Search Results (358)

Background: Immune mechanisms are increasingly implicated in the heterogeneity of schizophrenia spectrum disorders. Cytomegalovirus (CMV), a latent immunomodulatory herpesvirus, is linked to cognitive and immunological alterations, but its electrophysiological correlates remain largely unexplored. This study investigates the relationships among CMV serostatus, EEG features, inflammatory markers, and clinical–cognitive variables. Methods: In this prospective cross-sectional study, 123 patients with schizophrenia spectrum disorders underwent integrated clinical, cognitive, laboratory, and qualitative visual EEG assessments. CMV exposure was determined via IgG serology. Results: Global electroencephalographic EEG organization did not differ by CMV serostatus. However, a descriptive increase in resting-state sharp-wave discharges was observed in CMV-seronegative patients, independent of baseline cortical rhythms. Immunologically, CMV-seropositive individuals exhibited significantly higher total leukocyte counts, consistent with latent viral immune remodeling rather than overt systemic inflammation. Clinically, CMV-seropositive patients demonstrated descriptively higher scores on the disorganization dimension derived from the PANSS (Positive and Negative Syndrome Scale) five-factor consensus model. While these variations did not retain statistical significance after multiple testing correction, separate dimensional analyses revealed that patients exhibiting sharp waves demonstrated better overall cognitive functioning and superior performance within a memory-related item grouping. Notably, the presence of sharp-wave activity was independent of both peripheral inflammatory profiles and treatment-resistant status, underscoring a distinct electrophysiological phenotype. Conclusions: CMV exposure represents a modulating biological background associated with corrected leukocyte elevations and subtle electrophysiological variability, rather than a direct determinant of global clinical severity. The nominal EEG variations and their independent link to better-preserved memory performance highlight non-linear neuroimmune interactions. Given the cross-sectional design, these exploratory patterns warrant a non-causal interpretation but outline a foundation for future longitudinal investigations. Full article

Copy number variants (CNVs) are genomic rearrangements that carry a substantial risk for neurodevelopmental and neuropsychiatric disorders. Among these, recurrent deletions and duplications at the 16p11.2 locus are robustly associated with autism spectrum disorders, schizophrenia, epilepsy, and related conditions, yet also display marked variability in penetrance and phenotypic expression. Accumulating evidence indicates that 16p11.2 gene dosage influences multiple stages of brain development, from early progenitor dynamics and neuronal migration to synaptic formation, refinement, and plasticity. However, how disruptions across these processes are integrated over time, and how they relate to the observed variability and incomplete penetrance, remains poorly understood. In this review, we summarize the current evidence on the impact of 16p11.2 CNVs on brain development, focusing on cellular and circuit-level processes that shape neural connectivity. We discuss how gene dosage imbalance influences early developmental trajectories, synaptic formation and pruning, interneuron maturation, and activity-dependent plasticity, and consider how these processes interact across developmental stages. We suggest a conceptual framework wherein 16p11.2 CNVs do not impose fixed pathogenic outcomes, but rather they contribute towards developmental constraints that shape the timing and stability of neural circuit development. Consequently, these constraints increase vulnerability to neurodevelopmental and psychiatric outcomes in a context-dependent manner. Full article

