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Chronic ketamine exposure results in psychotic and cognitive symptoms that resemble those found in patients with schizophrenia. Emerging evidence suggests that patients with schizophrenia exhibit gut microbiota dysbiosis and decreased levels of short-chain fatty acids (SCFAs) and BDNF, which are related to the severity of psychotic and cognitive symptoms. Dietary inulin can regulate gut microbiota, SCFAs, and BDNF. However, the role of gut microbiota, SCFAs, and BDNF in chronic ketamine-induced schizophrenia-like behaviors is unclear. In this study, we found that chronic ketamine exposure for 28 days caused gut microbiota dysregulation, reduced the expression of SCFAs in serum, hippocampus, and feces, elevated gut permeability, downregulated the BDNF-TrkB-ERK1/2-CREB signaling pathway, caused neuronal damage, and decreased the expression of synaptic proteins Syn and PSD-95, which may lead to anxiety-like behaviors, prepulse inhibition (PPI) deficits, and spatial learning and memory deficits. In addition, inulin intervention reversed gut microbiota dysbiosis by decreasing the abundance of Show less

Clozapine is the most effective treatment for treatment-resistant schizophrenia but has been linked to cognitive impairment and brain volume reductions. The potential mechanisms underlying these effects remain unclear. Microglial exosomes, which carry microRNAs (miRNAs) and other cargo, act as immune-neuron communication vectors capable of modulating neuronal function and cognition. We compared cognitive performance and inflammatory markers across clozapine-treated individuals, haloperidol-treated individuals, and healthy controls. Human microglial cells were treated with clozapine and assessed for phenotypic changes and exosome production. Exosomes from control and clozapine-treated microglia were applied to neuroblastoma cells and primary murine cortical neurons to assess neurite outgrowth and brain-derived neurotrophic factor (BDNF) expression. C. elegans were exposed to exosomes and evaluated for lifespan, healthspan markers, and cognitive function via olfactory associative learning assays. Exosomal miRNA cargo was characterized by small RNA sequencing. Clozapine-treated individuals exhibited elevated systemic inflammatory markers and lower cognitive performance compared with healthy controls. Clozapine altered microglial morphology, reduced proliferation and migration, and significantly increased exosome production. Small RNA sequencing identified six dysregulated miRNAs in clozapine-induced microglial exosomes, including upregulation of miR-34a-5p. Exposure of neurons to clozapine-induced exosomes reduced neurite length, branch points, and BDNF expression. In C. elegans, clozapine-induced exosomes reduced lifespan and severely impaired learning and short-term memory. These findings identify a neuroimmune exosomal pathway through which clozapine-exposed microglia can impair neuronal structure and cognition, associated with dysregulated miRNA cargo. This work provides a framework linking microglial immune signalling, extracellular vesicle biology, and cognitive vulnerability during clozapine exposure. Show less

Neuroplasticity dysregulation is implicated in the early pathophysiology of schizophrenia. Nogo-A, a myelin- and neuron-associated inhibitor of structural plasticity, has been less studied in first-episode schizophrenia (FES) than brain-derived neurotrophic factor (BDNF). This study examined short-term changes in serum Nogo-A and BDNF in drug-naïve patients with FES. Thirty-nine drug-naïve FES patients and 43 healthy controls (HC) were assessed. Serum Nogo-A and BDNF were measured at baseline in both groups and re-measured in FES after achieving ≥20 % reduction in Positive and Negative Syndrome Scale total score (PANSS). Baseline Nogo-A levels were higher in FES than HC (p = .022) and increased further after treatment (p < .001). Baseline BDNF did not differ between groups (p = .069) and showed no significant change after treatment (p = .094). PANSS total and subscale scores decreased significantly after treatment (all p < .001). Baseline Nogo-A modestly discriminated FES from HC (AUC = 0.648, 95 % CI = 0.53-0.77, sensitivity 66.7 %, specificity 60.5 %). In multivariable analysis, only smoking independently predicted FES (OR = 3.69, 95 % CI = 1.48-9.23, p = .005), whereas Nogo-A was not retained. Serum Nogo-A is elevated at illness onset in FES and increases during early treatment, suggesting that peripheral Nogo-A may be associated with early illness-related and/or treatment-related biological changes. Although Nogo-A does not show sufficient performance as a stand-alone diagnostic biomarker, these findings should be interpreted cautiously given the relatively small sample size and naturalistic treatment design. Nogo-A may warrant further investigation as part of broader multi-marker approaches in early schizophrenia. Show less

