Search Results (140)

Introduction: Growing evidence indicates that diet quality significantly influences metabolic parameters and cognitive functioning. In healthy individuals, higher consumption of minimally processed foods and products rich in omega-3 fatty acids is associated with a more favorable lipid profile and better cognitive performance. Patients with schizophrenia present an increased risk of metabolic disturbances and reduced cognitive functioning. This suggests that this group may be particularly sensitive to nutritional factors. However, relatively few studies have simultaneously examined the relationships between diet, metabolism, and cognitive profile in patients with schizophrenia and healthy individuals. Aim: The aim of the study was to compare the relationships between the frequency of consumption of selected food categories and metabolic parameters (glycemia, lipid profile, and insulin resistance), as well as cognitive functions (Stroop Test, Trail Making Test, and verbal fluency), in patients with schizophrenia and healthy men. Methods: The study included 21 patients with schizophrenia and 20 healthy men. All participants completed a questionnaire assessing the frequency of food consumption. Blood samples were collected to determine glucose, insulin, HDL, LDL, and triglyceride levels, and the HOMA-IR index was calculated. Cognitive functioning was assessed using the Stroop Test (RCNb, NCWd) and the Trail Making Test (TMT-A and TMT-B), which measure psychomotor speed and visuospatial working memory, respectively, and the verbal fluency test (semantic and phonological). Correlation analyses were performed separately in both groups. Due to the small sample size, all correlations are treated as exploratory and are analyzed with correction for multiple comparisons. Results: Exploratory analyses identified several patterns of associations between the frequency of consumption of selected food categories, metabolic parameters, and cognitive performance in both healthy men and patients with schizophrenia. The observed patterns differed between groups, suggesting that clinical status and treatment-related factors may modify diet–metabolism–cognition relationships. These findings highlight potential pathways linking dietary habits with metabolic and cognitive outcomes and provide a basis for further hypothesis-driven research. Conclusions: Diet quality may be related to metabolic status and cognitive functioning. However, the pattern of these associations differs between patients with schizophrenia and healthy individuals. The findings suggest that diet may play a role in metabolic health and cognitive functioning, particularly in clinical populations. 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

Treatment-resistant schizophrenia (TRS) remains a significant clinical challenge due to limited therapeutic options and a poor understanding of its underlying biology. Recent findings suggest that immune system dysregulation may play a critical role in the pathophysiology of TRS. This systematic review aimed to synthesize current evidence on immunological abnormalities associated with TRS, with a focus on inflammatory markers, immune cell profiles, and the role of autoantibodies, and to explore their potential utility in diagnosis and treatment. A systematic review of the literature was conducted in accordance with PRISMA guidelines, incorporating clinical, molecular, and translational studies on immunological markers in patients with TRS. Included studies assessed cytokine levels, immune cell phenotypes, autoantibodies, genetic factors, and the effects of immunomodulatory therapies. Emphasis was placed on findings differentiating TRS from treatment-responsive schizophrenia. TRS is associated with distinct immune profiles, including elevated IL-6, IL-8, TNF-α, and sCD25 levels, overexpression of CD33 on monocytes and expansion of CD123+ plasmacytoid dendritic cells. Autoantibodies, particularly those targeting glutamatergic receptors, are more prevalent in TRS and decrease with clozapine treatment. Predictive models using IgM autoantibodies and genetic variants show promise for early identification of at-risk individuals. Emerging immunomodulatory treatments such as rituximab, levamisole, and senolytics are under investigation, offering potential for personalized strategies. Immunological dysfunction represents a reproducible and biologically relevant feature of TRS. Integration of immune biomarkers into clinical practice may enhance diagnostic precision and inform personalized therapeutic approaches. Future research should prioritize standardized biomarker protocols and longitudinal studies to validate causal associations and optimize treatment algorithms. Full article

