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Major depressive disorder (MDD) represents a sizable economic burden in Spain. Pharmacogenetic (PGx) screening to guide the choice of antidepressant medication (ADM) in MDD patients yields higher response and remission rates, which could reduce both healthcare and indirect costs. We built a cost-effectiveness probabilistic Markov model with microsimulation using Tree Age Pro 2022, simulating a patient cohort from the SNHS starting ADM for MDD, and comparing PGx screening before starting ADM versus no screening (No PGx). We carried out a probabilistic sensitivity analysis using the Monte Carlo simulation with microsimulation, set for 1000 iterations and 1000 microsimulation trials, both from societal and healthcare provider perspectives, for a time horizon of 3 years. From a societal perspective, the model estimated a mean cost of 3172.85€ and effectiveness of 2.64 quality-adjusted life years (QALYs) for the No PGx strategy, and a mean cost of 1687.02€ and effectiveness of 2.84 QALYs for the PGx strategy. The mean ICER was −7820.56 €/QALY. From a healthcare provider perspective (no indirect costs considered), the mean cost was 662.62€ for the No PGx strategy, and 446.60€ for the PGx strategy. The mean ICER was −1130.16 €/QALY. The heterogeneity of input data from the literature, the need for assumptions of homogeneous distribution of variables and events across population and time, and the inherent limitations of cost-effectiveness analysis should be considered. The model omits combined therapies (ADMs with mood stabilizers, antipsychotics, cognitive behavioral therapy...). PGx screening in MDD prior to ADM start is a dominant strategy in the SNHS. • Treatment failure rates in major depressive disorder are high and contribute to its economic impact • Pharmacogenetics-guided choice of antidepressants lower failure rates, which could reduce the associated economic burden • We analyzed the cost-effectiveness of this strategy with a Markov model • Microsimulation allows for a more accurate simulation of individual patients' characteristics • Pharmacogenetic screening when starting antidepressants is a dominant strategy [ABSTRACT FROM AUTHOR]

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. 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. 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. The sample size is small. 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. [Display omitted] • Compared to healthy controls, the normal ACTH MDD patients had higher Glx and lower GSH levels • Glx and GSH levels were inversely related to MDD severity • In the high ACTH MDD group, Glx positively correlated with delayed memory, and GSH with abstraction • Neurochemical differences in MDD patients' brains at varying HPA axis levels are linked to MDD severity and cognitive function [ABSTRACT FROM AUTHOR]

Psychomotor retardation (PMR) is a core feature of major depressive disorder (MDD), which is characterized by abnormalities in motor control and cognitive processes. PMR in MDD can predict a poor antidepressant response, suggesting that PMR may serve as a marker of the antidepressant response. However, the neuropathological relationship between treatment outcomes and PMR remains uncertain. Thus, this study examined electrophysiological biomarkers associated with poor antidepressant response in MDD. A total of 142 subjects were enrolled in this study, including 49 healthy controls (HCs) and 93 MDD patients. All participants performed a simple right-hand visuomotor task during magnetoencephalography (MEG) scanning. Patients who exhibited at least a 50 % reduction in disorder severity at the endpoint (>2 weeks) were considered to be responders. Motor-related beta desynchronization (MRBD) and inter- and intra-hemispheric functional connectivity were measured in the bilateral motor network. An increased MRBD and decreased inter- and intra-hemispheric functional connectivity in the motor network during movement were observed in non-responders, relative to responders and HCs. This dysregulation predicted the potential antidepressant response. Abnormal local activity and functional connectivity in the motor network indicate poor psychomotor function, which might cause insensitivity to antidepressant treatment. This could be regarded as a potential neural mechanism for the prediction of a patient's treatment response. • MDD patients with poor antidepressant response have increased MRBD. • MDD patients with poor antidepressant response have decreased inter- and intra-hemispheric functional connectivity in the motor network. [ABSTRACT FROM AUTHOR]

According to biopsychosocial models, experiencing parental child abuse increases susceptibility to adulthood psychopathology. However, there is a paucity of studies examining potential mechanisms of the parental child abuse and adulthood psychopathology relationship. The purpose of the current study was to determine if Time 2 (T2) trait self-esteem mediated levels of Time 1 (T1) retrospectively recalled parental child abuse predicting (T3) past-year major depressive disorder (MDD), generalized anxiety disorder (GAD), panic disorder (PD), alcohol use disorder (AUD), and substance use disorder (SUD) symptoms. The 18-year Midlife Development in the United States (MIDUS) study included participants (N = 3294; T1 average age of 45.62 years) assessed at three different time points, each spaced about nine years apart. We performed structural equation mediation modeling analyses to determine how maternal and paternal child abuse at T1 would independently predict T3 MDD, GAD, PD, AUD, and SUD symptoms. We also examined whether T2 self-esteem mediated these relations while controlling for adulthood T1 psychopathology symptoms, demographics, socioeconomic status, somatic symptoms, and parental psychopathology. Consistent with our hypotheses, higher T1 maternal and paternal abuse predicted increased T3 GAD, PD, AUD, and SUD symptoms via diminished T2 self-esteem as the mediator (% proportion mediated = 33.0–100). However, childhood paternal, but not maternal, abuse predicted adulthood MDD symptoms via reduced self-esteem. Findings remained after adjusting for covariates. Our research highlights the importance of understanding retrospectively recalled parental child abuse–adulthood psychopathology relations, their potential mechanisms, and self-esteem as a malleable treatment target for adults with heightened child abuse. • T1 parental abuse predicted higher T3 adult psychopathology via lower self-esteem. • SEM analyses showed that these mediational processes occurred across 18 years. • Past-year MDD, GAD, PD, AUD, and SUD symptoms at T3 were measured. • Paternal abuse, not maternal, predicted adult MDD via low self-esteem. • Findings stayed similar after adjusting for demographic, SES, and somatic variables. [ABSTRACT FROM AUTHOR]

Major Depressive Disorder (MDD) may exhibit impairments in cognitive flexibility. This study investigated whether the cognitive flexibility deficits in MDD are evident across general stimuli or specific to emotional stimuli, while exploring the underlying neuropsychological mechanism. A total of 41 MDD patients and 42 healthy controls (HCs) were recruited. Event-related potentials (ERPs) were recorded when participants performed a non-emotional and an emotional task switching paradigm (N-ETSP and ETSP), both of which assessed cognitive flexibility. Microstate and source localization analysis were applied to reflect brain activity among different brain areas during task switching. In the N-ETSP, MDD group showed larger P3 difference wave (Pd3) amplitudes and longer P2 difference wave (Pd2) latencies. In the ETSP, MDD group displayed smaller N2 difference wave (Nd2) amplitudes and larger Pd3 amplitudes. The comparison of sLORETA images of emotional switch task and emotional repeat task showed that MDD group had increased activation in the precentral gyrus in microstate2 of the P2 time window and had reduced activation in the middle occipital gyrus in microstate3 of the N2 time window. The cross-sectional design failed to capture dynamic changes in cognitive flexibility in MDD. MDD demonstrated impaired cognitive flexibility respond to both non-emotional and emotional stimuli, with greater impairment for negative emotional stimuli. These deficits are evident in abnormal ERPs component during the early attention stage and the later task preparation stage. Furthermore, abnormal emotional switching cost in MDD appears to be related to early abnormal perceptual control in the parietal-occipital cortex. • MDD exhibited impaired cognitive flexibility in general and negative stimuli. • Higher emotional switching cost of error rate, the lower brain activation in MDD. • MDD showed the abnormal early perceptual control in the parietal-occipital cortex. [ABSTRACT FROM AUTHOR]

Observational studies have shown that individual sleep traits habits are potential risk factors for major depression. However, it is not known whether there is a causal relationship between individual sleep traits habits such as continuous sleep duration, short sleep duration, short sleep duration, insomnia, nap during the day, snoring, and major depression. In this study, Mendelian randomization (MR) was used to predict major depressive disorder (MDD) in individuals sleep traits habits. Data were obtained from the genome-wide association study (GWAS). Nine MR analysis methods were used: Inverse Variance Weighted (IVW) [fixed effects/multiplicative random effects], simple mode, simple mode, weighted mode, simple median, weighted median, penalised weighted median, and MR-Egger, MR Egger (bootstrap). IVW was used as the main analysis method for the MR analysis of two samples, and the other methods were used as supplements. The results obtained through the IVW method supported a causal relationship between sleep duration and decreased risk of MDD (odds ratio, OR ivw : 0.998; 95 % CI: 0.996–0.999, P<0.001). Two-Sample MR, results showed that short sleep duration has a causal effect on the increased risk of MDD (odds ratio, OR ivw : 1.179; 95 % CI: 1.108–1.255, P<0.001). However, there were no sufficient evidence supported that long sleep duration has a causal effect on the decreased risk of MDD (odds ratio, OR ivw : 0.991; 95 % CI: 0.924–1.062, P = 0.793). A significant causal relationship between insomnia and increased risk of MDD was observed (OR: 1.233; 95 % CI: 1.214–1.253, P<0.001). Interestingly, our study also found that daytime napping has a causal effect on the increased risk of MDD (odds ratio, OR ivw : 1.519; 95 % CI: 1.376–1.678, P<0.001). The present results did not show a significant causal relationship between snoring and the risk of MDD (OR ivw : 1.000; 95 % CI: 0.998–1.002, P = 0.906). Obstructive sleep apnea (odds ratio, OR ivw : 1.021; 95 % CI: 0.972–1.072, P = 0.407) and morning person (odds ratio, OR ivw : 1.021; 95 % CI: 0.972–1.072, P = 0.407) have no causal effect on the increased risk of MDD. The study could not ascertain whether there were genetic differences among different ethnicities, nations, and regions, as it only included participants of European ancestry. In summary, our research provides genetic evidence for the relationship between individual sleep traits (short sleep duration, insomnia, daytime napping) and the increased risk of MDD. Interventions targeting lifestyle factors may reduce the risk of MDD. • This study explored the causality between lifestyle and major depressive disorder by Mendelian Randomization analysis. • This research provides genetic evidence supporting that sleep traits increase major depressive disorder risk. • The research primarily included European ancestry. The conclusions may not apply to other ethnic and regional groups. [ABSTRACT FROM AUTHOR]

