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Major Depressive Disorder (MDD) is a heterogenous and etiologically complex disease often presenting with divergent appetitive phenotypes including Hyperphagic MDD (characterized by an increased appetite) and Hypophagic MDD (characterized by a decrease in appetite) which are closely related to comorbidities, including cardiometabolic disorders. Hyperphagia is associated with atypical depression, decreased stress-hormone signaling, a pro-inflammatory status, hypersomnia, and poorer clinical outcomes. Yet, our understanding of associated biological correlates of Hyperphagic and Hypophagic MDD remain fragmented. We performed an exploratory study on peripheral blood RNA profiling using bulk RNAseq in unmedicated individuals with Hyperphagic and Hypophagic MDD (n = 7 and n = 13, respectively). At baseline, we discovered an increased expression of TADA2B in hyperphagic MDD with the significant enrichment of 72 gene ontology pathways mainly related to inflammation. In addition, we used the Maastricht Acute Stress Task to uncover stress-related transcriptomic profiles in Hyper- and Hypophagic MDD and discovered the upregulation of CCDC196 and the downregulation of SPATA33 in hyperphagic MDD. Gene ontology enrichment analysis after stress exposure showed pathways related to ribosomal activity. Limitations: The present findings are tempered primarily by the limited sample size, which requires independent replication of this exploratory study. However, stringent methods controlling for false positive findings mitigate the risk associated with sample size limitations. Limitations notwithstanding, findings suggest that hyper- and hypophagic MDD is associated with divergent RNA expression profiles in peripheral blood that are amplified by exposure to a controlled stress test. Our findings in a well-controlled study provide evidence for peripheral markers of a relevant endophenotype of MDD. [ABSTRACT FROM AUTHOR]

Dissociative symptoms are both a pathological consequence of exposure to psychological trauma as well as a side effect of N -methyl- d -aspartate (NMDA) receptor antagonist medications; therefore, accurate and valid assessment of these symptoms is important. The psychometric properties of the 23-item Clinician Administered Dissociative States Scale (CADSS) have been characterized in the ketamine and esketamine literatures. Here, we examine its performance in a sample with and without posttraumatic stress disorder (PTSD) and a history of exposure to psychological trauma. Participants with a history of psychological trauma with (N = 148) and without (N = 100) the diagnosis of PTSD and healthy participants without a psychiatric disorder or history of trauma (N = 28) were assessed with the 23-item CADSS and other psychometric and neuropsychological assessments. Analyses were performed to examine internal consistency, convergent and discriminant validity, factor structure, differential performance in populations reported to be more or less likely to report dissociative symptoms (e.g., patients with and without PTSD), and sensitivity to change resulting from exposure to trauma-related sights and sounds. The 23-item CADSS was found to have high internal consistency (Cronbach's alpha 0.91) and a single-factor structure. CADSS total scores in trauma-exposed participants with PTSD were higher than those in trauma-exposed participants without PTSD and non-traumatized non-PTSD participants. Finally, veterans with Iraq combat-related PTSD showed a significant increase in CADSS total score after exposure to combat-related slides and sounds. The 23-item CADSS, already validated as a tool to measure dissociation related to administration of NMDA receptor antagonist medication, performs in a reliable and valid manner in the assessment of dissociation in psychologically traumatized participants. • The 23-item Clinician Administered Dissociative States Scale (CADSS) was found to be psychometrically sound in a psychological trauma population including participants with and without posttraumatic stress disorder (PTSD) and a history of psychological trauma • CADSS scores were higher in PTSD participants than in those without PTSD • The study results support the fact that dissociation is a unitary construct • The study does not support the idea that subtypes of dissociation (amnesia, depersonalization, derealization, identity fragmentation) are constructs distinct from one another • The CADSS was found to be useful as a change measure, showing an increase in dissociation in veterans with PTSD following exposure to combat-related slides and sounds [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) has been associated with deficits in working memory as well as underlying gamma oscillation power. Consistent with this, overall reductions in cortical excitation have also been described with MDD. In previous work, we have demonstrated that the monoamine reuptake inhibitor venlafaxine increases gamma oscillation power in ex vivo hippocampal slices and that this is associated with concomitant increases in pyramidal arbour and reduced levels of plasticity‐restricting perineuronal nets (PNNs). In the present study, we have examined the effects of chronic treatment with pramipexole (PPX), a D3 dopamine receptor agonist, for its effects on gamma oscillation power as measured by in vivo electroencephalography (EEG) recordings in female BALB/c and C57Bl6 mice. We observe a modest but significant increase in 20–50 Hz gamma power with PPX in both strains. Additionally, biochemical analysis of prefrontal cortex lysates from PPX‐treated BALB/c mice shows a number of changes that could contribute to, or follow from, increased pyramidal excitability and/or gamma power. PPX‐associated changes include reduced levels of specific PNN components as well as tissue inhibitor of matrix metalloproteases‐1 (TIMP‐1), which inhibits long‐term potentiation of synaptic transmission. Consistent with its effects on gamma power, PNN proteins and TIMP‐1, chronic PPX treatment also improves working memory and reduces anhedonia. Together these results add to an emerging literature linking extracellular matrix and/or gamma oscillation power to both mood and cognition. [ABSTRACT FROM AUTHOR]

Major depression is a public health problem facing the world. This study aimed to identify the risk factors for major depression and clarify their causal effects. Data from the National Health and Nutrition Examination Survey (NHANES). Multifactorial logistic regression analysis was used to calculate the effect of each variable on major depression. Subgroup analyses and interaction tests were conducted to observe the stability of the association between them. Nonlinear correlations were explored using restricted cubic spline plots. The causal effects of serum Klotho on major depression were assessed using Mendelian randomization (MR) analysis. A total of 8359 participated in the study. After adjusting for all covariates, the risk of having major depression was 1.47 times higher for each unit rise in serum Klotho (OR = 1.47, 95 % CI = 1.07–2.02; P = 0.0183). MR analysis showed no causal relationship between serum Klotho levels and risk of major depression (OR = 1.09, 95 % CI = 0.91–1.30; P = 0.4120). Sensitivity analysis verified the reliability of the results. Serum Klotho is positively associated with an increased risk of major depression in the U.S. population, but MR analyses did not show genetic causality between Klotho and major depression in individuals of European ancestry. Based on the results of the current study, no indication maintaining high levels of Klotho may increase the risk of major depression. The main limitation of this study is the inconsistency of the cross-sectional study and the MR population. • Serum Klotho was first observed as a risk factor for major depression, but MR findings suggest no causal relationship. • J-shaped association between serum Klotho and major depression. • This study combines comprehensive data from a large-sample cross-sectional survey and a genomic analysis system. • No indication that serum Klotho may help improve major depression. [ABSTRACT FROM AUTHOR]

Childhood trauma, including emotional neglect, emotional abuse, physical abuse, and sexual abuse, may contribute to borderline personality features like affective instability, identity problems, negative relationships, and self-harm. This study aims to explore how different types of childhood trauma affect these features in bipolar versus unipolar depressive disorders. We included 839 participants of the Netherlands Study of Depression and Anxiety (NESDA) with a lifetime diagnosis of major depressive disorder single episode (MDD S; N = 443), recurrent major depressive disorder (MDD-R; N = 331), or bipolar disorder (BD; N = 65). Multivariate regression was used to analyze data from the Childhood Trauma Interview and borderline features (from the self-report Personality Assessment Inventory). On average, participants were 48.6 years old (SD: 12.6), with 69.2 % being women, and 50.3 % of participants assessed positive for childhood trauma. Adjusted analyses revealed that participants diagnosed with BD, followed by MDD-R, exhibited the highest number of borderline personality features. Additionally, within the entire group, a strong association was found between childhood trauma, especially emotional neglect, and the presence of borderline personality features. Given the high prevalence of childhood trauma and borderline personality features, screening for these factors in individuals with mood disorders is crucial. Identifying these elements can inform and enhance the management of the often fluctuating and complex nature of these comorbid conditions, leading to more effective and tailored treatment strategies. • Highest number of BPF was observed in BD followed by MD-recurrend and finally MD-single episode. • This order (BD > MD-recurrent > MD-single episode) was observed for all four main domains of BPD. • Within each diagnostic category, participants with a history of CT consistently showed higher average scores for BPF. • Emotional neglect was the most strongly associated factor, with the total number of BPF and its four main subscale scores. [ABSTRACT FROM AUTHOR]

