Schizophrenia (Heidelberg, Germany)最新文献

Schizophrenia is a disorder of still unknown aetiology characterized by positive, negative and cognitive symptoms. The first evident signs emerge at the end of adolescence and the beginning of adulthood as a psychotic episode. Patients are then treated with antipsychotics to ameliorate positive symptoms. However, this pharmacological approach is ineffective for negative and cognitive ones. Schizophrenia patients also exhibit metabolic and immune alterations, regardless of antipsychotic treatment. Clinical research in this field is challenging, as there is no way to identify people at risk before the first psychotic episode, and once it emerges, antipsychotic treatment is applied, worsening metabolic and immune profiles which may be detrimental for cognitive and negative symptoms. A faithful animal model of schizophrenia may be valuable to understand molecular events and brain regions involved in each of the symptoms, evaluate novel pharmacological compounds for unattended symptoms and explore objective diagnostic strategies. Here, we show that the selective dopamine D2 receptor deletion from parvalbumin interneurons, a mutation that results in schizophrenia-like phenotypes, causes intrinsic metabolic and immune defects in mice, in a similar way to what is described in schizophrenia patients. Mutant animals show dysglycaemia and dyslipidaemia, abnormal white blood cell counts, increased neutrophil-to-lymphocyte ratio, CD4/CD8 ratio imbalances, increased circulating C-reactive protein levels and reactive microglia. Therefore, selective dopamine D2 receptor deletion causes a wide spectrum of phenotypes resembling those described in patients. This animal line may be a useful research tool to expand our knowledge on the aetiology of schizophrenia.

Cognitive impairment is a core characteristic of schizophrenia. Immunosenescence has been consistently implicated in the cognitive dysfunction observed in neurodegenerative diseases, but how it may relate to cognitive deficits in schizophrenia is still unclear. We explored the associations between immunosenescence and cognitive impairment in patients with schizophrenia (SCZ, n = 65) and healthy controls (HCs, n = 39). Immunosenescence markers were assessed by flow cytometry and included the percentage of naïve or memory T cell subsets labeled by CD4+/CD8+, CD45RA+(naïve)/CD45RO (memory), or CD95+(memory), as well as the intracellular levels of selected cytokines (IL-1β, IL-6, TNF-α, and IFN-γ) in T cell subsets. T1-weighted magnetic resonance imaging was performed to assess the subcortical volume and cortical thickness. Participants were evaluated using the Positive and Negative Syndrome Scale and the Chinese version of the MATRICS Consensus Cognitive Battery.The results indicated that (1) Compared with HCs, SCZ patients were characterized by fewer naïve and more memory T cell subsets, accompanied by altered intracellular cytokine levels, indicating immunosenescence phenotypes. (2) The intracellular IL-1β level in naïve CD8+CD45RA+CD95+ T cells was associated with working memory deficit in SCZ patients. (3) In a moderated mediation model, the effect of the IL-1β level on the working memory score was mediated by the thickness of the right inferior parietal lobule (IPL_R), and the volume of the right choroid plexus (CP) moderated the indirect pathway between the IL-1β level and IPL_R thickness. Our findings highlighted immunosenescence-related T cell phenotypes and the CP as potential biomarkers of cognitive deficit in SCZ.

Formal thought disorder (FTD) is a core symptom of schizophrenia. The pathophysiology of FTD is still unclear. We focus on multiple cortical measures to capture the exact nature of brain alterations (e.g., plasticity, early brain development) in FTD dimensions. We included 70 schizophrenia patients. We assessed FTD, acquired structural neuroimaging scans, and analyzed cortical thickness, volume, surface area, and local gyrification (IGI). Results reveal negative FTD to be associated with different structural brain correlates compared to the positive and linguistic control FTD dimensions most prominent in markers of early brain development. Severity of positive and linguistic control FTD dimensions correlated positively with IGI of core language regions including temporal, Heschl's, and inferior frontal gyri. Severity of negative FTD dimension was inversely correlated with lGI of occipital and parietal regions. Findings propose distinguishable changes most prominent in markers of early brain development associated with FTD dimensions suggesting a distinct pathophysiology.