Rs768705 (TMEM161B) is one of the identified single nucleotide polymorphisms related to major depressive disorder (MDD). Paranoid personality traits are independently associated with the risk of MDD. This study aimed to investigate the interaction effect between rs768705 (TMEM161B) and paranoid personality traits on the new-onset risk of MDD in Chinese freshmen. A longitudinal study was conducted among 7642 Chinese freshmen without lifetime MDD at baseline in 2018. 158 new-onset MDD cases were ascertained in 2019. DNA samples were extracted to detect the genotype of rs768705. The diagnostic and statistical manual of mental disorders-IV criteria were used to determine MDD and personality disorder traits. Multiplicative interaction was assessed by logistic regression models. Tomas Andersson's method for calculating biological interactions was used to estimate the additive interaction. Rs768705(AG) (OR = 1.88, 95 % CI: 1.24–2.83) and paranoid personality traits (OR = 3.68, 95 % CI: 2.57–5.26) were significantly associated with the risk of MDD. The multiplicative interaction model with the product term of rs768705 and paranoid personality trait traits had a significant interaction effect (OR = 4.20, 95 % CI:1.62–10.91). There was also a significant additive interaction effect (RR = 7.08, 95 % CI:4.31–11.65) for the incidence of MDD. Seventy seven percent patients among new MDD cases were attributed to the additive interaction effect between rs768705 and paranoid personality traits. Rs768705 (AG) may interact with paranoid personality traits to increase the incidence of MDD among Chinese college students. Schools and psychosocial health organizations should pay more attention to individuals with paranoid personality traits for MDD intervention and prevention. • This was a 1-year longitudinal study conducted among 7642 Chinese freshmen. • There was an addictive interaction effect between rs768705 (AG) and paranoid personality traits on occurrence of MDD. • 77% of new MDD patients were attributed to the interaction effect of rs768705 (AG) & paranoid personality traits. [ABSTRACT FROM AUTHOR]

Treatable mental disorders, such as psychotic, major depressive disorder (MDD), and bipolar disorder (BD), contribute to a substantial portion of suicide risk, often accompanied by neurocognitive deficits. We report the association between cognitive function and suicidal ideation/suicide attempts (SI/SA) in individuals with schizoaffective disorder, BD, and MDD. A systematic search was conducted on PubMed, Ovid and Scopus databases for primary studies published from inception to April 2024. Eligible articles that reported on the effect size of association between cognition and SI/SA were pooled using a random effects model. A total of 41 studies were included for analysis. There was a negative association between executive functioning and SI/SA in schizoaffective disorder (SA: Corr = −0·78, 95 % CI [−1·00, 0·98]; SI: Corr = −0·06, 95 % CI [−0·85, 0·82]) and MDD (SA: Corr = −0·227, 95 % CI [−0·419, −0·017]; SI: Corr = −0·14, 95 % CI [−0·33, 0·06]). Results were mixed for BD, with a significant positive association between SA and global executive functioning (Corr = 0·08, 95 % CI [0·01, 0·15]) and negative association with emotion inhibition. Mixed results were observed for processing speed, attention, and learning and memory, transdiagnostically. There is heterogeneity across sample compositions and cognitive measures. We did not have detailed information on individuals with respect to demographics and comorbidities. We observed a transdiagnostic association between measures of cognitive functions and aspects of suicidality. The interplay of cognitive disturbances, particularly in reward-based functioning, may underlie suicidality in individuals with mental disorders. Disturbances in impulse control, planning, and working memory may contribute to self-injurious behavior and suicide. • Suicide attempt (SA) was associated with executive functioning in bipolar disorder. • SA was negatively associated with emotion inhibition in bipolar disorder. • Mixed findings were observed for attention and processing speed transdiagnostically. • Suicidal ideation (SI) was associated with executive functioning in schizophrenia. • SI was associated with executive functioning in major depressive disorder. [ABSTRACT FROM AUTHOR]

Both low vagally-mediated heart rate variability (HRV) and depression have been shown to be risk factors for cardiovascular disease (CVD). We recently identified an HRV cutpoint below which persons have an increased risk for several cardiometabolic disorders. However, no cutpoint exists to identify those at risk for depression. The association between daytime HRV and diagnostically validated depression cutoffs using the five-item World Health Organization Well-being Index (WHO-5) was examined in adults from the Mannheim Industrial Cohort Study (n = 9973; M age = 41.9[10.9]; 20 % women [ n = 1934]). The aim was to identify HRV cutpoints for individuals who may have clinical depression. Regression adjusting for age, sex, and linear trend showed a significant quadratic association between depression, indexed by WHO-5 scores and HRV, indexed by the root mean square successive differences (RMSSD) in milliseconds (ms) (p < 0.001). Logistic regression models adjusting for age, sex, and heart period (i.e., inter-beat intervals) compared the clinically depressed (WHO-5 ≤ 28) and those with a screening diagnosis of depression (WHO-5 ≤ 50) to the rest of the population. Significant odds ratios suggested two RMSSD values 25 ± 2 ms (OR = 1.39 [1.17, 1.64]) and 35 ± 2 ms (OR = 1.17 [1.02, 1.34]) that may be used to identify those with an elevated risk for depression. The sample was primarily German men. Fitness and anti-depressant use were not available. As HRV is a brief measure that can be used in clinical settings, our HRV cutpoints have implications for the early detection of those at risk for psychological and cardiometabolic disorders. • Major depressive disorder is among the most globally prevalent illnesses. • Early identification can reduce disease burden. • We found cutpoints for a physiological marker of depression using heart rate variability. • These clinical cutpoints can be used in primary care settings. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is a widespread mental health issue, impacting spatial and temporal aspects of brain activity. The neural mechanisms behind MDD remain unclear. To address this gap, we introduce a novel measure, spatiotemporal topology (SPT), capturing both the hierarchy and dynamic attributes of brain activity in depressive disorder patients. We analyzed fMRI data from 285 MDD inpatients and 141 healthy controls (HC). SPT was assessed by coupling brain gradient measurement and time delay estimation. A nested machine learning process distinguished between MDD and HC using SPT. Person's correlation tested the link between SPT's and symptom severity, and another machine learning method predicted the gap between patients' chronological and brain age. SPT demonstrated significant differences between patients and healthy controls (F = 2.944, p < 0.001). Machine learning approaches revealed SPT's ability to discriminate between patients and healthy controls (Accuracy = 0.65, Sensitivity = 0.67, Specificity = 0.64). Moreover, SPT correlated with the severity of depression symptom (r = 0.32. p FDR = 0.045) and predicted the gap between patients' chronological age and brain age (r = 0.756, p < 0.001). Evaluation of brain dynamics was constrained by MRI temporal resolution. Our study introduces SPT as a promising metric to characterize the spatiotemporal signature of brain function, providing insights into deviant brain activity associated with depressive disorders and advancing our understanding of their psychopathological mechanisms. • Spatial and temporal brain aberrations linked to Major Depressive Disorder (MDD). • SPT integrates spatial and temporal features as a potential MDD biomarker. • SPT effectively discriminates between MDD and healthy populations via machine learning. • SPT correlates with depression severity and predicts differences in brain-age predictions. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) affects multiple functional neural networks. Neuroimaging studies using resting-state functional connectivity (FC) have focused on the amygdala but did not assess changes in connectivity between the left and right amygdala. The current study aimed to examine the inter-hemispheric functional connectivity (homotopic FC, HoFC) between different amygdalar sub-regions in patients with MDD compared to healthy controls, and to examine whether amygdalar sub-regions' HoFC also predicts response to Serotonin Selective Reuptake Inhibitors (SSRIs). Sixty-seven patients with MDD and 64 matched healthy controls were recruited. An MRI scan focusing on resting state fMRI and clinical and cognitive evaluations were performed. An atlas seed-based approach was used to identify the lateral and medial sub-regions of the amygdala. HoFC of these sub-regions was compared between groups and correlated with severity of depression, and emotional processing performance. Baseline HoFC levels were used to predict response to SSRIs after 2 months of treatment. Patients with MDD demonstrated decreased inter-hemispheric FC in the medial (F3,120 = 4.11, p = 0.008, η2 = 0.096) but not in the lateral (F3,119 = 0.29, p = 0.82, η2 = 0.008) amygdala compared with healthy controls. The inter-hemispheric FC of the medial sub-region correlated with symptoms severity (r = −0.33, p < 0.001) and emotional processing performance (r = 0.38, p < 0.001). Moreover, it predicted treatment response to SSRIs 65.4 % of the cases. The current study did not address FC changes in MDD biotypes. In addition, structural connectivity was not examined. Using a unique perspective of the amygdalar distinct areas elucidated differential inter-hemispheric FC patterns in MDD patients, emphasizing the role of interhemispheric communication in depression. • Patients with Major Depressive Disorder (MDD) showed reduced inter-hemispheric functional connectivity (HoFC) in the medial amygdala compared to healthy controls. • HoFC in the medial amygdala was correlated with the severity of depression symptoms and emotional processing performance. • Baseline HoFC levels in the medial amygdala modestly predicted the response to Serotonin Selective Reuptake Inhibitors (SSRIs) after 2 months of treatment. • The findings emphasize the role of interhemispheric communication within amygdalar sub-regions in understanding depression. [ABSTRACT FROM AUTHOR]

