OBJECTIVE:Ketamine is a rapid-acting antidepressant with an incompletely understood mechanism of action. Pharmacometabolomics can identify pathways underlying its effects and response variability. Using data from the Bio-K trial (NCT03156504), a multisite open-label study, we characterised metabolomic signatures of intravenous (IV) racemic ketamine in adults with treatment-resistant depression (TRD). METHODS:Sixty-nine adults with TRD and major depressive disorder received three ketamine infusions (0.5 mg/kg). Remission was defined as MADRS ≤9 at 24 h post-third infusion. Metabolomic profiling used the Biocrates MxP® Q500 kit (>600 metabolites). Mixed-effects models assessed changes across time points (pre-dose, post-infusion 1, post-infusion 3), adjusting for age, sex, infusion length (first), and body mass index, with false discovery rate correction. RESULTS:Mean MADRS improved from 27.8 ± 5.8 to 11.1 ± 9.1 post-third infusion (p < 0.001); 54% achieved remission. Post-infusion 1, ketamine was associated with increased acylcarnitines, cortisol, amino acids (glutamine, glycine, BCAAs), and biogenic amines (GABA, putrescine), with reduced medium-chain acylcarnitines and glutamate. Post-infusion 3, C16, serotonin, and GABA elevations persisted while cortisol normalised. Remitters showed greater GABA synthesis increases, however, no metabolite change correlated with MADRS improvement after correction for multiple testing. CONCLUSIONS:Ketamine exposure was correlated with broad metabolic alterations spanning mitochondrial activation, neurotransmitter modulation, and neuroendocrine signalling. These findings represent metabolic correlates of ketamine exposure and remission, rather than validated predictors or established mechanistic drivers of antidepressant response. TRIAL REGISTRATION:ClinicalTrials.gov: NCT03156504.
OBJECTIVES:Depression involves interacting immune, oxidative, metabolic, neuroendocrine and neuroplasticity networks. This review evaluates mechanistic, preclinical, human and translational evidence for resveratrol in depression. METHODS:We conducted a structured narrative review of English-language literature to 30 June 2026 using PubMed, Web of Science Core Collection, Scopus and ScienceDirect, supplemented by Google Scholar and citation searching. After duplicate removal, 4,461 records were screened, 142 full texts assessed and 71 publications included. RESULTS:Antidepressant-like effects were reported across stress, endocrine, developmental, post-stroke, metabolic and gut-inflammatory models, involving SIRT1/AMPK, NF-κB/ NLRP3, Nrf2/HO-1, mitochondrial and ferroptosis pathways,monoaminergic and cAMP/PKA/CREB/BDNF signalling, and gut brain communication. However, many studies used preventive or concurrent dosing, male animals, high doses or non-oral routes. Human studies were few, heterogeneous and mainly non psychiatric, and do not establish efficacy for major depressive disorder. Nanoformulations may improve exposure, but depression specific clinical validation is lacking. CONCLUSIONS:Current evidence does not support resveratrol as monotherapy or an established depression treatment. It is better positioned as a mechanistic probe and hypothesis-generating adjunctive candidate. Future studies should prioritise therapeutic designs, pharmacokinetic monitoring, standardised outcomes and adequately powered adjunctive trials.
