs; moreover, SDH protein levels were measured using an enzyme-linked immunosorbent assay., Results: Activation in the frontal-temporal brain region during the VFTs was lower in patients with MDD than in HCs. The SDH level in the serum of MDD patients was also significantly lower than that in HCs (p = 0.003), which significantly affected right lateral frontal (p = 0.025) and right temporal (p = 0.022) lobe activation. Both attenuated frontal-temporal activation during the VFTs (OR = 1.531) and lower SDH levels (OR = 1.038) were risk factors for MDD., Conclusions: MDD patients had lower cerebral hemodynamic responses to VFTs; this was associated with mitochondrial dysfunction, as indicated by SDH protein levels. Furthermore, attenuated hemodynamic responses in frontotemporal regions and lower SDH levels increased the risk for MDD., Limitations: The sample size is relatively small. SDH protein levels in peripheral blood may not necessarily reflect mitochondrial energy generation in the central nervous system., Competing Interests: Declaration of competing interest The authors have no conflicts of interest in connection with this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Depression is accompanied by dyslipidemia, which may increase the risk of stroke and coronary heart disease. This study sought to quantitatively summarize the clinical data comparing peripheral blood triglyceride (TG) concentrations between patients with major depressive disorder (MDD) and healthy controls (HCs). Studies were searched in PubMed, EMBASE, PsycINFO, and Cochrane Databases up to March 2023. We also reviewed the reference lists of obtained articles. Mean (±SD) for TG concentrations were extracted, combined quantitatively using random-effects meta-analysis, and summarized as a standardized mean difference (SMD). Subgroup analysis and meta-regression was performed to explore the resource of heterogeneity. Thirty-eight studies measuring the concentrations of peripheral blood TG in 2604 patients with MDD and 3272 HCs were included. Meta-analysis results indicated that TG levels were significant higher in patients with MDD than in HCs (SMD = 0.31, 95% confidence interval [CI]: 0.16 to 0.46, Z46 = 4.05, p < 0.01). Heterogeneity was detected (χ2 = 269.97, p < 0.01, I2 = 85%). Subgroup analysis demonstrated significant differences in TG levels between patients with MDD and HCs depended on age, body mass index and drug use (p < 0.05), but no differences between groups. Meta-regression also found no significant variables. TG level was significantly elevated in depression, which may explain the increased risk of cardiovascular and cerebrovascular events in depression., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Xu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Inhibitory control function and proinflammatory cytokines play a role in the pathomechanisms underlying major affective disorders and suicidal behavior. However, the distinct or interactive effects of major affective disorders and suicidal symptom severity on inhibitory control function and proinflammatory cytokines remain unclear., Methods: This study included 287 patients with bipolar disorder, 344 with major depressive disorder, and 169 healthy controls. We categorized the participants into 3 groups based on Montgomery-Åsberg Depression Rating Scale (MADRS) item 10 (suicidal symptoms) score: 0, 2 or 3, and ≥4. The participants completed the go/no-go task and the measurements for C-reactive protein (CRP) and tumor necrosis factor-α (TNF-α) levels., Results: Errors in the go/no-go task were associated with suicidality (P = .040), regardless of the severity of suicidal symptoms and diagnosis. An elevated CRP level was especially associated with a Montgomery-Åsberg Depression Rating Scale item 10 score ≥4 (P = .001). An increased TNF-α level could distinguish bipolar disorder from major depressive disorder (P < .001)., Discussion: Our study indicated the distinct effects of major affective disorder diagnosis and suicide symptom severity on inhibitory control function and CRP and TNF-α levels. Importantly, individuals with the poorest inhibitory control function and highest CRP levels had more severe suicidal symptoms., (© The Author(s) 2024. Published by Oxford University Press on behalf of CINP.)

Whether proinflammatory cytokine dysregulation and cognitive dysfunction are associated with suicidal symptoms in adolescents and young adults with major depressive disorder (MDD) remains uncertain. We assessed the cognitive function and proinflammatory cytokine levels of 43 and 51 patients aged 15-29 years with MDD and severe and mild suicidal symptoms, respectively, as well as those of 85 age- and sex-matched healthy controls. Specifically, we measured serum levels of C-reactive protein, tumor necrosis factor-α (TNF-α), interleukin-2, and interleukin-6 and assessed cognitive function by using working memory and go/no-go tasks. The severity of the patients' suicidal symptoms was based on Item 10 of the Montgomery-Åsberg Depression Rating Scale; scores of ≤ 2 and ≥ 4 indicated mild and severe symptoms, respectively. The patients with MDD and severe suicidal symptoms had higher levels of C-reactive protein (p = .019) and TNF-α (p = .002) than did the patients with mild symptoms or the healthy controls. The number of errors committed on the go/no-go by patients with MDD and severe suicidal symptoms (p = .001) was significantly higher than those by patients with MDD and mild symptoms or by controls. After adjusting for nonsuicidal depressive symptoms, we observed suicidal symptoms to be positively associated with TNF-α levels (p = .050) and errors on the go/no-go task (p = .021). Compared with mild suicidal symptoms, severe symptoms are associated with greater serum levels of proinflammatory cytokines and inferior cognitive function in adolescents and young adults with MDD., (© 2024. The Author(s).)