Background: Schizophrenia is a heterogeneous disorder, and treatment-resistant schizophrenia (TRS) affects 20–30% of patients, yet objective biomarkers for its identification remain limited. Routine electroencephalography (EEG) offers a non-invasive window into cortical network dynamics, with previous studies reporting paroxysmal epileptiform activity and background slowing in a subset of patients. However, the biological significance of these findings—whether purely pathological or potentially compensatory—remains unclear. This study aimed to compare EEG abnormalities between TRS patients and those in clinical remission and to propose an integrative neurobiological interpretation. Methods: In a cross-sectional design, 89 patients with schizophrenia (39 TRS, 50 in remission) underwent routine EEG recordings using the international 10–20 system. TRS was defined according to TRRIP consensus criteria, requiring <20% symptom reduction after adequate antipsychotic trials. EEG analysis focused on the prevalence of interictal epileptiform discharges (IEDs) and the severity of background slowing, assessed on a 4-point ordinal scale. Results: IEDs were more than twice as prevalent in TRS patients compared to those in remission. Background slowing was significantly more severe in the TRS group, with the majority showing moderate-to-severe abnormalities versus predominantly normal-to-mild patterns in remission patients. Focal EEG abnormalities also followed this pattern. Multivariate analysis confirmed that both IEDs and background severity were independent predictors of TRS. Conclusions: EEG abnormalities, particularly IEDs and background slowing, are potential neurophysiological signatures associated with treatment resistance. We propose an integrative hypothesis suggesting that IEDs may originate as a failed compensatory mechanism—the brain’s attempt to restore network homeostasis. In chronic TRS these discharges become maladaptive, contributing to excitotoxicity and network dysfunction. This framework opens avenues for EEG-based stratification and novel therapeutic strategies targeting cortical excitability. Full article

Glutamate metabotropic receptors (mGluRs) and their molecular partners at the postsynaptic density (PSD) represent a highly dynamic molecular hub that integrates multiple neurotransmitter signals and regulates synaptic plasticity and metaplasticity, which are putatively involved in the pathophysiology of psychiatric illnesses, including schizophrenia. Group I mGluRs (mGluR1 and mGluR5) interact with PSD adaptor and scaffolding proteins, such as Homer, Shank, Norbin, and PICK1, as well as intracellular downstream effectors, creating a molecular network that resembles a Lego-like structure, where modular protein interactions fine-tune glutamatergic transmission. Evidence from preclinical research indicates that dysregulation of mGluR expression and function, along with disrupted PSD protein expression, may contribute to the pathophysiology of schizophrenia by altering glutamatergic neurotransmission and synaptic stability. Antipsychotic mechanisms of action may involve, at least in part, the modulation of mGluR activity mediated through PSD proteins. Notably, novel agents that enhance spinogenesis by acting at the level of PSD proteins, such as SPG302, may open promising avenues for therapeutics aimed at restoring synaptic integrity. While Group I mGluRs dominate postsynaptic regulation, Group II (mGluR2/3) and III (mGluR4/6/7/8) receptors -primarily presynaptic- inhibit neurotransmitter release and plasticity, offering complementary therapeutic avenues. Emerging strategies, such as allosteric modulators of mGluRs, aim to rebalance synaptic signaling in treatment-resistant schizophrenia. This review synthesizes how PSD proteins and mGluRs interact in schizophrenia, exploring their potential as druggable targets for novel therapies. Full article

Schizophrenia is a complex, chronic psychiatric disorder with significant global impact, characterized by persistent positive, negative, and cognitive symptoms that are not fully addressed by current treatments. This review aims to synthesize established theories and advancing mechanistic concepts and also critically compare the latest international treatment guidelines. Recent evidence expands beyond the traditional dopamine hypothesis to include glutamatergic, serotonergic, and cholinergic dysfunctions, as well as emerging mechanisms such as neuroinflammation, oxidative stress, iron dysregulation, and gut–brain interactions. A review of major international guidelines (APA, NICE, CINP, WFSBP, and others) confirms consensus on the use of second-generation antipsychotics as first-line therapy and the early introduction of clozapine for treatment-resistant cases. All guidelines emphasize the essential role of integrated psychosocial interventions, including cognitive behavioral therapy for psychosis, family psychoeducation, and supported employment. Differences remain regarding the prioritization of precision medicine, pharmacogenomics, and digital health innovations. Prognosis varies widely but improves with early intervention, sustained treatment adherence, and comprehensive physical health monitoring. Overall, schizophrenia care is evolving toward a precision-based, recovery-oriented model that integrates biological, psychological, and social strategies to improve long-term outcomes and quality of life. Full article