Research in functional asymmetry of Major Depressive Disorder (MDD) under different tasks is crucial for clinical diagnose. Fifty individuals with MDD and twenty healthy controls (HCS) were recruited for hemodynamic data collection under four fNIRS tasks (Emotional picture, Verbal fluency, Fingering and Negative emotional picture description task). Integral values and functional connectivity strength were employed to probe neural activation and functional connectivity in frontal and temporal lobes in MDD. Following, asymmetry characteristic of the frontal cortex between MDD and HCS under four tasks were carefully analyzed and compared. Individuals with MDD demonstrated heightened connectivity between the frontal and right temporal lobes and reduced connectivity between the frontal and left temporal lobes compared to HCS in all tasks. Additionally, MDD exhibited attenuated activation in the left frontal lobes and exaggerated activation in the right frontal lobes, diverging from HCS. Furthermore, the disparities in left-right asymmetry characteristic of frontal cortex activation between MDD and HCS were more pronounced during the combined task. Further research is required to grasp the neurophysiological mechanisms governing left-right asymmetry across various tasks and the influence of task-induced brain fatigue on cerebral cortex hemodynamics in MDD. The left-right asymmetry feature provides valuable neurophysiological insights for diagnosing MDD clinically. Variations in activation patterns and functional connectivity features between MDD and HCS are closely tied to the task chosen. Thus, in clinical practice, carefully selecting appropriate fNIRS tasks and relevant features can significantly improve the diagnostic accuracy of MDD. • Activation and functional connectivity of MDD under four fNIRS tasks were investigated. • A left-right asymmetry characteristics of frontal cortex was proposed to characterize MDD patients. • Task related characteristics for MDD patients were carefully compared and discussed. [ABSTRACT FROM AUTHOR]

[Display omitted] • A RCT study to investigate the efficacy of abdominal acupuncture for MDD patients. • Acupuncture can treat MDD by regulating the integration of functional networks. • It's the first time provided a marker to predict the efficacy of acupuncture. Abdominal acupuncture has definite efficacy for major depressive disorder (MDD). Our study examined how abdominal acupuncture regulates the integration within and between brain networks of MDD patients by neuroimaging and whether this functional integration can predict the efficacy. Forty-six female MDD patients were randomly divided into a fluoxetine + real acupuncture group (n = 22) and a fluoxetine + sham acupuncture group (n = 24). The differences in functional magnetic resonance imaging data in the intra- and inter-network functional connectivity (FC) of the default mode network (DMN), affective network (AN), salience network (SN), and cognitive control network (CCN) between the two groups were analyzed. The FCs in brain regions with the inter-group differences and support vector regression were used to predict the efficacy of abdominal acupuncture. Our results showed: that the intra- and inter-network FCs of DMN, AN, SN, and CCN could be changed by abdominal acupuncture. Using the baseline FCs within AN and DMN or AN–DMN as characteristics, combined with support vector regression, could better predict the efficacy of acupuncture. Our study suggests that abdominal acupuncture could treat MDD by regulating the integration of the functional networks DMN, AN, SN, and CCN. The baseline FCs within the DMN and AN or between them could be used as neural markers for predicting the efficacy of abdominal acupuncture. [ABSTRACT FROM AUTHOR]

• ・Glucocorticoids induced HMGB1 release in primary cultured microglia but not in neuron. • ・Dexamethasone-BSA, a membrane-impermeable GR agonist induced HMGB1 release. • ・Glucocorticoids triggered translocation of HMGB1 from nuclear to cytosol. Stress, a risk factor for major depressive disorder and Alzheimer disease, leads to the release of high-mobility group box-1 (HMGB1) protein, which in turn causes neuroinflammation. The mechanism underlying stress-induced HMGB1 release is unknown, but stress-associated glucocorticoids could be involved. Primary cultured rat cortical microglia and neurons were treated with corticosterone, a stress-associated glucocorticoid, and HMGB1 release was measured by ELISA and western blotting to test this hypothesis. With corticosterone treatment, significant HMGB1 was released in microglia but not in neuronal cell cultures. HMGB1 mRNA expression and HMGB1 protein expression in microglia were not affected by corticosterone treatment. Thus, the source of extracellular HMGB1 released into the medium is likely to be existing nuclear HMGB1 rather than newly synthesized HMGB1. Corticosterone-induced HMGB1 release in microglia culture was significantly attenuated by blocking glucocorticoid receptors but not mineralocorticoid receptors. Dexamethasone, a selective glucocorticoid receptor agonist, and dexamethasone-bovine serum albumin (BSA), a membrane-impermeable glucocorticoid receptor agonist used to confirm the membrane receptor-mediated effects of glucocorticoids, increased the release of HMGB1. Immunocytochemistry showed that HMGB1 translocated from the nucleus to the cytoplasm following dexamethasone or dexamethasone-BSA treatment through glucocorticoid receptors. The present findings suggest that glucocorticoids stimulate microglial membrane glucocorticoid receptors and trigger cytoplasmic translocation and extracellular release of nuclear HMGB1. Thus, under stress conditions, glucocorticoids induce microglial HMGB1 release, leading to a neuroinflammatory state that could mediate neurological disorders. [ABSTRACT FROM AUTHOR]

• Epigenetics played a crucial role in depression with suicide ideation (DSI). • Epigenetic molecules related to DSI interacted with each other. • Peripheral epigenetic molecules were potential suicidal biomarkers for DSI. Suicide ideation (SI) is the major cause of death in persons with depression, whereas effective and accurate biomarkers for suicidal behavior of persons with depression are still lack. Recently, manifold studies in vivo revealed that epigenetic alterations including DNA methylation, non-coding RNA regulation, RNA editing and histone modification, were associated with depressive severity and SI, and peripheral epigenetic molecules may be potential biomarkers for suicidal risk of persons with depression. Therefore, we firstly reviewed recent epigenetic advancements in depression with suicide ideation (DSI) according to studies based on human tissue. Furthermore, we discussed the significance and potential of minimally-invasive peripheral epigenetic molecules to identify potential suicidal biomarkers for DSI, aiming to promote early identification and therapeutic evaluation of DSI. [ABSTRACT FROM AUTHOR]

[Display omitted] • MOE ameliorates depressive behaviors by modulating the microbiota-gut-brain axis. • MOE restored sucrose preference in depressed mice. • MOE reversed CUMS-induced 5-HT reduction in the prefrontal cortex and hippocampus. • MOE increased gut lactobacilli in stressed mice. The gut microbiota has been posited as a target for the treatment of major depressive disorder. Herein, we investigated the effect of the hydroethanolic leaf extract of Mallotus oppositifolius (MOE) on the gut microbiota of mice and how this contributes to its known antidepressant-like effect. A 6-week chronic unpredictable mild stress (CUMS) procedure was employed in 7 groups of mice to induce depression. From the third week, oral MOE treatments (10, 30, 100 mg/kg) and two reference drugs, fluoxetine (12 mg/kg) and minocycline (40 mg/kg), known to affect the gut microbiota, were administered. The sixth and seventh groups were the vehicle stressed (VEH-S) and non-stressed groups (VEH-NS). Changes in depressive-like behaviors were assessed using sucrose preference test while the forced swimming test (FST) was used to assess sustained antidepressant-effect after treatment discontinuation. Moreover, changes in prefrontal cortex (PFC) and hippocampal serotonin (5-HT) levels were evaluated using enzyme-linked immunosorbent assay (ELISA). The effect of treatment on the profile of the gut microbiota of the groups was elucidated using 16S rRNA Oxford Nanopore sequencing. MOE and reference drugs reversed the depression-associated reduction in sucrose preference when compared to VEH-S. MOE (with peak effect at 30 mg/kg) reduced immobility while increasing swimming and climbing behaviors. MOE reversed CUMS-induced reduction of 5-HT concentration in PFC and hippocampus. The behavioral effects of MOE were associated with shifts in the gut microbiota of CUMS-exposed mice. The study has provided seminal evidence that MOE ameliorates CUMS-induced depressive symptoms by modulating gut microbiota and increasing brain 5-HT levels. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is a prevalent mental health condition characterized by persistent feelings of sadness and hopelessness, affecting millions globally. The precise molecular mechanisms underlying MDD remain elusive, necessitating comprehensive investigations. Our study integrates transcriptomic analysis, functional assays, and computational modeling to explore the molecular landscape of MDD, focusing on the DLPFC. We identify key genomic alterations and co-expression modules associated with MDD, highlighting potential therapeutic targets. Functional enrichment and protein–protein interaction analyses emphasize the role of astrocytes in MDD progression. Machine learning is employed to develop a predictive model for MDD risk assessment. Single-cell and spatial transcriptomic analyses provide insights into cell type–specific expression patterns, particularly regarding astrocytes. We have identified significant genomic alterations and co-expression modules associated with MDD in the DLPFC. Key genes involved in neuroactive ligand-receptor interaction pathways, notably in astrocytes, have been highlighted. Additionally, we developed a predictive model for MDD risk assessment based on selected key genes. Single-cell and spatial transcriptomic analyses underscored the role of astrocytes in MDD. Virtual screening of compounds targeting GPR37L1, KCNJ10, and PPP1R3C proteins has identified potential therapeutic candidates. In summary, our comprehensive approach enhances the understanding of MDD's molecular underpinnings and offers promising opportunities for advancing therapeutic interventions, ultimately aiming to alleviate the burden of this debilitating mental health condition. Key messages: Our investigation furnishes insightful revelations concerning the dysregulation of astrocyte-associated processes in MDD. We have pinpointed specific genes, namely KCNJ10, PPP1R3C, and GPR37L1, as potential candidates warranting further exploration and therapeutic intervention. We incorporate a virtual screening of small molecule compounds targeting KCNJ10, PPP1R3C, and GPR37L1, presenting a promising trajectory for drug discovery in MDD. [ABSTRACT FROM AUTHOR]