Nesfatin-1 and ghrelin, initially recognised as hormones involved in regulating energy, have emerged as crucial players with vital functions in various human body systems. In this study, we conducted a comparative assessment of nesfatin-1 and ghrelin responses in individuals experiencing metabolic stress due to diabetes, those with depressive diabetes characterised by both metabolic and mental stress, and healthy controls. We collected blood samples from a total of 90 participants, consisting of 30 people with type II diabetes mellitus (DM), 30 people with type II DM and major depressive disorders, and 30 healthy individuals. Diabetes was diagnosed based on glycated haemoglobin (HbA1c) levels, while depression was assessed using DSM-V criteria. Insulin resistance (HOMA-IR) was calculated, and serum ghrelin and nesfatin-1 levels were measured using ELISA kits. We observed statistically significant decreases in nesfatin-1 and ghrelin levels in the diabetic group (p < 0.0001). However, in the depressive diabetic group, nesfatin-1 levels increased significantly, while ghrelin levels decreased further. The nesfatin-1 to ghrelin ratio decreased in the diabetic group but increased significantly in the depressive diabetic group (p < 0.0001). Nesfatin-1 and ghrelin hormones exhibit parallel impacts in response to metabolic stress, but nesfatin-1 demonstrates contrasting actions compared to ghrelin when mental stress is added to metabolic stress. The findings of this study suggest that nesfatin-1 and ghrelin hormones may play active roles as protective, prognostic, and even etiological factors in various stress situations, particularly those involving mental stress, in addition to their known functions in regulating energy., (© 2024 The Author(s). Stress and Health published by John Wiley & Sons Ltd.)

Major depressive disorder (MDD) is a highly prevalent psychiatric disorder and a leading cause of disability worldwide. Brain-derived neurotrophic factor (BDNF), a signaling protein responsible for promoting neuroplasticity, is highly expressed in the central nervous system but can also be found in the blood. Since impaired brain plasticity is considered a cornerstone in the pathophysiology of MDD, measurement of BDNF in blood has been proposed as a potential biomarker in MDD. The aim of our study is to systematically review the literature for the effects of antidepressant treatments on blood BDNF levels in MDD and the suitability of blood BDNF as a biomarker for depression severity and antidepressant response. We searched Pubmed® and Cochrane library up to March 2024 in a systematic manner using Medical Subject Headings (MeSH). The search resulted in a total of 42 papers, of which 30 were included in this systematic review. Generally, we found that patients with untreated MDD have a lower blood BDNF level than healthy controls. Antidepressant treatments increase blood BDNF levels, and more evidently after pharmacological than non-pharmacological treatment. Neither baseline nor change in the blood BDNF level correlates with depression severity or treatment outcome, which undermines its use as a biomarker in MDD. Our review also highlights the importance of considering factors influencing the accuracy and reproducibility of BDNF measurements. We summarize considerations to help obtain more robust blood BDNF values and compile a list of recommendations to help streamline assessment of blood BDNF levels in future studies., Competing Interests: Declaration of competing interest EC is a co-founder and a board member of Kasvu Therapeutics and has received speaker fees from Janssen-Cilag. GMK has within the last 3 years received speaker fees from H. Lundbeck, Abbvie and Angelini and is a consultant for several pharmaceutical companies unrelated to this paper. LVK has within the last 3 years received speaker fees from Lundbeck and Teva. All other authors declare that they have no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

The main hurdles with current therapies for major depressive disorder (MDD) include lack of efficacy, therapeutic latency, and adverse drug reactions. Add-on therapy to conventional antidepressants may result in better therapeutic outcomes to overcome these obstacles. Sarcosine (N-methyl glycine), an endogenous amino acid that acts by modulating the NMDA receptor, is available as a dietary supplement. So, the present study was planned to evaluate the efficacy and safety of add-on sarcosine to SSRIs in MDD. In the present randomized, double-blind clinical trial (NCT04975100), 60 eligible participants with MDD were randomly assigned to either the test group (SSRI + sarcosine) or the control group (SSRI + placebo). Clinical and biochemical parameters like MADRS, CGI, serum BDNF, and serum glycine were assessed at baseline and eight weeks. The mean reduction in MADRS score was significant in both the control (-8.7, 95% CI: -11.0 to -6.4, p < 0.001) and the test group (-13.3, 95% CI: -14.9 to -11.7, p < 0.001), but the change in the test group was significantly greater (-4.6, 95% CI: -7.5 to -1.7, p = 0.003). The test group had a significantly higher response rate (p = 0.007) and remission rate (p = 0.038) compared to the control group. There was a significant increase in serum BDNF in both groups; however, the change in the test group was significantly higher than in the control group (p = 0.041). Similarly, the test group had a significantly higher increase in serum glycine than the control group (p < 0.001). Sarcosine may be considered an efficacious and safe add-on therapy to standard SSRIs in the management of MDD. ClinicalTrial.gov IdentifierNCT04975100., Competing Interests: Declaration of competing interest None to declare., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Major depressive disorder (MDD) is strongly associated with type 2 diabetes mellitus (T2DM). The kynurenine and serotonin pathways, as well as chronic low-grade inflammation, are being considered potential links between them. MDD associated with T2DM is less responsive to treatment than that without T2DM; however, the underlying mechanism remains unknown. We aimed to investigate the effects of inflammatory cytokines on the kynurenine and serotonin pathways in patients with comorbid MDD and T2DM and those with only MDD. We recruited 13 patients with comorbid MDD and T2DM and 27 patients with only MDD. We measured interleukin-6 and tumor necrosis factor-α (TNF-α) levels as inflammatory cytokines and metabolites of the kynurenine pathway and examined the relationship between the two. TNF-α levels were significantly higher in patients with comorbid MDD and T2DM than in those with only MDD in univariate (p = 0.044) and multivariate (adjusted p = 0.036) analyses. TNF-α showed a statistically significant effect modification (interaction) with quinolinic acid/tryptophan and serotonin in patients from both groups (β = 1.029, adjusted p < 0.001; β =  - 1.444, adjusted p = 0.047, respectively). Limitations attributed to the study design and number of samples may be present. All patients were Japanese with mild to moderate MDD; therefore, the generalizability of our findings may be limited. MDD with T2DM has more inflammatory depression components and activations of the kynurenine pathway by inflammatory cytokines than MDD without T2DM. Hence, administering antidepressants and anti-inflammatory drugs in combination may be more effective in patients with comorbid MDD and T2DM., (© 2023. The Author(s).)

