Search Results (376)

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

Background: Schizophrenia spectrum disorders (SSD) affect females differently than males, yet there is limited research on Physical Activity (PA) levels and sex differences in patients with SSD. This study aimed at comparing PA levels between female and male SSD patients and controls. Methods: Altogether, 132 SSD residents and outpatients (48 females and 84 males) and 113 controls (46 females and 67 males) were assessed using standardised clinical tools. PA was monitored for seven consecutive days using a tri-axial ActiGraph GT9X accelerometer and quantified using the Euclidean Norm Minus One (ENMO) as an index of overall movement intensity. Descriptive and regression analyses were conducted. Results: Most patients were unemployed and overweight; males were less educated, less often divorced, smoking more, and using more antipsychotics than females (p < 0.05). Patients were less likely to be married, educated, employed, and had higher BMI and smoking rates than controls. Among patients, there were no significant sex differences in daily PA levels. In the control group, males showed slightly higher PA levels than females, although this difference did not reach statistical significance. Objective PA levels were not significantly associated with clinical outcomes in either female or male patients with SSD. Conclusions: Patients with SSD exhibited similarly low levels of objectively measured PA regardless of sex, suggesting a “flattening” phenomenon of sex differences in PA. These findings highlight the need for interventions aimed at promoting PA in individuals with SSD and support further research to identify factors influencing PA engagement across sexes. Full article

Background/Objectives: Avoidant/restrictive food intake disorder (ARFID) and psychotic disorders are clinically distinct conditions yet occasionally co-occur in ways that complicate assessment and treatment. ARFID is characterised by avoidance of food due to sensory sensitivities, fear of aversive consequences, or low interest in eating, without body-image distortion. Recent meta-analytic evidence suggests that ARFID affects a substantial proportion of the population and is associated with a considerable social burden. Psychosis is characterised by positive symptoms (hallucinations and delusions), negative symptoms (avolition, blunted affect, and social withdrawal), and cognitive impairments affecting thought, perception, and behaviour. Methods: Across the limited literature, shared mechanisms between ARFID and psychotic disorders appear to converge on pathological avoidance, which may arise from sensory overstimulation, obsessive–compulsive features, or delusional beliefs about food. Case reports indicate that psychosis may both mimic ARFID and exacerbate food avoidance, while severe malnutrition can itself precipitate or worsen psychotic symptoms, blurring diagnostic boundaries. Results: Abnormalities in interoception, sensory sensitivity, and disrupted perception of bodily signals are manifestations of both ARFID and psychosis, suggesting a potential bridging pathway contributing to vulnerability and clinical overlap. Conclusions: Given the paucity of empirical studies and the reliance on isolated case reports, systematic investigation is mandatory and necessary to clarify shared mechanisms, refine differential diagnosis, and guide integrated treatment approaches. Given the heterogeneity of symptoms in comorbid patients, a personalised approach is suggested for treating these patients. Full article

Neurocognitive and metacognitive impairments are well-documented in schizophrenia spectrum disorders (SSDs). However, the relationship between these two domains remains underexplored, despite increasing interest in their combined impact on recovery and functional outcomes. Neurocognition refers to processes such as attention, memory, and executive functioning, and the neural systems that support these processes, both of which are frequently abnormal in SSDs and contribute to significant functional difficulties. Metacognition, in contrast, refers to the capacity to reflect on and integrate thoughts, emotions, and experiences into a coherent understanding of oneself and others. Although both domains are often studied in isolation, emerging evidence suggests a potential interdependence between neurocognition and metacognition, particularly regarding their influence on outcome. This scoping review explores empirical studies examining associations between neurocognition and metacognition in individuals with SSDs, specifically in the context of functional outcomes. We aim to clarify how these domains interact and explore their combined implications for recovery-oriented interventions and clinical practice. Findings may inform more integrated models of cognition and guide the development of dual-targeted treatment approaches to improve functional recovery in SSDs. Full article

Tryptophan (TRP) is a proteinogenic and nutritionally essential amino acid involved in the formation of numerous bioactive substances. A crucial role in the TRP molecule is played by indole, a bicyclic ring formed by benzene and pyrrole, which confers hydrophobic and antioxidant properties and the ability to act as a ligand for aryl hydrocarbon and pregnane X receptors. The first parts of the article examine sources, nutritional requirements, and three pathways of TRP catabolism. Physiologically, ~5% of dietary TRP is catabolized through the pathway forming serotonin and melatonin in the brain and enterochromaffin cells of the gut, ~85% through the pathway resulting in the formation of nicotinamide nucleotides and kynurenine and its derivatives in the liver and immune cells, and ~10% in gut microbiota to indole derivatives. Alterations of individual TRP catabolism pathways in aging, alcoholism, inflammatory bowel disease, metabolic syndrome, renal insufficiency, liver cirrhosis, cancer, and nervous diseases, e.g., depression, Alzheimer’s and Parkinson’s diseases, multiple sclerosis, and schizophrenia, are examined in the central section. The final sections are devoted to the benefits and adverse effects of TRP supplementation, the therapeutic use of various TRP metabolites, and the pharmacological targeting of enzymes, transporters, and receptors involved in TRP catabolism. It is concluded that all pathways of TRP catabolism are altered across a broad spectrum of human illnesses, and further investigation is needed to understand their role in disease pathogenesis better. The goal for clinical research is to explore options for TRP-targeted therapies and their integration into new therapeutic strategies. Full article

Background/Objectives: In recent years, MRI-based diffusion-weighted tractography techniques have uncovered additional white matter pathways that have significant roles in language processing and production. In this review, we aim to outline the major language centers of the brain and major language pathways along with association tracts that serve dual roles in both the language and limbic systems. According to the current dual-stream model of language processing, the brain’s language network is organized into a dorsal stream, responsible for mapping sound to articulation, and a ventral stream, which maps sound to meaning. Materials and Methods: The literature cited in this manuscript was identified through targeted searches of the PubMed database. Priority was given to peer-reviewed human studies, including original neuroimaging, cadaveric validation, and intraoperative stimulation studies. Non-peer-reviewed sources and publications lacking clear anatomical or functional correlation to language pathways were excluded. Results: Advances in functional MRI and diffusion weighted imaging techniques have revealed a more interconnected network, expanding our understanding beyond the classical dual-stream model of language processing. The Kamali limbic model proposed distinct ventral and dorsal limbic networks. Notably, several fiber pathways within the ventral limbic network may subserve both language and limbic functions. The association tracts with dual limbic-language functions form a critical basis for understanding the pathophysiology of language disorders accompanied by cognitive and emotional comorbidities observed in dyslexia, speech apraxia, aphasia, autism spectrum disorder, schizophrenia and post-traumatic stress disorder. Conclusions: Visualizing the language center and interconnected dual language and limbic fiber tracts highlights the importance of integrating language, executive function, and emotion in developing disease models and designing effective, targeted treatments for patients. Full article