Background: Clozapine (CLZ) is an atypical antipsychotic mainly prescribed for treatment-resistant schizophrenia. Beyond psychotic symptoms, patients often exhibit persistent cognitive impairments across domains such as attention, learning, and memory. The mechanisms by which CLZ may influence cognition and provide neuroprotection are not fully elucidated. Accordingly, this study examined how CLZ modulates lipopolysaccharide (LPS)-induced neurotoxicity in rats. Method: Rats were administered LPS to induce cognitive impairment and subsequently treated with CLZ. Behavioral assessments were performed using maze tests (elevated plus-maze (EPM), novel object recognition (NOR), and Y-maze). Biochemical analyses included cholinergic function (acetylcholine (ACh)), neurodegeneration-associated enzymes (glycogen synthase kinase-3 beta (GSK-3β), β-site amyloid precursor protein cleaving enzyme-1 (BACE-1), and dipeptidyl peptidase-4 (DPP-4)), oxidative stress markers (lipid Peroxidation (LPO), catalase, and reduced glutathione (GSH)), and apoptotic proteins (B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), and cleaved Caspase-3 (c-Caspase-3)). Results: CLZ treatment markedly improved performance in EPM, NOR, and Y-maze tasks, indicating recovery of cognitive function in LPS-exposed rats. At the molecular level, CLZ enhanced ACh levels, upregulated the anti-apoptotic protein Bcl-2, and restored antioxidant defenses (catalase and GSH). Conversely, CLZ reduced LPS-induced neurotoxicity by lowering GSK-3β activity, LPO, and pro-apoptotic markers (Bax and c-Caspase-3). Conclusion: The findings demonstrate that CLZ exerts neuroprotective effects in an LPS-induced rat model, improving cognition through modulation of cholinergic transmission, oxidative stress, and apoptosis pathways. These results clarify key mechanistic pathways through which CLZ may exert cognitive benefits and highlight its potential relevance for improving schizophrenia-related cognitive dysfunction. Further molecular studies are warranted to confirm and extend these observations toward clinical translation. Full article

Background: Electroconvulsive therapy (ECT) is a well-established intervention for severe and treatment-resistant psychiatric disorders, yet its use in adolescents remains limited, particularly in Europe. Data on its safety and effectiveness in this population are scarce. This study aimed to evaluate the clinical outcomes and tolerability of ECT in adolescents diagnosed with schizophrenia and schizoaffective disorder. Methods: We conducted a retrospective observational case series of 22 adolescents (mean age 16.7 ± 1.3 years) treated with ECT between 2017 and 2024 at a university psychiatric department. Diagnoses included paranoid schizophrenia (n = 15), catatonic schizophrenia (n = 2), and schizoaffective disorder (n = 5). Symptom severity was assessed with the Positive and Negative Syndrome Scale (PANSS) before and after the ECT course. Adverse events were evaluated based on daily clinical monitoring and medical records. Results: The overall response rate, defined as ≥50% reduction in total PANSS score, was 82% (schizophrenia: 82%; schizoaffective disorder: 80%). Mean PANSS total score decreased from 158.0 ± 22.6 to 72.1 ± 20.7 (p < 0.0001). Improvements were most pronounced in the general psychopathology and positive symptom domains. No serious adverse events were observed. The most common transient side effects were headache (41%), memory complaints (27%), and somnolence (22%). Conclusions: ECT appears to be an effective and safe treatment option for adolescents with treatment-resistant schizophrenia and schizoaffective disorder. These findings add to the limited European evidence base and support considering ECT earlier in the treatment course of severe adolescent psychosis. Larger, prospective studies with long-term follow-up are warranted to confirm these results. Full article