Background: Major Depressive Disorder (MDD) is a leading cause of disability and results in excessive utilization of healthcare resources worldwide. The Middle East and North Africa (MENA) region shows a high prevalence of depressive disorders. Generalized Anxiety Disorder (GAD) and MDD have the highest rate of comorbidity of all mood and anxiety disorders, ranging from 40 to 98% in drug studies. Comorbid GAD results in more significant impairment in MDD and increases the severity of symptoms. Although several clinical trials supported the safety and effectiveness of vortioxetine, no data regarding these aspects has been revealed in the MENA region. This study aimed to assess the safety and efficacy of vortioxetine in patients with comorbid GAD in the United Arab Emirates (UAE). Method: In a multicenter observational study, 118 patients with confirmed anxiety and depressive disorders were evaluated over four visits (baseline visit, two weeks, four weeks, and eight weeks) using MADRS and HAM-A scales to assess depression and anxiety severity, respectively by calculating mean change and the percent using Kendall's W test. Results: A significant mean difference in MADRS score was observed, with a gradual decrease of mean MADRS total scores over the assessment weeks (p < 0.001) as well as in HAM-A scores, from severe to moderate-severe anxiety through the four visits (p < 0.001). Furthermore, only one case was reported as a serious side effect. Nausea and insomnia were the most predominant side effects reported among the studied population. Conclusion: Vortioxetine was found effective and safe among patients with MDD and comorbid GAD. [ABSTRACT FROM AUTHOR]

Background: Evidence from various cohort studies indicate a potential association between depressive disorder and benign prostatic hyperplasia (BPH), yet findings are inconsistent. This study employs bidirectional two‐sample Mendelian randomisation (MR) analysis to explore the causal relationship between BPH and major depressive disorder (MDD). Methods: Genetic variants strongly associated with MDD were extracted as instrumental variables conducted by the Psychiatric Genomics Consortium (PGC). Two sets of genetic variants associated with BPH were extracted from the recent FinnGen and Medical Research Council‐Integrative Epidemiology Unit Consortium of BPH as the discovery and replication stages, respectively. Bidirectional MR analysis employed methods such as inverse variance weighted, MR‐Egger, weighted median, maximum likelihood, and weighted mode. The inverse variance weighted method was primarily used to evaluate the causal relationship. Results: MR analysis in both the discovery and replication stages showed a significant causal relationship between MDD and the risk of BPH (discovery stages, odds ratio (OR) = 1.1146, 95% CI 1.0058–1.2353, P = 0.03852; replication stage, OR: 1.0042, 95% CI 1.0019–1.0065, P = 0.0004). No causal relationship was found between BPH and MDD risk in the reverse MR analysis. Conclusions: Our findings highlight a significant association between MDD and an increased risk of BPH development. Further investigation is needed to elucidate the underlying mechanisms linking depression and BPH. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Treatment-resistant depression (TRD) is a severe public health problem and a condition uncommonly addressed by psychological therapies. This paper presents a theoretical model, grounded in established learning principles and in the perspective of behavioral activation (BA), to explain its constitution and development. Method: A review of theoretical models and empirical research on TRD was conducted in major databases. Results: The model reflects how patients with TRD are more susceptible to becoming trapped in their condition by seeking to avoid discomfort through avoidance and escape behaviors, which increasingly drives them away from sources of positive reinforcement. Based on this model, a BA-based intervention protocol is suggested for the treatment of TRD. Through six phases (in a total of thirteen sessions), the protocol guides the intervention towards the reestablishment of personalized routines to increase the probability of reinforcement and reduce avoidance behaviors. Conclusions: Although the model holds significant potential to become an effective intervention in TRD, future research will allow the evaluation of the efficacy of the protocol as a standalone intervention. [ABSTRACT FROM AUTHOR]

Non-suicidal self-injury (NSSI) is an increasingly concerning issue that is linked to a range of mental health problems. However, little is known about the potential neurophysiological mechanisms underlying risk decision-making in Major depressive disorder (MDD) patients with NSSI—the present study aimed to fill this important literature gap. A total of 81 MDD patients (with NSSI: n = 40, without NSSI: n = 41) and 44 matched healthy controls (HC) underwent a modified version of the Iowa Gambling Task (IGT) while an electroencephalogram was recorded. Feedback-related negativity (FRN) and P300 were examined during the feedback stage of the risky decision-making process. Behavioural findings revealed that individuals diagnosed with MDD displayed a greater tendency to make risky decisions compared to the control group. Furthermore, MDD patients with NSSI demonstrated a significantly more negative ΔFN (i.e., the difference in neural response to losses compared to gains) than those without NSSI. Further, NSSI patients showed a larger difference ΔFN (loss minus gain), which was associated with enhanced impulsivity. Collectively, the findings suggest that there is an altered processing of risky decision-making in the electrophysiology of patients with MDD who engage in NSSI. The ΔFN may serve as a psychophysiological marker indicating risk for NSSI. • Major depressive disorder (MDD) patients had severe decision-making(DM) defects. • The MDD patients with NSSI showed more negative ΔFN during Iowa gambling task (IGT). • MDD-NSSI patients showed a larger difference ΔFN, which correlated enhanced impulsivity. [ABSTRACT FROM AUTHOR]

This study aims to elucidate the neuroimaging changes associated with major depressive disorder (MDD) and their relationship with genetic characteristics. We conducted a global-brain functional connectivity (GFC) and genetic-neuroimaging correlation analysis on 42 MDD patients and 42 healthy controls (HCs), exploring the correlation between GFC abnormalities and clinical variables. Results showed that compared to HCs, MDD patients had significantly decreased GFC values in the bilateral posterior cingulate cortex/precuneus and increased GFC values in the left and right cerebellum Crus I/II. Additionally, a negative correlation was observed between the GFC values of the left cerebellum Crus I/II and subjective support scores, as well as social support revalued scale total scores. We identified genes associated with GFC changes in MDD, which are enriched in biological processes such as synaptic transmission and ion transport. Our findings indicate the presence of abnormal GFC values in severe depression, complementing the pathological research on the condition. Furthermore, this study provides preliminary evidence for the correlation between social support levels and brain functional connectivity, offering insights into the potential association between GFC changes and gene expression in MDD patients. [ABSTRACT FROM AUTHOR]

Objectives: To report an observational case series study of sustained, once-weekly continuation transcranial magnetic stimulation (TMS) provided with the aim of maintaining remission in patients with major depressive disorder (MDD). Methods: Once-weekly TMS treatments were provided to 7 patients (median age of 54 years) with chronic relapsing MDD: 4 of these patients entered the study in remission according to the six-item Hamilton depression rating scale (HAM-D6) and were followed for more than 12 months, and 3 patients entered the study in HAM-D6 partial remission/relapse and were followed for more than 6 months. Results: All patients remained clinically well throughout the study. The 4 patients who entered in remission were maintained in HAM-D6 remission or partial remission. The 3 patients who entered the study in HAM-D6 partial remission/relapse were maintained free of clinical depression. Conclusions: Seven patients with a history of relapsing MDD were provided with once-weekly continuation TMS and remained free of clinical relapse for more than 6 or 12 months. While the study had a small sample size, the clear, real-world outcomes warrant further investigation. [ABSTRACT FROM AUTHOR]

• Plasma levels of BDNF, proBDNF, tPA and PAI-1 changed in MDD. • BDNF/proBDNF and tPA/PAI-1 were associated with MDD and antidepressive treatment. • Interaction of tPA and PAI-1 was important in MDD by regulating BDNF/proBDNF ratio. • The combination of tPA + PAI + BDNF showed the best diagnostic value for MDD. 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. [ABSTRACT FROM AUTHOR]

