Schizophrenia (Heidelberg, Germany)最新文献

Intervention for social cognition could be key to improving social functioning in patients with schizophrenia. A first step towards its clinical implementation involves interviewing patients about their subjective difficulties with social cognition as they experience them in the real world. The present study focused on the clinical subtypes classified by the discrepancies between the subjective difficulties in social cognition and actual cognitive impairment. A total of 131 outpatients with schizophrenia and 68 healthy controls were included. Objective measurement of social cognition was performed using a test battery covering four representative domains, and subjective difficulties were determined by a questionnaire covering the same domains. A two-step cluster analysis explored the potential classification of social cognition in patients with schizophrenia. There was little correlation between the objective performance on social cognition tasks and subjective difficulties in social cognition. The analysis yielded three clusters: the low-impact group (low objective impairment and low subjective difficulties), the unaware group (high objective impairment but low subjective difficulties), and the perceptive group (moderate objective impairment and high subjective difficulties). Positive, negative, and general symptoms were more severe in the two groups that showed impaired performance on the social cognition tasks (i.e., the unaware and perceptive groups) than those in the low-impact group. Neurocognition and functional capacity were the lowest in the unaware group, and social functioning was the lowest in the perceptive group. Awareness about the clinical subtypes of social cognition could serve as a guidepost for providing individualized, targeted interventions.

Schizophrenia is a complex neuro-psychiatric disorder including positive symptoms, negative symptoms, and cognitive deficits. A key cognitive dysfunction in schizophrenia is a deficit in visual working memory (VWM). VWM involves three distinct stages: encoding, maintenance, and retrieval. The deficit in any one stage would produce the same symptom (i.e., poor VWM), although their causes are not the same. In this study, we used a retro-cue VWM task that provides helpful cues at different stages: early in maintenance (early cue), late in maintenance (late cue), or during retrieval (retrieval cue). This modification would help "tag" or identify the cognitive stage(s) most responsible for impaired VWM performance in schizophrenia. Additionally, we took advantage of this tagging feature and applied 6 Hz transcranial alternating current stimulation (tACS) over the right dorsolateral prefrontal cortex (DLPFC) and right posterior parietal cortex (PPC)-which has previously been shown to enhance VWM in low-performing healthy individuals-to examine whether tACS would improve a specific stage or all stages of VWM processing in schizophrenia. We observed that cues significantly enhanced performance in low-performing patients, who benefited equally from early and late maintenance cues, but not from retrieval cues. These low-performers also responded well to theta tACS in their overall VWM performance as opposed to a specific VWM stage. No improvement effect was observed in high-performing patients for both retro cue and tACS. Together, our data suggest that 1) low-performing patients' VWM deficits likely stem from poor memory consolidation rather than retrieval, 2) right frontoparietal theta tACS can improve low-performing patients' VWM performance, and 3) such facilitatory tACS effect is not selective of a specific VWM stage and thus is likely driven by an improvement in overall visual attention.

Patients suffering from schizophrenic psychosis show reduced synaptic connectivity compared to healthy individuals, and often, the use of cannabis precedes the onset of schizophrenic psychosis. Therefore, we investigated if different types of cannabinoids impact methylation patterns and expression of schizophrenia candidate genes concerned with the development and preservation of synapses and synaptic function in a SH-SY5Y cell culture model. For this purpose, SH-SY5Y cells were differentiated into a neuron-like cell type as previously described. Effects of the cannabinoids delta-9-THC, HU-210, and Anandamide were investigated by analysis of cell morphology and measurement of neurite/dendrite lengths as well as determination of methylation pattern, expression (real time-qPCR, western blot) and localization (immunocytochemistry) of different target molecules concerned with the formation of synapses. Regarding the global impression of morphology, cells, and neurites appeared to be a bit more blunted/roundish and to have more structures that could be described a bit boldly as resembling transport vesicles under the application of the three cannabinoids in comparison to a sole application of retinoic acid (RA). However, there were no obvious differences between the three cannabinoids. Concerning dendrites or branch lengths, there was a significant difference with longer dendrites and branches in RA-treated cells than in undifferentiated control cells (as shown previously), but there were no differences between cannabinoid treatment and exclusive RA application. Methylation rates in the promoter regions of synapse candidate genes in cannabinoid-treated cells were in between those of differentiated cells and untreated controls, even though findings were significant only in some of the investigated genes. In other targets, the methylation rates of cannabinoid-treated cells did not only approach those of undifferentiated cells but were also valued even beyond. mRNA levels also showed the same tendency of values approaching those of undifferentiated controls under the application of the three cannabinoids for most investigated targets except for the structural molecules (NEFH, MAPT). Likewise, the quantification of expression via western blot analysis revealed a higher expression of targets in RA-treated cells compared to undifferentiated controls and, again, lower expression under the additional application of THC in trend. In line with our earlier findings, the application of RA led to higher fluorescence intensity and/or a differential signal distribution in the cell in most of the investigated targets in ICC. Under treatment with THC, fluorescence intensity decreased, or the signal distribution became similar to the dispersion in the undifferentiated control condition. Our findings point to a decline of neuronal differentiation markers in our in vitro cell-culture system under the application of cannabinoids.