Schizophrenia is a severe mental disorder characterized by hallucinations, delusions and cognitive dysfunction, imposing a substantial burden on individuals and society. While antipsychotic medications such as risperidone effectively control positive symptoms, their efficacy in ameliorating cognitive impairment and aggressive behavior remains limited. Repetitive transcranial magnetic stimulation (rTMS), a non-invasive neuromodulation technique, has recently demonstrated potential in adjunctively improving cognitive and behavioral dimensional symptoms in schizophrenia patients. However, the effects of combined rTMS-risperidone therapy on these symptoms and associated serum biomarkers are not yet adequately supported by clinical evidence. This study aimed to evaluate the effects of repetitive transcranial magnetic stimulation (rTMS) combined with risperidone on cognitive function, aggressive behavior and serum biomarkers in patients with schizophrenia. Eighty patients were randomly assigned to a risperidone monotherapy group or a combination therapy group (40 each) for a 4-week intervention. Results showed that the combination group achieved significantly greater reductions in cognitive factor scores (11.39±2.44 vs. 12.84±2.13) and aggressive behavior scores compared to the monotherapy group (all P<0.05). Serum analysis revealed that the combination group also demonstrated superior modulation of biomarkers, including greater reductions in pro-inflammatory factors (TNF-α, IL-8, IL-18) and greater increases in anti-inflammatory (IL-10) and neurotrophic factors (BDNF, VEGF-A, FGF-2) (all P<0.05), while no significant differences were observed in PDGF-BB and HGF between the two groups. These findings suggest that rTMS combined with risperidone more effectively improves cognitive and aggressive symptoms in schizophrenia and is associated with favorable changes in serum inflammatory and neurotrophic markers. Show less

Studies have reported that the prevalence of aggression is higher in individuals with schizophrenia compared to the general population. Various factors, including genetic variations, contribute to the emergence of aggression in patients with schizophrenia. Among these, the monoamine oxidase A (MAOA) and brain-derived neurotrophic factor (BDNF) genes are considered key genetic factors potentially influencing aggressive behavior in schizophrenia. This study investigated the association of BDNF rs6265 and MAOA rs1465108 polymorphisms with aggression in schizophrenia. A total of 150 patients diagnosed with schizophrenia were included in the study. The MAOA rs1465108 and BDNF rs6265 polymorphisms were analyzed using the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method. Aggression was evaluated using the Buss-Perry Aggression Questionnaire. Suicide risk, childhood trauma, and impulsivity which were related to aggression were evaluated using the Suicide Probability Scale, the Childhood Trauma Questionnaire, and the Barratt Impulsiveness Scale, respectively. Negative and positive symptoms of schizophrenia were assessed using the Scale for the Assessment of Negative Symptoms (SANS) and the Scale for the Assessment of Positive Symptoms (SAPS), respectively. No direct genotype associations were observed between aggression and the BDNF rs6265 and MAOA rs1465108 polymorphisms. However, impulsivity, SAPS, and SANS scores were significantly associated with aggression. These findings highlight that aggression in schizophrenia is primarily shaped by environmental and clinical factors rather than by BDNF or MAOA variants. Show less