Major Depressive Disorder (MDD) poses significant public health challenges globally and in Southeast Asia, with substantial impairment and disease burden. Understanding its prevalence and associated risk factors is crucial for effective intervention. This study aims to describe the prevalence shifts, correlates, and comorbidities of MDD in Singapore. Data were collected from the second Singapore Mental Health Study (SMHS 2016), a national cross-sectional survey comprising 6126 adult residents. The WHO Composite International Diagnostic Interview assessed MDD and comorbidities. Statistical analyses, including logistic regression, were conducted to examine the associations and trends. The lifetime weighted prevalence of MDD in SMHS 2016 was 6.2 %, with an overall increase from 5.8 % in 2010. Significant associations were found between MDD and age, marital status, and comorbid physical disorders. Young adults and divorced/separated individuals exhibited higher MDD prevalence. Chronic pain was significantly associated with MDD. The study's cross-sectional design limits causal inference, and selective non-response might affect prevalence estimates. However, the study benefits from a large, nationally representative sample and standardized methodologies. Young and middle-aged adults, and divorced/separated individuals demonstrate elevated MDD prevalence, warranting targeted interventions. Individuals with comorbidities, particularly chronic pain, constitute a high-risk and vulnerable population. Comprehensive assessment and treatment plans should involve multidisciplinary teams and integrated care approaches to better address the complex needs of these individuals. Our study also highlights specific interventions for schools, families, communities, and workplaces. Despite Singapore's relatively low prevalence compared to Western nations, MDD remains cross-culturally valid emphasizing the need for early intervention and preventive public health measures. • Lifetime weighted prevalence of Major Depressive Disorder (MDD) was 6.2 %. • Young adults, and separated or divorced individuals, exhibited higher MDD prevalence. • Chronic pain showed the highest comorbidity with MDD. [ABSTRACT FROM AUTHOR]

Functional connectivity has been shown to fluctuate over time. The present study aimed to identifying major depressive disorders (MDD) with dynamic functional connectivity (dFC) from resting-state fMRI data, which would be helpful to produce tools of early depression diagnosis and enhance our understanding of depressive etiology. The resting-state fMRI data of 178 subjects were collected, including 89 MDD and 89 healthy controls. We propose a spatio-temporal learning and explaining framework for dFC analysis. A yet effective spatio-temporal model is developed to classifying MDD from healthy controls with dFCs. The model is a stacking neural network model, which learns network structure information by a multi-layer perceptron based spatial encoder, and learns time-varying patterns by a Transformer based temporal encoder. We propose to explain the spatio-temporal model with a two-stage explanation method of importance feature extracting and disorder-relevant pattern exploring. The layer-wise relevance propagation (LRP) method is introduced to extract the most relevant input features in the model, and the attention mechanism with LRP is applied to extract the important time steps of dFCs. The disorder-relevant functional connections, brain regions, and brain states in the model are further explored and identified. We achieved the best classification performance in identifying MDD from healthy controls with dFC data. The top important functional connectivity, brain regions, and dynamic states closely related to MDD have been identified. The data preprocessing may affect the classification performance of the model, and this study needs further validation in a larger patient population. The experimental results demonstrate that the proposed spatio-temporal model could effectively classify MDD, and uncover structural and temporal patterns of dFCs in depression. • A spatio-temporal learning model for identifying MDD with dFC • An explanation method for uncovering structure and time-varying pattern • The brain regions and brain states from altered functionality in MDD [ABSTRACT FROM AUTHOR]

Background: Observational studies have indicated that breakfast skipping and gut microbiome dysbiosis are associated with a higher risk of major depressive disorder (MDD). However, it remains unknown whether the alteration of gut microbes is implicated in the associations between breakfast skipping and MDD. Methods: Leveraging genome-wide association studies (GWAS) on breakfast skipping, gut microbes, and MDD, we conducted a two-step Mendelian randomization (MR) study to determine the causal associations between breakfast skipping (N = 193,860) and MDD (N = 1,815,091), and evaluate the role of gut microbes (N = 18,340). Genetic variants with a P-value less than 5E-08 were selected as instrumental variables (IVs). The false discovery rate (FDR) method was employed to correct the P-values for multiple tests in gut microbes. Results: Breakfast skipping was associated with an increased risk of MDD (odds ratio [OR] = 1.36, 95%CI = 1.12–1.65, P = 0.002), but no effect of MDD on breakfast skipping was observed (β per doubling odds of MDD =-0.001, 95%CI=-0.024 to 0.023, P = 0.957). After adjusting for multiple comparisons, the MR analysis provided little evidence for an association between breakfast skipping and the abundance of any gut microbes (PFDR>0.05). Among the 21 gut microbes with IVs available, only the abundance of Class Actinobacteria was causally associated with a reduced risk of MDD (OR = 0.85, 95%CI = 0.75–0.97, PFDR=0.015). Conclusions: Our findings demonstrated that breakfast skipping was associated with an increased risk of MDD, but provided little evidence supporting the role of the abundance of gut microbes in it. Further efforts with a large sample size are warranted to clarify the findings. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is characterized by psychomotor retardation whose underlying neural source remains unclear. Psychomotor retardation may either be related to a motor source like the motor cortex or, alternatively, to a psychomotor source with neural changes outside motor regions, like input regions such as visual cortex. These two alternative hypotheses in main (n = 41) and replication (n = 18) MDD samples using 7 Tesla MRI are investigated. Analyzing both global and local connectivity in primary motor cortex (BA4), motor network and middle temporal visual cortex complex (MT+), the main findings in MDD are: 1) Reduced local and global synchronization and increased local‐to‐global output in motor regions, which do not correlate with psychomotor retardation, though. 2) Reduced local‐to‐local BA4 – MT+ functional connectivity (FC) which correlates with psychomotor retardation. 3) Reduced global synchronization and increased local‐to‐global output in MT+ which relate to psychomotor retardation. 4) Reduced variability in the psychophysical measures of MT+ based motion perception which relates to psychomotor retardation. Together, it is shown that visual cortex MT+ and its relation to motor cortex play a key role in mediating psychomotor retardation. This supports psychomotor over motor hypothesis about the neural source of psychomotor retardation in MDD. [ABSTRACT FROM AUTHOR]

Background: The study aimed to explore the influence of gender on the prevalence of various somatic symptoms and their associations with suicidal ideation (SI) among patients with major depressive disorder (MDD). Methods: We recruited 3,275 patients with MDD from the National Survey on Symptomatology of Depression (NSSD), among whom 1,745 patients had SI. The clinical characteristics and the prevalence of somatic symptoms across 20 dimensions in MDD patients with SI were compared between male and female patients. Spearman correlation analysis and logistic regression analysis were used to explore the relationship between somatic symptoms and SI. Results: In patients with SI, 32.2% of female participants attributed the onset of MDD to physical concerns, whereas 27% of male patients held a similar perspective (P = 0.032). Female patients exhibited a higher prevalence of early insomnia (64.6% vs. 70.2%) and a lower prevalence of hypersomnia (17.2% vs. 12.9%) and urinary system symptoms (25.0% vs. 17.8%). Logistic regression analysis indicated that female patients displayed a broader range of somatic symptoms identified as risk factors for SI, including increased appetite, respiratory symptoms, circulatory system symptoms, limb pain, and various others. Conclusion: This study unveils gender-specific patterns in somatic symptoms among MDD patients with SI, highlighting the clinical significance of these symptoms in diagnosis and intervention. Understanding how physical concerns contribute to MDD, especially among females, underscores the need for tailored clinical approaches. Recognizing and addressing these symptoms could guide more effective suicide prevention strategies and enhance MDD management in clinical practice. [ABSTRACT FROM AUTHOR]

Background: The presence of a mental illness is a known risk factor for suicide mortality and other suicide-related behaviours, including suicidal ideation. We examined prevalence of mental illnesses among adults with and without suicidal ideation in Canada during the pandemic. Data and methods: We used pooled data from the 2020, 2021, & 2023 Survey on COVID-19 and Mental Health to estimate the prevalence of moderate to severe symptoms of generalized anxiety disorder, major depressive disorder, and posttraumatic stress disorder among adults who reported suicidal ideation, compared to those who did not report suicidal ideation. We also conducted the analyses across sociodemographic factors and COVID-19 pandemic-related experiences. Results: Among adults in Canada who reported suicidal ideation, 83.0% also screened positive for at least one of the three mental illnesses. The prevalence of mental illnesses did not differ significantly across sociodemographic factors or pandemic-related experiences. In contrast, the prevalence of at least one mental illness among adults without suicidal ideation was much lower (21.2%), and this prevalence differed by sociodemographic factors and pandemic-related experiences. Interpretation: During the COVID-19 pandemic, most adults in Canada with suicidal ideation had moderate to severe symptoms of mental illness. [ABSTRACT FROM AUTHOR]