Background: Clozapine remains the only antipsychotic with proven efficacy in treatment-resistant schizophrenia (TRS). However, it is effective in only about 40% of patients and is associated with numerous adverse drug reactions. Personalization of clozapine therapy is therefore of critical importance in clinical psychiatry. MiRNA expression may serve as a promising exploratory marker for understanding individual variability in clozapine efficacy and safety. Methods: In this study, we determined the complete miRNA expression profile in TRS patients before initiation of clozapine and after four weeks of treatment. Results: In 15 inpatients with TRS receiving 4-week clozapine monotherapy, PANSS total decreased from 98.8 ± 13.19 to 80.47 ± 14.63 (p = 0.001). The most frequent adverse drug reactions were hypersalivation (n = 13), drowsiness/sedation (n = 12), and prolonged sleep (n = 12). We detected 24 differentially expressed miRNAs after clozapine. Changes in hsa-miR-129-5p, hsa-miR-6068, and hsa-miR-6814-5p correlated with improvements in positive symptoms; hsa-miR-128-1-5p tracked general psychopathology; and hsa-miR-6814-5p aligned with global improvement (lower PANSS total, higher PSP). Safety signals included associations of hsa-miR-4472 with asthenia/fatigue and prolonged sleep, hsa-miR-4510 with prolonged sleep, hsa-miR-615-3p and hsa-miR-4715-3p with tachycardia, and hsa-miR-329-1-5p with weight gain. Conclusions: Because miRNAs regulate the expression of a wide range of genes, including those involved in clozapine’s efficacy and safety, these findings underscore the need for further studies integrating pharmacoepigenetic and pharmacogenetic biomarkers. Our preliminary findings suggest that specific miRNAs could be candidate biomarkers associated with clozapine response in TRS, although these results require validation in larger and controlled studies. Full article

Treatment-resistant psychiatric disorders represent a major clinical challenge, with a significant proportion of patients remaining refractory to conventional pharmacological and psychotherapeutic interventions. Deep brain stimulation (DBS), a neurosurgical technique delivering targeted electrical impulses to specific brain regions, has emerged as a promising intervention across a spectrum of refractory psychiatric conditions. This comprehensive narrative review synthesizes current evidence on the efficacy, safety, and practical considerations of DBS for treatment-resistant major depressive disorder, obsessive–compulsive disorder, bipolar disorder, schizophrenia, addictions, Tourette’s syndrome, anorexia nervosa, post-traumatic stress disorder, and refractory aggression in autism spectrum disorder with severe intellectual disability. Across most conditions, DBS demonstrates clinically meaningful symptom reductions, with response and remission rates in depression and obsessive–compulsive disorder approaching 48% and 35%, respectively. For Tourette’s syndrome and refractory aggression in autism, over two-thirds of patients’ experience > 50% symptom reduction. Preliminary data in bipolar disorder, schizophrenia, addictions, and anorexia nervosa are encouraging but limited by small sample sizes and methodological heterogeneity. Safety profiles are generally acceptable, with the majority of adverse events being device- or procedure-related; psychiatric adverse effects and rare serious complications underscore the importance of careful patient selection and monitoring. However, the literature is constrained by inconsistent study designs, a paucity of randomized controlled trials, heterogeneity in DBS targets and stimulation parameters, and limited long-term and quality-of-life outcomes. Optimization of anatomical targeting, stimulation protocols, and patient selection criteria remains an ongoing challenge. Future directions require larger, rigorously controlled trials with standardized outcome measures, integration of neurobiological biomarkers, and multidisciplinary collaboration. In summary, while DBS offers transformative potential for select cases of refractory psychiatric illness, its application must be guided by scientific rigor, ethical prudence, and individualized patient-centered care. Full article