Introduction: Early recognition and indicated prevention is a promising approach to decrease the incidence of Major depressive episodes (MDE), targeting the patients during their clinical high-risk state of MDE (CHR-D). The identification of a set of stressors at the CHR-D increases the success of indicated prevention with personalized early interventions. The study evaluated stressors in the early phase of depression, developed on the basis of a patient survey on stressors. Methods: Sixty-eight inpatients (ICD10: F3x.xx) with a reported high risk state for major depressive episode (CHR-D) were included in the current study. Stressors during CHR-D were retrospectively explored using a semi-structured clinical interview supplemented by open-ended questions. A qualitative explorative content analysis was provided to identify a pattern of stressors during the prodromal phase of the patients, based on the patient's perspective. A frequency analysis was performed for the evaluation of the prevalence of reported source of stress. Results: All patients reported stressors in the prodromal phase of depression. Results demonstrates that patients with depressive disorder typically report multiple stressors, with the most common number being four. First, 18 stressors-groups were identified during coding. Interpersonal conflicts and disappointments in close relationships were most frequently reported stressors during the prodromal phase at 44.1%. The second most frequent stressor mentioned was the high qualitative or quantitative demands at work (38.2%). The third frequent source of stress was changes in close relationships and in family relationships (33.8%). Based on the categories of stressors described in the patient survey during the prodromal phase we suggested a model of stressors in CHR-D during the prodromal phase of the MDE. Discussion: The identification of a set of stressors at the early stage of MDE may increase opportunities for early intervention. In everyday clinical practice, preventive psychiatry needs clinical and adapted instruments for recording stressors in today's society. This knowledge is necessary in order to develop precisely indicated prevention for depressive disorders. [ABSTRACT FROM AUTHOR]

Early flow cytometry studies revealed T cell activation in major depressive disorder (MDD). MDD is characterised by activation of the immune-inflammatory response system (IRS) and the compensatory immunoregulatory system (CIRS), including deficits in T regulatory (Treg) cells. This study examines the number of cannabinoid type 1 (CB1) and type 2 (CB2) receptor-bearing T/B lymphocytes in MDD, and the effects of in vitro cannabidiol (CBD) administration on CB1/CB2-bearing immunocytes. Using flow cytometry, we determined the percentage of CD20+CB2+, CD3+CB2+, CD4+CB2+, CD8+CB2+ and FoxP3+CB1+ cells in 19 healthy controls and 29 MDD patients in 5 conditions: baseline, stimulation with anti-CD3/CD28 with or without 0.1 µg/mL, 1.0 µg/mL, or 10.0 µg/mL CBD. CB2+ was significantly higher in CD20+ than CD3+ and CD4+ and CD 8+ cells. Stimulation with anti-CD3/CD8 increases the number of CB2-bearing CD3+, CD4+ and CD8+ cells, as well as CB1-bearing FoxP3+ cells. There was an inverse association between the number of reduced CD4+ CB2+ and IRS profiles, including M1 macrophage, T helper-(Th)-1 and Th-17 phenotypes. MDD is characterised by lowered basal FoxP3+ CB1+% and higher CD20+ CB2+%. 33.2% of the variance in the depression phenome (including severity of depression, anxiety and current suicidal behaviours) is explained by CD20+ CB2+ % (positively) and CD3+ CB2+% (inversely). All five immune cell populations were significantly increased by 10 µg/mL of CBD administration. Reductions in FoxP3+ CB1+% and CD3+ /CD4+ CB2+% contribute to deficits in immune homoeostasis in MDD, while increased CD20+CB2+% may contribute to the pathophysiology of MDD by activating T-independent humoral immunity. [ABSTRACT FROM AUTHOR]

Purpose: This study aims to examine time trends in the ability to correctly identify schizophrenia and major depression within the German general population from 1990 to 2020, as an indicator of changing mental health literacy (MHL). Additionally, we investigated shifts in the use of stigmatizing language. Methods: Our analysis is based on four waves of representative population surveys in Germany in 1990/1993 (West Germany: N = 2044, East Germany: N = 1563), 2001 (N = 5025), 2011 (N = 2455), and 2020 (N = 3042) using identical methodology. Respondents were presented with an unlabelled case vignette describing a person who exhibited symptoms of either schizophrenia or major depression. Participants were then asked to name the problem described in the vignette using an open-ended question. Results: From 1990/1993 to 2020, correct identification of schizophrenia increased from 18% to 34% and from 27% to 46% for major depression. However, derogatory labels remained constant throughout all survey waves, particularly for schizophrenia (19% in 1990/1993 and 18% in 2020). For depression, more trivializing and potentially devaluing statements were recorded. Conclusion: Despite the increasing use of psychiatric terminology among the general population, the persistence of derogatory labels suggests that improved MHL, reflected in higher recognition rates, may not automatically translate into a reduction in stigmatizing language. With depression, a normalization and trivialization of a severe illness could pose new challenges to people with major depression. Dedicated efforts to combat the stigma of severe mental illness are still needed. [ABSTRACT FROM AUTHOR]

This study endeavors to deepen our understanding of the subject matter by exploring, within a real-world sample, the impact of menopausal status on the antidepressant treatments response. The whole sample included a total of 447 patients, 156 male and 291 female, 110 pre-menopause and 181 post-menopause. In our sample post-menopause women showed a worse response to antidepressants than pre-menopause women (p = 0.006), and this difference seems to be unrelated to age or brain aging. [ABSTRACT FROM AUTHOR]

Major depression (MD) is recurrent and devastating mental disease with a high worldwide prevalence. Mounting evidence suggests neuroinflammation triggers cellular immune dysregulation, characterized by increased proportions of circulating monocytes, and T helper 17 cells and proinflammatory cytokines, thereby increasing susceptibility to MD. However, there is ambiguity in the findings of clinical studies that investigate CD4+ T regulatory (Treg) cells in MD. The proportion of CD4+ Treg cell from blood mononuclear cells was examined using flow cytometry in healthy controls (HCs: n = 96) and patients with first (FEMD: n = 62) or recurrent (RMD: n = 41) disease episodes of MD at baseline (T0; hospital admission) and after a two-week antidepressant treatment (T14). All participants underwent comprehensive neuropsychological assessments. The initial scores on emotional assessments in patients with MD significantly differed from those of HCs. Both FEMD and RMD patients exhibited a significant decrease in CD4+ Treg cell proportion at baseline compared to HCs. Treg cell proportion rose significantly from T0 to T14 in FEMD patients, who responded to antidepressant therapy, whereas no significant changes were observed in FEMD patients in non-response as well as RMD patients. The improvement of 24-item Hamilton Depression Scale was correlate with changes of Treg cell proportion from T0 to T14 in FEMD patients in response, and the change in Treg cell proportion over a 14-day period exhibited an AUC curve of 0.710. A decrease in the proportion of CD4+ Treg cells points towards immune system abnormalities in patients with MD. Furthermore, our finding suggests that the immune activation state varies across different stages of depression. • Regulatory T cell proportion was decreased in major depression patients • Regulatory T cells may involve in early depression treatment • Regulatory T cells indicate distinct immune states at various stages of depression [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is characterized by increased T helper (Th)1 polarization, T cell activation (e.g., CD71+ and CD40L+), and cannabinoid receptor type 2 bearing CD20+ B cells; and lower T regulatory (Treg) numbers. To delineate the effects of adverse childhood experiences (ACEs) and recurrence of illness (ROI) on activated T and CB2-bearing B populations, and Tregs, including FoxP3 + CD152+, FoxP3 + GARP+, and FoxP3 + CB1+ cells. We measured ROI, ACEs, the number of activated T cells, Tregs, and CD20 + CB2+ B cells, in 30 MDD patients and 20 healthy controls. A larger part of the variance in the depression phenome (40.8 %) was explained by increased CD20 + CB2+ and activated T cells, and lowered Tregs. ROI and lifetime suicidal behaviors were significantly and positively associated with CD20 + CB2+, CD3 + CD71+, CD3 + CD40L+, CD4 + CD71+, CD4 + CD40L+, and CD4HLADR+ numbers. ROI was significantly correlated with CD8 + CD40L+ numbers. The sum of ACEs was significantly associated with CD20 + CB2+, CD3 + CD40L+, CD4 + 40 L+ numbers, T cell activation (positively) and Treg (inversely) indices. One replicable latent vector could be extracted from activated T cells, lifetime and current suicidal behaviors, number of depressive episodes, and severity of depression, and 48.8 % of its variance was explained by ACEs. ACE-induced activation of T effector and cytotoxic cells and B cells with autoimmune potential, coupled with lowered Treg numbers are a key component of depression. The findings indicate that increasing ROI, the phenome of depression and suicidal behaviors, are caused by autoimmune processes, which are the consequence of ACEs and increasing sensitization of immune responses. • Adverse childhood experiences (ACEs) activate T effector and cytotoxic cells, B cells with autoimmune potential, and reduce Treg cell numbers. • ACE-enhanced immune-inflammatory processes are pivotal in depression. • ACEs heighten immune response, leading to autoimmunity and increased illness recurrence, the phenomenon of depression and suicidal behaviors. [ABSTRACT FROM AUTHOR]