BACKGROUND:Stress-related psychiatric disorders such as anxiety and depression require robust preclinical models for mechanistic exploration. In this study, we utilized adult zebrafish (Danio rerio) to investigate behavioral, molecular, and metabolic differences between anxiety- and depression-like states. METHODS:Anxiety was modeled using acute predator exposure, whereas depression was induced via a 21-day chronic unpredictable stress (CUS) protocol. Evaluations included behavioral assays, histopathology, immunohistochemistry, untargeted metabolomic profiling, and gene expression analyses. RESULTS:Behavioral assays revealed divergent phenotypes: the anxiety group displayed erratic movement and reduced exploration, whereas the depression-like group exhibited reduced locomotor activity, impaired social behavior, cognitive deficits, and increased immobility in the tail test. Histopathological analysis showed more severe neuronal degeneration in depression. Immunohistochemical staining indicated higher expression of stress markers (BDNF, BMAL1, 5HT4) in both groups, with stronger accumulation in depression. Metabolomics showed widespread upregulation of neurotransmitter-related metabolites in depression, while the anxiety group exhibited selective changes and essential fatty acid depletion. Gene expression revealed broader upregulation of neuropeptides, inflammatory cytokines, and monoamine-related genes in depression. CONCLUSION:Our findings highlight the ability of zebrafish to model distinct stress-induced affective disorders and underscore how stress duration shapes neurobehavioral and molecular outcomes, supporting their translational utility in psychiatric research.
OBJECTIVES:This study compared high-intensity interval training (HIIT) versus moderate continuous training (MCT) as preconditioning on hippocampal BDNF, TrkB, and TNF-α gene expression in rats exposed to acute noise stress. METHODS:Forty-two male Wistar rats were randomised into seven groups (n = 6): control, time-control, stress, HIIT, MCT, HIIT+stress, and MCT+stress. Exercise groups underwent 8-week treadmill training (5 sessions/week). HIIT (6x2-min intervals, 85-90% Vmax) or MCT (22-min continuous, 65-70% Vmax). Stress groups received a single 4-hour noise exposure. Hippocampal mRNA was quantified via real-time PCR. RESULTS:Both HIIT and MCT significantly upregulated BDNF versus time-control, with HIIT eliciting greater increases. MCT significantly elevated TrkB versus time-control. Noise stress reduced BDNF and TrkB while increasing TNF-α. Both exercise protocols attenuated these alterations. Under stress, HIIT+stress exhibited significantly higher TrkB than MCT+stress. MCT elevated TNF-α versus time-control, but stress-induced increases were similarly mitigated in both preconditioned groups. Correlation analysis revealed strong positive correlations between BDNF and TrkB and moderate correlations between BDNF and TNF-α, and TrkB and TNF-α. CONCLUSION:HIIT and MCT differentially modulate hippocampal gene expression. While MCT effectively upregulates basal TrkB, HIIT provides superior protection against stress-induced TrkB suppression, highlighting intensity-specific neuroprotective adaptations and integrated pathway regulation among BDNF, TrkB, and TNF-α.
BACKGROUND:Autism spectrum disorders (ASD) is a neurodevelopmental disorder. Neuroinflammation and bloodbrain barrier (BBB) dysfunction have role in the pathophysiology of ASD. Trigonelline (TRI) exerted neuroprotective effects. We aimed to investigate TRI's effects on autistic phenotype, gene expression of tight junction proteins associated with BBB integrity, neuroinflammation and histopathological changes in the hippocampus in valproic acid (VPA) - induced autism in rats. METHODS:Pregnant Wistar rats received single subcutaneous injection of VPA (600mg/kg) on day 12 of gestation. Animals were treated with normal saline or TRI for one week. Repetitive behaviours, anxiety-like behaviour, memory function, and social interactions were assessed. The thickness and dark neurons of the CA1 and CA3 regions of hippocampus were examined. The inflammatory genes, including Tlr4, Tnf-α, and Il-1β, along with claudins (Cldn -3, Cldn-5, and Cldn-12), were measured in the hippocampus. RESULTS:TRI significantly attenuated autistic behaviors. TRI reduced the expression of inflammatory markers and modulated the expression of claudins. TRI increased the thickness and decreased the number of dark neurons in the CA1 and CA3 regions. CONCLUSIONS:TRI reduced autistic behaviours probably through attenuation of neuroinflammation, preservation of the hippocampus, and modulation of gene expressions of tight junction proteins associated with the BBB permeability.