Cognitive deficits and overweight are prominent challenges in the treatment of psychosis, which have a direct impact on patients' quality of life. We aim to determine whether there is an association of overweight with cognitive performance and whether there are sex differences in this association. We included 170 individuals with first-episode psychosis (FEP) (mean age 23.08 years, 32.9% females) attending an early intervention service who underwent clinical, biometric, and cognitive assessments by the MATRICS Consensus Cognitive Battery. A set of two-way analyses of covariance (ANCOVAs) were conducted for each cognitive test. Sex, overweight, and their interaction were included as factors. Nearly 34% of the participants were overweight without differences between males and females. The excess of weight did not exert any main effect on cognition; however, overweight females performed significantly worse than non-overweight females in processing speed, verbal learning and memory, reasoning and problem-solving, and global cognitive function, whereas in males, there were no differences. Our findings highlight that sex matters in the study of metabolic and cognitive factors in FEP to develop targeted interventions based on sex perspectives.

Understanding the role of aberrant salience (AS) in psychosis is crucial for comprehending schizophrenia spectrum disorders (SSDs). Researchers emphasize the importance of salience attribution in schizophrenia, acknowledging its interaction with environmental stressors and multiple neurotransmitter systems. Childhood trauma and adversities (CTA) play a significant role in SSDs, potentially contributing to prodromal symptoms characterized by AS. While empirical evidence supports the relationship between AS and SSD, the interplay between different AS patterns, CTA, and psychotic symptoms remains unclear. Clinical diagnosis followed DSM-5 criteria, and participants completed assessments including the Aberrant Salience Inventory (ASI), Childhood Trauma Questionnaire - Short form (CTQ-SF), and Positive and Negative Symptom Scale (PANSS). Latent profile analysis (LPA) was employed to identify distinct AS profiles within the sample, with subsequent analyses examining differences in psychopathological variables among these profiles. Among 262 participants, four distinct AS profiles emerged from LPA: low AS, high AS with severe symptoms and CTA, intermediate AS with sexual abuse correlation, and chronic AS with specific childhood trauma associations. Profile distinctions included differences in age, hospitalizations, psychotic symptoms, and CTA. Logistic regression analyses showed significant associations between the four profiles and emotional and sexual abuse, physical neglect and clinical variables. Subtyping individuals with SSD based on AS revealed four distinct profiles, each with unique clinical characteristics and associations with CTA. Future studies should investigate whether these profiles correspond to diverse treatment outcomes. These findings highlight the complexity of schizophrenia presentation and underscore the importance of considering individualized diagnostic and therapeutic approaches.

Neuroimaging studies have revealed that the mechanisms of auditory hallucinations are related to morphological changes in multiple cortical regions, but studies on brain network properties are lacking. This study aims to construct intra-individual structural covariance networks and reveal network changes related to auditory hallucinations. T1-weighted MRI images were acquired from 90 schizophrenia patients with persistent auditory hallucinations (pAH group), 55 schizophrenia patients without auditory hallucinations (non-pAH group), and 83 healthy controls (HC group). Networks were constructed using the voxel-based gray matter volume and the intra-individual structural covariance was based on the similarity between the morphological variations of any two regions. One-way ANCOVA was employed to compare global and local network metrics among the three groups, and edge analysis was conducted via network-based statistics. In the pAH group, Pearson correlation analysis between network metrics and clinical symptoms was conducted. Compared with the HC group, both the pAH group (p = 0.01) and the non-pAH group (p = 3.56 × 10^-4) had lower nodal efficiency of the left medial superior frontal gyrus. Compared to the non-pAH group and HC group, the pAH group presented lower nodal efficiency of the temporal pole of the left superior temporal gyrus (p = 1.09 × 10^-3; p = 7.67 × 10^-4) and right insula (p = 0.02; p = 8.99 × 10^-6), and lower degree centrality of the right insula (p = 0.04; p = 1.65 × 10^-5). The pAH group had a subnetwork with reduced structural covariance centered by the left temporal pole of the superior temporal gyrus. In the pAH group, the normalized clustering coefficient (r = -0.36, p = 8.45 × 10^-3) and small-worldness (r = -0.35, p = 9.89 × 10^-3) were negatively correlated with the PANSS positive scale score. This study revealed network changes in schizophrenia patients with persistent auditory hallucinations, and provided new insights into the structural architecture related to auditory hallucinations at the network level.