Background and objective: Genetic polymorphism studies in families and twins indicated the heritability of depression. However, the association between genes with genetic polymorphism and depression provides various findings and remains unclear. Therefore, we conducted a systematic review and meta-analysis to determine the genes with their polymorphism associated with the symptomatic depression known as major depressive disorder (MDD). Materials and methods: PubMed and Scopus were searched for relevant studies published before May 22, 2023 (1968–2023), and 62 were selected for this review. The study's bias risk was investigated using the Newcastle–Ottawa scale. Gene functional enrichment analysis was investigated for molecular function (MF) and biological process (BP) and pathways. A meta-analysis of the studied genes that were replicative in the same single nucleotide polymorphism was conducted using a random-effect model. Results: The 49 genes involved in MDD were studied and engaged in several pathways, such as tryptophan metabolism or dopaminergic and serotonergic synapses. Based on gene overlapping in MF and BP, 13 genes with polymorphisms were identified as related to MDD. Most of them were only studied once. Solute carrier family 6 member 4 (SLC6A4) overlapping between MF and BP and brain-derived neurotrophic factor (BDNF) as unique to BP were replicative studied and used in the meta-analysis. The polymorphism of SLC6A4 SS and LS genotypes increased the occurrence of MDD development but not significantly [odd ratio (OR) = 1.39; 95% confidence interval (CI) = 0.87–2.22; P = 0.16 and OR = 1.13; 95% CI = 0.84–1.53; P = 0.42, respectively]. A similar result was observed for BDNF rs6265 GG (OR = 1.26; 95% CI = 0.78–2.06; P = 0.35) and BDNF rs6265 AA genotypes (OR = 1.12; 95% CI = 0.77–1.64; P = 0.56). These studies indicated low bias and significant heterogeneity. Conclusion: At least 13 studied genes with polymorphisms were involved in MDD development according to MF and BP, but not significantly. These results suggest that MDD development risk factors might require genetic and other factors for interaction and induction. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background/Objectives: Empowerment in medicine and psychiatry involves patients gaining control over health-related decisions, improving treatment adherence, outcomes, and satisfaction. This concept is especially significant in psychiatric care due to the complex challenges of mental health conditions, including stigma and impairment of emotional and cognitive functioning. We aim to investigate the correlations between patient trust, decision-making involvement, symptom severity, and perceived empowerment among individuals with Major Depression. Methods: Patients with Major Depressive Disorder were recruited in the "Policlinico G. Rodolico" psychiatry outpatient clinic from November 2022 to June 2023. Inclusion criteria: ages 18–65, ability to consent, stable condition, psychiatric medication history, and recent consultation. Exclusion criteria: psychotic features, bipolar disorder, substance abuse, high suicide risk, and severe comorbidities. Measures included the User Scale for Measuring Empowerment in Mental Health Services (SESM), Trust in Oncologist Scale (TiOS), Clinical Decision-Making Style for Patients (CDMS-P), and Hamilton Depression Rating Scale (HAM-D). Analysis used Kendall's Tau correlation and Two-One-Sided Tests procedure. Results: Seventy-three patients completed the study. No relationship was found between decision-making involvement and perceived empowerment (τ = −0.0625; p = 0.448), or between trust in psychiatrists and empowerment (τ = 0.0747; p = 0.364). An inverse correlation existed between patient involvement in therapy management and trust (τ = −0.2505; p = 0.002). Depression severity inversely correlated with empowerment (τ = −0.2762; p = <.001), but not with trust or decision-making involvement. Conclusions: The lack of significant correlations suggests that decision-making involvement and trust alone may not suffice to enhance empowerment. Trust may encourage patient passivity, while skepticism might drive active involvement. Higher empowerment is associated with less depressive symptoms, highlighting its potential connection with patient outcomes. [ABSTRACT FROM AUTHOR]

Compromised mitochondrial electron transport chain (ETC) activities are associated with depression in humans and rodents. However, the effects of the enhancement of mitochondrial ETC activities on depression remain elusive. We recently reported that an extremely low-frequency electromagnetic field (ELF-EMF) of as low as 10 μT induced hormetic activation of mitochondrial ETC complexes in human/mouse cultured cells and mouse livers. Chronic social defeat stress (CSDS) for 10 consecutive days caused behavioral defects mimicking depression in mice, and using an ELF-EMF for two to six weeks ameliorated them. CSDS variably decreased the mitochondrial ETC proteins in the prefrontal cortex (PFC) in 10 days, which were increased by an ELF-EMF in six weeks. CSDS had no effect on the mitochondrial oxygen consumption rate in the PFC in 10 days, but using an ELF-EMF for six weeks enhanced it. CSDS inactivated SOD2 by enhancing its acetylation and increased lipid peroxidation in the PFC. In contrast, the ELF-EMF activated the Sirt3-FoxO3a-SOD2 pathway and suppressed lipid peroxidation. Furthermore, CSDS increased markers for mitophagy, which was suppressed by the ELF-EMF in six weeks. The ELF-EMF exerted beneficial hormetic effects on mitochondrial energy production, mitochondrial antioxidation, and mitochondrial dynamics in a mouse model of depression. We envisage that an ELF-EMF is a promising therapeutic option for depression. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental Approach Key Results Conclusion and Implications Drug repurposing (DR) offers a compelling alternative to traditional drug discovery's lengthy, resource‐intensive process. DR is the process of identifying alternative clinical applications for pre‐approved drugs as a low‐risk and low‐cost strategy. Computational approaches are crucial during the early hypothesis‐generating stage of DR. However, ‘large‐scale’ data retrieval remains a significant challenge. A computational workflow addressing such limitations might improve hypothesis generation, ultimately benefit patients and advance DR research.We introduce a novel computational workflow (combining free‐accessible computational platforms) to provide ‘proof‐of‐concept’ of the pre‐approved drug's suitability for repurposing. Three key phases are included: target fishing (via reverse pharmacophore mapping), target identification (via disease‐ and drug‐target pathway identification) and retrospective literature and drug‐like analysis (via in silico ADMET properties determination). Istradefylline is a Parkinson's disease‐approved drug with literature‐attributed antidepressant properties remaining unclear. Practically applied, istradefylline's antidepressant activity was assessed in the context of major depressive disorder (MDD).Data mining aided by target identification resulted in istradefylline potentially representing a novel antidepressant drug class. Retrieved drug targets (KYNU, MAO‐B, ALOX12 and PLCB2) associated with selected MDD pathways (tryptophan metabolism and serotonergic synapse) generated a hypothesis that istradefylline increased extracellular 5‐HT levels (MAO‐B inhibition) and reduced inflammation (KYNU, ALOX12 and PLCB2 inhibition).The practically applied workflow's generated hypothesis aligns with known experimental data, validating the effectiveness of this novel computational workflow. It is a low‐risk and low‐cost DR computational tool providing a bird's‐eye view for exploring alternative clinical applications of pre‐approved drugs. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is a serious and disabling condition characterized by abnormal mood changes. Clinical guidelines for depression treatment recommend antidepressant medications, with benzodiazepines acting as short-term synergists. However, little is currently known about the prevalence and associated clinical risk factors of benzodiazepine use among Chinese patients with MDD. This study aimed to explore the prevalence and clinical risk factors associated with benzodiazepine use in this population. A total of 2742 patients with MDD (males/females = 816/1926, aged 14–60 years) participated in this cross-sectional observational study. General information and psychosis assessments were collected online. Depressive symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9), anxiety symptoms using the Generalized Anxiety Disorder-7 (GAD-7), and sleep problems and suicidal tendencies using the third and ninth items of the PHQ-9. Multivariable logistic regression analysis models were employed to identify factors associated with benzodiazepine use. The prevalence of benzodiazepine use among patients with MDD was 42.9 %. Among these patients, 99.6 % used a single benzodiazepine, with oxazepam being the most frequently prescribed. Age, severity of sleep problems, depressive symptoms, and anxiety symptoms were significantly correlated with benzodiazepine use (all P < 0.001). The cross-sectional design of this study precludes establishing causal relationships. Our findings indicate a high prevalence of benzodiazepine use among Chinese patients with MDD. Factors such as severe depressive symptoms, anxiety symptoms, age, and sleep problems appear to be associated with benzodiazepine use. These results underscore the importance of vigilance regarding benzodiazepine use in patients with MDD. • Prevalence of benzodiazepine use in patients with MDD in China is notably high. • Age is significantly associated with increased risks of benzodiazepine use. • Anxiety, depressive symptoms or sleep problem contribute to the use of benzodiazepine. [ABSTRACT FROM AUTHOR]

Changes in sleep and circadian function are leading candidate markers for the detection of relapse in Major Depressive Disorder (MDD). Consumer-grade wearable devices may enable remote and real-time examination of dynamic changes in sleep. Fitbit data from individuals with recurrent MDD were used to describe the longitudinal effects of sleep duration, quality, and regularity on subsequent depression relapse and severity. Data were collected as part of a longitudinal observational mobile Health (mHealth) cohort study in people with recurrent MDD. Participants wore a Fitbit device and completed regular outcome assessments via email for a median follow-up of 541 days. We used multivariable regression models to test the effects of sleep features on depression outcomes. We considered respondents with at least one assessment of relapse (n = 218) or at least one assessment of depression severity (n = 393). Increased intra-individual variability in total sleep time, greater sleep fragmentation, lower sleep efficiency, and more variable sleep midpoints were associated with worse depression outcomes. Adjusted Population Attributable Fractions suggested that an intervention to increase sleep consistency in adults with MDD could reduce the population risk for depression relapse by up to 22 %. Limitations include a potentially underpowered primary outcome due to the smaller number of relapses identified than expected. Our study demonstrates a role for consumer-grade activity trackers in estimating relapse risk and depression severity in people with recurrent MDD. Variability in sleep duration and midpoint may be useful targets for stratified interventions. • High intraindividual variability in sleep parameters is associated with worse depression outcomes over time. • An intervention targeting sleep consistency in MDD could reduce the risk of relapse by up to 20 %. • Wearable technologies can collect information that is useful for predicting depression outcomes. [ABSTRACT FROM AUTHOR]