Background/Objectives: Autistic traits are distributed dimensionally across psychiatric populations, yet their systematic assessment in mood and psychotic spectrum disorders remains limited. While elevated autistic traits have been documented in schizophrenia spectrum disorders, evidence in bipolar disorder (BD) and major depressive disorder (MDD) is scarce, and no studies have applied the clinician-rated PANSS Autism Severity Score (PAUSS) to mood disorder populations. This study aims to investigate the presence and severity of autistic traits across psychotic spectrum disorder (PSD), BD, and MDD in an outpatient sample using the PAUSS. Methods: In this cross-sectional naturalistic outpatient study, clinically stable adult patients with MDD, BD, or PSD, without autism spectrum disorder, were assessed with the Brief Psychiatric Rating Scale (BPRS) and PAUSS. Group comparisons, adjusted models, correlation analyses, principal component analysis, and multinomial logistic regression were performed. Results: A total of 165 patients were included (MDD, n = 84, BD, n = 45, PSD, n = 36). Compared with the mood disorder groups, PSD patients were younger and showed higher BPRS scores. PSD was also characterized by significantly higher PAUSS total, social, and communication scores, whereas PAUSS RRB did not differ in univariate analyses. In the overall sample, BPRS severity correlated positively with all PAUSS dimensions, while age showed only weak or non-significant associations. Diagnosis-stratified analyses revealed that the association between psychopathology and autistic traits was present in MDD and BD, but not in PSD. PCA showed that autistic trait dimensions converged on a broad common profile and differed across diagnostic groups, with PSD showing the most distinct pattern. In multinomial logistic regression, higher BPRS, higher PAUSS social and communication scores, and younger age independently distinguished PSD from MDD and BD; PAUSS RRB showed an inverse association only in the multivariable model. Conclusions: This study supports a transdiagnostic perspective on autistic traits in adult psychiatric populations, highlighting disorder-specific differences across diagnostic categories. Social and communication impairments emerged as key dimensions distinguishing PSD from mood disorders. Assessing autistic traits in psychiatric settings may improve diagnostic precision and inform personalized, stratified treatment approaches. Full article

Background/Objectives: Vitamin D is a nutrient-related secosteroid system with endocrine, paracrine, immunological, and neurodevelopmental actions relevant to nutritional psychiatry. Psychiatric research has often treated vitamin D either as a cross-sectional correlate of depression or as a non-specific supplement expected to act across heterogeneous diagnostic categories. This narrative review aimed to develop a more discriminating framework in which vitamin D is considered a lifespan neuroimmune and immunometabolic signal whose psychiatric relevance depends on developmental timing, biological context, and phenotype. Methods: Evidence was integrated from developmental epidemiology, neonatal dried-blood-spot studies, randomized trials, meta-analyses, Mendelian randomization studies, clinical guidelines, and mechanistic neuroscience. The review focuses on prenatal and neonatal 25-hydroxyvitamin D, vitamin D-binding protein, free and bioavailable vitamin D, vitamin D receptor signaling, immune and microglial pathways, neurotransmitter systems, neurotrophic signaling, mitochondrial function, oxidative stress, hypothalamic–pituitary–adrenal-axis regulation, and the gut–microbiota–immune–brain axis. Results: The available evidence does not support vitamin D as a universal treatment for psychiatric disorders. Instead, vitamin D deficiency and altered vitamin D biology appear most relevant in biologically and clinically defined risk states, including neurodevelopmental vulnerability, inflammatory depression, psychosis liability, severe mental illness with nutritional deprivation, metabolic comorbidity, and cognitive frailty. Mechanistic data support plausible links with cytokine biology, the tryptophan–kynurenine pathway, dopaminergic and serotonergic systems, stress regulation, and neuroimmune homeostasis. Conclusions: Vitamin D should be conceptualized in psychiatry as a context-dependent neuroimmune and immunometabolic signal rather than a generic psychotropic intervention. Future studies should prioritize biomarker-enriched, developmentally timed, nutrition-centered models of precision prevention and adjunctive care. Full article

