Search Results (912)

Background: Suicide attempts often co-occur with bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCH). Although impairments of the serotonin (5-HT) system have been associated with suicide attempts, it remains unclear whether these alterations reflect suicidal behavior or are confounded by underlying psychiatric diagnosis. This study used a genotype-informed dynamic model of the 5-HT presynapse to disentangle the effects of suicide attempts and psychiatric diagnosis. Methods: We applied a personalized dynamic model of the 5-HT presynapse to 392 psychiatric patients (with BD, MDD, or SCH), categorized by suicide attempt status, and 140 unaffected individuals. The model incorporated five variants across TPH2, SLC6A4, and MAOA genes simulating individual-specific concentration changes of five 5-HT-related molecular species. Model outputs were summarized by six statistical measures (mean, median, maximum, standard deviation, skewness, and kurtosis) and compared across groups. Results: No significant differences were found across groups defined by suicide attempt status and unaffected individuals. However, diagnosis significantly influenced 5-hydroxyindoleacetic acid (5-HIAA) mean, median, maximum, and standard deviation (all p < 0.05). BD patients had lower 5-HIAA levels than SCH patients (mean: p = 0.013; median: p = 0.013; maximum: p = 0.014; standard deviation: p = 0.014). MDD patients also showed lower 5-HIAA levels than SCH patients for the same measures, with differences approaching significance. No significant difference was observed between BD and MDD patients. A diagnosis-by-suicide attempt status interaction was observed for 5-HIAA skewness (p = 0.013). Conclusions: Model-derived 5-HT profiles were shaped primarily by diagnosis, while temporal dynamics of 5-HIAA, rather than its absolute levels, was associated with suicide attempt status. Thus, personalized dynamic modeling incorporating genetic variants may aid in detecting subtle molecular signatures across diagnoses and suicidal behavior. Full article

Major Depressive Disorder (MDD) represents a global challenge due to its high prevalence worldwide. Inflammation is the most extensively studied and plausible biological pathway involved in the onset of MDD. Individuals with MDD often exhibit low-grade inflammation, characterized by immune system dysregulation and activation of pro-inflammatory pathways. Elevated inflammation is also associated with a reduced response to antidepressant therapies, suggesting that targeting inflammation could represent a promising therapeutic approach for MDD. MDD frequently co-occurs with other pathological conditions, including cardiometabolic, autoimmune, and chronic pain disorders. These comorbidities further complicate MDD treatment and contribute to reduced antidepressant efficacy. Like MDD, these disorders are characterized by a strong inflammatory component, and several cytokines and pro-inflammatory mechanisms altered in MDD are also found in these comorbid conditions. This narrative review explores inflammation as a shared biological mechanism in MDD and its most frequent comorbidities, to provide a comprehensive understanding of the interplay between inflammation and these comorbid conditions. Persistent low-grade inflammation may help explain the high rate of bidirectional co-occurrence between MDD and its comorbidities. Moreover, it may represent a target for better understanding the molecular mechanisms driving this co-occurrence, potentially contributing to the development of tailored treatment and improving antidepressants response rates. Full article