Given the great interest in identifying reliable predictors of the response to antidepressant drugs, the present study investigated whether polygenic scores (PGS) for Major Depressive Disorder (MDD) and antidepressant treatment response (ADR) were related to the complex trait of antidepressant response in the Early Medication Change (EMC) cohort. In this secondary analysis of the EMC trial (N = 889), 481 MDD patients were included and compared to controls from a population-based cohort. Patients were treated over eight weeks within a pre-defined treatment-algorithm. We investigated patients' genetic variation associated with MDD and ADR, using PGS and examined the association of PGS with treatment outcomes (early improvement, response, remission). Additionally, the influence of two cytochrome P450 drug-metabolizing enzymes (CYP2C19, CYP2D6) was determined. PGS for MDD was significantly associated with disorder status (NkR2 = 2.48 %, p < 1*10−12), with higher genetic burden in EMC patients compared to controls. The PGS for ADR did not explain remission status. The PGS for MDD and ADR were also not associated with treatment outcomes. In addition, there were no effects of common CYP450 gene variants on ADR. The study was limited by variability in the outcome parameters due to differences in treatment and insufficient sample size in the used ADR genome-wide association study (GWAS). The present study confirms a polygenic contribution to MDD burden in the EMC patients. Larger GWAS with homogeneity in antidepressant treatments are needed to explore the genetic variation associated with ADR and realize the potential of PGS to contribute to specific response subtypes. • Polygenic risk for MDD was higher in EMC patients than in population-based controls. • Depressive episodes might be linked with higher genetic burden for the disorder. • No significant association between ADR-PGS and treatment response could be found. [ABSTRACT FROM AUTHOR]

Anhedonia is a core symptom of depression that is closely related to prognosis and treatment outcomes. However, accurate and efficient treatments for anhedonia are lacking, mandating a deeper understanding of the underlying mechanisms. A total of 303 patients diagnosed with depression and anhedonia were assessed by the Snaith-Hamilton Pleasure Scale (SHAPS) and magnetic resonance imaging (MRI). The patients were categorized into a low-anhedonia group and a high-anhedonia group using the K -means algorithm. A data-driven approach was used to explore the differences in brain structure and function with different degrees of anhedonia based on MATLAB. A random forest model was used exploratorily to test the predictive ability of differences in brain structure and function on anhedonia in depression. Structural and functional differences were apparent in several brain regions of patients with depression and high-level anhedonia, including in the temporal lobe, paracingulate gyrus, superior frontal gyrus, inferior occipital gyrus, right insular gyrus, and superior parietal lobule. And changes in these brain regions were significantly correlated with scores of SHAPS. These brain regions may be useful as biomarkers that provide a more objective assessment of anhedonia in depression, laying the foundation for precision medicine in this treatment-resistant, relatively poor prognosis group. • rs-fMRI was used to distinguish high and low levels of anhedonia in patients with depression. • The temporal lobe and superior parietal lobule may be an important hub for anhedonia in depression. • Imaging biomarkers for anhedonia in depression can provide more objective assessment, laying a foundation for precision medicine. [ABSTRACT FROM AUTHOR]

Repetitive transcranial magnetic stimulation (rTMS) is a safe and effective treatment for major depressive disorder (MDD); however, this treatment currently lacks reliable biomarkers of treatment response. TMS-evoked potentials (TEPs), measured using TMS-electroencephalography (TMS-EEG), have been suggested as potential biomarker candidates, with the N100 peak being one of the most promising. This study investigated the association between baseline N100 amplitude and 1 Hz right dorsolateral prefrontal cortex (R-DLPFC) accelerated rTMS (arTMS) treatment in MDD. Baseline TMS-EEG sessions were performed for 23 MDD patients. All patients then underwent 40 sessions of 1 Hz R-DLPFC (F4) arTMS over 5 days and a follow-up TMS-EEG session one week after the end of theses arTMS sessions. Baseline N100 amplitude at F4 showed a strong positive association (p <.001) with treatment outcome. The association between the change in N100 amplitude (baseline to follow-up) and treatment outcome did not remain significant after Bonferroni correction (p =.06, corrected; p =.03, uncorrected). Furthermore, treatment responders had a significantly larger mean baseline F4 TEP amplitude during the N100 time frame compared to non-responders (p <.001). Topographically, after Bonferroni correction, F4 is the only electrode at which its baseline N100 amplitude showed a significant positive association (p <.001) with treatment outcome. Lack of control group and auditory masking. Baseline N100 amplitude showed a strong association with treatment outcome and thus demonstrated great potential to be utilized as a cost-effective and widely adoptable biomarker of rTMS treatment in MDD. • Baseline F4 N100 amplitude showed a strong association (p<.001) with 1Hz R-DLPFC rTMS treatment outcome. • Treatment responders had a larger mean F4 TEP amplitude during the N100 time frame compared to non-responders (p <.001). • N100 amplitude at F3 and F4 had the strongest association with outcome (F3: p = 0.015, uncorr.; F4 p <.001, corrected). • Our results suggest that N100 amplitude has great potential to be a cost-effective and widely-adoptable biomarker. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is progressively recognized as a stress-related disorder characterized by aberrant brain network dynamics, encompassing both structural and functional domains. Yet, the intricate interplay between these dynamic networks and their molecular underpinnings remains predominantly unexplored. Both structural and functional networks were constructed using multimodal neuroimaging data from 183 MDD patients and 300 age- and gender-matched healthy controls (HC). structural-functional connectivity (SC-FC) coupling was evaluated at both the connectome- and nodal-levels. Methylation data of five HPA axis key genes, including NR3C1, FKBP5, CRHBP, CRHR1, and CRHR2, were analyzed using Illumina Infinium Methylation EPIC BeadChip. We observed a significant reduction in SC-FC coupling at the connectome-level in patients with MDD compared to HC. At the nodal level, we found an imbalance in SC-FC coupling, with reduced coupling in cortical regions and increased coupling in subcortical regions. Furthermore, we identified 23 differentially methylated CpG sites on the HPA axis, following adjustment for multiple comparisons and control of age, gender, and medication status. Notably, three CpG sites on NR3C1 (cg01294526, cg19457823, and cg23430507), one CpG site on FKBP5 (cg25563198), one CpG site on CRHR1 (cg26656751), and one CpG site on CRHR2 (cg18351440) exhibited significant associations with SC-FC coupling in MDD patients. These findings provide valuable insights into the connection between micro-scale epigenetic changes in the HPA axis and SC-FC coupling at macro-scale connectomes. They unveil the mechanisms underlying increased susceptibility to MDD resulting from chronic stress and may suggest potential pharmacological targets within the HPA-axis for MDD treatment. • We replicated a significant SC-FC decoupling at the connectome level in MDD patients. • We identified disruptions in methylation levels at multiple CpG sites within key genes of the HPA axis in MDD patients. • We found a significant association between the methylation levels of disrupted CpG sites and the observed SC-FC decoupling. • Our findings support that chronic stress-related epigenetic changes play a pivotal role in the pathogenesis of MDD. [ABSTRACT FROM AUTHOR]

It is previously reported that the Montgomery–Åsberg Depression Rating Scale (MADRS) anhedonia factor score is correlated with scales assessing function in patients with major depressive disorder (MDD). This was an analysis of a database including 5 long-term, extension studies of prior controlled trials, which evaluated the effects of open-label, maintenance treatment with vortioxetine (5-20 mg/day over 1-year) in adults with MDD. We assessed the association of changes in MADRS anhedonia factor scores with changes in the Clinical Global Impression of Severity (CGI-S), Sheehan Disability scale (SDS), and the SF-36. A minimal clinically important change (MCIC) for MADRS anhedonia factor scores was determined using the CGI-S as anchor. In patients who had completed the prior controlled studies, MADRS anhedonia factor scores continued to improve over 1-year of maintenance treatment (mean ± SE change from baseline of −6.2 ± 0.2 at Month 12). Change in MADRS anhedonia factors score correlated with change in CGI-S (Week 4, r = 0.71), SDS (Week 24 r = 0.60) and SF-36 domains (Week 24 r = −0.19 to −0.61) scores. Using a 1 level improvement on CGI-S as anchor, the MCIC for MADRS anhedonia factor scores versus baseline were − 4.6 at Week 4, −5.5 at Week 24, and − 5.3 at Week 52. Neither the MADRS scale, nor the primary studies, were specifically designed to assess anhedonia. These open-label data suggest that patients treated with vortioxetine continued to show clinically relevant improvements in their anhedonia over 1-year of maintenance therapy. Improvements in anhedonia correlated with improvements in measures of functioning and quality of life. • Anhedonia symptoms continued to improve over 1-year of maintenance therapy. • MADRS anhedonia factor scores correlated with measures of functioning & well-being. • The MCIC for MADRS anhedonia factor scores ranged from −4.7 to −5.5 across visits. [ABSTRACT FROM AUTHOR]

