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Objective and quantitative neuroimaging biomarkers are crucial for early diagnosis of major depressive disorder (MDD). However, previous studies using machine learning (ML) to distinguish MDD have often used small sample sizes and overlooked MDD's neural connectome and mechanism. To address these gaps, we applied Dynamic Graph Convolutional Nets (DGCNs) to a large multi-site dataset of 2317 resting state functional MRI (RS-fMRI) scans from 1081 MDD patients and 1236 healthy controls from 16 Rest-meta-MDD consortium sites. Our DGCN model combined with the personal whole brain functional connectivity (FC) network achieved an accuracy of 82.5 % (95 % CI:81.6-83.4 %, AUC:0.869), outperforming other universal ML classifiers. The most prominent domains for classification were mainly in the default mode network, fronto-parietal and cingulo-opercular network. Our study supports the stability and efficacy of using DGCN to characterize MDD and demonstrates its potential in enhancing neurobiological comprehension of MDD by detecting clinically related disorders in FC network topologies., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

As a major mental health disorder, symptoms of schizophrenia (SCZ) include delusions, reduced motivation, hallucinations, reduced motivation and a variety of cognitive disabilities. Many of these symptoms are now known to be associated with abnormal regulation of the immune system. Low blood levels of cytokines and chemokines have been suggested to be one of the underlying causes of SCZ. However, their biological roles at different stages of SCZ remain unclear. Our objective was to investigate expression patterns of cytokines and chemokines at different stages of onset and relapse in SCZ patients and to conduct an analysis of their relationship to disease progression. We also aimed to identify immune features associated with different disease trajectories in patients with SCZ. Gene set enrichment analysis (GSEA) was used to interrogate the GSE27383 dataset and identify key genes associated with inflammation. These results led us to recruit 36 healthy controls, 40 patients with first-episode psychosis (FEP), and 39 patients with SCZ relapse. Meso Scale Discovery technology was used to independently validate serum levels of 35 cytokines and chemokines. This was followed by a meta-analysis to gain a more comprehensive understanding of the role of interleukin-8 (IL-8/CXCL8) in SCZ. Analysis of the GSE27383 database revealed 3596 genes with distinct expression patterns. A significant portion of these genes were identified as inflammation-related and showed remarkable enrichment in three key pathways: IL-17, cytokine-cytokine receptor, and AGE-RAGE signaling in diabetic complications. We observed co-expression of CXCL8 and IL-16 within these three pathways. In a subsequent analysis of independently validated samples, a notable discrepancy was detected in the inflammatory status between individuals experiencing FEP and those in relapse. In particular, expression of CXCL8 demonstrated superior predictive capability in FEP and relapsed patients. Notably, results of the meta-analysis confirmed that Chinese and European populations were consistent with the overall results (Z = 4.60, P < 0.001; Z = 3.70, P < 0.001). However, in the American subgroup, there was no significant difference in CXCL8 levels between patients with SCZ compared to healthy controls (Z = 1.09, P = 0.277). Our findings suggest that the inflammatory response in patients with SCZ differs across the different stages, with CXCL8 emerging as a potential predictive factor. Collectively, our data suggest that CXCL8 has the potential to serve as a significant immunological signature of SCZ subtypes. Trial registration: The clinical registration number for this trial is ChiCTR2100045240 (Registration Date: 2021/04/09)., Competing Interests: Declaration of competing interest The authors declare that this study was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

People with an evening chronotype have an increased risk of experiencing a major depressive disorder (MDD). It is unclear if this effect is predominantly related to the initial development of MDD or also present in recurrent episodes. The current study aimed to investigate if the association between chronotype and depressive severity in MDD patients is comparable in MDD patients with first and recurrent episodes. 386 MDD patients, 70.7% females and aged between 16 and 64, participated in the study. The Morningness - Eveningness Questionnaire (MEQ), Pittsburgh Sleep Quality Index (PSQI), Multidimensional Fatigue Inventory (MFI20), and Quick Inventory of Depressive Symptomatology (QIDS-SR16) were administered to participants to determine chronotype, sleep quality, fatigue level, and depressive severity, respectively. Multivariate regression models were utilized to analyze how chronotype influences depressive severity. The study showed that chronotype, sleep quality, and fatigue level were all associated with depressive severity. Eveningness significantly predicted an increase in depressive severity independently of sleep quality and fatigue level only in patients with the first episode (-0.068, p  = 0.010), but not in patients with recurrent episodes (0.013, p  = 0.594). Circadian-focused treatment should be considered in first-episode depression only.