Background/Objectives: Schizophrenia (SCH), bipolar disorder (BPD), and major depressive disorder (MDD) are increasingly viewed as neuroimmune disorders shaped by viral exposure and inflammation. Disorder-specific immunovirological profiles, however, remain poorly defined. Methods: In this cross-sectional study, we assessed Epstein–Barr Virus (EBV) and Herpes Simplex Virus type 1 (HSV-1) seropositivity and measured serum CRP, IL-6, and IL-1β in 708 participants: 110 with SCH, 121 with BPD, 135 with MDD, and 342 healthy controls (HC). Statistical analyses included Shapiro–Wilk tests for normality; Kruskal–Wallis with Bonferroni-adjusted Dunn post hoc comparisons; and logistic regression adjusted for age, sex, and marital status. Results: EBV seropositivity was higher in SCH (90.9%) than in HC (78.9%) (OR = 3.46, 95% CI: 1.68–7.12; p = 0.001) but not in BPD or MDD. HSV-1 seropositivity was elevated in BPD (83.5%) versus HC (67.0%) (OR = 2.29, 95% CI: 1.34–3.92; p = 0.003), with no differences in SCH or MDD. Inflammatory biomarkers were significantly increased in SCH and MDD compared to HC (p < 0.001), while BPD showed no differences. Conclusions: The findings delineate distinct immunovirological patterns across major psychiatric disorders. Schizophrenia was characterized by EBV seropositivity accompanied by systemic inflammatory activation, bipolar disorder by HSV-1 seropositivity in the absence of inflammatory changes, and major depressive disorder by inflammatory dysregulation independent of viral exposure. These disorder-specific profiles highlight heterogeneity in neuroimmune pathways and underscore the potential relevance of biomarker-based stratification for generating hypotheses regarding targeted antiviral or anti-inflammatory interventions in psychiatric populations. Full article

Major depressive disorder (MDD) is a leading contributor to global disability. Despite advances in neurobiological research, no reliable peripheral biomarkers are currently available for diagnosis or monitoring. Copper (Cu), an essential trace element involved in redox balance and monoamine metabolism, has been repeatedly associated with MDD, though evidence remains inconsistent. To systematically evaluate and quantify differences in serum Cu concentrations between individuals with MDD and healthy controls, and to explore potential moderators, including sex, age, and analytical methodology. We conducted a systematic review and meta-analysis of observational studies reporting serum Cu levels in MDD patients versus controls. Data were extracted regarding diagnostic criteria, measurement methods, sample characteristics, and study quality. Subgroup and sensitivity analyses were performed based on demographic and methodological variables. Twenty-four studies, including 8617 participants (2736 MDD, 5881 controls), were analyzed. The pooled analysis revealed significantly higher Cu levels in MDD patients (Mean Difference (MD) = 2.22 µmol/L; 95% CI: 0.97–3.48; p = 0.001), although heterogeneity was high (I² = 98.6%). Sub-analysis in females confirmed the association (MD = 1.39 µmol/L; 95% CI: 0.65–2.12; p = 0.009). Results remained robust in sensitivity analyses. Begg’s test did not indicate possible publication bias. Our findings support an association between altered Cu homeostasis and MDD. Elevated Cu levels were observed in most studies, including among females and in subclinical cases, suggesting a potential role as a trait biomarker. Standardization in measurement and longitudinal designs is needed to confirm Cu’s clinical utility. Full article

Background: Major depressive disorder (MDD) and inflammatory bowel disease (IBD) form a “bidirectional vicious cycle” through the gut–brain axis: psychological and emotional abnormalities can induce intestinal inflammation, while intestinal inflammation can in turn exacerbate mental health disorders. Ferroptosis is an iron-dependent form of regulated cell death that is driven by lipid peroxidation. Although this process has been molecularly defined in recent years, its role in the context of IBD and MDD remains insufficiently investigated. This study investigates the molecular roles of ferroptosis-related genes (FRGs) in both conditions and explores potential therapeutic strategies targeting these genes. Methods: We first identified differentially expressed FRGs (DE-FRGs) by comparing normal and disease samples. Subsequently, we screened for DE-FRGs in both IBD and MDD and named them Co-DEGs. Correlation analyses of these co-FRGs were performed, including comparisons between disease and control groups, as well as associations between Co-DEGs and immune cell infiltrations. Four distinct machine learning algorithms were employed to identify the core Co-DEGs associated with both IBD and MDD. Moreover, analyses of drug sensitivity, molecular docking, and molecular dynamics simulations were carried out to predict potential therapeutic agents for both conditions. Finally, single-cell sequencing analysis was also performed. Results: We identified 29 Co-DEGs in both IBD and MDD. Machine learning analysis identified RPL8 as a key common biomarker exhibiting a consistent expression trend in both diseases. A predictive approach integrating molecular docking and molecular dynamics simulations indicated that LE135, a compound targeting RPL8, is the most promising therapeutic candidate. Conclusions: These discoveries enhance the understanding of the shared and distinct regulatory mechanisms of FRGs in gut–brain axis disorders. We have pinpointed key biomarkers and predicted potential therapeutic agents that may offer dual-targeting strategies for both IBD and MDD. Full article