OBJECTIVES:The aim of this study was to assess the associations of psychometric, biochemical, and genetic parameters of the serotonin and dopamine systems with violent criminal behavior. METHODS:Male participants who had no criminal records (n=110) and those who had committed interpersonal violent crimes (n=143) were included in the study. Aggression levels were estimated by means of the Buss-Perry questionnaire (BPAQ-24). The Structure of Temperament Questionnaire-Compact (STQ-77), potentially linked to monoamine neurotransmitter activity, was administered to profile temperament traits. Concentrations of monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were estimated in urine samples. The HTR2A rs6313 and DRD4 rs1800955 polymorphisms were genotyped by real-time PCR. RESULTS:Offenders demonstrated higher levels of aggression, and decreased concentrations of 5-HIAA and HVA as compared with controls. According to the final model of multivariate binary logistic regression, total BPAQ scores (B = 0.047; p < 0.001), HVA concentrations (B = -0.004; p < 0.001), and the STQ-77 Empathy (EMP) scale (B = 0.225; p = 0.004) were the independent markers discriminating violent criminal behavior with an overall classification accuracy of 86.1%. CONCLUSION:Thus, the complex interplay between heightened aggression, reduced HVA levels, and specific temperament traits constitutes a neurobehavioral signature of violent criminal behavior.
OBJECTIVES:Clozapine, the gold-standard antipsychotic for treatment-resistant schizophrenia causes severe metabolic complications, including metabolic syndrome and increased type 2 diabetes (T2D) risk. A better understanding of the genetic factors influencing clozapine pharmacokinetics and the associated metabolic risk could inform precision medicine approaches to clozapine prescribing. METHODS:Using a series of genetic-epidemiological approaches, we aimed to identify candidate biomarkers associated with clozapine-induced metabolic dysfunction. Mendelian randomisation (MR) was employed to investigate evidence of causal relationships between clozapine metabolism and cardiometabolic traits. RESULTS:Higher plasma clozapine and clozapine-norclozapine ratio were associated with a higher risk of T2D and blood pressure. The phenome-scan-colocalization-MR pipeline identified traits influenced by clozapine-metabolism loci that might serve as markers of cardiometabolic risk. This pipeline identified 28 colocalizing markers associated with clozapine pharmacokinetic loci. Subsequent MR highlighted associations for 16 of these 28 biomarker candidates with cardiometabolic outcomes, which included haematological markers and excretory traits. CONCLUSIONS:These findings are hypothesis-generating and do not, in the absence of prospective clinical validation, establish causal relationships between clozapine and the identified cardiometabolic traits. They may inform the development of biomarker-guided monitoring approaches for risk stratification and early intervention, enabling a shift from reactive monitoring to predictive approaches in managing clozapine-induced metabolic dysfunction with appropriate clinical validation.
OBJECTIVES:To identify changes in RNA levels in Brodmann's area 9 (BA 9) from people with schizophrenia compared to controls and to understand the contribution of those changes to the molecular pathology of the disorder. METHODS:BA 9 RNA levels, measured in 81 people with schizophrenia and 70 healthy controls using the Affymetrix Human Exon 1.0 ST Array, were compared using JMP Genomics 9.0. Differences in levels of RNA between diagnosis were accepted at fold changes of 1.0 ± ≥ 0.2 and p < 0.01. The potential effects of these changes in RNA were determined using the Panther Gene Ontology Classification System and Qiagen Ingenuity Pathways. RESULTS:Levels of 17,304 RNAs were measured in BA 9, with 47 RNA levels being altered (29 higher) in schizophrenia. These changes in RNA levels should affect water homeostasis, regulation of extracellular space volume, potassium buffering, CSF circulation, interstitial fluid resorption, waste clearance, neuroinflammation, osmosensation, cell migration, calcium signalling and transport, gap junctions and membrane transport. CONCLUSIONS:Changes in gene expression we report in BA 9 from people with schizophrenia are involved in important biochemical pathways that could contain new drug targets and could be involved in the molecular pathology of the disorder.