Background: Depression, anxiety and schizophrenia among older persons have become global public health challenges. However, the burden of these disorders in ageing and aged countries has not been analysed., Aims: To investigate the burden of depression, anxiety and schizophrenia among older adults in ageing and aged countries., Methods: Using data from the Global Burden of Disease Study 2019, we calculated the estimated annual percentage change (EAPC) in the age-standardised incidence rates (ASIR) and age-standardised disability-adjusted life years (DALYs) rates (ASDR) for depression, anxiety and schizophrenia of older people in ageing countries (China, India, Indonesia) and aged countries (Japan, Italy, Portugal) between 1990 and 2019. Trends in incidence and DALYs were analysed by gender and age., Results: In 2019, the highest incidence of depression, anxiety and schizophrenia in the older population in aged countries was in Japan (927 271.3 (752 552.3-1 125 796.5), 51 498.2 (37 625.7-70 487.3) and 126.0 (61.0-223.2), respectively), while the highest incidence in ageing countries was in China (5 797 556.9 (4 599 403.4-7 133 006.5), 330 256.1 (246 448.9-445 987.4) and 1067.7 (556.2-1775.9), respectively). DALYs for these disorders were similar, with the highest in Japan and China. From 1990 to 2019, the ASIR for depressive disorders decreased in aged countries but increased in ageing countries; the ASIR for anxiety disorders and schizophrenia declined in both ageing and aged countries. The ASDR for depressive disorders was consistent with the ASIR but not for anxiety disorders and schizophrenia. The ASIR for depressive disorders was higher in older women, while the opposite was observed in anxiety disorders and schizophrenia. Notably, the conditions of burden of depressive disorders, anxiety disorders and schizophrenia in the 65-70-year-old age group were the most burdensome., Conclusions: The incidence and DALYs of these three mental disorders increased while exhibiting differences between ageing and aged countries. Raising awareness about formulating health policies for preventing and treating mental disorders in the older population is necessary to reduce the future burden posed by the ageing challenge., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Sleep deprivation (SD) has been suggested to have a rapid antidepressant effect. There is substantial evidence that neuroinflammation and neuroplasticity play critical roles in the pathophysiology and treatment of depression. Here, we investigated the mechanisms of SD to alleviate depression-like behaviors of mice, and the role of neuroinflammation and neuroplasticity in it., Methods: Adult male C57BL/6 J mice were subjected to chronic restraint stress (CRS) for 6 weeks, and 6 h of SD were administrated. Behavioral tests were performed to measure depression-like behaviors. RNA-sequencing and bioinformatic analysis were performed in the anterior cingulate cortex (ACC). The differentially expressed genes were confirmed by quantitative real-time polymerase chain reaction (RT-qPCR). Neuroinflammation and neuroplasticity were measured by western blotting and immunofluorescence staining., Results: Behavioral tests demonstrated that SD swiftly attenuated the depression-like behaviors induced by CRS. RNA-sequencing identified the upregulated immune and inflammatory pathways after CRS exposure were downregulated by SD. Furthermore, SD reversed the levels of immune and inflammation-related mRNA, pro-inflammatory factors and microglia activation in ACC. Additionally, the impaired neuroplasticity elicited by CRS in the prefrontal cortex (PFC) and ACC were improved by SD., Limitations: More in-depth studies are required to determine the role of different SD protocols in depressive symptoms and their underlying mechanisms., Conclusions: Our study revealed the rapid antidepressant effect of SD on CRS mice through the reduction of the neuroinflammatory response in ACC and the improvement of neuroplasticity in PFC and ACC, providing a theoretical basis for the clinical application of SD as a rapid antidepressant treatment., Competing Interests: Declaration of competing interest All the authors declare