Low dietary diversity is a key driver of undernutrition and remains a significant public health challenge in low- and middle-income countries. This study evaluated the effect of nutritional counselling and the provision of livestock feed, aimed at sustaining milk production during dry periods, on the dietary diversity of women and children in a pastoralist setting. Methods: A cluster randomized controlled trial was conducted among households in Laisamis subcounty, north-eastern Kenya, which were assigned to one of three arms: (1) an intervention arm providing livestock feed during critically dry periods, (2) an intervention arm providing livestock feed plus enhanced nutritional counselling (provided once a week, covering topics including hygiene and sanitation, breastfeeding, maternal nutrition, immunization and complementary feeding) or (3) a control arm. The dietary diversity of mothers and children was assessed every six weeks over two years. Panel difference-in-difference regression models were used to estimate intervention effects on dietary outcomes including child minimum dietary diversity (MDD), minimum acceptable diet (MAD), women’s dietary diversity (MDD-W) and food security. Results: A total of 1734 households participated (639 in arm 1, 585 in arm 2, and 510 in the control arm). The provision of livestock feed alone had significant gains in child MAD (OR 1.20; 95% CI 1.08–1.34), child MDD (OR 1.15; 1.11–1.20), and MDD-W (OR 1.10; 1.01–1.19) whereas combined livestock feed with counselling, reduced child food poverty (OR 0.89; 95% CI 0.81–0.99), increased child MAD (OR 1.39; 1.22–1.52), and improved MDD-W (OR 1.21; 1.16–1.28) relative to control. Neither intervention increased child minimum meal frequency relative to control. Purchasing livestock was associated with higher odds of meeting dietary-diversity indicators but a lower meal frequency (OR 0.80; 0.80–0.90); in contrast, cash-transfer receipt was linked to reduced odds of achieving child MDD (OR 0.90; 0.87–0.94), child MAD (OR 0.95; 0.85–0.97), and women’s MDD (OR 0.73; 0.54–0.89). Conclusions: Livestock feed provision sustains milk consumption and improves dietary diversity in pastoralist populations. When combined with nutritional counselling, these interventions strengthen the link between animal and human health, with important implications for food security. Full article

Annexin A3 (ANXA3) is a calcium-binding protein that plays a role in membrane phospholipid metabolism and inflammation, and significant alterations have been shown in some psychotic disorders. Because its association with major depressive disorder (MDD) is unclear, we aimed to compare serum ANXA3 levels in patients with MDD and healthy controls and to investigate their relationship with depression severity. Serum ANXA3 concentrations in 90 patients diagnosed with MDD and 90 healthy controls were measured by ELISA. Depression severity was assessed using the Beck Depression Inventory (BDI). Serum ANXA3 levels were significantly lower in patients with MDD compared to controls (p < 0.001). ANXA3 showed negative correlations with neutrophil count, platelet count, neutrophil-to-lymphocyte ratio (NLR), glucose, creatinine, and ALT levels, and positive correlations with lymphocyte and red blood cell counts. We found that low ANXA3 levels, high NLR, and glucose dysregulation predicted greater depression severity. Using ROC analysis, we demonstrated that ANXA3 has high discriminatory power in distinguishing moderate to severe cases of MDD (AUC > 0.90). ANXA3 may serve as a biomarker of depression severity. Further studies are needed to clarify its clinical utility and confirm whether ANXA3 alterations represent state or trait markers of depression. Full article