Adolescent-onset schizophrenia (AOS; onset between ages 13 and 18) represents a rare but severe subtype of schizophrenia that disrupts crucial neurodevelopmental and psychosocial milestones. Marked by prominent cognitive deficits, negative symptoms, and poor long-term outcomes, AOS poses unique diagnostic and therapeutic challenges distinct from adult-onset cases. A comprehensive search of PubMed/MEDLINE (January 2003–February 2025) and reference lists of prior reviews identified twenty-four primary studies addressing pharmacological, psychosocial, and neurobiological aspects of AOS. Synthesis of this evidence highlights atypical antipsychotics such as aripiprazole and brexpiprazole as well-tolerated first-line options for positive symptom reduction, while clozapine remains the most effective treatment for resistant AOS. High-dose olanzapine offers comparable efficacy but carries greater metabolic risk. Psychosocial approaches—including cognitive behavioral therapy (CBT) and motivational enhancement therapy (MET)—enhance adherence, insight, and functional recovery when integrated with pharmacotherapy. Converging neuroimaging and biomarker data reveal persistent neuroinflammatory and glutamatergic dysregulation, characterized by elevated interleukin-6 (IL-6), C-C motif chemokine ligand 11 (CCL11), and dorsomedial prefrontal hypoglutamatergia, suggesting immune-mediated and developmental mechanisms underlying symptom persistence. Emerging research on neuromodulation and N-methyl-D-aspartate (NMDA)-targeted strategies further broadens the therapeutic landscape. Collectively, these findings highlight the importance of early, developmentally informed, and multidisciplinary interventions tailored to adolescents. Strengthening longitudinal, biomarker-guided, and neuromodulation-inclusive studies will be critical for refining precision treatment models and informing future clinical and policy frameworks for adolescent psychosis care. Full article

Background/Objectives: Despite continuous pharmacological advances, the treatment of schizophrenia remains challenging, and suboptimal outcomes are still too frequent. There are currently limited new approved drugs without resistance. Methods: For this reason, drug repurposing presents a promising solution for identifying existing drugs with therapeutic effects for schizophrenia. In this study, we provide a workflow of signature-based drug repurposing methodology. We initially utilized a dataset from Gene Expression Omnibus which consists of RNA sequence data from blood-derived leukocyte samples from individuals with schizophrenia and control subjects, and conducted an analysis. Results: This analysis identified 1205 statistically significant differentially expressed genes, of which 150 upregulated and 150 downregulated genes were used in the CMap and L1000CDS2 tools. Then, each database generated a list of potential compounds that could reverse the disease’s signature and potentially have therapeutic effects for schizophrenia. Subsequently, the compounds associated with the disease, as identified in the research, were chemically clustered, and then their modes of action were predicted. In the last stage, we conducted a literature review to evaluate the relationship of these modes of action with the disease. Conclusions: This systematic analysis provided a list of potential drugs for schizophrenia treatment so that their efficacy can be evaluated in the wet-lab experiments, which is the next stage of drug repurposing. Full article

Background: Clozapine is the only antipsychotic medication proven effective in patients with treatment-resistant schizophrenia (TRS). However, many patients have serum concentrations outside the recommended therapeutic window, and clozapine exhibits substantial interindividual variability. This study aimed to (1) examine clozapine dosage and blood concentrations in patients with TRS; (2) investigate the effects of sex and age on dosage and blood concentrations; (3) assess clinical response to clozapine treatment; and (4) develop a random forest (RF) model to predict therapeutic response using clinical and therapeutic drug monitoring (TDM) data. Methods: Dried blood spots were used to measure concentrations of clozapine, norclozapine, and clozapine N-oxide. Clinical symptoms were assessed using the Brief Psychiatric Rating Scale (BPRS). The RF algorithm was applied to analyze the relationships between biochemical and demographic factors and clinical response to clozapine. Results: A total of 754 blood samples from 167 patients were analyzed. Men received higher doses than women, and glucose levels were elevated in both sexes. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve was 0.986 for the training set and 0.852 for the testing set. Accuracy, precision, recall, and F1-score (training/testing) were 0.938/0.786, 0.936/0.736, 0.934/0.780, and 0.935/0.757, respectively. The SHapley Additive exPlanations (SHAP) analysis indicated that baseline BPRS score, treatment duration, age, and clozapine concentration were important variables contributing to the output of the model. Conclusions: Our model achieved satisfactory predictive performance for clinical response and provides valuable insights into personalized prediction of clozapine efficacy. Full article