Mental illnesses often manifest through behavioral changes, with speech serving as a key medium for expressing thoughts and emotions. The use of computational linguistics on speech data in mental illnesses is a promising approach to uncover objective biomarkers for the early detection of mental illnesses. This study analyzed speech transcripts from 80 youths at ultra-high risk of psychosis (UHR) and 329 healthy controls, examining text features such as sentiment variability, cohesion, lexical sophistication, morphology, syntactic sophistication, and lexical diversity. Factor analysis revealed five key linguistic themes: Sentiment Intensity and Variability, Linguistic Register Alignment, Phonographic Uniqueness and Recognizability, Morphological Complexity and Imageability, and Lexical Richness and Typicalness. Regression analysis indicated UHR speech is characterized by diminished sentiment variability (β = -0.07), deviation from linguistic registers (β = -0.16), fewer phonographic neighbors (β = -0.11), lower morphological complexity (β = -0.36), and more predictable lexical structures (β = 0.05). Optimized machine learning (ML) models trained on Boruta-selected features achieved a mean AUC of 0.70. Our findings highlight the potential of sentiment and linguistic analyses in speech for training ML models to aid in early detection and monitoring of mental health conditions.

Traditional classification systems based on broad nosological categories do not adequately capture the high heterogeneity of mental illness. One possible solution to this is to move to a multi-dimensional model of mental illness, as has been proposed by the Research Domain Criteria and Hierarchical Taxonomy of Psychopathology frameworks. In this study, we explored the dimensional structure of psychotic disorders. We focused on the question whether combining measures of psychosis with cognitive and depression-related measures results in meaningful, clinically relevant, and valid latent dimensions in a sample of early psychosis (n = 113) and chronic schizophrenia patients (n = 43, total n = 156). We used exploratory factor analysis to identify the symptom dimensions in the Lausanne Psychosis data, a multi-modal prospective data set that includes a broad behavioral assessment of patients diagnosed with psychotic disorders. We evaluated the validity of these dimensions by regressing them to several functioning measures. Our analysis revealed three dimensions: Cognition, Depression/Negative, and Thought Disorder, explaining 49.2% of the variance. They were related to measures of functioning, the R² ranging between 0.38 and 0.42. This study advances the development of a multi-dimensional characterization of psychotic disorders by identifying three symptom dimensions with predictive validity in people with psychosis.

Few cohort studies have examined the relationship between inflammation and increased clozapine blood levels. The purpose of this study was to investigate the relationship between the neutrophil-to-lymphocyte ratio (NLR), a marker of inflammation, and the clozapine concentration-to-dose (C/D) ratio during clozapine titration. We retrospectively investigated the medical records of all patients at Nozoe Hills Hospital who met the following criteria: 1) patients with schizophrenia who were first treated with clozapine between April 2020 and July 2024 and 2) patients for whom clozapine blood levels were measured for at least two consecutive weeks after the start of clozapine treatment. The study included 143 blood samples from 28 patients collected within 6 weeks of starting clozapine treatment. A linear mixed model with random intercepts was used to determine the correlation between the clozapine C/D ratio and NLR in samples repeatedly measured within an individual. Fixed effects for the C/D ratio included NLR, week, and the interaction between NLR and week. A significant fixed effect of NLR on C/D ratio was observed (estimate: 0.70; 95% confidence interval: 0.47-0.92; P < 0.0001). The fixed effect of NLR was attenuated over time due to a significant negative interaction between NLR and week. The fixed effect of NLR remained significant even after excluding the six patients who had fever during clozapine titration. This study suggests a positive correlation between the C/D ratio and NLR during clozapine titration. Our findings indicate that subclinical inflammation in the early titration phase affects the pharmacokinetics of clozapine.

Patients with schizophrenia have excess cardiovascular risk, contributing to a reduced life expectancy of 15-20 years compared with the general population. To improve the understanding of the development and clinical trajectory of cardiovascular disease in patients with schizophrenia, we are conducting a prospective cohort study with comprehensive cardiovascular and psychiatric follow-up examinations every third year from baseline. In the present study, we aimed to describe and analyze the baseline results of this prospective cohort. The prospective cohort study enrolled participants with recent-onset schizophrenia (planned: n = 100), chronic schizophrenia (planned: n = 200), and controls for recent-onset patients (planned: n = 100) in the North Denmark Region from 2015-2019. We included 70 patients with recent-onset schizophrenia (mean age, 24.5 years; males, 54%; mean illness duration, 1 year), 165 patients with chronic schizophrenia (mean age, 49.5 years; males, 57%; mean illness duration, 21.1 years), and 85 controls for recent-onset patients (mean age, 24.4 years; males, 53%). At baseline, cardiovascular risk factors were highly prevalent in patients with schizophrenia (metabolic syndrome: 60%, hypercholesterolemia: 13%, diabetes: 13%, hypertension: 4%). Conversely, the prevalence of manifest cardiac disease, including heart failure, coronary artery disease, and atrial fibrillation/flutter was overall low (~1%). In conclusion, point-prevalences of cardiovascular risk factors were relatively high in patients with schizophrenia, while severe cardiac disease was less pronounced at baseline. Further prospective assessment is planned to determine and understand cardiovascular disease progression, and whether there are differences in the clinical trajectory between patients with recent-onset/chronic schizophrenia and controls over time.