AbstractObjectiveMethodsResultsConclusions\nKEY POINTSTherapeutic drug monitoring (TDM) is an important tool for treatment optimisation. Its usefulness has recently been demonstrated for some first-line antidepressants; however, few studies have been reported on the relationship between blood levels of mirtazapine and its antidepressant effects. The aim of this study was to investigate the association between blood concentration of mirtazapine and antidepressant response.59 outpatients treated with mirtazapine for depression were recruited and followed up for three months in a naturalistic setting. Hamilton Depression Rating Scale-21 (HAMD-21) was administered at baseline, month 1, and month 3 to assess antidepressant response. Mirtazapine serum concentration was measured at steady state. Linear regression analysis and nonlinear least-squares regression were used to estimate association between serum concentration of mirtazapine and antidepressant response.Our results showed no overall association between serum concentration of mirtazapine and symptom improvement at month 1 and month 3. A marginally significantly higher serum concentration of mirtazapine was found in responders vs non-responders at month 3.The study suggests that serum concentration of mirtazapine is not strongly associated with the antidepressant efficacy of mirtazapine. This is probably attributed to its pharmacodynamic profile, even though higher blood levels seem to be marginally more effective.Mirtazapine plasma levels association with response is mild and do not follow the same curve of other antidepressantsMirtazapine higher plasma levels may show some benefit in a subgroup of patientsTherapeutic drug monitoring may help during antidepressant treatment [ABSTRACT FROM AUTHOR]

Introduction: Major Depression (MD) is a common mental disorder. In East Asian ancestry, the association, causality, and shared genetic basis between bloodbased biomarkers and MD remain unclear. Methods: We investigated the relationships between blood-based biomarkers and MD through a cross-sectional study and Mendelian randomization (MR) analysis. Cross-trait analysis and enrichment analyses were used to highlight the shared genetic determinants and biological pathways. We conducted summary data-based MR to identify shared genes, which were then validated using a transcriptome dataset from drug-naïve patients with MD. Results: In the cross-sectional study, C-Reactive Protein showed the significantly positive correlation with depressive symptoms, while hematocrit, hemoglobin, and uric acid exhibited significantly negative correlations. In MR analysis, basophil count (BASO) and low-density lipoprotein cholesterol (LDLc) had a significant causal effect on MD. The enrichment analysis indicated a significant role of inflammatory cytokines and oxidative stress. The shared genes MFN2, FAM55C, GCC2, and SCAPER were validated, with MFN2 identified as a pleiotropic gene involved in MD, BASO, and LDLc. Discussion: This study highlighted that BASO and LDLc have a causal effect on MD in East Asian ancestry. The pathological mechanisms of MD are related not only to inflammatory cytokines and oxidative stress but also to down regulation of MFN2 expression and mitochondrial dysfunction. [ABSTRACT FROM AUTHOR]

Background: Food addiction (FA) is strongly associated with depressive symptoms. The reliability and validity of the Modified Yale Food Addiction Scale 2.0 (mYFAS 2.0) were not previously determined in clinical samples in Brazil. This study aimed to assess the psychometric properties of the Brazilian version of the mYFAS 2.0 in adult individuals with depressive disorders. Methods: The data stems from a survey investigating FA in a convenience sample of subjects diagnosed with a depressive disorder. Participants answered mYFAS 2.0 and scales for binge eating, depressive and anxiety symptoms, and alcohol and nicotine use. Height and weight were measured to calculate the Body Mass Index (BMI). We evaluated the factor structure, reliability, convergent, discriminant, criterion, and incremental validity. Results: The sample encompassed 303 participants with a mean age of 37.03 ± 11.72 years, 84.16% of whom were women. The Cronbach's alpha for the mYFAS 2.0 was satisfactory (alpha = 0.915). The best goodness-of-fit model was a single factor, and mYFAS 2.0 showed convergent validity with binge eating and discriminant validity with the alcohol and nicotine use measures. Food addiction presented a weak positive correlation with depressive and anxiety symptoms and BMI. Three food addiction symptoms provided the best balance between sensitivity (80.95%) and specificity (74.81%). Incremental validity over binge eating symptoms was confirmed (t = 4.040, β = 0.681, p < 0.001). Conclusions: The Brazilian mYFAS 2.0 performed satisfactorily in this clinical sample of participants with a depressive disorder. These findings suggest it may be a brief, useful, and valid food addiction screening tool for this group. Plain English Summary: Food addiction is a dysfunctional consumption of energetically dense, hyper-palatable, and ultra-processed foods that may lead to addictive behaviors. It is associated with mental disorders such as eating, mood, and anxiety disorders, which negatively impact the quality of life for individuals affected. Therefore, healthcare providers need to assess food addiction. The Modified Yale Food Addiction Scale 2.0 (mYFAS 2.0) is a brief instrument consisting of 13 questions developed to assess FA. Although it was previously adapted for Brazilian Portuguese in a non-clinical sample, this is the first study in Brazil to investigate this tool in a psychiatric sample. The main aim of our study was to evaluate the psychometric properties of the Brazilian version of the mYFAS 2.0 in individuals with a Depressive Disorder. The results suggested that mYFAS 2.0 had satisfactory psychometric properties in this sample, and it may be a brief, useful, and valid scale to screen food addiction in individuals with depressive states. [ABSTRACT FROM AUTHOR]

Depression is a significant risk factor for other serious health conditions, such as heart failure, dementia, and diabetes. In this study, a quantitative method was developed to detect depressive states in individuals using electrocardiogram (ECG) and photoplethysmogram (PPG) signals. Data were obtained from 59 people affiliated with the high-specialized medical center of Bajio T1, which consists of medical professionals, administrative personnel, and service workers. Data were analyzed using the Beck Depression Inventory (BDI-II) to discern potential false positives. The statistical analyses performed elucidated distinctive features with variable behavior in response to diverse physical stimuli, which were adeptly processed through a machine learning classification framework. The method achieved an accuracy rate of up to 92% in the identification of depressive states, substantiating the potential of biophysical data in increasing the diagnostic process of depression. The results suggest that this method is innovative and has significant potential. With additional refinements, this approach could be utilized as a screening tool in psychiatry, incorporated into everyday devices for preventive diagnostics, and potentially lead to alarm systems for individuals with suicidal thoughts. [ABSTRACT FROM AUTHOR]

Background: Extensive observational evidence has suggested an association between depression and type 2 diabetes (T2D). However, the causal relationships between these two diseases require further investigation. This study aimed to evaluate the bidirectional causal effect between two types of depression and T2D using two-sample Mendelian randomization (MR). Methods: We applied two-step MR techniques, using single-nucleotide polymorphisms (SNPs) as the genetic instruments for analysis. We utilized summary data from genome-wide association studies (GWASs) for major depression (MD), depressive status (frequency of depressedmood in the last two weeks), T2D, and other known T2D risk factors such as obesity, sedentary behavior (time spent watching television), and blood pressure. The analysis utilized inverse variance weighted (IVW), MR-Egger regression, weightedmedian, weighted mode, MR pleiotropy residual sum, and outlier methods to determine potential causal relationships. Results: The study found that MD was positively associated with T2D, with an odds ratio (OR) of 1.26 (95% CI: 1.10-1.43, p = 5.6×10-4) using the IVW method and an OR of 1.21 (95% CI: 1.04-1.41, p = 0.01) using the weighted median method. Depressive status was also positively associatedwithT2D, with anORof 2.26 (95%CI: 1.03-4.94, p = 0.04) and an OR of 3.62 (95% CI: 1.33-9.90, p = 0.01) using the IVWandweighted median methods, respectively. No causal effects of MD and depressive status on T2D risk factors were observed, and T2D did not influence these factors. Conclusion: Our study demonstrates a causal relationship between depression and an increased risk of developing T2D, with both major depression and depressive status being positively associated with T2D. [ABSTRACT FROM AUTHOR]