BACKGROUND AND AIMS:Recent translational and clinical research emphasise the concept of interacting neurochemical disruptions as a ground for the development of psychosis. At the same time, literature highlighted neurostructural and functional alterations in ASD. However, evidence linking biochemical markers to psychotic symptoms in the context of ASD is still scarce. In this perspective, we aim to investigate biochemical correlations and predictive biological factors of psychotic symptoms in autism, also considering gender differences. METHODS:For this study, we recruited a total of 22 ASD adult patients assessed through the Psychotic Spectrum - Self-Report version (PSY-SR). Furthermore, a blood sample was drawn in order to perform biochemical evaluations. All biochemical parameters were detected with an ELISA kit. RESULTS:considering gender differences, male patients showed higher micromolar HCy levels.Spearman correlation analyses revealed significant correlations between PSY total and single domains and biochemical correlates such as TRP metabolites, plasmic 5-HT and BDNF. Finally, linear regression analyses, revealed specific patterns of negative and positive biochemical predictors (particularly those with the kynurenine pathway) for psychotic symptoms in ASD. CONCLUSIONS:Globally, our work highlighted that, in ASD adults, psychotic symptoms may be associated with specific biochemical alterations, in particular linked to the kynurenine pathway, BDNF and 5-HT.
OBJECTIVE:Social anxiety disorder (SAD) is common debilitating condition marked by intense fear of negative evaluation in social situations. It frequently co-occurs with other psychiatric disorders and substantially impairs quality of life. Although its aetiology remains unclear, like many other complex psychiatric disorders, SAD is thought to arise from interactions among biological and environmental factors. Increasing attention has been given to the role of neuropeptides, neurohormones, and immune system processes, particularly inflammation, in its pathophysiology. This review aims to evaluate and synthesise scientific evidence on the potential biochemical correlates of SAD in clinical populations, concentrating on inflammatory markers, neuropeptides, and growth factors. METHODS:Electronic databases (PubMed, Scopus, and Web of Science) were searched according to PRISMA guidelines, resulting in 27 studies included in the final analysis. RESULTS:The research into biochemical correlates of SAD has yielded promising but inconclusive results, particularly regarding inflammation, microbiome changes, and immune system interactions. Overall, the evidence supports the hypothesis that the inflammatory cascade plays a role in the persistence of the disorder. CONCLUSIONS:Although some markers show promise in advancing our understanding of SAD's pathophysiology, further research is necessary to clarify their roles and validate their potential in diagnostics and treatment.
OBJECTIVES:This study aimed to investigate the shared and distinct activation patterns between a hallucination capture task and a task consisting of exposure to an avatar representing the participants' most distressful auditory verbal hallucination (AVH) (Avatar task).Methods: Twenty participants with schizophrenia and persistent AVHs were recruited. During an fMRI session, they performed the Avatar task and the hallucination capture task. Whole-brain analyses were performed for each task. The potentially shared and distinct activations between tasks were examined using a region of interest (ROI) approach. To avoid inflating the number of brain regions tested, we selected as ROIs brain regions involved in language (left inferior frontal gyrus), emotional processing (amygdala) and social cognition (dorsomedial prefrontal cortex). RESULTS:We found that participants with AVHs exhibited significant activation in the left inferior frontal gyrus during the hallucination capture task. In contrast, they showed significant activation in the left amygdala and the left dorsomedial prefrontal cortex during the Avatar task. Conjunction and disjunction analyses produced similar results. CONCLUSIONS:The exposure to the AVH avatar specifically activated regions involved in emotional processing and social cognition, suggesting that the Avatar task is relevant for exploring the neural mechanisms involved in dialogical therapies for AVH.