Functional impairment is common in patients with major depressive disorder (MDD). The Functioning Assessment Short Test (FAST) provides a detailed clinician-rated assessment of functioning across multiple aspects of daily life. This study aimed to establish clinically relevant response thresholds for the FAST in patients with MDD receiving antidepressant treatment. Data were derived from three 8-week clinical trials of antidepressant therapy in patients with MDD that included assessment of functioning using the FAST as a pre-specified endpoint. The minimal clinically important difference (MCID) and threshold for response in terms of change in FAST total score were determined using anchor-based methods. After 8 weeks of antidepressant treatment, the mean reduction in FAST total score in patients considered clinically minimally improved (Clinical Global Impression–Improvement [CGI-I] score of 3) was 7–9 points (~20 % reduction). The threshold for functional response (reduction in FAST total score from baseline in patients with a CGI-I score of ≤2 at week 8) was 16–19 points (~50 % reduction). The threshold for functional response was higher in patients with MDD and comorbid generalized anxiety disorder than in those with MDD alone (mean reduction in FAST total score at 8 weeks: 26 points [63 %]). Short-term studies. These results provide further validation of the FAST for assessing functioning in patients with MDD. In patients with MDD, the suggested MCID for FAST total score is 7–9 points and the proposed threshold for response is a reduction from baseline of approximately 50 %. • Patients with major depressive disorder (MDD) experience functional impairments that impact all aspects of their daily life • The Functioning Assessment Short Test (FAST) provides a detailed assessment of functional impairments in patients with MDD • In patients with MDD, the minimal clinically important difference in FAST total score after 8 weeks therapy was 7–9 points • A reduction in FAST total score of approximately 50 % after 8 weeks of antidepressant treatment was indicative of response • The threshold for functional response was higher in patients with comorbid anxiety than in those with MDD alone [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is one of the leading causes of burden of disease globally. We aimed to investigate whether global functioning is impaired in patients with MDD in full or partial remission compared to healthy control individuals (HC). We conducted a systematic review and meta-analysis according to the PRISMA guideline. We searched the databases PubMed, EMBASE and PsycINFO from January 1st 1980 to February 1st 2023. We included studies of adults with a diagnosis/former diagnosis of MDD with assessment of global functioning performed during a state of full or partial remission. The methodological quality was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist. Standardised mean differences (SMD) using random-effects models were calculated as the summary measure. We further performed meta-analyses of the mean raw score in patients with MDD for individual functioning scales. Forty-two studies, comprising 17,999 patients with MDD and 35,550 HC, were included, 14 of which included both patients with MDD in full or partial remission and HC. Global functioning was lower in patients with MDD in full or partial remission compared with HC (SMD -2.00, 95 % CI: −0.9 to −3.03, 15 comparisons, I2: 99.8 %). Important information about the study participants and setting was not reported for most studies, or the reporting was unclear. Patients with MDD have lower levels of functioning compared with HC also when in full or partial remission. Assessment of functioning should be an essential component of managing patients with MDD, also during remission. • Global functioning is lower in patients with MDD in full or partial remission compared with HC. • Male sex might be associated with lower functioning in patients with MDD. • Assessment of functioning in patients with MDD in full or partial remission is recommended as an essential component of care. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is a prevalent and disabling mood disorder, thought to be linked with brain white matter (WM) alterations. Prior diffusion tensor imaging (DTI) studies have reported inconsistent changes in fractional anisotropy (FA) across different brain regions in MDD patients. However, none of these studies utilized raw t-map data for WM meta-analysis in MDD. Our study aims to address this gap by conducting a whole-brain-based meta-analysis of FA in MDD using Seed-based d mapping via permutation of subject images (SDM-PSI), combining reported peak coordinates and raw statistical parametric maps. Following PRISMA guidelines, we performed a systematic search and meta-analysis to compare FA in MDD patients with healthy controls (HC). Our goal was to identify WM abnormalities in MDD, using SDM, which could shed light on the disorder's pathogenesis. The meta-analysis included 39 studies with 3696 participants (2094 with MDD, 1602HC). It revealed that MDD patients, in comparison to HC, have lower FA in the corpus callosum (CC) and anterior thalamic projections (ATP). Subgroup analyses indicated that the CC is a more stable pathogenic factor in MDD. Meta-regression analyses showed no linear correlation between the mean age, percentage of female patients, duration of depression, and FA abnormalities. This suggests that WM impairments in interhemispheric connections and anterior thalamocortical circuits are significant in the pathogenesis of MDD. • A whole-brain meta-analysis was performed using SDM-PSI, combining peak coordinates and raw t-map. • Patients with MDD relative to healthy controls have lower FA in the CC and anterior ATP. • The VBA method may be more sensitive than the TBSS method for white matter meta-analysis of MDD. • Subgroup analyses indicated that the CC is a more stable pathogenic factor in MDD. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. The sample size is relatively small. SDH protein levels in peripheral blood may not necessarily reflect mitochondrial energy generation in the central nervous system. • Patients with major depressive disorder (MDD) exhibited lower cerebral hemodynamic responses to verbal fluency tests. • These reduced hemodynamic responses were associated with mitochondrial dysfunction, as indicated by lower levels of SDH protein. • Additionally, attenuated hemodynamic responses in the frontotemporal regions and decreased SDH levels were found to increase the risk for MDD. [ABSTRACT FROM AUTHOR]

Objectives: Melancholic depression (MD) is a common subtype of major depressive disorder (MDD). It is difficult to treat because its neurobiological basis is poorly understood. Therefore, to investigate whether MD patients have any structural changes in gray matter (GM) and the molecular foundation of these changes, we combined voxel‐based morphometry (VBM) analysis with neurotransmitter system‐derived mapping from public data. Methods: 137 drug‐naive MDD patients and 75 healthy controls (HCs) were recruited for structural magnetic resonance imaging. The imaging results were analyzed using VBM analysis. MDD patients were then divided into MD and nonmelancholic depression (NMD) subgroups according to their scores on the Montgomery–Asberg Depression Rating Scale (MADRS) and the Hamilton Depression Rating Scale. Next, we analyzed the spatial correlation between the changes in the gray matter volume (GMV) maps and the neurotransmitter receptor/transporter protein density maps provided by the JuSpace toolbox. Results: Compared to HCs, patients with MD had significant GMV reduction in the bilateral hippocampus, bilateral thalamus, right amygdala, and right posterior cingulate cortex (PCC)/precuneus. Compared to patients with NMD, MD patients had significant GMV reduction in the bilateral PCC/precuneus and lateral occipital cortex. Moreover, compared to HCs, changes in GMV introduced by MD were spatially associated with the serotonin transporter, cannabinoid receptor, and μ‐opioid receptor. Compared to NMD patients, changes in GMV introduced by MD were spatially associated with the vesicular acetylcholine transporter. Conclusion: The present study discovered abnormal GMV alterations in patients with subtypes of depression. We also found a series of neurotransmitter receptors that may be associated with the alterations. The findings of the current study may provide a more comprehensive understanding of the molecular mechanisms underlying the structural abnormalities in subtypes of depression and potentially offer new insights into developing new therapeutic strategies. [ABSTRACT FROM AUTHOR]

AbstractBackground: Perceived purpose in life (PIL) is linked with many vital health outcomes, including Major Depressive Disorder (MDD). Methods: In this study, biomarkers associated with depression and PIL were investigated using Brain Network Activation (BNA) based quantitative electroencephalography (QEEG) and event-related potential (ERP) measures in a sample of individuals with MDD. Data were analyzed before and after a 36-session, Deep transcranial magnetic stimulation (TMS) program. Results: At baseline, the study observed that increased slow-frequency resting-state activity in the frontal and temporal regions correlated with higher levels of depression and reduced PIL. Additionally, a reduced P3b amplitude was found to predict elevated depressive symptoms. However, with the application of Deep TMS treatment notable improvements were observed in both depression (p < .001. d = 2.15) and PIL (p < .001, d = 1.59) levels. The treatment also successfully regulated resting-state QEEG (delta/beta) and ERP characteristics (P200 latency), bringing them closer to healthy levels. Conclusions: This attenuation of brain activity patterns relating to depression is encouraging as it suggests that effects were robust and are more likely to be sustained over time. This study represents the first exploration of the effects of Deep TMS on PIL and relevant QEEG and ERP biomarkers. The initial evidence suggests that Deep TMS holds promise in enhancing both PIL and neurophysiological health. Future investigations should continue exploring the utility of Deep TMS in targeting a wide range of neuropsychological and physical health conditions, leveraging objective biomarkers such as QEEG and ERP. [ABSTRACT FROM AUTHOR]

Background: Major depressive disorder (MDD) is one of the most common psychiatric disorders worldwide. Hypericumperforatum (HP) is a traditional herb that has been shown to have antidepressant effects, but its mechanism is unclear. This study aims to identify the molecular targets of HP for the treatment of MDD. Methods: We performed differential analysis and weighted gene co-expression network analysis (WGCNA) with blood mRNA expression cohort of MDD and healthy control to identify DEGs and significant module genes (gene list 1). Three databases, CTD, DisGeNET, and GeneCards, were used to retrieve MDD-related gene intersections to obtain MDD-predicted targets (gene list 2). The validated targets were retrieved from the TCMSP database (gene list 3). Based on these three gene lists, 13 key pathways were identified. The PPI network was constructed by extracting the intersection of genes and HP-validated targets on all key pathways. Key therapeutic targets were obtained using MCODE and machine learning (LASSO, SVM-RFE). Clinical diagnostic assessments (Nomogram, Correlation, Intergroup expression), and gene set enrichment analysis (GSEA) were performed for the key targets. In addition, immune cell analysis was performed on the blood mRNA expression cohort of MDD to explore the association between the key targets and immune cells. Finally, molecular docking prediction was performed for the targets of HP active ingredients on MDD. Results: Differential expression analysis and WGCNA module analysis yielded 933 potential targets for MDD. Three disease databases were intersected with 982 MDD-predicted targets. The TCMSP retrieved 275 valid targets for HP. Separate enrichment analysis intersected 13 key pathways. Five key targets (AKT1, MAPK1, MYC, EGF, HSP90AA1) were finally screened based on all enriched genes and HP valid targets. Combined with the signaling pathway and immune cell analysis suggested the effect of peripheral immunity on MDD and the important role of neutrophils in immune inflammation. Finally, the binding of HP active ingredients (quercetin, kaempferol, and luteolin) and all 5 key targets were predicted based on molecular docking. Conclusions: The active constituents of Hypericumperforatum can act on MDD and key targets and pathways of this action were identified. [ABSTRACT FROM AUTHOR]