Introduction: Schizophrenia is characterised by distributed abnormalities in electrophysiological dynamics and large-scale brain networks, yet unimodal EEG or MRI alone cannot fully explain how fast neural computations relate to spatially organised circuit dysfunction. Multimodal EEG–MRI approaches offer a bridge across temporal and anatomical scales by explicitly modelling cross-modal coupling. Methods: Following PRISMA 2020 guidance, we conducted a systematic, mechanistic review of human studies (adults ≥ 18 years) comparing schizophrenia-spectrum groups with healthy controls using EEG combined with at least one MRI modality (fMRI, structural MRI, and/or diffusion MRI) and explicit EEG–MRI integration (e.g., EEG-informed fMRI, joint ICA, mCCA/MCCA, coupled matrix–tensor factorisation, DCM-based fusion). Searches were performed in PubMed/MEDLINE, Embase, Web of Science, Scopus, PsycINFO, IEEE Xplore, ResearchGate, and Google Scholar for January 2000–December 2025, supplemented by citation tracking. Risk of bias was assessed with ROBINS-I, and due to heterogeneity, results were synthesised narratively by integration of families. Results: From 148 records, 23 studies met the inclusion criteria. Studies used mainly simultaneous EEG–fMRI at 3T and spanned resting-state designs and task paradigms dominated by auditory processing (oddball, MMN/N100–P200, ASSR/aeGBR), with additional work in affective context, working memory, semantic processing (N400), sensory gating, and pharmacologic challenge. Across tasks, the most reproducible multimodal signature was disrupted coupling between electrophysiological markers and the recruitment of large-scale networks, rather than isolated changes in EEG or fMRI metrics. Target detection/oddball paradigms converged on reduced late ERP responses (especially P300, sometimes N2) alongside reduced expression or loss of coupling to salience/ventral attention and control circuitry (including ACC/anterior insula/TPJ). Resting-state studies most consistently indicated altered “coupling rules” (frequency specificity, timing/lag structure, and directionality), including abnormalities detectable even when unimodal summaries were weak. Extended multimodal studies (adding sMRI/DTI and/or classification) suggested that combining modalities can improve discrimination, though performance was sensitive to sample size, demographic imbalance, and feature-selection/validation choices. Conclusions: Multimodal EEG–MRI studies support schizophrenia as a disorder involving persistent structural and circuit-level abnormalities whose functional expression varies dynamically across cognitive states and task demands. Future progress will depend on harmonised acquisition/artefact-control practices for simultaneous EEG–fMRI, larger and more diverse samples (including early/CHR and longitudinal designs), and cross-site replication of mechanistically interpretable coupling biomarkers. Full article

Background/Objectives: Psychotic relapse affects over 80% of individuals with schizophrenia-spectrum disorders, driving long-term disability and hospitalization. Clinical relapse management relies on symptomatic monitoring without objective neurobiological tools to guide individualized antipsychotic decisions. Methods: This systematic review synthesizes evidence on neurophysiological, blood-based, molecular, neuroimaging, and digital biomarkers for relapse prediction in schizophrenia-spectrum disorders. Results: Following the PRISMA 2020 guidelines, five databases were searched through March 2026 for longitudinal biomarker studies. Quality was assessed using the Newcastle-Ottawa Scale and PROBAST; findings were synthesized narratively due to substantial heterogeneity. From the 6812 citations screened, 21 studies were included across clinical high-risk, first-episode, and established illness populations. Conclusions: Mismatch negativity and P300 event-related potential (P300) showed the most consistent associations with relapse vulnerability, with mismatch negativity demonstrating relative independence from antipsychotic effects. Inflammatory and neuroendocrine markers—interleukin-6, C-reactive protein, and cortisol awakening response—predicted poor treatment response in multiple longitudinal investigations. Peripheral blood gene expression profiling identified TCF4 network dysregulation as a candidate molecular marker of impending relapse. Neuroimaging models did not outperform standard clinical variables. Digital phenotyping showed ecological promise but remains methodologically nascent. No single biomarker achieves sufficient accuracy for clinical implementation. Neurophysiological and inflammatory markers are the most tractable candidates for monitoring protocols. Future research should prioritize multimodal longitudinal designs, external validation, and systematic antipsychotic confounding control. Among the biomarkers reviewed, mismatch negativity and the interleukin-6/cortisol awakening response combination represent the most tractable candidates for pilot clinical implementation, particularly in specialized early psychosis services and antipsychotic dose-reduction research contexts; no biomarker currently achieves sufficient accuracy for routine use in maintenance treatment decisions. Full article

Complex psychosis is a clinically relevant rehabilitation construct rather than a formal diagnostic category and refers to psychotic illness associated with treatment-resistant symptoms, functional impairment, and additional cognitive, psychiatric, neurodevelopmental, or physical health complexity. In this clinician-oriented narrative review, we synthesised current evidence on rehabilitation interventions for adults with complex psychosis, integrating direct evidence from specialist rehabilitation settings with indirect evidence from schizophrenia-spectrum studies when clinically informative. We searched major clinical databases, prioritised guidelines, systematic reviews, meta-analyses, and controlled studies, and organised the synthesis by functional domain and pathway relevance. Evidence was strongest for cognitive remediation, particularly when combined with broader psychiatric rehabilitation or vocational support, for family interventions in relapse prevention, and for individual placement and support in competitive employment. Social–cognitive and metacognitive interventions appear clinically valuable, although transfer to real-world functioning is more variable. Community-based rehabilitation, supported accommodation, illness self-management, and ecological adaptation strategies remain central to functional recovery when embedded within multidisciplinary pathways. Digital and virtual interventions are promising adjuncts, but their efficacy remains heterogeneous and implementation challenges include engagement, privacy, and service integration. Overall, rehabilitation in complex psychosis is most convincing when it is personalised, measurement-based, and delivered through integrated service models linking assessment, intervention selection, supported living, and recovery-oriented care. Full article