Recent years have seen a proliferation of interest in psychological networks, which conceptualise psychopathology as networks of inter-connected, mutually reinforcing symptoms. It has been hypothesised that the topological structure of such networks is associated with clinical presentation. Analysing data from a longitudinal study of participants diagnosed with psychosis, we identify substantial inter-individual variability in network structure, problematising causal inference from cross-sectional networks. Additionally, we do not find strong evidence for an association between network structure and clinical relapse.

This study investigates the computational mechanisms underlying visual working memory (VWM) deficits in schizophrenia (SZ) under distraction. Combining 60 SZ patients and 61 demographically matched healthy controls (HC), we employed a modified delayed-estimation task with varying set sizes (1/3) and distractor numbers (0/2). Results showed universally impaired VWM performance in SZ across conditions, though distraction did not disproportionately worsen their deficits. Using the variable precision model, we found that distractors significantly increased resource allocation variability (reflecting heterogeneity in attentional resource distribution) in HC, but not in SZ. This counterintuitive pattern suggests SZ patients' VWM processes are less perturbed by external distractions, potentially linked to reduced flexibility in cognitive control. Our findings highlight the nonlinear interplay of multiple cognitive dysfunctions in SZ, where their combined effects exceed simple additive models, offering new insights into the mechanistic complexity of cognitive deficits in the disorder.

Relapses are frequent in schizophrenia and other psychotic disorders. While long-acting injectable antipsychotics (LAIs) are effective in preventing hospital admissions and improving adherence and patient outcomes, they are still under-utilised. Furthermore, evidence from newer formulations and longitudinal studies, despite their commonly long-term use, remains limited. To address this scarcity of data, this study aims to evaluate the long-term effectiveness and acceptability of once-monthly Aripiprazole long-acting injectable (ALAI), the only third-generation antipsychotic available in long-acting formulation. In this pragmatic, independent, ten-year mirror-image study conducted within a large urban mental health service in London, UK, we assessed hospital admission rates and treatment retention over 5 years following ALAI initiation in a naturalistic adult cohort. Frequency and length of hospitalisations in the 5 years pre- and post-initiation were recorded using electronic records, as were discontinuation rates and reasons. Separate analyses were performed comparing outcomes between treatment completers and discontinuers, as well as between those with schizophrenia vs other diagnoses. In total, 135 patients were included in the study (63% with Schizophrenia, 37% with other diagnoses). The discontinuation rate was 47% at 5 years (23.7%, 13.6%, 7.9%, 7.3% and 5.3% in years 1 to 5 respectively). Among the 53% who completed 5 years of ALAI treatment, we observed an 88.5% reduction in mean number (1.57 to 0.18, p < 0.001) and a 90% reduction in mean length of hospitalizations compared to 5 years pre-ALAI initiation (103 to 10 days, p < 0.0001). Median admissions and length fell from 1 to 0 and 68 to 0 days (p < 0.001), respectively. In contrast, discontinuers (47%) exhibited inferior outcomes and showed only a 29.9% reduction in admissions over 5 years. Patients were more likely to discontinue due to poor compliance and ineffectiveness and rarely due to tolerability issues. Apart from switching to ALAI from another LAI, there were no major clinical or demographic predictors of treatment continuation. Outcomes were consistent independent of diagnosis. Potential confounders however must not be overlooked, such as the exclusion of a large number of patients due to strict eligibility criteria as well as changes to healthcare policy over the study period. This is the first study to report 5-year hospitalisation and treatment persistence outcomes with ALAI. Its sustained use was associated with substantial reductions in hospital use, with 85% of completers requiring no further admissions, compared to 30% of discontinuers. These real-world findings support the long-term value of ALAI and may help address common barriers to LAI adoption in clinical decision-making.