Major Depressive Disorder (MDD) is a heterogeneous disorder that affects twice as many women than men. Precluding advances in more tailored and efficacious treatments for depression is the lack of reliable biomarkers. While depression is linked to elevations in inflammatory immune system functioning, this relationship is not evident among all individuals with depression and may vary based on symptom subtypes and/or sex. This systematic review and meta-analysis examined whether inflammatory immune peripheral markers of depression are sex-specific. PRISMA guidelines were followed for the systematic review, and a comprehensive search strategy that identified studies from PubMed and PsycInfo was applied. Studies were included if they reported C-reactive protein (CRP), interleukin (IL)-6, tumor necrosis factor (TNF)-α and/or IL-1β for males and/or females among depressed and healthy adults. We identified 23 studies that satisfied these inclusion criteria. Random-effects meta-analysis models were fit, and measures of association were summarized between levels of circulating markers of inflammation in depressed and healthy males and females. Sex-based analyses revealed elevated levels of CRP among females with depression (Cohen's d = 0.19) relative to their healthy counterparts (p = 0.02), an effect not apparent among males (Cohen's d = -0.01). Similarly, levels of IL-6 were increased among females with depression compared to healthy controls (Cohen's d = 0.51; p = 0.04), but once again this was not found among males (Cohen's d = 0.16). While TNF-α levels were elevated among individuals with depression compared to controls (p = 0.01), no statistically significant sex differences were found. The meta-analysis for IL-1β resulted in only three articles, and thus, results are presented in the supplemental section. This meta-analysis advances our understanding of the unique involvement of inflammatory biomarkers in depression among men and women, which may help inform more tailored sex-specific treatment approaches in the future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

This study investigates the relationship between psychotic symptoms and suicide attempts in young first-episode, drug-naive Chinese Han outpatients diagnosed with Major Depressive Disorder (MDD). The prevalence of Psychotic Major Depressive Disorder (PMD) was found to be 8.3% among the enrolled MDD patients. The study assessed 1289 participants using various scales to evaluate the severity of clinical symptoms, including the CGI-S, the HAMD, the HAMA, and the PANSS positive subscale. Additionally, thyroid hormone and glucolipid metabolism indicators were examined. The findings indicate that among patients with PMD, 41.12% had recent suicide attempts, while 6.54% had previous suicide attempts. Patients who recently attempted suicide exhibited higher scores on the HAMA and CGI scales, along with elevated serum levels of Thyroid-Stimulating Hormone (TSH) and total cholesterol (TC), as well as higher systolic and diastolic blood pressure. Notably, TSH levels independently correlated with recent suicide attempts in PMD patients, with an impressive area under the receiver operating characteristic curve (AUROC) of 0.923. Furthermore, the subgroup of patients with previous suicide attempts displayed longer illness duration and higher HAMD scores. Duration of illness and HAMD were found to be independently associated with previous suicide attempts among PMD patients, with a combined predictive effect showing a robust AUROC of 0.910. In conclusion, this study highlights the significant prevalence of recent and previous suicide attempts among young Chinese Han outpatients with PMD. The identification of risk factors, especially the link between TSH levels and recent suicide attempts, offers valuable insights for clinicians to develop targeted interventions and preventive strategies for this vulnerable patient population., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background & Aims: Growing evidence suggests that neurotransmitters may be associated with cognitive decline in MDD. This study primarily investigated the differences in cognitive functions between MDD patients and healthy controls, and explored the potential association between neurotransmitters and cognitive function of MDD patients., Methods: This cross-sectional study enrolled 87 first-diagnosed and drug-naïve patients with MDD and 50 healthy controls. Neurotransmitters (glutamine, glutamic acid, γ-2Aminobutiric acid, kainate, vanillylmandelic acid (VMA), 3-methoxy 4-hydroxyphenyl ethylene glycol (MHPG), noradrenaline (NE), homovanillic acid, dihydroxy-phenyl acetic acid (DOPAC), dopamine (DA), tryptophane, kynurenine, 5-HT, 5-hydroxyindoleacetic acid) were measured using LC-MS/MS and cognitive functions were assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Then associative analyses with adjustment (female, age, BMI, education) by multiple linear regression between neurotransmitters and cognitive functions especially in MDD patients were performed., Results: MDD patients had lower RBANS scores in immediate memory, delayed memory and RBANS scores after adjustment. Neurotransmitters were associated with the cognitive levels of MDD patients after adjustment: DOPAC and DOPAC/DA had positive association with immediate memory score; DOPAC, DOPAC/DA and (VMA+MHPG)/NE were positively associated with attention score; NE was negatively associated with language score; DOPAC/DA was positively associated with both delayed memory and RBANS scores., Conclusion: Patients had greater cognitive impairment especially in memory. Furthermore, plasma neurotransmitter may be related to MDD and play an important role in cognitive impairment in MDD, especially in memory and attention., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Previous research has shown that patients with major depressive disorder (MDD) develop immune dysfunction. However, the exact alterations of cluster of differentiation (CD)4 + T helper (Th) lymphocytes in MDD remains unclear. This meta-analysis aimed to examine the specific changes in CD4 + Th cells. A comprehensive search of PubMed, EMBASE, Web of Science, and PsycINFO databases was conducted to identify studies investigating CD4 + Th, Th1, Th2, Th17, and T regulatory (Treg) cell counts in the peripheral blood of MDD patients and healthy controls (HCs), covering the period