Methamphetamine use can produce psychotic symptoms almost indistinguishable from schizophrenia (SCZ). Variation in DNA methylation may be closely implicated in the etiology and longitudinal development of psychiatric disorders. However, the relationship between psychotic symptoms, functional disability, and DNA methylation is still unclear. This study consists of three periods: discovery, validation, and follow-up. In the discovery stage, we employed genome-wide DNA methylation profiling (Illumina 450K) in peripheral blood mononuclear cells to test whether DNA methylation associates with psychotic symptoms and function state in representative SCZ and methamphetamine-induced psychotic disorder (MIP) patients. Then, we found seven differentially methylated regions/genes (DMRs, in UBA6, APOL3, KIF17, MLLT3, GRM8, CSNK1E, SETDB1) overlapping with genetic variants reported in previous studies of psychosis. In the validation stage, we compared the above-mentioned seven genes by MethLight qPCR method in Chinese Han males (N = 109 SCZ patients, N = 99 methamphetamine use disorder with MIP patients, N = 150 methamphetamine use disorder without MIP patients, N = 282 normal controls, age range: 18-50 years). GRM8 showed robustly altered methylation, which has passed rigorous filtration in subsequent validation, suggesting a remarkable contribution to SCZ and MIP. In addition, hypermethylation of GRM8 showed a significant association with the total scores of the Positive Negative Syndrome Scale and WHO disability assessment schedule II in both baseline and follow-up periods. Our findings suggest that increased CpG methylation in the promoter of GRM8 is a potential candidate epigenetic biomarker of psychotic symptoms in transdiagnostic samples of SCZ and MIP.

Hyperactivity of the human anterior hippocampus has been reported to spread from its CA1 subfield to the subiculum around the onset of first-episode psychosis and could be a cellular target for early therapeutic intervention in the schizophrenia prodrome. However, to what extent CA1 hyperactivity actually causes schizophrenia-related symptoms remains unknown. Here, we mimic this endophenotype by direct optogenetic activation of excitatory cells in the homologous mouse region, ventral CA1 (vCA1) and assess its consequence in multiple schizophrenia-related behavioural tests. We find that hyperactivity of vCA1 causes hyperlocomotion and impairments of spatial and object-related short-term habituation (spatial novelty-preference and novel-object recognition memory) and spatial working memory, whereas social interaction, spatial exploration, and anxiety remain unaltered. Stimulation of the ventral subiculum, in contrast, only increased locomotion and exploration. In conclusion, CA1 hyperactivity may be a direct driver of prodromal cognitive symptoms and of aberrant salience assignment leading to psychosis.

Several multivariate prognostic models have been published to predict outcomes in patients with first episode psychosis (FEP), but it remains unclear whether those predictions generalize to independent populations. Using a subset of demographic and clinical baseline predictors, we aimed to develop and externally validate different models predicting functional outcome after a FEP in the context of a schizophrenia-spectrum disorder (FES), based on a previously published cross-validation and machine learning pipeline. A crossover validation approach was adopted in two large, international cohorts (EUFEST, n = 338, and the PSYSCAN FES cohort, n = 226). Scores on the Global Assessment of Functioning scale (GAF) at 12 month follow-up were dichotomized to differentiate between poor (GAF current < 65) and good outcome (GAF current ≥ 65). Pooled non-linear support vector machine (SVM) classifiers trained on the separate cohorts identified patients with a poor outcome with cross-validated balanced accuracies (BAC) of 65-66%, but BAC dropped substantially when the models were applied to patients from a different FES cohort (BAC = 50-56%). A leave-site-out analysis on the merged sample yielded better performance (BAC = 72%), highlighting the effect of combining data from different study designs to overcome calibration issues and improve model transportability. In conclusion, our results indicate that validation of prediction models in an independent sample is essential in assessing the true value of the model. Future external validation studies, as well as attempts to harmonize data collection across studies, are recommended.

Social disconnection, including objective social isolation and subjective loneliness, is linked to substantial health risks. Yet, little is known about the predictors of social disconnection in individuals with mental illness. Here, we used machine learning to identify predictors of social isolation and loneliness in schizophrenia (N = 72), a psychiatric condition associated with social disconnection. For comparison, we also included two other groups: a psychiatric comparison sample of bipolar disorder (N = 48) and a community sample enriched for social isolation (N = 151). We fitted statistical models of social isolation and loneliness within and across groups. Each model included five candidate predictors: social avoidance motivation, depression, nonsocial cognition, social anhedonia, and social cognition. The results showed that social anhedonia explained unique variance in social isolation and loneliness in all samples, suggesting that it contributes to social isolation and loneliness broadly. However, nonsocial cognition explained unique variance in social isolation only within schizophrenia. Thus, social anhedonia could be a potential intervention target across populations, whereas nonsocial cognition may play a unique role in determining social disconnection in schizophrenia.