The increasing difficulty of handling industrial and agricultural wastes has generated interest in reusing materials such as Cement Kiln Dust (CKD) and Rice Husk Ash (RHA) for sustainable soil stabilization. This study examined the enhancement of lateritic soil with the incorporation of CKD (0–12%) and RHA (0–25%) by weight. An integrated experimental and Artificial Neural Network (ANN) methodology was utilized to evaluate and forecast geotechnical features. Laboratory assessments were conducted to measure Atterberg limits, Maximum Dry Density (MDD), Optimum Moisture Content (OMC), and Unconfined Compressive Strength (UCS) at 0, 7, and 28 days of curing. The results indicated significant enhancements in soil characteristics with CKD-RHA combinations. Artificial Neural Network models, including GELU, LOGSIG-3, and Leaky ReLU activation functions, accurately predicted the UCS, MDD, and OMC, achieving R² values as high as 0.980. This work underscores the efficacy of CKD-RHA mixtures in improving soil stability and the promise of ANN models as excellent prediction instruments, fostering sustainable and economical construction methodologies. Full article

Purpose: Genetic polymorphisms within specific genes play a role in both the genetic predisposition to Major Depressive Disorder (MDD) and the variation observed in responses to antidepressant treatments. Pharmacogenetics examines how these polymorphisms affect medication response. This review highlights significant disparities in the pharmacogenetic influences on antidepressant response, with a focus on ethnic and sex-based differences. Methods: This review synthesizes findings from a comprehensive literature search conducted between 2000 and 2025. It utilized databases such as PubMed, Scopus, and Web of Science, using search terms including “pharmacogenetics”, “antidepressants”, “Major Depressive Disorder”, “CYP450”, “neuroplasticity”, and “genetic variations”. This review integrates pharmacogenetics with neurotransmitters and their transporters, neuroplasticity, growth factors, and the cytochrome P450 family, providing promising insights for personalized MDD treatment strategies. We analyzed and synthesized findings from over 50 relevant studies, focusing on those with a clear emphasis on genetic associations with antidepressant efficacy and adverse effects. Results: Pharmacogenetic analysis facilitates personalized antidepressant prescriptions by identifying key genetic variants that influence treatment outcomes. Specifically, variations in CYP2D6 and CYP2C19 can significantly impact drug metabolism and tolerability. A high percentage of patients with non-normal metabolizer phenotypes are predisposed to adverse drug reactions or ineffective responses. Furthermore, this review identifies significant ethnic and sex-based disparities in treatment response. For example, the L allele of the 5-HTTLPR polymorphism confers a higher likelihood of response and remission following SSRI treatment in white people compared to Asians. Additionally, in women, specific 5-HTTLPR polymorphisms have a more pronounced influence on mood and MDD pathophysiology, with a significant reduction in mood in response to tryptophan depletion. Conclusions: Integrating pharmacogenetic insights, encompassing genetic factors, neurotransmitter pathways, neuroplasticity, and the influence of ethnicity and sex, is crucial for developing personalized antidepressant treatment strategies. This will ultimately optimize patient recovery and minimize adverse effects. Full article