Background: Sexual dysfunction is a frequent adverse effect of antipsychotic treatment and a major contributor to poor adherence and reduced quality of life. Evidence regarding the impact of switching to prolactin-sparing antipsychotics in routine clinical practice remains limited. This study evaluated changes in sexual function following initiation or switch to cariprazine in real-world patients with schizophrenia spectrum disorders. Methods: In this prospective observational study, adult outpatients were either initiated on cariprazine de novo (Group A) or switched from a previous antipsychotic due to clinically significant sexual dysfunction (Group B). Sexual function was assessed using the Psychotropic-Related Sexual Dysfunction Questionnaire (SALSEX) at baseline and Month 3. Secondary measures included serum prolactin levels and Brief Psychiatric Rating Scale (BPRS) an CGI scores. Effect sizes were calculated using Cohen’s d. Results: Forty-two patients were included (Group A: n = 14; Group B: n = 28). In Group B, mean SALSEX total scores significantly decreased from 8.04 ± 2.76 to 2.41 ± 2.06 (Δ = −5.63; p < 0.001; d = 2.27). Prolactin levels also significantly decreased after switching (p = 0.012). In Group A, SALSEX scores showed a statistically significant but clinically modest reduction (2.79 ± 2.01 to 1.23 ± 1.24; p = 0.023; d = 0.93), with no evidence of treatment-emergent sexual dysfunction. Improvements in sexual function were not associated with changes either in BPRS or CGI scores, baseline symptom severity, sex, or testosterone levels. Conclusions: Switching to cariprazine in patients with antipsychotic-related sexual dysfunction was associated with large and clinically meaningful improvement in sexual function in routine practice. The effect appeared independent of overall symptom improvement and endocrine normalization thresholds, supporting the clinical value of prolactin-sparing switching strategies. Full article

Background: Cognitive and psychiatric disorders are caused by a complex interplay between genetic predisposition, environmental exposures, and dynamic molecular regulation in the brain. Animal models provide a controlled environment for examining these mechanisms, and advances in transcriptome and epigenomic technologies have greatly expanded our knowledge of disease-relevant pathways. Objective: This scoping review systematically maps and synthesizes the epigenetic and transcriptomic findings from the established animal models of four neuropsychiatric conditions—autism spectrum disorder (ASD), schizophrenia, depression, and Rett syndrome—drawing on a PRISMA-ScR-guided literature search. The review characterizes the breadth of evidence, identifies convergent and divergent molecular pathways, and highlights the translational gaps and therapeutic implications. Methods: Research employing chromatin accessibility testing, genome-wide DNA methylation mapping, single-cell and bulk RNA sequencing, histone modification profiling, and multi-omics integration in mouse and other validated animal models was thoroughly reviewed. A quality appraisal of the primary experimental studies (n = 63) was performed using a modified CAMARADES checklist. Results: Beyond generalized cellular stress responses, multi-omics analysis emphasizes the cell-type- and context-dependent nature of epigenetic changes in animal models, including isoform-specific histone modifications and model-dependent binding of HDAC/MeCP2 complexes to genes involved in synaptic plasticity. Single-cell RNA sequencing analyses have uniformly shown transcriptional changes in parvalbumin-positive (PV+) interneurons. Conclusions: The specific convergence of epigenetic disruptions in neural circuits involved in synaptic structure and inhibitory function could play a role in the generation of neuropsychiatric phenotypes in animal models, highlighting the importance of circuit- and cell-type-specific epigenetics while pointing to potential therapeutic avenues. Full article