Background: Observational data posits a correlation between reproductive traits and nonalcoholic fatty liver disease (NAFLD), but their causal inference is still unclear. This investigation seeks to elucidate the causal influence of reproductive traits on NAFLD and determine the intervening role of health condition and socioeconomic status in these connections. Methods: Utilizing a Mendelian Randomization (MR) approach, this research leveraged a comprehensive dataset from the Genome-wide Association Study (GWAS) database. The study incorporated body mass index, major depression, educational level, household income and Townsend deprivation index as intermediary variables. Initially, a bidirectional two-sample MR study was conducted to explore the genetic associations between reproductive traits and NAFLD. Then, two-step MR analyses were implemented to quantify the extent of mediation by these indicators. The weighted inverse variance method was the primary analytical approach, complemented by several sensitivity analyses to affirm the robustness of the MR assumptions. Finally, these findings were validated in the FinnGen research. Results: The bidirectional MR analysis indicated that earlier reproductive traits (age at menarche, age at first sexual intercourse, and age at first birth) were associated with an elevated risk of NAFLD, absent any evidence of the reverse relationship. Body mass index accounted for 35.64% of the association between premature menarche and NAFLD. Additionally, body mass index, major depression, educational level and household income mediated 41.65%, 14.35%, 37.88%, and 18.59% of the connection between early sexual intercourse and NAFLD, respectively. Similarly, these same variables elucidated 36.36%, 15.58%,41.56%, and 22.73% of the correlation between younger age at first birth and NAFLD. Conclusion: Our study elucidated the causal relationships between reproductive traits and NAFLD. Potential underlying mechanisms may involve factors such as body mass index, major depression, educational attainment and household income. [ABSTRACT FROM AUTHOR]

Neuropsychiatric conditions represent a major medical and societal challenge. The etiology of these conditions is very complex and combines genetic and environmental factors. The latter, for example, excessive maternal or early postnatal inflammation, as well as various forms of psychotrauma, often act as triggers leading to mental illness after a prolonged latent period (sometimes years). Matrix metalloproteinase‐9 (MMP‐9) is an extracellularly and extrasynaptic operating protease that is markedly activated in response to the aforementioned environmental insults. MMP‐9 has also been shown to play a pivotal role in the plasticity of excitatory synapses, which, in its aberrant form, has repeatedly been implicated in the etiology of mental illness. In this conceptual review, we evaluate the experimental and clinical evidence supporting the claim that MMP‐9 is uniquely positioned to be considered a drug target for ameliorating the adverse effects of environmental insults on the development of a variety of neuropsychiatric conditions, such as schizophrenia, bipolar disorder, major depression, autism spectrum disorders, addiction, and epilepsy. We also identify specific challenges and bottlenecks hampering the translation of knowledge on MMP‐9 into new clinical treatments for the conditions above and suggest ways to overcome these barriers. [ABSTRACT FROM AUTHOR]

Given the limitations of available studies, the objective of this study was to explore the role played by current and remitted major depression in the occurrence of comorbid insomnia disorder for apneic patients. Data from 1488 apneic patients were extracted from the medical reports of polysomnographic recordings available in the database of the Sleep Laboratory. The presence of comorbid insomnia disorder in these apneic patients was defined based on the diagnostic criteria of the American Academy of Sleep Medicine Work Group. The risk of comorbid insomnia disorder associated with current or remitted major depression in apneic patients was investigated using multivariate logistic regression models. After adjustment for the main confounding factors, multivariate logistic regression analyses revealed that remitted and current major depression were significantly associated with the occurrence of comorbid insomnia disorder in apneic patients. The findings of this study seem to indicate that comorbid insomnia disorder could be a residual symptom and a marker of major depression in apneic patients, which justifies the establishment of an adequate treatment for major depressive episodes and their potential residual symptoms to allow the better management of comorbid insomnia disorder and the better prevention of its potential negative consequences in this particular subpopulation. [ABSTRACT FROM AUTHOR]

Anhedonia constitutes a core symptom of major depressive disorder (MDD) mediating the ultimate goal of MDD treatment: functional remission. Anhedonia is also present in other clinical populations, including patients with chronic pain. Recent data links anhedonia to insulin resistance (IR). Some researchers have underlined a different dimension of anhedonia as a temperament/personality trait. The objective of this post-hoc analysis was to explore the links between anhedonia (main outcome) and (1) IR, (2) temperamental, personality, and schizotypy traits (exposures). The study population included patients with MDD, fibromyalgia, and healthy controls. Participants were split into groups: (1) insulin resistant (IR[+] n = 69, HOMA-IR ≥ 2.1) and (2) insulin sensitive (IR[−] n = 69, HOMA-IR < 2.1). Anhedonia was significantly higher in the IR[+] group than the IR[−] group. IR was a predictor of higher anhedonia levels. IR[+] vs. IR[−] participants showed higher levels of anxiety and lower levels of hyperthymic affective temperaments, as well as conscientiousness and emotional stability personality traits. Depressive, irritable, and anxious temperaments, cognitive disorganization, and introvertive anhedonia positively predicted anhedonia, while hyperthymic temperament, conscientiousness, extraversion, and emotional stability traits negatively predicted anhedonia. IR partially mediated the relationship between depressive temperament and anhedonia. In sum, IR, affective temperaments, and personality traits are predictors of anhedonia. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is associated with inflammation and a high level of comorbidities. Atypical depression (AD) is a MDD subtype based on DSM criteria, that could have specific underlying biological mechanisms. AD is associated with elevated cardiovascular (CVD) comorbidities, higher risk of suicide attempts, hypersomnia, and anxiety disorder. In this study, we aim to investigate if AD and polysomnographic parameters could be associated with low-grade inflammation (LGI). LGI is defined by a range from 3 to 10 mg/L of C-reactive protein levels. We carried out a retrospective cohort study in which 765 individuals with MDD were split into two groups: with and without LGI. Our results exhibit differences between the groups for the polysomnographic parameters, with the LGI group showing parameters already associated with inflammation such as reduced rapid eye movement sleep and elevated hypoxemia markers (identified as CVD risk factor). We found that AD is associated with LGI (OR 1.48; p = 0.047) after adjustment. Likewise, we found an LGI prevalence in AD higher (34.8%) than in MDD without atypical features (26.8%). Overall, these results confirm the low-grade inflammation feature of AD and highlight polysomnographic parameters associated with LGI that could also act as risk factors in this context. [ABSTRACT FROM AUTHOR]

Simple Summary: This review delves into the differences between two important groups of dopamine-producing brain cells, found in regions called the ventral tegmental area and the substantia nigra. While these cells are located close to each other, they play different roles in the brain and are affected differently by diseases like Parkinson's. Understanding these differences is key to developing better treatments and more selective, without causing unwanted effects on other brain functions. This review discusses how these cells are structured, how they connect to other parts of the brain, how they function, and the differences during development. The goal is to provide insights that could lead to more precise therapies, targeting specific groups of cells without harming others. This research is important for advancing treatments for brain disorders and improving our understanding of the brain's complex wiring. Dopaminergic neurons in the ventral tegmental area (VTA) and the substantia nigra pars compacta (SNpc) comprise around 75% of all dopaminergic neurons in the human brain. While both groups of dopaminergic neurons are in close proximity in the midbrain and partially overlap, development, function, and impairments in these two classes of neurons are highly diverse. The molecular and cellular mechanisms underlying these differences are not yet fully understood, but research over the past decade has highlighted the need to differentiate between these two classes of dopaminergic neurons during their development and in the mature brain. This differentiation is crucial not only for understanding fundamental circuitry formation in the brain but also for developing therapies targeted to specific dopaminergic neuron classes without affecting others. In this review, we summarize the state of the art in our understanding of the differences between the dopaminergic neurons of the VTA and the SNpc, such as anatomy, structure, morphology, output and input, electrophysiology, development, and disorders, and discuss the current technologies and methods available for studying these two classes of dopaminergic neurons, highlighting their advantages, limitations, and the necessary improvements required to achieve more-precise therapeutic interventions. [ABSTRACT FROM AUTHOR]

Objective: There is growing interest in how peers' genotypes may influence health (i.e., peer social genetic effects). The authors sought to clarify the nature of peer social genetic effects on risk for drug use disorder, alcohol use disorder (AUD), major depression, and anxiety disorder. Method: Cox models were used with data from a population-based Swedish cohort (N=655,327). Outcomes were drug use disorder, AUD, major depression, and anxiety disorder registrations between ages 17 and 30 from medical, criminal, and pharmacy registries. The authors indexed peer social genetic effects with peers' family genetic risk scores (FGRSs) for the same disorders, which are personalized measures of genetic risk inferred from diagnoses in first- to fifth-degree relatives. Results: Across disorders, peer FGRSs predicted increased risks of proband registration (hazard ratio range, 1.01–1.59), with stronger effects for drug use disorder and AUD than for major depression and anxiety disorder. Peer social genetic effects were stronger for school classmates than for geographically proximal peers, and for peers from upper secondary school (ages 16–19) versus peers from lower secondary school (ages 7–16). Peer social genetic effects remained significant following statistical control for sociodemographic confounders, whether peers were affected, and peers' FGRS for educational attainment. Peer social genetic effects were more pronounced for probands at higher genetic risk. Conclusions: The genetic makeup of adolescents' peers has long-reaching consequences on risks for drug use disorder, AUD, major depression, and anxiety disorder. Individuals at high genetic risk are more sensitive to social genetic effects. Alternative hypotheses such as sociodemographic stratification, exposure to affected peers, and genetic predispositions for educational attainment did not explain the risk associated with peer social genetic effects for substance use and psychiatric disorders. [ABSTRACT FROM AUTHOR]