Background/Objectives: Major depressive disorder (MDD) represents a leading cause of global disability, with approximately one-third of patients exhibiting treatment resistance (TRD) despite adequate pharmacological interventions. This treatment gap underscores the urgent need for novel therapeutic strategies. Recently, a series of data suggests that botulinum neurotoxin of type A (BoNT-A), traditionally used for neuromuscular and cosmetic indications, could constitute a potential antidepressant tool. This narrative review critically examines the current preclinical and clinical findings of BoNT-A in MDD. Methods: A comprehensive search of PubMed, Scopus, and Web of Science was conducted up to June 2025, including randomized controlled trials, observational studies, animal models, and mechanistic investigations. Search terms included “Botulinum Toxin,” “BoNT type A”, “Depression”, “Major Depressive Disorder”, “Facial Feedback”, and “Neurobiology”. Results: Some randomized and observational studies would indicate that glabellar BoNT-A injections might lead to significant reductions in depressive symptoms in patients with MDD and TRD. Proposed mechanisms include both peripheral modulation of emotional expression and brain effects, such as reduced amygdala hyperactivity, increased BDNF expression, and enhanced monoaminergic transmission. Preclinical studies confirm that BoNT-A modulates limbic and brainstem circuits, possibly implicated in affective regulation. The few comparative studies suggest therapeutic efficacy comparable to that of SSRIs, with a more rapid onset. Preliminary data also support its application in bipolar depression and comorbid anxiety disorders. Conclusions: The available literature would indicate that BoNT-A might constitute a promising candidate at least as an adjunctive treatment in MDD, although the impact of current findings is limited due to the methodological heterogeneity and the small sample sizes of patients examined. Further large-scale, placebo-controlled trials are warranted to elucidate the mode of action of BoNT-A and to validate or not its clinical effectiveness. Full article

Mood disorders, including major depressive disorder (MDD) and bipolar disorder (BD), are among the leading causes of disability worldwide and are frequently associated with treatment resistance, functional impairment, and high comorbidity with metabolic dysfunction. Increasing evidence implicates insulin resistance (IR) as a key pathophysiological factor linking metabolic and psychiatric illness. IR is associated with chronic low-grade inflammation, hypothalamic–pituitary–adrenal (HPA) axis dysregulation, impaired neuroplasticity, mitochondrial dysfunction, and altered reward processing mechanisms that may contribute to core depressive features such as anhedonia, cognitive slowing, and emotional dysregulation. These processes are further exacerbated by the metabolic side effects of many psychotropic medications, creating a self-perpetuating cycle that worsens both psychiatric and physical health outcomes. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), initially developed for type 2 diabetes and obesity, have emerged as promising candidates to address this metabolic–psychiatric interface. Beyond improving glycemic control and promoting weight loss, GLP-1 RAs exert central actions relevant to mood disorders, including modulation of dopaminergic reward pathways, enhancement of hippocampal neurogenesis, attenuation of neuroinflammation, and regulation of appetite and energy balance. Preclinical studies demonstrate that GLP-1 RAs reduce microglial activation, promote hippocampal neurogenesis, and normalize stress-induced behavioral changes. Early clinical trials in patients with metabolic disorders suggest improvements in depressive symptoms, quality of life, and cognitive function, with some effects independent of weight loss or glycemic outcomes. Observational evidence also indicates reduced antidepressant use and psychological distress in diabetic and obese populations receiving GLP-1 RAs. While these findings are promising, large randomized controlled trials in primary psychiatric populations are lacking. Key challenges include clarifying dose–response relationships, disentangling central from peripheral effects, and addressing safety and adherence concerns in individuals with comorbid psychiatric conditions. Future research should focus on biomarker-informed stratification, comparative trials with standard treatments, and integration of GLP-1 RAs into multimodal care frameworks. Overall, GLP-1 RAs represent a biologically plausible and clinically relevant approach to bridging metabolic and psychiatric care, with the potential to improve outcomes in patients with mood disorders who carry a high metabolic burden. Full article

Major depressive disorder (MDD) is the most common mood disorder among adults. Despite the wide use of pharmacological agents by those with MDD, the evidence indicates that only a small fraction of patients benefits, and many individuals using antidepressant therapy relapse. Side effects are numerous with antidepressants, which can be a factor in patient medication compliance. Along with psychotherapy and fine-tuning lifestyle components, another emerging option in treating MDD is the use of bioactive natural products known as nutraceuticals. We present the scientific findings specific to select nutraceuticals (e.g., omega-3 fatty acids, S-adenosyl-methionine, folate-based compounds, and vitamin D) either as a monotherapy or as adjunctive therapy to a pharmaceutical antidepressant, for treatment of MDD. Many studies demonstrate that nutraceuticals result in a decrease in depressive symptoms with fewer side effects as traditional medications and have the potential to improve the result of antidepressants, especially in individuals experiencing resistance to medication. From a therapeutic perspective, a holistic approach incorporating psychotherapy, pharmacological therapy, and lifestyle factors (inclusive of nutraceutical use) appears most logical and could provide for enhanced treatment efficacy. Full article