BACKGROUND & OBJECTIVE:Elevated advanced glycation end products (AGEs) are linked to metabolic dysfunction in schizophrenia-spectrum disorders, but previous studies have shown methodological heterogeneity and overlapping cohorts. We systematically reviewed and quantified differences in blood-based and skin AGE levels between patients and healthy controls. METHODS:Following PRISMA 2020, databases were searched up to January 2025. Independent case-control studies with quantitative AGE measurements were analysed using random-effects models, strictly excluding overlapping cohorts. RESULTS:Nine independent studies (584 patients, 630 controls; N = 1,214) were included. Patients exhibited significantly higher AGE levels than controls (SMD = 0.63, 95% CI 0.26-1.00; p = 0.0008), with substantial heterogeneity (I2 = 88.4%). Subgroup analyses showed significant elevations in both blood-based measurements (k = 6, SMD = 0.47) and skin (k = 4, SMD = 0.87). Measurement modality was not a significant moderator (p = 0.20). The association remained significant in high-quality studies (k = 5, SMD = 0.70). CONCLUSIONS:AGE levels are significantly elevated in schizophrenia-spectrum disorders, although substantial heterogeneity remains. Further longitudinal studies controlling for metabolic and geographic factors are needed.
OBJECTIVES:Suicidal behaviour is biologically heterogeneous, and dysregulation of cerebrospinal fluid (CSF) metabolites has been implicated in suicidal death. We conducted a systematic review and meta-analysis to evaluate these alterations in individuals dying by suicide compared with non-suicidal deaths. METHODS:This review followed PRISMA 2020 guidelines and was prospectively registered in PROSPERO (CRD420251242059). PubMed, Web of Science, and Scopus were systematically searched. Random-effects meta-analyses were performed, calculating standardised mean differences (SMDs) with 95% confidence intervals (CIs). Quality assessment and sensitivity analyses of included studies were done and heterogeneity assessed using I2 statistic. RESULTS:Of 1,814 records, seven case-control studies (195 suicidal deaths; 267 controls) met inclusion criteria and were rated moderate-to-good quality on the Newcastle-Ottawa scale. Eight metabolites were reported, but meta-analysis was feasible for serotonin and 5-hydroxyindoleacetic acid (5-HIAA) only. No significant differences were observed for serotonin (SMD (95%CI) = -0.43 (-1.62-0.76); p = 0.48) and 5-HIAA (SMD (95%CI) = 0.34 (-0.54-1.21); p = 0.45). Substantial heterogeneity was present, but sensitivity analyses showed robust estimates. CONCLUSIONS:Current evidence does not demonstrate significant differences in CSF serotonin or 5-HIAA levels in suicidal deaths. Methodological heterogeneity and limited data underscore the need for rigorously designed standardised post-mortem studies.
INTRODUCTION:Schizophrenia spectrum disorders (SSD) commonly involve deficits in social cognition and facial processing. The N170 and N250 event-related potentials (ERP), indexing perceptual and recognition stages of face processing respectively, have shown alterations in schizophrenia. Given diagnostic advances, an updated analysis is necessary to examine these ERP across SSD, including high-risk individuals and those exhibiting schizotypal traits. OBJECTIVES:To update previous meta-analysis findings by evaluating the effects of SSD on N170 and N250 amplitude and latency. METHOD:Studies comparing N170 and N250 amplitude and latency between individuals with SSD and healthy controls were identified through a literature search, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendations. RESULTS:Results showed a small reduction in N170 amplitudes in SSD (n = 50), statistically significant in SSD but not in schizotypy or high-risk individuals. A small but significant difference was also found for N170 latency, whereas no significant effects were observed for N250 amplitude or latency. DISCUSSION:Findings indicate reduced N170 amplitudes and subtle latency alterations in SSD, reflecting early-stage visual perceptual deficits, with no consistent differences observed for N250 amplitude or latency, suggesting relative preservation of later face processing stages. The main limitation of this work is the high heterogeneity across studies analysed.