Schizophrenia spectrum disorders (SSD) are severe psychiatric conditions characterized by disturbances in cognition, emotion, and behavior, with increasing evidence suggesting an involvement of the gut microbiome in their pathophysiology. This PRISMA-informed structured review synthesizes 114 studies using a taxa-centered framework that maps microbial changes across SSD stages and phenotypes and serves as a structural basis for identifying cross-study patterns. Across heterogeneous cohorts, convergent alterations include depletion of short-chain fatty acid (SCFA)-producing taxa (including Faecalibacterium, Roseburia, and Coprococcus) and enrichment of potentially pro-inflammatory and fermentative taxa (such as Proteobacteria, Enterobacteriaceae, Streptococcus, Collinsella, and Desulfovibrio). These taxonomic patterns suggest potential functional alterations, including reduced SCFA availability. Reduced abundance of butyrate-producing taxa has been associated with impaired intestinal barrier function and increased microbial translocation (e.g., lipopolysaccharide), which may contribute to the activation of immune pathways, including Toll-like receptor 4 signaling and elevated inflammatory markers such as IL-6 and TNF-α. Additional alterations reported across studies include changes in lactate metabolism, bile acid profiles, aromatic amino acid metabolism, and the tryptophan-kynurenine pathway. These pathways may interact with neurobiological processes relevant to SSD, including glutamate-GABA balance, NMDA receptor function, microglial activation, and synaptic regulation, although much of the current evidence remains associative. Multi-kingdom studies and fecal microbiota transplantation models provide further support for the functional relevance of these observations, though causal relationships remain to be fully established. Overall, SSD-associated dysbiosis appears to reflect ecosystem-level metabolic alterations rather than isolated taxonomic abnormalities, supporting a Microbiota–Gut–Immune–Glia conceptual framework and highlighting the gut ecosystem as a potential therapeutic target. Full article

Preliminary evidence has indicated that attachment style may be an important variable that can influence emotion regulation among individuals with experiences of psychosis. Yet there is a dearth of therapeutic approaches examined that address both constructs. More integrative approaches, such as Metacognitive Reflection and Insight Therapy (MERIT), may be well suited to address these concerns given its integrative approach to increasing insight. To explore this, this article presents a case report of an individual diagnosed with schizoaffective disorder who completed 24 sessions of MERIT. This individual presented with constricted affect and limited ability to access emotional content. Emotion regulation was measured before, during, and after treatment, while attachment security to the therapist was measured during and after treatment. Reliable change index (RCI) analyses of the individual’s scores revealed significant changes in domains of subjective emotion regulation abilities and attachment security to the therapist. A qualitative analysis of session transcripts is presented as well. Treatment was found to be feasible and acceptable to the client, and improvements were noted in the areas of emotion regulation and attachment security to the therapist. Clinical implications and limitations are also discussed. Full article

The regulation of chloride levels is a crucial part of controlling inhibitory signals, but does not occur uniformly throughout the body. Recent data suggest that chloride is regulated within localized “microdomains” which are defined by the interaction of KCC2 and NKCC1, structural restraints on cells due to their internal structure, the metabolic condition of the cell, and the external environment modified by astrocytes. The gradients of chloride concentrations within these compartment-specific microdomains define the local chloride reversal potential, and thereby determine the directionality (i.e., whether excitatory or inhibitory), magnitude, and timing of GABAergic inhibition. The disruption of this organized chloride gradient within microdomains impairs the stability of inhibitory activity at multiple levels of integration, including dendritic input, spike timing, interneuron synchronization, and network oscillation. Disturbances in inhibitory stability have been found in a variety of diseases, including epilepsy, neonatal seizure, neuropathic pain, and schizophrenia-spectrum disorders. This supports the hypothesis that disturbances in chloride homeostasis lead to a loss of stability in cortical circuits. This review will provide a synthesis of the molecular, spatial, and circuit level principles involved in the regulation of chloride and discuss how failures of these mechanisms produce clinically relevant disturbances in inhibitory signal processing. In addition, we will be discussing new therapeutic strategies for the restoration of chloride homeostasis, including KCC2 repair, selective modulation of NKCC1, targeting astrocytes, and microenvironmental engineering. Overall, the studies reviewed here provide a unified model for understanding the pathophysiology of inhibitory dysfunction, and demonstrate that the regulation of chloride microdomains provides a novel and promising area of research for translational intervention. Full article