up to June 22, 2024. Our findings revealed that patients with MDD might exhibit higher CD4 + Th cells (SMD=0.26, 95 %CI, 0.02 to 0.50), CD4 + /CD8 + cell ratios (SMD=0.51, 95 %CI, 0.14 to 0.89), Th1/Th2 cell ratios (SMD=0.15, 95 %CI, 0.01 to 0.30) and lower Th1 (SMD=-0.17, 95 %CI, -0.30 to -0.03), Th2 (SMD=-0.25, 95 %CI, -0.40 to -0.11), and Treg cells (SMD=-0.69, 95 %CI, -1.27 to -0.11). However, no significant difference was observed in terms of Th17 cells and Th17/Treg cell ratios between MDD patients and the HCs. Heterogeneity was large (I 2 :18.1-95.2 %), and possible sources of heterogeneity were explored (e.g., age, depression scale, country, and antidepressant use). Our findings indicate that peripheral CD4 + T cells in depressed patients exhibit features of adaptive immune dysfunction, as evidenced by increased CD4 + Th cells and CD4 + /CD8 + and decreased Treg cells. These findings offer insights into the underlying mechanism of MDD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

Objective: Major depressive disorder (MDD) is often accompanied by psychotic symptoms. However, few studies have examined the relationship between psychotic symptoms and endocrine factors in adolescent patients with MDD. Therefore, this study aimed to investigate the prevalence and related endocrine clinical factors of psychotic symptoms in Chinese adolescent patients with MDD., Methods: In total, 601 patients (aged 12-18) with MDD were recruited. The Patient Health Questionnaire - 9 items (PHQ - 9) was utilized for assessing depressive symptoms. Psychotic symptoms were assessed through clinical interviews. Prolactin (PRL), thyroid-stimulating hormone (TSH), triiodothyronine (T3), free triiodothyronine (FT3), thyroxine (T4), and free thyroxine (FT4) were also measured., Results: The incidence of psychotic symptoms in adolescent patients with MDD was 22.6%. The findings demonstrated that age, self-harming behavior, PHQ-9 score, FT4, and normalized PRL were independently associated with psychotic symptoms in patients with MDD (All p < 0.05)., Conclusions: PRL and FT4 levels are more likely to be abnormally elevated in major depressive adolescents with psychotic symptoms. Prolactin and thyroid hormones in patients with MDD should be paid more attention., (© 2024. The Author(s).)

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., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Li et al.)

Purpose: Major depressive disorder (MDD) is frequently accompanied by the symptoms of clinical anxiety. Since our previous research has found that n-3 PUFA supplementation alleviates anxiety in MDD, this study was aimed to further explore whether n-3 PUFA supplementation improves anxiety symptoms in depression by directly manipulating fatty acid levels., Methods: A secondary analysis of biomarker data (erythrocyte fatty acid composition) collected as part of the randomized clinical trial which investigated the adjunctive effect of n-3 PUFAs was conducted on 72 venlafaxine-treated outpatients with first-diagnosed, drug-naïve depression. All participants with longitudinal biomarker data were included in the association analysis to determine how n-3 PUFA supplementation influences fatty acid composition and alleviates anxiety symptoms in depression., Results: Decreases of the C20:3n6 were found in all participants at both follow-up time points (χ 2  = 96.36, p = 0.000). The n-3 index (χ 2  = 10.59, p = 0.001), EPA (χ 2  = 24.31, p = 0.000), and C22:5n3/C20:5n3 ratio (χ 2  = 10.71, p = 0.001) were increased, while C22:4n6 (χ 2  = 7.703, p = 0.006) was decreased in n-3 PUFA group compared to the placebo group. The improvement in anxiety symptoms positively correlates with the extent of reduction of C16:0, C18:0, and total fatty acid levels as well as D5 desaturase activity (p < 0.05)., Conclusion: These data suggest that the anxiolytic effect exerted by n-3 PUFAs in first-diagnosed, drug-naïve depression is manipulated by erythrocyte fatty acid levels. Saturated fatty acid levels have an important role in predicting the severity of anxiety symptoms., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Major depressive disorder (MDD) is a psychiatric illness that can jeopardize the normal growth and development of adolescents. Approximately 40% of adolescent patients with MDD exhibit resistance to conventional antidepressants, leading to the development of Treatment-Resistant Depression (TRD). TRD is associated with severe impairments in social functioning and learning ability and an elevated risk of suicide, thereby imposing an additional societal burden. In this study, we conducted plasma metabolomic analysis on 53 adolescents diagnosed with first-episode drug-naïve MDD (FEDN-MDD), 53 adolescents with TRD, and 56 healthy controls (HCs) using hydrophilic interaction liquid chromatography-mass spectrometry (HILIC-MS) and reversed-phase liquid chromatography-mass spectrometry (RPLC-MS). We established a diagnostic model by identifying differentially expressed metabolites and applying cluster analysis, metabolic pathway analysis, and multivariate linear support vector machine (SVM) algorithms. Our findings suggest that adolescent TRD shares similarities with FEDN-MDD in five amino acid metabolic pathways and exhibits distinct metabolic characteristics, particularly tyrosine and glycerophospholipid metabolism. Furthermore, through multivariate receiver operating characteristic (ROC) analysis, we optimized the area under the curve (AUC) and achieved the highest predictive accuracy, obtaining an AUC of 0.903 when comparing FEDN-MDD patients with HCs and an AUC of 0.968 when comparing TRD patients with HCs. This study provides new evidence for the identification of adolescent TRD and sheds light on different pathophysiologies by delineating the distinct plasma metabolic profiles of adolescent TRD and FEDN-MDD., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Accelerated brain ageing has been observed in multiple psychiatric disorders. This study examined whether relationships between age and plasma neurofilament light (NfL) protein differed in individuals with psychiatric disorders (major depressive disorder (n = 42), bipolar affective disorder (n = 121), treatment-resistant schizophrenia (TRS, n = 82)) compared to two healthy control (HC) groups (n = 1,926 and n = 59). Compared to two independent HC samples, individuals with TRS demonstrated