Background/Objectives: Mental disorders pose a significant public health challenge, affecting millions worldwide. Given the limitations of current therapies, many patients experience inadequate responses and adverse effects. Intermittent hypoxia (IH) has demonstrated anxiolytic, antidepressant, and neuroprotective properties in various protocols. This study investigated the effects of acute IH (13% O2, 1 h), fluoxetine (FLX) and their combination on depression-like behavior, serum corticosterone, and inflammatory cytokine levels induced by acute restraint stress in C57BL/6 female mice. Methods: Behavioral assessments included the tail suspension test, forced swim test, and open field test. Results: The combined IH + FLX treatment exhibited a synergistic effect, reducing immobility time and increasing latency time, respectively, in the tail suspension test (46%, p = 0.0014; 73%, p = 0.0033) and forced swim test (56%, p = 0.0082; 48%, p = 0.0322) compared to the ARS group. Biochemical analysis revealed that individual and combined treatments significantly reduced most inflammatory interleukins by up to 96%. Corticosterone levels were reduced by 30% only in the IH group. Conclusions: These findings highlight the potential of a one-hour IH session, particularly when combined with fluoxetine, to alleviate depressive-like behaviors and exert anti-inflammatory effects, suggesting a promising therapeutic approach for depression. [ABSTRACT FROM AUTHOR]

Abstract Background Food addiction (FA) is strongly associated with depressive symptoms. The reliability and validity of the Modified Yale Food Addiction Scale 2.0 (mYFAS 2.0) were not previously determined in clinical samples in Brazil. This study aimed to assess the psychometric properties of the Brazilian version of the mYFAS 2.0 in adult individuals with depressive disorders. Methods The data stems from a survey investigating FA in a convenience sample of subjects diagnosed with a depressive disorder. Participants answered mYFAS 2.0 and scales for binge eating, depressive and anxiety symptoms, and alcohol and nicotine use. Height and weight were measured to calculate the Body Mass Index (BMI). We evaluated the factor structure, reliability, convergent, discriminant, criterion, and incremental validity. Results The sample encompassed 303 participants with a mean age of 37.03 ± 11.72 years, 84.16% of whom were women. The Cronbach’s alpha for the mYFAS 2.0 was satisfactory (alpha = 0.915). The best goodness-of-fit model was a single factor, and mYFAS 2.0 showed convergent validity with binge eating and discriminant validity with the alcohol and nicotine use measures. Food addiction presented a weak positive correlation with depressive and anxiety symptoms and BMI. Three food addiction symptoms provided the best balance between sensitivity (80.95%) and specificity (74.81%). Incremental validity over binge eating symptoms was confirmed (t = 4.040, β = 0.681, p

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

Given the limitations of available studies, the objective of this study was to explore the role played by current and remitted major depression in the occurrence of comorbid insomnia disorder for apneic patients. Data from 1488 apneic patients were extracted from the medical reports of polysomnographic recordings available in the database of the Sleep Laboratory. The presence of comorbid insomnia disorder in these apneic patients was defined based on the diagnostic criteria of the American Academy of Sleep Medicine Work Group. The risk of comorbid insomnia disorder associated with current or remitted major depression in apneic patients was investigated using multivariate logistic regression models. After adjustment for the main confounding factors, multivariate logistic regression analyses revealed that remitted and current major depression were significantly associated with the occurrence of comorbid insomnia disorder in apneic patients. The findings of this study seem to indicate that comorbid insomnia disorder could be a residual symptom and a marker of major depression in apneic patients, which justifies the establishment of an adequate treatment for major depressive episodes and their potential residual symptoms to allow the better management of comorbid insomnia disorder and the better prevention of its potential negative consequences in this particular subpopulation.

Nahida Nayaz Ahmed,1,&ast; Shuja Reagu,2,&ast; Samia Alkhoori,3 Amina Cherchali,4 Pradeep Purushottamahanti,5 Urooj Siddiqui4 1SEHA Mental Health & Wellbeing Services, College of Medicine and Health Sciences of the United Arab Emirates University, Abu Dhabi, United Arab Emirates; 2Weill Cornell Medicine, Doha, Qatar; Hamad Medical Corporation, Doha, Qatar; 3Rashid Hospital, Dubai Health, Dubai, United Arab Emirates; 4Viatris Middle East FZ-LLC, Dubai, United Arab Emirates; 5Global Medical Affairs, Viatris Inc., Bangalore, India&ast;These authors contributed equally to this workCorrespondence: Pradeep Purushottamahanti, Psychiatry Medical Lead, Global Medical Affairs, Viatris, 11th Floor, Prestige Tech Park Platina-3, Kadubeesanahalli, Bengaluru, 560103, India, Email pradeep.purushottamahanti@viatris.comAbstract: Up to 75% of individuals with major depressive disorder (MDD) may have residual symptoms such as amotivation or anhedonia, which prevent full functional recovery and are associated with relapse. Globally and in the Gulf region, primary care physicians (PCPs) have an important role in alleviating stigma and in identifying and monitoring the residual symptoms of depression, as PCPs are the preliminary interface between patients and specialists in the collaborative care model. Therefore, mental healthcare upskilling programmes for PCPs are needed, as are basic instruments to evaluate residual symptoms swiftly and accurately in primary care. Currently, few if any electronic enablers have been designed to specifically monitor residual symptoms in patients with MDD. The objectives of this review are to highlight how accurate evaluation of residual symptoms with an easy-to-use electronic enabler in primary care may improve functional recovery and overall mental health outcomes, and how such an enabler may guide pharmacotherapy selection and positively impact the patient journey. Here, we show the potential advantages of electronic enablers in primary care, which include the possibility for a deeper “dive” into the patient journey and facilitation of treatment optimisation. At the policy and practice levels, electronic enablers endorsed by government agencies and local psychiatric associations may receive greater PCP attention and backing, improve patient involvement in shared clinical decision-making, and help to reduce the general stigma around mental health disorders. In the Gulf region, an easy-to-use electronic enabler in primary care, incorporating aspects of the Hamilton Depression Rating Scale to monitor amotivation, and aspects of the Montgomery-Åsberg Depression Rating Scale to monitor anhedonia, could markedly improve the patient journey from residual symptoms through to full functional recovery in individuals with MDD.Keywords: electronic tools, functional recovery, knowledge gaps, major depression, primary care, residual outcomes

Background and Aim of Study: Depression severity can be profoundly impacting the life of individuals, while its persistence can provoke the conviction that recovery is unattainable. One of the extreme consequences is the request for euthanasia. However, during major depression cognition can be significantly impaired. In this study, we comment on the exemplar case of a Belgian lady, Mrs. Godelieva de Troyer, who made that request and obtained the desired outcome. The aim of the study: to consider a specific case of a patient with major depressive disorder and the role of doctors in informing the decision about medically assisted death. Material and Methods: The history of the request made by Mrs. Godelieva is described. The procedure was followed by the reactive initiatives of the son of the lady, who made a formal complaint against the procedure that brought his mother to death and appealed the European Court of Justice. Results: A description of what happened is briefly reported, including considerations on the clinical treatments received by Mrs. Godelieva, the roles interpreted by the doctors she consulted and, finally, the appropriateness of the decision taken. Conclusions: In revisiting this case, the decision-making process during major depression episodes and the authenticity and robustness of end-of-life choices in similar cases are critically examined. Comments are made on the frequency of cognitive impairments during major depressive episodes and the need to provide depressed people the necessary support during their important choices.

Brain age has become an important analysis object in the diagnosis and mechanism research of neurodegenerative diseases. There is no consistent conclusion on whether major depression increases the brain age of patients, and few studies in this direction have been conducted in the Chinese population. In this paper, a REST-meta-MDD (resting-state functional magnetic resonance imaging dataset of major depressive disorder) dataset collected from 25 hospitals in China was used to construct a convolutional neural network model based on high-resolution T1-weighted three-dimensional magnetic resonance images of brain structures to predict the brain age of patients and calculate the difference from the actual age. The mean absolute error and correlation coefficients of the final results were 3.16 and 0.93, and the mean brain age of the patients with major depression increased by 3.94 years compared with the healthy group, further confirming that major depression accelerates brain aging, and the severity of the disease is related to the gender, age, and education of the patients. Compared with the traditional machine learning algorithms, the average absolute error of the results obtained by this model is smaller and the correlation coefficient is higher.