OBJECTIVES:Maternal separation (MS) stress is a risk factor for abnormal behaviors including autism-like behaviors. The blood brain barrier (BBB) dysfunction is involved in the pathophysiology of autism spectrum disorder (ASD). Pentoxifylline (PTX), a methylxanthine commonly used for peripheral vascular disease, has been shown that exerted neuroprotective effects. This study aims to examine the effects of PTX on autistic-like behaviors in MS mice, considering its possible effects on gene expression of claudins (CLDNs), as main molecules regulates BBB integrity. METHODS:Forty male mice were used. While control, unstressed, mice treated with normal saline, MS mice treated with normal saline or PTX at doses of 10, 20, and 30 mg/kg for 2 weeks via intraperitoneal injection. Three-chamber sociability, shuttle box, and marble burying tests were performed. Gene expression of Cldn -1, Cldn- 5 and Cldn- 12 was assessed in the hippocampus. RESULTS:PTX improved the sociability and social preference indexes, improved passive avoidance memory and decreased repetitive behaviors. PTX decreased Cldn- 5 while increased Cldn -1 and Cldn- 12 genes in the hippocampus. CONCLUSIONS:PTX mitigated autism-like behaviors in MS mice, probably via regulating of mRNA expression of Cldn -1, Cldn -5 and Cldn- 12 in the hippocampus.
OBJECTIVE:To characterise proteomic changes associated with depression risk across different follow-up periods and develop predictive models integrating protein and clinical features. METHODS:Olink proteomic data from the UK Biobank were analysed using logistic regression and Cox proportional hazards models to identify depression-associated proteins. Time-specific analyses were performed within 1-, 5-, and 10-year follow-up windows. Depression was defined using ICD-10 codes. GO and KEGG enrichment analyses were conducted, and predictive proteins were selected using sequential forward selection prior to XGBoost modelling. RESULTS:Among 52,121 participants, 2,442 developed depression. Distinct plasma protein signatures were identified across followup windows. Within 1 year, BRK1, MME, LRPAP1, and LRP1 were significantly associated with depression. Within 5 years, MMP12, SPP1, and SPON2 were among 287 unique associated proteins, while TGM2, OMG, and UBAC1 were representative markers among 509 proteins identified within 10 years. LEP was consistently selected across all time windows and in the overall population. The combined protein-clinical XGBoost model achieved the best performance within the 1-year follow-up window (AUC = 0.808, 95% CI: 0.696-0.911), outperforming protein-only and clinical-only models. CONCLUSION:Circulating plasma proteins have predictive value for depression risk, with LEP emerging as a robust biomarker across multiple time horizons.
OBJECTIVES:Recent research focused on the impact of Neandertal alleles on dopamine-related brain traits. A joint measure of these alleles was reported to be associated with lower dopamine synthesis, presumably leading to reduced activity of the reward system. To isolate single variants, we selected rs3025343 near the dopamine beta hydroxylase gene, which contains a likely introgressed allele. rs3025343 is an established variant for reward system-related psychiatric traits. METHODS:We hypothesised that the rs3025343 minor allele reduces responses to conditioned reward stimuli in the mesolimbic dopamine system. We tested this hypothesis in a large sample of healthy subjects who underwent fMRI while performing the 'Desire-Reason-Dilemma' paradigm, which allows investigation of reward-related brain responses. RESULTS:Consistent with our expectation, the rs3025343 minor allele was associated with reduced reward-related activation in core regions of the mesolimbic reward system, i.e. the ventral striatum and the ventral tegmental area, as well as with anteroventral and anterior cingulate regions of the extended reward system. CONCLUSIONS:These findings provide the first evidence that the likely introgressed minor allele of rs3025343 contributes to a reduced response of the mesolimbic reward system. Further studies in independent samples are needed to replicate these associations and to understand their functional roles.