a stronger positive relationship between age and NfL levels. Individuals with BPAD had a stronger negative relationship between age and NfL levels compared to the large normative HC cohort, but not locally-acquired HCs. These findings show that plasma NfL levels are differentially associated with age in individuals with TRS and BPAD compared to healthy individuals., Competing Interests: Declaration of competing interest The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The authors acknowledge the financial support of the CRC for Mental Health. The Cooperative Research Centre (CRC) programme is an Australian Government Initiative. The authors acknowledge the CRC Scientific Advisory Committee, in addition to the contributions of study participants, clinicians at recruitment services, staff at the Murdoch Children's Research Institute, staff at the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Aging, and research staff at the Melbourne Neuropsychiatry Centre, including coordinators Merritt, A., Phassouliotis, C., and research assistants, Burnside, A., Cross, H., Gale, S., and Tahtalian, S. Participants for this study were sourced, in part, through the Australian Schizophrenia Research Bank (ASRB), which is supported by the National Health and Medical Research Council of Australia (Enabling Grant N. 386500), the Pratt Foundation, Ramsay Health Care, the Viertel Charitable Foundation and the Schizophrenia Research Institute. We thank the Chief Investigators and ASRB Manager: Carr, V., Schall, U., Scott, R., Jablensky, A., Mowry, B., Michie, P., Catts, S., Henskens, F., Pantelis, C., Loughland, C. We acknowledge the help of Jason Bridge for ASRB database queries. The authors are grateful for assistance from Brett Trounson and Dr Christopher Fowler and the team at The Florey Oak St Biobank., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Major depressive disorder (MDD) is notably underdiagnosed and undertreated due to its complex nature and subjective diagnostic methods. Biomarker identification would help provide a clearer understanding of MDD aetiology. Although machine learning (ML) has been implemented in previous studies to study the alteration of microRNA (miRNA) levels in MDD cases, clinical translation has not been feasible due to the lack of interpretability (i.e. too many miRNAs for consideration) and stability., Methods: This study applied logistic regression (LR) model to the blood miRNA expression profile to differentiate patients with MDD (n = 60) from healthy controls (HCs, n = 60). Embedded (L1-regularised logistic regression) feature selector was utilised to extract clinically relevant miRNAs, and optimized for clinical application., Results: Patients with MDD could be differentiated from HCs with the area under the receiver operating characteristic curve (AUC) of 0.81 on testing data when all available miRNAs were considered (which served as a benchmark). Our LR model selected miRNAs up to 5 (known as LR-5 model) emerged as the best model because it achieved a moderate classification ability (AUC = 0.75), relatively high interpretability (feature number = 5) and stability (ϕ̂Z=0.55) compared to the benchmark. The top-ranking miRNAs identified by our model have demonstrated associations with MDD pathways involving cytokine signalling in the immune system, the reelin signalling pathway, programmed cell death and cellular responses to stress., Conclusion: The LR-5 model, which is optimised based on ML design factors, may lead to a robust and clinically usable MDD diagnostic tool., Competing Interests: Declaration of competing interest There are no conflict of interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: This cross-sectional study aimed to characterize the differences of metabolic profiles and atherogenicity between various levels of fatigue severity in patients with major depressive disorder (MDD), and examine the extent to which metabolic abnormality correlates with fatigue severity., Methods: We recruited 119 patients with MDD and assessed fatigue severity using Krupp's Fatigue Severity Scale. Blood samples were collected to determine plasma levels of fasting glucose, high-density lipoprotein cholesterol (HDL-C), triglycerides, total cholesterol and low-density lipoprotein cholesterol. The atherogenic index of plasma (AIP) was calculated as log10 (triglycerides/HDL-C)., Results: MDD with severe fatigue were more likely to be younger (43.3 ± 10.3 years vs. 49.4 ± 8.5 years, p = 0.001), had a younger age of onset (34.7 ± 9.7 years vs. 40.7 ± 9.5 years, p = 0.001), demonstrated higher HAMD scores (18.0 ± 7.6 vs. 10.9 ± 7.5, p < 0.001), as well as lower HDL-C levels (48.5 ± 10.8 vs. 55.3 ± 13.9, p = 0.003), a greater prevalence of low HDL-C (43.9% vs. 22.6%, p = 0.015) and higher AIP levels (0.4 ± 0.3 vs. 0.3 ± 0.3, p = 0.046). Both a decreased plasma HDL-C level (OR = 0.95, 95% CI = 0.91-0.99, p = 0.009) and a diagnosis of low HDL-C (OR = 3.29, 95% CI = 1.27-8.57, p = 0.015) were significantly correlated with an increased risk of fatigue severity., Conclusion: HDL-C could potentially protect patients with MDD from severe fatigue and the associated risk of cardiovascular disease., Competing Interests: Declaration of competing interest The authors report no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: It is widely known that sex differences have a significant impact on patients with major depressive disorder (MDD). This study aims to evaluate the sex-related connection between serum trace elements and changes in neurometabolism in the anterior cingulate cortex (ACC) of MDD patients., Methods: 109 untreated MDD patients and 59 healthy controls underwent proton magnetic resonance spectroscopy ( 1 H-MRS) under resting conditions. We measured metabolic ratios in the ACC from both sides. Additionally, venous blood samples were taken from all participants to detect calcium (Ca), phosphorus, magnesium (Mg), copper (Cu), ceruloplasmin (CER), zinc (Zn), and iron (Fe) levels. We performed association and interaction analyses to explore the connections between the disease and gender., Results: In individuals with MDD, the Cu/Zn ratio increased, while the levels of Mg, CER, Zn and Fe decreased. Male MDD patients had lower Cu levels, while female patients had an increased Cu/Zn ratio. We observed significant gender differences in Cu, CER and the Cu/Zn ratio in MDD. Male patients