Schizophrenia is a severe mental disorder whose molecular mechanisms remain poorly understood. Investigating brain-derived neurotrophic factor (BDNF)-dependent signaling pathways and their contribution to schizophrenia pathogenesis is a promising research direction in schizophrenia research. BDNF activates multiple intracellular cascades, among which the MAPK/ERK pathway plays a central role. In this study, expression levels of key regulatory proteins of the MAPK/ERK signaling pathway (ERK1/2, STAT3, STAT5, NF-κB, IGF1R, IRS1, IR, TSC2, and CREB1) were examined in lysates of peripheral blood mononuclear cells (PBMCs) from schizophrenia patients using multiplex analysis. The study group included 58 patients diagnosed with schizophrenia (F20); the control group included 60 healthy individuals. The results revealed significantly increased expression of ERK1/2 and STAT3, along with decreased NF-κB levels, in PBMCs from schizophrenia patients compared to controls. Moreover, patients with leading positive symptoms exhibited elevated expression of CREB1 and ERK1/2. These findings suggest that dysregulation of the MAPK/ERK signaling may play a significant role in the pathogenesis schizophrenia. BDNF-dependent signaling pathways may therefore represent promising targets for diagnostics and therapy of this disorder. Show less

Serotonergic psychedelics are re-emerging as therapeutic candidates across psychiatry, particularly for treatment-resistant depression. Their rapid and sustained antidepressant effects, alongside evidence for neuroplastic, dopaminergic, and glutamatergic modulation, have prompted interest in whether they could address depressive and negative symptoms in schizophrenia spectrum disorders (SSDs). This narrative review summarizes mechanistic, preclinical, and early clinical findings relevant to psychedelic use in SSDs. Schizophrenia and major depressive disorder share disturbances in dopamine, glutamate, and neuroplasticity, and both involve large-scale network abnormalities. Schizophrenia is associated with widespread dysconnectivity, mesocortical hypodopaminergia, and striatal hyperdopaminergia linked to NMDA receptor hypofunction. Depression is characterized by fronto-limbic and default mode network hyperconnectivity, mesolimbic hypodopaminergia, and reduced cortical glutamatergic tone. Depressive symptoms within SSDs may reflect an intermediate phenotype combining depressive-like hyperconnectivity with schizophrenia-related global dysconnectivity, suggesting that psychedelics' capacity to transiently increase network flexibility and recalibrate maladaptive connectivity may be clinically relevant. Preclinical studies show increased dendritic spine density, enhanced BDNF expression, restored reward sensitivity, and modulation of network dynamics after psychedelic administration. Clinically, uncontrolled exposure appears associated with increased psychosis-related presentations, whereas limited case reports suggest controlled administration may be tolerated in carefully selected, clinically stable individuals with SSDs. To date, only one early-phase trial (MDMA in schizophrenia) is ongoing, and no randomized trials have evaluated psilocybin or LSD in SSDs. Overall, psychedelics are biologically and mechanistically plausible but remain unproven for depressive and negative symptoms in SSDs, which partially overlap. Carefully designed, safety-focused early-phase studies in clinically stable patients are therefore a prerequisite for broader clinical application. Show less

Facial and Emotional Recognition Systems are technologies that primarily use AI and machine learning to analyze various inputs like facial expression, speech, and physiological signals, to identify and classify human emotions and link them to a variety of epigenomic traits and states. We conducted a Meta-Meta Analysis via Pharmacogenomics (PGx) and Genome-Wide Association Studies (GWAS) across two separate manifestations, including facial physics and emotional expressions. Applying GWAS datasets, 10 GWAS datasets were included, and following multiple filtrations, a GWAS Meta-Meta analysis led to a Secondary Gene List (SGL) of 586 members. Additionally, various indepth silico analyses, such as Protein-Protein Interactions (PPIs), refined 300 genes into a unified network, then, by adding 10 GARS genes, 309 genes remained. A different analysis of PPIs uncovered 141 connected genes (Final Gene List: FGL); more precisely, we conducted a PGx-based approach on this FGL. Finally, 1,480 annotations were found, among them, 682 annotations were significant; thus, we considered the genes with at least one significant annotation and found 54 Pharmacogenes in FGL (PGx-FGL). Through this in-depth analysis, we identified strong, significant top phenotypic roles for both DRD2 and BDNF linking genes in 48,780,906 subjects. Our PGx-based GWAS meta-meta-analyses, coupled with genetic and epigenetic liability testing, connected Facial and Emotional Recognition Systems to Spectrum Disorders (Attention-Deficit Hyperactivity Disorder: ADHD and Autism), Schizophrenia, Depression, and Anxiety. We propose that these findings could have heuristic therapeutic targeting potential and, as such, require intensive further clinical support. Show less