no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Objective: To explore the factors influencing anhedonia at baseline and use them as confounding factors. To further investigate the correlation between overt aggression and anhedonia during the acute phase of major depressive disorder., Methods: In this eight-week prospective study, 384 major depressive disorder patients were recruited from the outpatient section of Shanghai Mental Health Center from May 1, 2017, to October 30, 2018. Standard treatments were performed with escitalopram or venlafaxine for participants. Depressive symptoms, overt aggression, and anhedonia were assessed using the 17-item Hamilton Rating Scale for Depression, Modified Overt Aggression Scale, and Snaith-Hamilton Pleasure Scale at baseline, and in the 4th and 8th weeks., Results: Obsessive-compulsive symptoms and the duration of untreated psychosis were positively associated with aggression (P < 0.05). Patients with aggressive behaviour had worse cognitive impairment and severe anhedonia of pleasurable sensory experiences (P < 0.05). For anhedonia, being female (tau&#95;b = -0.23, P = 0.012) was a protective factor, while number of recurrent, melancholic features, current obsessions, previous combination drug therapies, depressive symptoms, and aggressive behaviour were risk factors (P < 0.05). Social anhedonia related to interests/pastimes, and pleasurable sensory experiences were more severe in major depressive disorder patients with aggressive behaviour in the acute phase (P < 0.05)., Conclusions: Anhedonia persisted in major depressive disorder patients with aggressive behaviour after standardized treatment during the acute phase. Being female protected the pleasures from social interaction and sensory experience. However, the number of depressive episodes, melancholic features, current obsessive symptoms, previous combination drug therapies, depressive symptoms, and aggressive behaviour was positively associated with anhedonia., Competing Interests: Declaration of competing interest The authors have no competing interests to report., (Copyright © 2023. Published by Elsevier Ltd.)

Objective: Inflammatory cytokines disturbance is the main result of immune dysregulation, which is widely described in major depressive disorder (MDD). However, the potential causal relationship between these two factors has not been discovered. Therefore, the purpose of this study was to investigate the causal relationship between inflammatory cytokines and MDD risk by using the two-sample Mendelian randomization (MR) analysis. Method: Two genetic instruments obtained from publicly available gene profile data were utilized for the analysis. We obtained the genetic variation data of 41 inflammatory cytokines from genome-wide association studies (GWAS) meta-analysis of 8293 individuals of Finnish descent. The MDD data, including 135,458 MDD cases and 344,901 controls, were obtained from the Psychiatric Genomics Consortium Database. For the Mendelian randomization (MR) estimation, several methods were employed, namely, MR-Egger regression, inverse-variance weighted (IVW), weighted median, and MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO) methods. Result: A causal relationship was identified between the genetically proxied levels of Interleukin (IL) -18, IL-1β, and Regulated upon activation normal T cell expressed and secreted (RANTES) and the risk of MDD (OR = 0.968, 95%CI = 0.938, 0.998, p = 0.036; OR = 0.875, 95%CI = 0.787, 0.971, p = 0.012; OR = 0.947, 95%CI = 0.902, 0.995, p = 0.03; respectively). However, our Mendelian randomization (MR) estimates provided no causality of MDD on inflammatory cytokines. Conclusion: Our study elucidates the connection between inflammatory cytokines and MDD by using MR analysis, thereby enhancing our comprehension of the potential mechanisms. By identifying these associations, our findings hold substantial implications for the development of more effective treatments aimed at improving patient outcomes. However, further investigation is required to fully comprehend the exact biological mechanisms involved., 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 © 2023 Wang, Jin, Cheng, Guan, Zheng and Zhang.)