showed a reduced N-acetyl aspartate (NAA)/phosphocreatine + creatine (PCr + Cr) ratio in the left ACC. The NAA/PCr + Cr ratio decreased in the right ACC in patients with MDD. In the left ACC of male MDD patients, the Cu/Zn ratio was inversely related to the NAA/PCr + Cr ratio, and Fe levels were negatively associated with the GPC + PC/PCr + Cr ratio., Conclusions: Our findings highlight gender-specific changes in Cu homeostasis among male MDD patients. The Cu/Zn ratio and Fe levels in male MDD patients were significantly linked to neurometabolic alterations in the ACC., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Purpose: Elevated bilirubin levels have been associated with major depressive disorder (MDD); however, the exact impact of bilirubin on MDD and the underlying molecular mechanisms remain unclear. Here, we explored the influence of bilirubin on MDD and sought to identify the mechanisms via which bilirubin induces depressive-like behavior., Patients and Methods: Forty patients who were diagnosed with MDD and received treatment with selective serotonin reuptake inhibitors (SSRIs) were included, with 43 healthy volunteers serving as controls. Clinical symptoms were evaluated using Hamilton depression rating scale-24 (HAMD-24) and the Hamilton anxiety rating scale. Serum concentrations of total bilirubin (TBIL) and indirect bilirubin (IBIL) were measured at baseline and after treatment using an automated biochemical analyzer. The connection between clinical symptoms and TBIL or IBIL was examined using Pearson correlation. Chronic restraint stress (CRS) was employed to generate a rat model of depression. TBIL, IBIL in rat serum were measured by ELISA. Reactive oxygen species (ROS) contents in rat hippocampal tissues were quantified by flow cytometry. The levels of microglial markers and the extent of neuronal damage in the rat hippocampus were assessed by immunofluorescence and transmission electron microscopy, respectively., Results: Serum TBIL and IBIL levels were higher in patients with MDD than in the healthy controls. After treatment with SSRIs, the serum levels of TBIL and IBIL in MDD patients were significantly reduced. The levels of TBIL and IBIL were associated with HAMD-24 in MDD patients. Compared with the controls, the serum levels of TBIL, IBIL and the hippocampal ROS contents were elevated in CRS-exposed rats. Fluoxetine lowered inflammatory factor levels, mitigated oxidative stress., Conclusion: Our findings indicate a possible correlation between elevated serum bilirubin and depressive symptoms. Increases in ROS levels, along with neuronal damage, may represent pathological mechanisms underlying MDD., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. and declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The absence of clinically-validated biomarkers or objective protocols hinders effective major depressive disorder (MDD) diagnosis. Compared to healthy control (HC), MDD exhibits anomalies in plasma protein levels and neuroimaging presentations. Despite extensive machine learning studies in psychiatric diagnosis, a reliable tool integrating multi-modality data is still lacking., Methods: In this study, blood samples from 100 MDD and 100 HC were analyzed, along with MRI images from 46 MDD and 49 HC. Here, we devised a novel algorithm, integrating graph neural networks and attention modules, for MDD diagnosis based on inflammatory cytokines, neurotrophic factors, and Orexin A levels in the blood samples. Model performance was assessed via accuracy and F1 value in 3-fold cross-validation, comparing with 9 traditional algorithms. We then applied our algorithm to a dataset containing both the aforementioned protein quantifications and neuroimages, evaluating if integrating neuroimages into the model improves performance., Results: Compared to HC, MDD showed significant alterations in plasma protein levels and gray matter volume revealed by MRI. Our new algorithm exhibited superior performance, achieving an F1 value and accuracy of 0.9436 and 94.08 %, respectively. Integration of neuroimaging data enhanced our novel algorithm's performance, resulting in an improved F1 value and accuracy, reaching 0.9543 and 95.06 %., Limitations: This single-center study with a small sample size requires future evaluations on a larger test set for improved reliability., Conclusions: In comparison to traditional machine learning models, our newly developed MDD diagnostic model exhibited superior performance and showed promising potential for inclusion in routine clinical diagnosis for MDD., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Exercise has acute, positive effects on mood and can lead to antidepressant effects over time when repeated regularly. The mechanisms underlying the antidepressant effects of exercise training are not well known, limiting the prescription of exercise training for depression. Serum Insulin-Like Growth Factor-1 (IGF-1) appears dysregulated in those with Major Depressive Disorder (MDD), suggesting MDD could inhibit or alter the IGF-1 response to exercise. In healthy individuals, exercise has been shown to acutely increase serum IGF-1, which may act positively on the dysregulated IGF-1 system in MDD. Therefore, the purpose of this study was to examine the sensitivity of serum IGF-1 levels to an acute maximal exercise bout in adults with MDD and healthy controls. Additionally, clinical and behavioral factors of MDD are likely to affect this system, such as depression severity, antidepressant usage and physical activity habits. Baseline data were used from a larger trial in Germany (SPeED Study) collected from individuals with mild to moderate MDD (n=113) and healthy controls (n=34) that were matched for age, sex, and education. Demographics, depression severity (Hamilton Depression Rating Scale-17), self-reported antidepressant usage, MVPA (International Physical Activity Questionnaire-Short Form), and blood draws before and after a maximal exercise test were collected. Multiple linear regressions were conducted to determine relationships between depression severity, antidepressant usage, and physical activity with peripheral IGF-1 levels following acute exercise. Covariates included demographic factors and IGF-1 pre-exercise (baseline levels). Acute IGF-1 changes occurred similarly in depression (mean ± SD; 11.3 ± 12.9) as well as healthy adults (11.3 ± 20.4: p>0.05). Neither depression severity, antidepressant use, nor regular physical activity were significant predictors of peripheral IGF-1 levels at baseline or following exercise. Individuals with MDD are likely to have favorable exercise-induced IGF-1 changes regardless of clinical and behavioral differences. Acute exercise increases peripheral IGF-1 briefly, and in response to repeated exercise bouts, the IGF-1 system could normalize over time. The normalization of the IGF-1 system might be a possible mechanism underlying mood increases that occur during exercise with exercise training research warranted., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., Competing Interests: Declaration of competing interest All authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: C-reactive protein (CRP) levels have been implicated in the severity and symptomatology of major depressive disorder (MDD). The aim of this study was to explore the structure of depressive symptoms in patients with MDD according to different groups of CRP levels using network analysis., Methods: The study included 864 individuals (mean age = 54.05, 67.48 % male) diagnosed with MDD from the 2015-2020 National Health and Nutrition Examination Survey (NHANES). Analyses examined how depressive symptoms and CRP level were related to each other, and how the network structure of depressive symptoms differed across groups with different CRP levels., Results: A direct positive correlation was observed between CRP levels and specific depressive symptoms (e.g., appetite change, energy loss, and feelings of worthlessness). Moreover, there was a stronger correlation between depressive symptoms in the medium CRP and high CRP groups compared to the low CRP group. Furthermore, it was observed that there were notable structural differences between the high-CRP and moderate-CRP groups., Limitations: The study is based on cross-sectional data, which precludes the drawing of causal conclusions. Furthermore, it does not take into account confounding factors such as body mass index (BMI) and lifestyle., Conclusions: The findings underscore the pivotal role of CRP as a marker of the severity of depressive symptoms. Routine CRP level testing and anti-inflammatory therapies may be beneficial for depressed patients with elevated CRP levels in clinical practice., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: To identify alterations in the immune profiles in outpatients with major depression (MDD), and its associations with key features, such as suicidal ideation, neuroticism, cognitive symptoms, and the depression phenome while accounting for metabolic syndrome (MetS)., Methods: In this case-control study, we assayed 48 serum cytokines, chemokines, and growth factors in 67 healthy controls and 66 MDD outpatients. Around 50 % of the outpatient MDD and control participants had a diagnosis of MetS., Results: Ten differentially expressed proteins (DEPs) were upregulated in outpatient MDD (i.e., CXCL12, tumor necrosis factor [TNF]β, platelet-derived growth factor [PDGF], CCL11, interleukins [IL]9, IL4, CCL5, CCL2, CCL4, IL1 receptor antagonist [IL1RN]), indicating an immune and defense response. Six DEPs were downregulated (vascular endothelial growth factor A [VEGFA], IL12, CCL3, colony stimulating factor [CSF]1, IL1B, nerve growth factor [NGF]), indicating lowered neurogenesis and neuron death regulation. Significant interactions between outpatient MDD and MetS caused a) substantial increases in IL4, IL17, TNF, TNFB, CCL2, CCL5, PDGF, IL1RN; and b) downregulation of VEGFA and FGF. A large part of the variance in neuroticism (26 %), suicidal behaviors (23 %), and the MDD phenome (31 %) was predicted by immunological data and interactions between MetS and CCL5, TNFB or VEGFA., Conclusion: Outpatient MDD is characterized by a cytokine profile with neurotoxic potential which partly explains neuroticism, suicidal behaviors, and the phenome's severity. Lowered IL-10 and activated cytokine profiles with neurotoxic potential are characteristics of outpatient MDD and other depression phenotypes, including severe first-episode inpatient MDD. The presence of MetS in outpatient MDD considerably activates immune profiles with neurotoxic potential. Consequently, immune studies in MDD should always be performed in subjects with and without MetS., Competing Interests: Declaration of competing interest The authors have no commercial or other competing interests concerning the submitted paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Major depressive disorder (MDD) is a prevalent mental disorder globally. Increasing evidence suggests that Environmental Metal (EM) play a crucial role in MDD. Therefore, this study investigated the roles of barium (Ba), cesium (Cs), nickel (Ni), manganese (Mn), lead (Pb), mercury (Hg), cadmium (Cd), and tin (Sn) in the etiology of MDD., Methods: The study included 72 MDD patients and 75 healthy controls (HCs) from the Second People's Hospital of Zhumadian, China. Inductively coupled plasma mass spectrometer (ICP-MS) measured the metal levels in serum and urine samples from both groups., Results: Significant differences in serum and urine levels of EMs were observed between MDD patients and HCs. After adjusting for age, gender, and BMI, logistic regression and quantile regression models revealed significant associations between EMs and MDD. In serum samples, higher Sn levels (OR = 1.22, p  = 0.044) increased MDD risk, whereas higher Cs levels (OR = 0.02, p  < 0.001), Cd (OR = 0.06, p = 0.047), and Mn (OR = 0.54, p  = 0.016) decreased MDD risk. In urine samples, higher Ba levels (OR = 0.94, p  = 0.015), Ni (OR = 0.87, p  = 0.0024), Sn (OR = 1.62, p  < 0.001), and Mn (OR = 0.77, p  = 0.037) were significantly associated with MDD. Sn significantly positively predicted HAMD-24 scores at the 0.50 and 0.75 quantiles (β = 0.96, p  = 0.018; β = 1.25, p  = 0.008) as did Pb (β = 5.15, p  = 0.001; β = 4.19, p  = 0.004). Ba positively predicted depressive symptoms across all quantiles (all p  < 0.05). Hg positively predicted HAMD-24 scores at the 0.50 quantile (β = 9.20, p  = 0.050)., Conclusion: These findings underscore EMs' importance in depression, aiding in targeted interventions for varying degrees of depression and necessitating future studies to clarify causality and mechanisms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Sun, Ding, Lu, Yan and Cao.)