Psychotic and affective disorders, including schizophrenia (SCZ) and depression (MDD), affect millions of people globally. The overlapping symptoms of these diseases and the lack of objective diagnostic tools could lead to misdiagnosis. Recent studies suggest that the analysis of plasma lipid levels may help to develop new diagnostic tools. In this study, we investigated the plasma lipidome of psychiatric patients and healthy controls to identify disease-specific lipid species. Using untargeted mass spectrometry, we profiled blood plasma lipids from 416 patients with common psychotic and affective disorders and 272 healthy individuals from two different cohorts. We observed lipidome alterations in SCZ and MDD consistent with earlier findings. In total, 144 lipids showed significant changes, with 107 of them being concordant across both disorders, and 37 being discordant. Lipids that differentiated SCZ from MDD were mainly triacylglycerols with polyunsaturated fatty acid residues decreased in MDD. In an additional group of 111 patients with bipolar, schizotypal, and schizoaffective disorders, these lipid markers suggested a trend toward separating psychotic and affective disorders. Furthermore, a logistic regression model trained on lipid data distinguished SCZ from MDD with an ROC AUC of 0.83. Taken together, these results suggest that blood lipid profiling may aid in the objective differentiation of psychotic and affective disorders. Full article

Full waveform inversion (FWI) comprehensively utilizes phase and amplitude information of seismic waves to obtain high-resolution subsurface medium parameter models, applicable to both active-source and passive-source seismic data. Passive-source seismic exploration, using natural earthquakes or ambient noise, reduces costs and environmental impact, with growing marine applications in recent years. Its rich low-frequency content makes passive-source FWI (PSFWI) a key research focus. However, PSFWI inversion quality relies heavily on accurate virtual source reconstruction. While multi-dimensional deconvolution (MDD) can handle uneven source distributions, it struggles with irregular receiver sampling. We propose a robust MDD method based on multi-domain stepwise interpolation to improve reconstruction under non-ideal source and sampling conditions. This approach, validated via an adaptive PSFWI strategy, exploits MDD’s insensitivity to source distribution and incorporates normalized correlation objective functions to reduce amplitude errors. Numerical tests on marine and complex scattering models demonstrate stable and accurate velocity inversion, even in challenging acquisition environments. Full article

Background: Major depressive disorder (MDD) is a prevalent and disabling psychiatric illness with complex etiologies involving both genetic and environmental factors. While environmental stress is a known risk factor of MDD, the molecular mechanisms linking stress exposure to persistent depressive phenotypes remain incompletely understood. Methods: We established a 24-hour restraint stress-induced depression model in mice and performed integrated transcriptomic and proteomic analyses of the medial prefrontal cortex (mPFC) to investigate stress-related molecular alterations. Results: Behavioral assessments confirmed persistent depression-like phenotypes, including anhedonia and behavioral despair, lasting up to 35 days post-stress. RNA sequencing identified differentially expressed genes related to dopaminergic signaling and oxidative stress. Proteomic analysis identified 105 differentially expressed proteins involved in immune response and energy metabolism. Integrated multi-omics analysis highlighted convergent disruptions in immune regulation, metabolism, and epigenetic processes. Notably, clemastine exerts its antidepressant-like effects in part by mitigating neuroinflammation and preserving mitochondrial function. Conclusions: These findings provide novel insights into the molecular basis of stress-induced depression and suggest that clemastine is a potential therapeutic candidate. Full article