In less than 30 years, Deep Brain Stimulation (DBS) has evolved from an antiparkinsonian rescue intervention into a flexible neuromodulatory therapy with the potential for personalized, adaptive, and enhancement-focused interventions. In this review we collected evidence from seven areas: (i) modern eligibility criteria, and ways to practically improve on these, outside of ‘Core Assessment Program of Surgical Interventional Therapies in Parkinson’s Disease’ (CAPSIT-PD); (ii) cost-effectiveness, where long-horizon models now show positive incremental net monetary benefit for Parkinson’s disease, and rechargeable-devices lead the way in treatment-resistant depression and obsessive–compulsive disorder; (iii) anatomical targets, from canonical subthalamic nucleus (STN) / globus pallidus internus (GPi) sites, to new dual-node and cortical targets; (iv) mechanistic theories from informational lesions, antidromic cortical drive, and state-dependent network modulation made possible by optogenetics and computational modeling; (v) psychiatric and metabolic indications, and early successes in subcallosal and nucleus-accumbens stimulation for depression, obsessive–compulsive disorder (OCD), anorexia nervosa, and schizophrenia; (vi) procedure- and hardware-related safety, summarized through five reviews, showing that the risks were around 4% for infection, 4–5% for revision surgery, 3% for lead malposition or fracture, and 2% for intracranial hemorrhage; and (vii) future directions in connectomics, closed-loop sensing, and explainable machine learning pipelines, which may change patient selection, programming, and long-term stewardship. Overall, the DBS is entering a “third wave” focused on a better understanding of neural circuits, the integration of AI-based adaptive technologies, and an emphasis on cost-effectiveness, in order to extend the benefits of DBS beyond the treatment of movement disorders, while remaining sustainable for healthcare systems. Full article

Background/Objectives: Clozapine remains the gold standard for treatment-resistant schizophrenia. However, its narrow therapeutic window and risk of severe side effects require close monitoring of both clozapine and its primary metabolite, norclozapine. Existing therapeutic drug monitoring (TDM) methods are limited by delays, high costs, and operational complexity. This study introduces three rapid point-of-care (POC) assays utilizing a miniature mass spectrometer (Mini-MS) to quantify clozapine and norclozapine in plasma, whole blood, and dried blood spots (DBSs), facilitating applications across diverse clinical settings. Methods: The analytical performance of the assay was evaluated for sensitivity, specificity, reproducibility, and correlation with reference methods. Clinical samples from two hospitals were analysed and validated against conventional liquid chromatography tandem mass spectrometry (LC-MS/MS) reference standards at New South Wales Health Pathology (NSWHP) and Tsinghua University laboratories. Results: The Mini-MS assay accurately quantified both analytes within therapeutic ranges across all matrices. Inter-assay coefficients of variation ranged from 7.9 to 14.1% for clozapine and from 1.6 to 14.6% for norclozapine. Accuracy fell between 85 and 117% in plasma and blood extracts. Strong linearity was demonstrated (R² = 0.98–0.99) over the concentration range of 10–1000 ng/mL. Results from the Mini-MS analysis showed excellent correlations with LC-MS/MS results (r = 0.998). Conclusions: In this proof-of-concept study, the Mini-MS-based POC assays enable rapid, reliable quantification of clozapine and norclozapine, with performance comparable to conventional laboratory methods. This platform supports real-time TDM, facilitating timely dose adjustments, adherence monitoring, and ultimately improving patient outcomes. Full article