Brain-derived neurotrophic factor (BDNF) is a key regulator of neuroplasticity, synaptic integrity and cognitive function and its dysregulation has been implicated across major psychiatric disorders. However, its transdiagnostic association with cognitive performance remains incompletely understood. In this cross-sectional study, 160 participants were examined, including individuals with schizophrenia (SCZ), bipolar disorder (BD), major depressive disorder (MDD) and healthy controls (HC) (n = 40 per group). Serum BDNF concentrations were measured using enzyme-linked immunosorbent assay (ELISA). Cognitive performance was assessed using the Montreal Cognitive Assessment (MoCA), Trail Making Tests (TMT-A/B) and Digit Span (Forward/Backward). Significant group differences were observed for both serum BDNF levels and cognitive performance. Serum BDNF concentrations were lowest in SCZ (18.2 ± 4.6 ng/mL) and MDD (19.5 ± 5.1 ng/mL), intermediate in BD (23.7 ± 5.9 ng/mL) and highest in HC (26.3 ± 6.2 ng/mL) (F(3156) = 15.47, p < 0.001). Cognitive impairment followed a parallel gradient, with SCZ exhibiting the most severe deficits (p < 0.001). Across the full cohort, serum BDNF showed moderate positive associations with global cognition (MoCA: r = 0.42, p < 0.001) and working memory (Digit Span Backward: r = 0.38, p < 0.001) and a negative association with executive dysfunction as indexed by TMT-B completion time (r = -0.46, p < 0.001). These findings indicate that serum BDNF is modestly but consistently associated with cognitive performance across major psychiatric disorders, supporting its role as a transdiagnostic neurobiological correlate of impaired neuroplasticity rather than a disorder-specific or deterministic biomarker. Show less

Disruption of metabolic interactions between astrocytes and neurons, in particular of the lactate shuttle, may contribute to neurodevelopmental and psychiatric disorders such as autism spectrum disorder (ASD) and schizophrenia. The enzyme glycine decarboxylase (GLDC), predominantly expressed in astrocytes, degrades glycine and plays a critical role in regulating NMDA receptor function and cellular metabolism. Here, we investigated whether administration of lactate would reverse schizophrenia-like phenotypes in a mouse model for psychosis with 4 copies of the Gldc gene (4cG mice). Adult male and female 4cG and wildtype mice were subjected to acute L-lactate intraperitoneal administration one hour before behavioral testing and brain collection for biochemical assays. Y-maze spontaneous alternation test, prepulse inhibition of acoustic startle test, and the three-chamber social interaction test were performed for behavioral analysis, and Western blots for protein estimations. In 4cG mice, acute lactate administration one hour before assessment rescued short-term memory deficits, acoustic startle habituation deficits, and normalized deficits in social preference behavior. Furthermore, lactate treatment restored the expression of PGC1α, a master regulator of mitochondrial biogenesis, and brain-derived neurotrophic factor (BDNF), a protein essential for synaptic plasticity. The results suggest a role for astrocytic metabolism in modulating neuronal function, and potential molecular mechanisms underlying the reversal of behavioral phenotypes. The results indicate that exogenous lactate may reverse key pathophysiological and behavioral deficits in a mouse model for schizophrenia and that lactate supplementation may be useful as a therapeutic strategy for schizophrenia and related disorders. Show less