Background: The relationship between gut microbiota and vertigo, specifically Benign Paroxysmal Vertigo (BPV) and Vertigo of Central (VC), remains underexplored., Aim and Hypotheses: This study aims to investigate the causal relationships between gut microbiota and two types of vertigo, BPV and VC. Additionally, the study seeks to explore the mediation effects of metabolic, inflammatory, and psychological factors on these relationships. We hypothesize that specific taxa of gut microbiota have a causal effect on the risk of developing BPV and VC. The mediation effects of HbA1c, obesity, major depression, and interleukin-18 levels significantly influence the relationships between gut microbiota and vertigo., Method: Utilizing a bidirectional two-sample Mendelian randomization approach, this study investigated causal associations between gut microbiota and the two types of vertigo. A network MR assessed mediation effects of HbA1c, major depression, obesity, and interleukin-18 levels, with data sourced from several consortia, including MiBioGen., Results: Distinct gut microbiota displayed varying influences on BPV and VC risks. A total of ten taxa affect BPV. Among these, two taxa have an odds ratio (OR) greater than 1, including one class, one order. Conversely, eight taxa have an OR less than 1, encompassing four families, three genera, and one order. The OR for these taxa ranges from 0.693 to 0.930, with p-values between 0.006 and 0.048. For VC, eight taxa were found to have an impact. Five of these taxa exhibit an OR greater than 1, including four genera and one phylum. The OR for these taxa ranges from 1.229 to 2.179, with p-values from 0.000 to 0.046. The remaining three taxa have an OR less than 1, comprising one family and two genera, with an OR range of 0.445 to 0.792 and p-values ranging from 0.013 to 0.050. The mediation analysis for BPV shows that major depression, obesity, and HbA1c are key mediators between specific taxa and BPV. Major depression mediates 28.77% of the effect of family Rhodospirillaceae on BPV. Obesity mediates 13.90% of the effect of class Lentisphaeria/order Victivallales. HbA1c mediates 11.79% of the effect of genus Bifidobacterium, 11.36% of family Bifidobacteriaceae/order Bifidobacteriales. For VC, interleukin-18 levels and major depression are significant mediators. Interleukin-18 levels mediate 6.56% of the effect of phylum Actinobacteria. Major depression mediates 6.51% of the effect of genus Alloprevotella., Conclusion: The study highlights potential causal links between gut microbiota and vertigo, emphasizing metabolic and psychological mediators. These insights underscore the therapeutic potential of targeting gut health in vertigo management., (© 2024. The Author(s).)

Older adults with major depressive disorder (MDD) or early cognitive decline during the subjective cognitive decline (SCD) stage may exhibit neuropsychiatric symptoms such as anxiety, depression, and subtle cognitive impairment. The clinicopathological features and biological mechanisms of MDD differ from those of SCD among older adults; these conditions thus require different treatment strategies. This study enrolled 82 participants above 50 years old with normal cognitive levels from the communities to examine biomarker-behavior correlations between MDD (n = 23) and SCD (n = 23) relative to a normal control (NC) group (n = 36). Multidomain assessments were performed for all participants, including immunomagnetic reduction tests to detect plasma beta-amyloid (Aβ), total tau (Tau), phosphorylated tau-181 (p-Tau181), neurofilament light chain, and glial fibrillary acidic protein (GFAP). This study observed that depressive symptoms in MDD were associated with amyloid pathology (plasma Aβ40 vs. HADS-D: R = 0.45, p = 0.031; Aβ42/Aβ40 vs. HADS-D: R = -0.47, p = 0.024), which was not observed in the NC (group difference p < 0.05). Moreover, cognitive decline in MDD was distinguished by a mixed neurodegenerative process involving amyloid (plasma Aβ42 vs. facial memory test: R = 0.48, p = 0.025), tau (Tau/Aβ42 vs. digit symbol substitution test (DSST): R = -0.53, p = 0.01), and astrocytic injury (plasma GFAP vs. Montreal cognitive assessment score: R = -0.44, p = 0.038; plasma GFAP vs. DSST: R = -0.52, p = 0.014), findings that did not apply to the NC (group difference p < 0.05). Moreover, this study revealed different biomarker-behavior correlations between individuals with SCD and the NC. Compared with the NC, cognitive decline in the SCD group might be unrelated to amyloid pathology and instead might be early manifestations of tau pathology. This study underscores the difference in clinicopathological features between MDD and SCD among older adults, which differ from those of the NC. These findings enhance our understanding of the mechanisms underlying MDD and SCD in older individuals., (© 2024. The Author(s).)