Objective: Subjective cognitive decline (SCD) is highlighted in patients with major depressive disorder (MDD), which impairs objective cognitive performance and worsens the clinical outcomes. Immune dysregulation is supposed to be the potential mechanism of cognitive impairment. However, the peripheral immune biomarkers in patients troubled with MDD and SCD are not conventionally described., Methods: A prospective-observational study was conducted for 8 weeks. Subjective cognitive function was measured using the Chinese version of the 20-item perceived deficits questionnaire-depression (PDQ-D) and depression symptoms were evaluated with Hamilton Depression Rating Scale-17 (HDRS-17). Luminex assays were used to measure 48 immune cytokines in plasma at baseline. Integrating these results and clinicopathological features, a logistic regression model was used to develop a prognostic prediction., Results: Totally, 114 patients were enrolled in this study. Among the patients who completed follow-up, 56% (N = 50) had residual subjective cognitive decline, and 44% (N = 50) did not. The plasma levels of FGF basic, INF-γ, IL-1β, MCP-1, M-CSF and SCF were increased and the levels of IL-9, RANTES and PDGF-BB were decreased in the SCD group. Additionally, Basic FGF, IFN-γ, IL-1β, and SCF were positively correlated and IL-9, RANTES, and PDGF-BB were negatively correlated with the PDQ-D scores after treatment. Notably, combinations of cytokines (SCF and PDGF-BB) and PDQ-D scores at baseline showed good performance (The area under the receiver operating characteristic curve = 0.818) in the prediction of subjective cognitive decline., Conclusion: A prognostic model based on protein concentrations of SCF, PDGF-BB, and scores of PDQ-D showed considerable accuracy in predicting residual subjective cognitive decline in depression., (© 2023. The Author(s).)

Major depressive disorder is a burdensome condition with few treatment options, and traditional antidepressants are characterized by slow onset. Sub-anesthetic ketamine has rapid-onset effects for the treatment of major depressive disorder (MDD), the mechanisms of which remain elusive. In this study, we explored whether neuroplasticity, autophagy, and ferroptosis in the habenular nucleus are involved in the rapid antidepressant process of ketamine. The results showed that Chronic Restraint Stress (CRS) treated rats exhibited decreased neuroplasticity, inhibition of autophagy, and enhanced ferroptosis. Depression-like symptoms were significantly improved after ketamine treatment in CRS rats, with changes in physiological parameters. Ketamine-treated CRS rats showed a significant improvement in habenular nuclear neuroplasticity. Electron microscopy observed that ketamine triggered autophagy, with increased levels of autophagy-related proteins. Ferroptosis was inhibited by ketamine by electron microscopy, with increased FTH1 and GPX4 levels and decreased Tfr1 levels. In conclusion, our findings demonstrate that ketamine may exert rapid antidepressant effects by improving neuroplasticity, activating autophagy, and inhibiting ferroptosis in the nuclear complex., (Copyright © 2022 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background: Sub-anesthetic ketamine has rapid-onset effects for the treatment of major depressive disorder (MDD). However, the mechanism underlying ketamine's antidepressant properties remains unclear. Recent studies have reported an interrelationship between autophagy and the inflammasome, both of which are involved in the pathophysiology of MDD. In this study, we assess whether ketamine exerts its antidepressant effects via an association with the autophagy-NLRP3 inflammasome pathway., Methods: We established a depressive-like rat model by treating Wistar Kyoto rats with chronic restraint stress (CRS) for 28 days. Microglial cells from newborn Sprague-Dawley rats were used for in vitro experiments., Results: We found sub-anesthetic ketamine treatment reversed depressive-like behavior in CRS rats. Ketamine triggered autophagy in the microglia of prefrontal cortex (PFC) and (hippocampus) HPC, with increased levels of LC3B, decreased levels of p62 protein, and elevated autophagosomes both in vivo and in vitro. Moreover, NLRP3 inflammasome activation was also inhibited by ketamine, with reduced expression of NLRP3-ASC-CASP1 assembly and decreased IL-1β levels in cerebrospinal fluid (CSF) as