Cognitive impairment in schizophrenia (SCZ) is associated with neuroinflammation and neurotrophic dysregulation. The role of pro-inflammatory interleukins and brain-derived neurotrophic factor (BDNF) in cognitive deficits remains unclear. We aimed to examine the associations between IL-1β, IL-2, IL-6, BDNF, and cognitive function in patients with SCZ with typical or atypical antipsychotics. Participants included 162 healthy controls (mean age = 33.6 ± 2.0 years), 88 patients with SCZ receiving typical antipsychotics (36.4 ± 6.4 years), and 62 receiving atypical antipsychotics (34.0 ± 4.0 years). Cognitive performance was evaluated using a battery of attentional, executive, and visuospatial working memory tasks. Data were analyzed using machine-learning approaches, multivariate statistics, and structural equation modeling. SCZ Patients exhibited marked cognitive impairments alongside lower BDNF concentrations and elevated interleukin levels, with the greatest deviations observed among those receiving typical antipsychotic treatment. Higher medication dosages and longer illness duration were associated with greater cognitive decline and stronger neuroimmune dysregulation. The findings indicate that elevated cytokines and reduced neurotrophic support may contribute to cognitive impairment, whereas persistent cognitive dysfunction can further amplify inflammatory activity. This complexity suggests the need to broaden current assessment approaches and systematically examine biomarkers together with clinical features. Show less

Maternal immune activation (MIA) is a key environmental risk factor for neurodevelopmental disorders such as schizophrenia. MicroRNAs are critical regulators of brain development, yet their role in MIA-induced pathology remains unclear. We found that miR-322-5p was significantly upregulated in the prefrontal cortex of MIA-exposed offspring and directly targeted the 3' untranslated region of brain-derived neurotrophic factor (BDNF), inhibiting its expression. This upregulation impaired BDNF/TrkB/AKT signaling and reduced the synaptic protein PSD95, leading to hypoactivity, cognitive deficits, social impairments, and disrupted sensorimotor gating. Inhibition of miR-322-5p or overexpression of BDNF in the prefrontal cortex restored signaling and reversed both behavioral and molecular abnormalities. These results identify miR-322-5p as a key mediator of MIA-induced neuropathology via repression of BDNF signaling and suggest its potential as a therapeutic target in neurodevelopmental disorders. Show less

Individuals with schizophrenia spectrum disorders experience impairments across multiple domains, including cognition, quality of life, and social functioning. Structured exercise interventions may improve these outcomes. We hypothesised that aerobic and combined (aerobic plus resistance) exercise programs would enhance cognitive function, reduce symptom severity, and improve well-being. A PRISMA-guided search of PubMed, EMBASE, PsycINFO, Web of Science, SciELO, and ClinicalTrials.gov (2009-2024) identified 17 randomized controlled trials. Standardized mean differences (SMDs) were pooled using a random-effects model. Subgroup analyses examined age and gender. Risk of bias was assessed using RoB 2, publication bias with Egger's test, and certainty of evidence through GRADE. Structured exercise produced a moderate-to-large improvement in overall well-being (SMD = 0.68; 95% CI: 0.43-0.93; p < .001). Significant benefits were also observed in cognition (SMD = 0.59), symptom severity (SMD = 0.71), quality of life (SMD = 0.60), and social functioning (SMD = 0.55). Age and gender moderated treatment effects, with the strongest benefits in males and individuals aged 36-45. Sensitivity analyses confirmed the robustness of results. Mechanistic evidence suggests that improvements may be mediated through increased brain-derived neurotrophic factor (BDNF) and reduced inflammatory signaling. Structured exercise is an effective adjunctive intervention for schizophrenia spectrum disorders, improving psychiatric and functional outcomes beyond standard care. Findings support the integration of personalized, scalable exercise programs within routine psychiatric treatment. Show less