OBJECTIVE:To prepare evidence-based guidelines on psychosis prevention. METHODS:We reviewed evidence on risk factors for/age at onset of psychosis, tools to assess clinical high-risk of psychosis (CHR-P), transition rates, risk calculation/ethical considerations around risk communication, CHR-P biological/clinical correlates, efficacy/cost-effectiveness of interventions/psychosis prevention services. The World Federation of Societies of Biological Psychiatry framework was used to grade evidence regarding interventions/services, elaborating guidelines with evidence-/consensus-based clinical recommendations to prevent psychosis in CHR-P subjects. RESULTS:At the service organisation level, (i) psychosis indicated prevention services might be implemented in close collaboration with early intervention services for psychosis to minimise duration of untreated illness, (ii) intake age criteria should be between 14 to 35, (iii) services should allow access to persons with cannabis use disorder. At the assessment and risk communication level, in clinical settings: (iv) staff in mental health services should be trained in administering/rating CHR-P assessment tools, (v) administer them, (vi) be trained in using/interpreting risk calculators, and (vii) in communicating risk, (viii) only use validated risk calculators, keeping a human-to-human interaction. Also, (ix) prevention services should assess comorbid mental disorders. At the intervention level: (x) staff should offer treatment for abstinence from cannabis, (xi) offer evidence-based treatment for comorbid mental disorders, and (xii) offer treatment for CHR-P based on patient preference, following the 'first do no harm' principle. CONCLUSIONS:Prevention services should be implemented, including interventions for cannabis use, reducing the duration of untreated psychosis, and treating comorbid mental disorders.
OBJECTIVES:Transdiagnostic genetic factor models organise shared liability across psychiatric disorders, but they may leave systematic pairwise genetic overlap unexplained after accounting for shared liability. METHODS:Using publicly available Psychiatric Genomics Consortium cross-disorder published genetic correlations, we computed edge-level residual genetic correlations (observed minus model-implied) for all disorder pairs. We summarised residual misfit by ranking the largest residual edges and by aggregating residual edges into disorder-level hub indices. Uncertainty was propagated via Monte Carlo sampling using reported standard errors. RESULTS:Residual structure was concentrated in a subset of disorders rather than being uniformly distributed. The largest positive residual edge was obsessive-compulsive disorder (OCD)-anxiety (∼0.35), followed by prominent residual links including OCD-Tourette syndrome, attention-deficit/hyperactivity disorder (ADHD)-cannabis use disorder, and autism spectrum disorder (ASD)-ADHD. At the node level, OCD emerged as the most consistent residual hub, with ADHD typically second. Hub rankings did not map one-to-one onto disorder uniqueness, indicating complementary information captured by edge-level residuals. CONCLUSIONS:Higher-order genetic factors capture broad shared liability but leave structured residual associations between specific disorder pairs. Examining residual patterns can clarify the limits of transdiagnostic architectures and inform more explainable models and targeted follow-up.
OBJECTIVES:The gut microbiome-gut-brain axis (MGBA) has been associated in the pathophysiology of depression; however, the expanding literature remains fragmented across metabolic signalling, immune-inflammatory pathways, stress physiology and dysbiosis outcomes. METHODS:Abstracts were retrieved from bibliographic databases (Lens.org, PubMed, DOAJ, Europe PMC) for studies published between 2014 and 2024 investigating associations between the gut microbiome and depression using 16S rRNA sequencing. Following text preprocessing, Latent Dirichlet Allocation (LDA) was applied to identify latent thematic topics. Topic proportions were subsequently embedded using principal component analysis (PCA), t-distributed stochastic neighbour embedding (t-SNE), and uniform manifold approximation and projection (UMAP). RESULTS:Topic modelling revealed distinct interconnected thematic domains within the gut microbiome depression literature, encompassing metabolic and short chain fatty acid pathways, immune inflammatory mechanisms, stress and hypothalamic pituitary adrenal (HPA) axis regulation, probiotic and interventional work, microbial diversity and compositional metrics, neurochemical and neuroplasticity, developmental cohorts, and sequencing- or methodology-focused research. CONCLUSIONS:Computational synthesis indicates that research on the gut microbiome depression axis is structured around multiple convergent mechanistic themes. This thematic landscape highlights dominant areas of mechanistic focus, providing a conceptual framework to guide future experimental design, mechanistic validation and translational research.