Background The objective of this systematic review was to analyze the effects of the physical activity (PA) intervention as an adjuvant strategy to pharmacological treatment in people with treatment-resistant depression (TRD) and non-remitted depression (NRD). Methods A search strategy was realized from five databases: PubMed, Cochrane Central Register of Controlled Trials, Scopus, SPORTDiscus, and Web of Science. Eleven articles attained the inclusion criteria. The Physiotherapy Evidence Database and Oxford’s Evidence Levels were used to classify the quality appraisal. Results The more significant outcome for this analysis was the improvement of depression by PA or exercise in TRD and NRD. According to the FITT (Frequency, Intensity, Time, and Type) principle, there was some variability in the PA intervention, and except for one article, they all were classified as excellent in terms of quality description. Conclusions This review highlights the potential of PA intervention as an adjuvant program to improve different traits of TRD and NRD. The remission of depression seems to be higher after PA intervention, showing improvements in quality of life, sleep quality, executive function, and vitality.

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

Summary In bipolar disorders, abnormalities of sleep patterns and of circadian rhythms of activity are observed during mood episodes, but also persist during euthymia. Shared vulnerabilities between mood disorders and abnormalities of sleep patterns and circadian rhythms of activity have been suggested. This exploratory study investigated the association between polygenic risk scores for bipolar disorder and major depressive disorder, actigraphy estimates of sleep patterns, and circadian rhythms of activity in a sample of 62 euthymic individuals with bipolar disorder. The polygenic risk score – bipolar disorder and polygenic risk score – major depressive disorder were calculated for three stringent thresholds of significance. Data reduction was applied to aggregate actigraphy measures into dimensions using principal component analysis. A higher polygenic risk score – major depressive disorder was associated with more fragmented sleep, while a higher polygenic risk score – bipolar disorder was associated with a later peak of circadian rhythms of activity. These results remained significant after adjustment for age, sex, bipolar disorder subtype, body mass index, current depressive symptoms, current tobacco use, and medications prescribed at inclusion, but not after correction for multiple testing. In conclusion, the genetic vulnerabilities to major depression and to bipolar disorder might be associated with different abnormalities of sleep patterns and circadian rhythms of activity. The results should be replicated in larger and independent samples. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is considerably heterogeneous in terms of comorbidities, which may hamper the disentanglement of its biological mechanism. In a previous study, we classified the lifetime trajectories of MDD-related multimorbidities into seven distinct clusters, each characterized by unique genetic and environmental risk-factor profiles. The current objective was to investigate genome-wide gene-by-environment (G × E) interactions with childhood trauma burden, within the context of these clusters. We analyzed 77,519 participants and 6,266,189 single-nucleotide polymorphisms (SNPs) of the UK Biobank database. Childhood trauma burden was assessed using the Childhood Trauma Screener (CTS). For each cluster, Plink 2.0 was used to calculate SNP × CTS interaction effects on the participants' cluster membership probabilities. We especially focused on the effects of 31 candidate genes and associated SNPs selected from previous G × E studies for childhood maltreatment's association with depression. At SNP-level, only the high-multimorbidity Cluster 6 revealed a genome-wide significant SNP rs145772219. At gene-level, MPST and PRH2 were genome-wide significant for the low-multimorbidity Clusters 1 and 3, respectively. Regarding candidate SNPs for G × E interactions, individual SNP results could be replicated for specific clusters. The candidate genes CREB1, DBH , and MTHFR (Cluster 5) as well as TPH1 (Cluster 6) survived multiple testing correction. CTS is a short retrospective self-reported measurement. Clusters could be influenced by genetics of individual disorders. The first G × E GWAS for MDD-related multimorbidity trajectories successfully replicated findings from previous G × E studies related to depression, and revealed risk clusters for the contribution of childhood trauma. • First G × E GWAS with childhood trauma for MDD-related multimorbidity trajectories. • Most G × E findings for high MDD-multimorbidity Clusters 5–6. • Significant correlation between cluster probability and CTS (high vs low risk clusters). • stronger genetic findings in the clusters with higher childhood trauma burden. • Differential effects of candidate genes in different comorbidity clusters. [ABSTRACT FROM AUTHOR]

Intervention: Electroconvulsive therapy (ECT) is a commonly used treatment for severe psychiatric illness in older adults, including in the 'older old' population aged 80 years and above. However, there can sometimes be a reluctance to treat the 80+ year old age group with ECT due to medical comorbidities, frailty, and concerns about cognition. Objective, Design, Setting, and Participants: This multi‐site, longitudinal Australian study aimed to investigate the effectiveness and safety of ECT in older old people compared with younger age groups. Data from 310 people receiving ECT for depression at three participating hospitals was collected in a naturalistic setting, between 2015 and 2022. Measurements: Clinical ratings were conducted pre‐ECT and end‐acute ECT using the Montgomery–Åsberg Depression Rating Scale (MADRS). Cognitive outcomes were assessed using the Montreal Cognitive Assessment (MoCA). Results: Older old adults demonstrated a significant reduction MADRS scores at post‐treatment. They were more likely to meet remission criteria compared with the younger age groups. Older old adults were also less likely to show clinically significant cognitive decline post‐ECT, and were more likely to show clinically significant cognitive improvement post‐ECT compared with younger age groups. Conclusions: ECT is highly effective in treating severe psychiatric illness in older old adults. Relative to the younger age groups, the older old group were more likely to remit with ECT and a greater proportion showed cognitive improvement post‐ECT. These findings suggest that ECT should be considered as a valuable and safe treatment option for older old individuals with depression. [ABSTRACT FROM AUTHOR]

Extending on previous findings that computerized Memory Specificity Training (c-MeST) improves memory specificity and depressive symptoms in Major Depressive Disorder (MDD) in adults, this study aimed to assess the effects of c-MeST in youth with MDD on memory specificity and depression in addition to other treatment. Participants aged 15–25 (N = 359, 76 % female; M age = 19.2, SD = 3.1), receiving predominantly psychological therapy or counseling (85 %) and/or antidepressants (52 %) were randomized to usual care and c-MeST or usual care. Cognitive and clinical outcomes were assessed at baseline and at one, three, and six-month follow-ups. The usual care and c-MeST group reported higher memory specificity at one-month (d = 0.42, p =.022), but not at three or six months (d 's < 0.15, p 's > 0.05). The rate of MDE was numerically lower in the c-MeST group at each follow-up time-point, but group was not a statistically significant predictor at one month (64 % usual care and c-MeST vs. 68 % usual care, OR = 0.81, p =.606), three months (67 % usual care and c-MeST vs. 72 % usual care, OR = 0.64, p =.327) or six months (55 % usual care and c-MeST vs. 68 % usual care, OR = 0.56, p =.266). The usual care and c-MeST group did report lower depressive symptoms at one month (d = 0.42, p =.023) and six-months (d = 0.84, p =.001), but not three-months (d = 0.13, p >.05). c-MeST may reduce symptoms in youth with MDD when provided alongside other treatments. However, there are significant limitations to this inference, including high attrition in the study and a need for more data on the acceptability of the intervention. • Overgeneral memory appears to maintain depressive symptoms. • Computerized memory specificity training (c-MeST) improved memory specificity. • Depressive symptoms were reduced at one and six-month follow-up. • The effects occurred in addition to receiving other mental health support. • C-MeST may be a beneficial adjunct for youth with major depressive disorder. [ABSTRACT FROM AUTHOR]

Exosomes, natural nanovesicles that contain a cargo of biologically active molecules such as lipids, proteins, and nucleic acids, are released from cells to the extracellular environment. They then act as autocrine, paracrine, or endocrine mediators of communication between cells by delivering their cargo into recipient cells and causing downstream effects. Exosomes are greatly enriched in miRNAs, which are small non-coding RNAs that act both as cytoplasmic post-transcriptional repression agents, modulating the translation of mRNAs into proteins, as well as nuclear transcriptional gene activators. Neuronal exosomal miRNAs have important physiologic functions in the central nervous system (CNS), including cell-to-cell communication, synaptic plasticity, and neurogenesis, as well as modulating stress and inflammatory responses. Stress-induced changes in exosomal functions include effects on neurogenesis and neuroinflammation, which can lead to the appearance of various neuropsychiatric disorders such as schizophrenia, major depression, bipolar disorder, and Alzheimer's and Huntington's diseases. The current knowledge regarding the roles of exosomes in the pathophysiology of common mental disorders is discussed in this review. [ABSTRACT FROM AUTHOR]