well as in the serum. Increased BDNF levels and synaptophysin levels were detected in the ketamine-treated group. The rapid anti-depressive effects, elevation of autophagy, reduction in NLRP3, and neuroplasticity-related factors induced by ketamine could be significantly blocked by the autophagy inhibitor Baf A1 (0.1 mg/kg)., Conclusions: Our findings demonstrate that sub-anesthetic doses of ketamine exert their antidepressant-like effects by inhibiting inflammation and initiating neuroprotection via autophagy activation. These data might help expand future investigations on the antidepressant properties of ketamine., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Sleep disturbances and benzodiazepine (BZD)/Z-drug use are common in patients with bipolar disorder (BD)., Objective: To investigate the short- and long-term effects of BZD/Z-drug use during acute affective episode., Methods: Participants diagnosed with BD as well as sleep disturbance chose BZDs/Z-drugs or not at will. Manic and depressive symptoms were assessed by Mental Disorders Questionnaire (MDQ) and Quick Inventory of Depressive Symptoms (QIDS) as self-reporting surveys. The participants were assessed by trained evaluators at baseline and months 1, 3, 6, and 9., Results: 61 patients with BD combined sleep disturbances were studied. At baseline, patients who used BZDs/Z-drugs had more amount of mood stabilizers ( p = 0.038), other psychotropic medications ( p = 0.040), and more risk of suicide attempt ( p = 0.019). The BZD/Z-drug group had a significantly higher QIDS reductive ratio as compared with the no BZD/Z-drug group at month 1; no significant differences in the variability of MDQ, QIDS reductive ratio, or recurrence rate were found between these two groups at baseline, month 1, month 3, month 6, or month 9., Conclusions: During acute affective episode, patients with BD combined sleep disturbance who took BZDs/Z-drugs tended to use more amount of mood stabilizers. Polytherapy of BZDs/Z-drugs or other psychiatric drugs could increase suicide attempt during an acute affective episode. BZD/Z-drug use, however, had a significant effect on helping depressive symptoms alleviate during affective period., Competing Interests: All authors have no conflict of interest to declare., (Copyright © 2022 Yiming Chen et al.)

Atypical antipsychotics are highly effective antischizophrenic medications but their clinical utility is limited by adverse metabolic sequelae. We investigated whether upregulation of macrophage migration inhibitory factor (MIF) underlies the insulin resistance that develops during treatment with the most commonly prescribed atypical antipsychotic, olanzapine. Olanzapine monotherapy increased BMI and circulating insulin, triglyceride, and MIF concentrations in drug-naive schizophrenic patients with normal MIF expression, but not in genotypic low MIF expressers. Olanzapine administration to mice increased their food intake and hypothalamic MIF expression, which led to activation of the appetite-related AMP-activated protein kinase and Agouti-related protein pathway. Olanzapine also upregulated MIF expression in adipose tissue, which reduced lipolysis and increased lipogenic pathways. Increased plasma lipid concentrations were associated with abnormal fat deposition in liver and skeletal muscle, which are important determinants of insulin resistance. Global MIF-gene deletion protected mice from olanzapine-induced insulin resistance, as did intracerebroventricular injection of neutralizing anti-MIF antibody, supporting the role of increased hypothalamic MIF expression in metabolic dysfunction. These findings uphold the potential pharmacogenomic value of MIF genotype determination and suggest that MIF may be a tractable target for reducing the metabolic side effects of atypical antipsychotic therapy.

Cross-disorder studies are identifying shared genetic variations among common mental illnesses - including schizophrenia, bipolar disorder, and major depression - which are classified as independent disorders in the current diagnostic system. These cross-disorder studies are challenging the traditional system of diagnosing mental disorders based on clinical symptoms, but it remains to be seen whether or not they will lead to an improved method of classifying psychiatric disorders that can, in turn, lead to better outcomes for individuals suffering from these conditions.