Inflammasomes are cytosolic multiprotein complexes that detect pathogens, cellular stress, and damage-associated molecular signals, thereby orchestrating innate immune responses. Increasing evidence suggests that dysregulated inflammasome activation contributes to persistent neuroinflammation and to a wide range of neuropsychiatric disorders, including mood disorders, schizophrenia, Alzheimer’s disease, and autism spectrum disorders. Together, these findings emphasize the critical role of neuroimmune interactions in the pathophysiology of mental disorders. Recent molecular studies have substantially advanced our understanding of the crosstalk among neurons, microglia, astrocytes, and peripheral immune cells, uncovering complex regulatory networks mediated by cytokines, neurotrophins, and neurotransmitters. By examining key inflammatory mediators and cell type-specific mechanisms, this review consolidates current knowledge and proposes conceptual frameworks to guide future investigations and facilitate the development of targeted therapeutic strategies for neuropsychiatric disorders. Full article

Elucidating the pathophysiological mechanisms of mental disorders remains a critical challenge in psychiatric research. Recent studies have highlighted the potential involvement of cytoskeletal and molecular motor abnormalities in the development of mental disorders such as schizophrenia and autism spectrum disorder (ASD). Although schizophrenia and ASD differ clinically, both disorders are increasingly regarded as neurodevelopmental conditions and share vulnerabilities in synapse formation and neural circuit maturation. This review synthesizes the latest findings on the relationship between cytoskeletal and molecular motor abnormalities and mental disorders. The cytoskeleton, composed of microtubules, actin filaments, and intermediate filaments, along with molecular motors such as kinesins, dyneins, and myosins, plays crucial roles in neurodevelopment, synapse formation, and neurotransmission. In schizophrenia, decreased expression of the microtubule-associated protein MAP2 and abnormalities in the DISC1 gene have been reported, potentially leading to dendritic morphological abnormalities and neurodevelopmental disorders. Additionally, abnormalities in molecular motors such as KIF17 and KIF1A have been implicated in schizophrenia pathophysiology. Myosin Id has been identified as a risk gene for ASD. Furthermore, abnormalities in actin-related proteins such as SHANK3 and CYFIP1 have been shown to cause synaptic dysfunction. These findings suggest that mental disorders arise from complex pathologies involving multiple cytoskeletal and molecular motor-related protein abnormalities. Future research should focus on elucidating the functions of individual proteins and adopting a comprehensive approach that includes glial cells. Advances in this field may deepen our understanding of the pathophysiological mechanisms of mental disorders and potentially lead to the development of novel therapeutic strategies. Full article

Background: Dual disorders (DDs) describe the coexistence of substance use disorder (SUD) and another mental health condition, commonly within psychotic and affective categories. These conditions represent a significant challenge in clinical management due to their bidirectional interactions and complexity. This study aims to evaluate the efficacy and safety of quetiapine, a second-generation antipsychotic, in patients with schizophrenia spectrum disorders and comorbid substance use disorders. Methods: A total of 28 participants with schizophrenia spectrum disorder and comorbid SUD underwent psychometric evaluations at baseline (T0), one month (T1) and three months post-initiation of quetiapine treatment (T2), administered at a mean dosage of 165 mg/day. Key outcome measures included psychopathological burden (PANSS), aggressivity (MOAS), substance craving (VAS Craving), and quality of life (Q-LES-Q-SF scales). Results: Quetiapine demonstrated significant reductions in psychopathological symptoms, with decreased PANSS total scores (p < 0.001). Positive symptoms (p < 0.001), negative symptoms (p = 0.002), substance craving (p = 0.001), and aggressivity (p = 0.006) also showed notable reductions. Quality of life significantly improved across Q-LES-Q-SF scores (p < 0.001). Quetiapine was well-tolerated, with no dropouts related to drug-induced side effects. Conclusions: This study provides preliminary evidence supporting the efficacy and safety of quetiapine in individuals with dual disorders. Improvements in psychopathology, substance craving, and quality of life underscore the importance of integrating tailored and comprehensive treatment strategies to address the multifaceted challenges of this challenging population. Full article