Background: Depression is a common mental illness worldwide. Neuroimaging techniques, such as magnetic resonance imaging and functional magnetic resonance imaging, play an essential role in diagnosing and evaluating depression. This study is based on magnetic resonance imaging (MRI)-related research to explore the comparison of brain function and structure between patients with severe depression and normal individuals, and to conduct meta-analysis. Methods: We conducted searches in various databases such as PubMed, Web of Science, Embase, and Cochrane Library to obtain research data on comparing brain function and structure between patients with severe depression and healthy individuals. The search Keywords: included "Major Depressive Disorder", "Brain Function", "Brain Structure", "Depression", "MRI", and "Magnetic Resonance". The quality assessment was conducted using the bias risk assessment tool recommended by the Cochrane Collaborative Network. Literature was screened following the predetermined inclusion and exclusion criteria, and Anisotropic Effect-Size Seed-Based Differential Mapping (AES-SDM) was used for systematic meta-analysis. Regression analysis was performed on age, gender, disease duration, years of education, and treatment status. Results: After a thorough screening process, 10 documents were selected for subsequent analysis. These studies consisted of 477 study subjects, including 231 depression patients and 246 healthy individuals. The proportion of women was 36%-75%, and the disease duration was 3-60 months. The patients in 4 documents had first attacks, and the patients in the other 6 documents had multiple attacks. The baseline conditions of the 10 included documents were consistent and comparable. None of the studies reported blinding methods, and none of the results had incomplete data. The Regional homogeneity (ReHo) levels in the left precuneus (BA7), lentiform nucleus (BA48), and left prefrontal lobe (BA32) were significantly increased in the depression group, with voxel numbers of 358, 116, and 181, respectively. Conversely, the left postcentral gyrus (BA4), left cerebellar area (hemispheric lobule I, IV/V, lingual gyrus, fusiform gyrus), left fusiform gyrus (BA30), and right cingulate gyrus (BA23) were significantly reduced, with voxel numbers of 17, 50, and 124, respectively. Furthermore, regression analysis showed that gender, age, disease duration, years of education, and disease severity were potential influencing factors, and the disease duration demonstrated the most significant impact on the left cingulate gyrus (SDM = 2.777). Conclusion: There are significant differences in brain function and structure between patients with major depression and healthy individuals. Furthermore, our findings reveal a substantial correlation between the severity of depressive symptoms and brain function and structure indicators. These findings provide novel research directions and ideas for the diagnosis and treatment of depression. [ABSTRACT FROM AUTHOR]

• Most depressed youths had changes in symptoms associated with specific CBT modules. • The types of CBT modules associated with changes varied across youths. • Behavioral activation was most frequently associated with decreases in symptoms. • Baseline characteristics did not predict the type of modules that were impactful. • There may be many pathways to symptom improvement for youths with depression. Prior research suggests that the effects of specific cognitive-behavioral therapy (CBT) modules on symptom outcomes can be estimated. We conducted a study utilizing idiographic and nomothetic methods to clarify which CBT modules are most effective for youth depression, and for whom they are most effective. Thirty-five youths received modular CBT for depression. Interrupted time series models estimated whether the introduction of each module was associated with changes in internalizing symptoms, whereby significant symptom reduction would suggest a therapeutic response to the module. Regression models were used to explore whether participant characteristics predicted subgroups of youths based on their estimated response to certain types (e.g., cognitive) of modules, and whether group membership was associated with posttreatment outcomes. Thirty youths (86%) had at least one module associated with a significant change in internalizing symptoms from premodule delivery to postmodule delivery. The specific modules associated with these changes varied across youths. Behavioral activation was most frequently associated with symptom decreases (34% of youths). No participant characteristics predicted estimated response to module type, and group membership was not significantly associated with posttreatment outcomes. Youths display highly heterogeneous responses to treatment modules, indicating multiple pathways to symptom improvement for depressed youths. [ABSTRACT FROM AUTHOR]

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While major depression has been linked to changes in white matter architecture, it remains unclear whether risk factors for depression are directly associated with these alterations. We reexamined white matter fiber tracts in individuals with depressive symptoms and investigated the connection between genetic and environmental risk for depression and structural changes in the brain. We included 19,183 participants from the UK Biobank imaging cohort, with depression status and adverse life experience based on questionnaire data and genetic liability for depression quantified by polygenic scores. The integrity of 27 white matter tracts was assessed using mean fractional anisotropy derived from diffusion magnetic resonance imaging. White matter integrity was reduced, particularly in thalamic and intracortical fiber tracts, in individuals with depressive symptoms, independent of current symptom status. In a group of healthy individuals without depression, increasing genetic risk and increasing environmental risk were associated with reduced integrity in relevant fiber tracts, particularly in thalamic radiations. This association was stronger than expected based on statistical dependencies between samples, as confirmed by subsequent in silico simulations and permutation tests. White matter alterations in thalamic and association tracts are associated with depressive symptoms and genetic risk for depression in unaffected individuals, suggesting an intermediate phenotype at the brain level. [ABSTRACT FROM AUTHOR]

Correct classification of irritability is extremely important to assess prognosis and treatment indications of juvenile mood disorders. We assessed factors associated with low versus high parent- and self-rated irritability using the affective reactivity index (ARI) in a sample of 289 adolescents diagnosed with a bipolar or a major depressive disorder. Bivariate analyses were followed by multilinear logistic regression model. Factors significantly and independently associated with high versus low parent-rated ARI score were: more severe emotional dysregulation and bipolar disorders diagnosis. Factors significantly and independently associated with high versus low self-rated ARI score were: lower children depression rating scale (CDRS-R) difficulty of having fun item score, greater children depression inventory (CDI-2) self-report score, more severe emotional dysregulation, and greater CDRS-R appetite disturbance item score. High parent-rated irritability was strictly related with a bipolar disorder diagnosis, whereas high youth-rated irritability was related to depressive phenotype characterized by appetite/food-intake dysregulation, mood lability, and less anhedonia and apathy. [ABSTRACT FROM AUTHOR]

Objective: To analyze the risk factors of major depressive disorder (MDD) after spinal cord injury (SCI). Methods: Patients with SCI in our hospital from February 2020 to February 2023 were selected as the study objects. According to the Hamilton Depression Scale (HAMD) score, patients with 36-75 points were included in the major depression group, and 0-35 points were included in the non-major depression group. The general sociological characteristics (age, gender, educational level, place of residence, family economic status, payment method of medical expenses, marital status) and disease-related characteristics (course of disease, cause of injury, neurological level of injury, type of injury, degree of pain) of all patients were collected, and the items with differences were selected for logistic regression analysis to analyze the risk factors for major depression in patients with spinal cord injury. Results: Totally 216 patients were enrolled in our study, including 45 patients (18.98%) had moderate-to-severe depression and 175 patients (81.02%) had non-severe depression. Univariate analysis showed that gender (χ² = 11.865, P < .001), course of disease (χ² = 12.967, P < .001), family economic status (χ² = 8.610, P = .003), educational level (χ² =15.287, P < .001), neurological level of injury (χ² = 9.013, P = .003) and pain level (χ² = 16.673, P < .001) were statistically significant differences between the 2 groups. Multivariate logistic regression analysis showed that gender [odds ratio (OR) (95 % CI) = 3.986 (1.743-9.116), P = .001], course of disease [OR (95 % CI) = 4.033 (1.818-8.947), P = .001], family economic status [OR (95 % CI) = 3.136 (1.449-6.785), P = .004], educational level [OR (95 % CI) = 4.332 (1.998-9.388), P = .000], neurological level of injury [OR (95 % CI) = 2.848 (1.414-5.734), P = .003], and pain level [OR (95 % CI) = 5.767 (2.309-14.404), P < .001] were risk factors for major depressive disorder in SCI patients. Conclusion: Gender, disease duration, family economic status, education level, level of nerve injury, and pain level may be the independent risk factors of MDD incidence in patients with spinal cord injury. [ABSTRACT FROM AUTHOR]

Repetitive transcranial magnetic stimulation (rTMS) has proven effective in the treatment of major depression. The underlying mechanisms of action are still poorly understood. We aimed to evaluate the changes in the levels of neuroactive steroids, neurotrophins and immunological biomarkers before and after rTMS treatment and assess the relationship of this change between clinical response and cognitive functions after monotherapy rTMS treatment. Twenty-three patients with major depressive disorder (MDD) and 25 matched healthy controls were included in the study. The Hamilton Depression Rating Scale (HDRS), Trail Making Test A and B forms and Digit Span Test were administered. Biomarkers (BDNF, TNF-α, IL-1ß, NAS) were run in the peripheral blood at the end of the first month that rTMS was administered daily and at the end of the 2nd month when that rTMS was administered once a week. Appropriate conditions were provided so that the relevant biomarkers were not affected by the biorhythm. After rTMS monotherapy, an increase in BDNF and allopregnanolone, a decrease in TNF-α, IL-1ß, DHEA, and DHEA-S levels was found to be statistically significant. The scores on cognitive tests increased with the treatment. Positive significant correlations was found between BDNF levels and cognitive tests at the end of the first and second months. Our findings suggest that the effects of rTMS treatment may be related to the neuroendocrine, neurotrophin, and immunological mechanisms. rTMS treatment is found to have positive effects on cognitive functions in the short term. [ABSTRACT FROM AUTHOR]

Electroconvulsive therapy (ECT) is an effective treatment for major depression, but its working mechanisms are poorly understood. Modulation of excitation/inhibition (E/I) ratios may be a driving factor. Here, we estimate cortical E/I ratios in depressed patients and study whether these ratios change over the course of ECT in relation to clinical effectiveness. Five-minute resting-state electroencephalography (EEG) recordings of 28 depressed patients were recorded before and after their ECT course. Using a novel method based on critical dynamics, functional E/I (fE/I) ratios in the frequency range of 0.5–30 Hz were estimated in frequency bins of 1 Hz for the whole brain and for pre-defined brain regions. Change in Hamilton Depression Rating Scale (HDRS) score was used to estimate clinical effectiveness. To account for test–retest variability, repeated EEG recordings from an independent sample of 31 healthy controls (HC) were included. At baseline, no differences in whole brain and regional fE/I ratios were found between patients and HC. At group level, whole brain and regional fE/I ratios did not change over the ECT course. However, in responders, frontal fE/I ratios in the frequencies 12–28 Hz increased significantly (pFDR < 0.05 [FDR = false discovery rate]) over the ECT course. In non-responders and HC, no changes occurred over time. In this sample, frontal fE/I ratios increased over the ECT course in relation to treatment response. Modulation of frontal fE/I ratios may be an important mechanism of action of ECT. [ABSTRACT FROM AUTHOR]

Background: One potential cause of comorbidity is the direct causal effect of one disorder – A – on risk for subsequent onset of disorder B. Could genetic risk scores be utilized to test for such an effect? If disorder A causally impacts on risk for disorder B, then genetic risk for disorder A should be lower in cases of disorder A with v. without a prior onset of B. Methods: In all individuals (n = 905 736) born in Sweden from 1980 to 1990, from six psychiatric and drug use disorders (major depression, anxiety disorders, alcohol use disorder, drug use disorder, bipolar disorder, and schizophrenia), we formed 14 pairs of disorders A and B. In these pairs, we compared, using Cox proportional hazards models, the predictive effect of the familial-genetic risk score (FGRS) for disorder B in those who had v. had not had a prior onset of disorder A. Results: In all pairs, the impact of the FGRS for disorder B was significantly stronger in cases without v. with a prior history of disorder A. These effects were similar across sex, stable across levels of FGRS and not likely due to clinician bias. In many of our disorder pairs, previous clinical studies suggest a mechanism for a causal effect of disorder A on B. Conclusions: Our findings provide indirect evidence that the occurrence of one psychiatric or substance use disorder often has a causal effect on risk for subsequent disorders. This mechanism may substantially contribute to the widespread comorbidity among psychiatric conditions. [ABSTRACT FROM AUTHOR]

Background: To determine whether genetic risk factors for major depression (MD) and alcohol use disorder (AUD) interact with a potent stressor – death of spouse, parent, and sibling – in predicting episodes of, respectively, MD and AUD. Methods: MD and AUD registrations were assessed from national Swedish registries. In individuals born in Sweden 1960–1970, we identified 7586, 388 459, and 34 370 with the loss of, respectively, a spouse, parent, and sibling. We started following subjects at age 18 or the year 2002 with end of follow-up in 2018. We examined time to event – a registration for MD within 6 months or AUD within a year – on an additive scale, using the Nelson–Aalen estimator. Genetic risk was assessed by the Family Genetic Risk Score (FGRS). Results: In separate models controlling for the main effects of death of spouse, parent, and sibling, FGRS, and sex, significant interactions were seen in all analyses between genetic risk for MD and death of relative in prediction of subsequent MD registration. A similar pattern of results, albeit with weaker interaction effects, was seen for genetic risk for AUD and risk for AUD registration. Genetic risk for bipolar disorder (BD) and anxiety disorders (AD) also interacted with event exposure in predicting MD. Conclusions: Genetic risk for both MD and AUD act in part by increasing the sensitivity of individuals to the pathogenic effects of environmental stressors. For prediction of MD, similar effects are also seen for genetic risk for AD and BD. [ABSTRACT FROM AUTHOR]

Background: Ketamine is increasingly used for treatment‐resistant depression (TRD) while its mechanism of action is still being investigated. In this systematic review, we appraise the current evidence of metabolomic biomarkers for racemic ketamine and esketamine in patients with TRD and healthy controls (HCs). Methods: A comprehensive search of several databases (Ovid MEDLINE®, Embase, and Epub Ahead of Print) was performed from each database's inception to June 29, 2022, in any language, was conducted. We included studies wherein the metabolomic biomarkers for racemic ketamine or esketamine were investigated in TRD or HCs. Our main outcomes were to examine changes in metabolites among patients treated with ketamine/esketamine and explore the association with response to ketamine/esketamine. Results: A total of 1859 abstracts were screened of which 11 were included for full‐text review. Of these, a total of five articles were included (N = 147), including three RCTs (n = 129) and two open‐label trials (n = 18). All studies used racemic ketamine; one study additionally used esketamine. The included studies evaluated patients with treatment‐resistant bipolar depression (n = 22), unipolar depression (n = 91), and HCs (n = 34). The included studies reported alteration in several metabolites including acylcarnitines, lipids, kynurenine (KYN), and arginine with ketamine in TRD. Studies suggest the involvement of energy metabolism, KYN, and arginine pathways. In HCs, acetylcarnitine decreased post‐infusion, whereas inconsistent findings were observed after the ketamine infusion in TRD patients. Conclusions: This systematic review provides preliminary evidence that ketamine may cause changes in several important pathways involved in energy metabolism and inflammation. Larger and more rigorous studies are needed. [ABSTRACT FROM AUTHOR]

Objective: Observational studies have reported that mental disorders are comorbid with temporomandibular joint disorder (TMD). However, the causal relationship remains uncertain. To clarify the causal relationship between three common mental illnesses and TMD, we conduct this Mendelian Randomization (MR) study. Methods: The large-scale genome-wide association studies data of major depression, bipolar disorder and schizophrenia were retrieved from the Psychiatric Genomics Consortium. The summary data of TMD was obtained from the Finn-Gen consortium, including 211,023 subjects of European descent (5,668 cases and 205,355 controls). The main approach utilized was inverse variance weighting (IVW) to evaluate the causal association between the three mental disorders and TMD. Five sensitivity analyses including MR-Egger, Maximum Likelihood, Weighted median, MR. RAPS and MR-PRESSO were used as supplements. We conducted heterogeneity tests and pleiotropic tests to ensure the robustness. Results: As shown by the IVW method, genetically determined major depression was associated with a 1.65-fold risk of TMD (95% CI = 1.10–2.47, p < 0.05). The direction and effect size remained consistent with sensitivity analyses. The odds ratios (ORs) were 1.51 (95% CI = 0.24–9.41, p > 0.05) for MR-Egger, 1.60 (95% CI = 0.98–2.61, p > 0.05) for Weighted median, 1.68 (95% CI = 1.19–2.38, p < 0.05) for Maximum likelihood, 1.56 (95% CI = 1.05–2.33, p < 0.05) for MR. RAPS, and 1.65 (95% CI = 1.10–2.47, p < 0.05) for MR-PRESSO, respectively. No pleiotropy was observed (both P for MR-Egger intercept and Global test >0.05). In addition, the IVW method identified no significant correlation between bipolar disorder, schizophrenia and TMD. Conclusion: Genetic evidence supports a causal relationship between major depression and TMD, instead of bipolar disorder and schizophrenia. These findings emphasize the importance of assessing a patient’s depressive status in clinical settings. [ABSTRACT FROM AUTHOR]