Schizophrenia (Heidelberg, Germany)最新文献

The pharmacological treatment of negative symptoms in schizophrenia remains a major unmet need. Among these, impairments in social functioning - manifesting as reduced adaptability and social withdrawal - are particularly disabling, as they persist beyond remission of positive symptoms and impede social reintegration. To investigate the neurobiological basis of behavioral impairments, we employed the tgDISC1 rat, a translational model overexpressing the human non-mutant Disrupted-in-Schizophrenia-1 (DISC1) gene. This overexpression results in DISC1 protein aggregation and aberrant signaling- molecular features identified in a subset of schizophrenia patients identified by elevated DISC1 aggregates in cerebrospinal fluid. Behaviorally, the tgDISC1 rats exhibited a selective loss of social novelty preference in the 3-Chamber task while maintaining intact social interest, indicating a specific deficit in social adaptability rather than social motivation. Here, we tested whether continuous administration of atypical antipsychotics amisulpride or clozapine would rescue social deficits in tgDISC1 rats. Treatment with amisulpride (0.2 and 0.8 mg/kg/day for two weeks) fully restored social novelty preference, whereas clozapine had no effect. Control tasks for anhedonia, short-term working memory, and explorative behavior confirmed that their phenotype was not secondary to global motivational or cognitive impairments. Together, these findings demonstrate that amisulpride, a selective D2/D3 receptor antagonist, rescues social adaptability deficits linked to aberrant DISC1 signaling. The results also highlight the success of our precision psychiatry approach: the biological definition of a subset of schizophrenia by identifying DISC1 protein aggregates, the generation of a corresponding animal model and a successful pharmacotherapy of a clinically relevant phenotype.

Few neuroimaging studies have examined other specified schizophrenia spectrum and other psychotic disorder (OSSO). We sought to identify features differentiating patients with OSSO from those with schizophrenia spectrum disorders (SSD) and healthy controls (HC) using auditory seed-based functional connectivity (FC) analysis. Patients with OSSO (n = 88), patients with SSD (n = 81), and HC (n = 85), matched for age, sex, and education, underwent resting-state functional magnetic resonance imaging (rs-fMRI) and clinical evaluation. To reduce heterogeneity of OSSO, individuals with specific subtypes of OSSO, i.e., pure delusion and delusion with attenuated auditory hallucinations (AHs) were only included. Using five auditory seeds, we conducted seed-to-voxel and seed-to-region of interest (ROI) analyses. We also conducted between- and within-network connectivity analyses of 13 networks, and correlations of altered FC with symptomatology were explored. The SSD group showed significantly greater connectivity between the superior temporal gyrus (STG) and precuneus, and between the temporal pole cortex (TP) and precuneus, compared to the OSSO group. Overall auditory seed-based hypoconnectivity and middle temporal gyrus-based hyperconnectivity were observed in both groups compared to HC. In OSSO, hallucination severity was positively associated with insula-putamen connectivity, whereas delusional and negative symptoms showed inverse correlations with TP-insula and STG-Heschl's gyrus connectivity, respectively. In SSD, hallucination severity correlated positively with STG-Heschl's gyrus and TP-insula connectivity whereas negative symptoms correlated negatively with STG-insula connectivity. These findings suggest that there are distinct differences in FC between patients with OSSO and patients with SSD, which supports the proposal that OSSO should be treated as a separate clinical syndrome with distinct neural connectomes. Future research may explore whether interventions targeting these altered connectivity patterns could help reduce the risk of progression from OSSO to SSD.

According to the excitation-inhibition imbalance theory, GABAergic and glutamatergic systems influence the clinical symptoms, particularly cognitive deficits in schizophrenia spectrum disorders (SSD). These systems have been found disrupted in the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC) in SSD, and may contribute to P300 abnormalities in electroencephalography recordings. Therefore, we explored the relationships among MRS-derived GABA and Glx levels in the ACC and left DLPFC (lDLPFC), auditory P3b subcomponent amplitudes and latencies, cognition, and symptom severity in SSD. In total, 107 patients and 107 healthy controls (HC) were included in the study, with the exact numbers varying across specific analyses. We grouped patients into higher (SSD+, N = 41) and lower (SSD-, N = 65) symptom severity clusters based on PANSS total scores. P3b amplitudes were lower in SSD patients than HC at central and parietal sites. SSD+ exhibited widespread P3b amplitude reductions, significant at parietal and trend-level at central and frontal regions, while SSD- showed a trend-level amplitude reduction limited to the parietal region. GABA levels in the lDLPFC were higher in SSD- compared to controls and were positively associated with P3b amplitudes at central and parietal sites within SSD- and overall SSD group. Although P3b amplitudes positively correlated with the BACS composite scores and behavioral performance, lDLPFC GABA levels showed no direct association with cognitive or behavioral performance. ACC GABA, ACC Glx, and lDLPFC Glx levels showed no group differences or P3b associations. Our findings suggest P3b amplitude reductions as a marker of cognitive dysfunction in SSD, more pronounced in patients with higher illness severity, and that enhanced lDLPFC GABA may contribute to offsetting these reductions. Our work provides the first empirical evidence of the interplay between the GABAergic system and cortical electrophysiological signal patterns associated with cognitive dysfunction in SSD.

Subclinical paranoia is present in the relatives of patients with psychosis but it is also relatively common in the general population. Dopamine neurotransmission is increased in people with psychosis and is linked with positive symptoms, such as paranoia. Here, we examined if neuromelanin-sensitive MRI, a proxy of long-term dopamine turnover, is different between those with (n = 25) and without (n = 77) a first-degree relative with psychosis (N = 102). We further tested whether neuromelanin-sensitive MRI was associated with the experience of subclinical paranoia as measured by the paranoia checklist. We found that there was no difference in neuromelanin-sensitive MRI signal between those with and without a first-degree relative. However, neuromelanin-sensitive MRI was significantly associated with the frequency subscore of the paranoia checklist, irrespective of familial risk (255 of 1879 voxels at p < 0.05, p_corrected = 0.03). This relationship was further supported by the association of neuromelanin-sensitive MRI and community assessment of psychic experience paranoia frequency subscore (316 of 1879 voxels at p < 0.05, p_corrected = 0.01). In summary, we show that subclinical paranoid thoughts are associated with a proxy of long-term dopamine turnover regardless of whether the person has a relative with psychosis or not. Thus, neuromelanin-MRI associates with positive subclinical symptomatology in those without psychotic illness, in addition to the link observed in patients.

One-third of schizophrenia patients exhibit treatment resistance, underscoring the need for mechanism-based interventions. We report that deep brain stimulation of the substantia nigra pars reticulata has acutely alleviated persistent auditory hallucinations by 64% in a treatment-resistant schizophrenia patient. Deep brain stimulation normalized hallucination-correlated elevation of intraoperative electrocortical theta-gamma phase-amplitude coupling at language-related cortical areas. These findings suggest aberrant cortical synchronization may be involved in the generation of verbal hallucinations and highlight subcortical modulation as a potential therapeutic strategy.

Schizophrenia is a severe mental disorder with substantial clinical, economic, and humanistic impacts. This targeted literature review evaluated the burden of schizophrenia on patients and caregivers in Japan. Data were collected from PubMed, Ichushi, CiNii, J-STAGE, and the Cochrane Database (2013-2023) and supplementary materials from medical associations, government agencies, and patient organizations (2018-2023). The review focused on epidemiology, clinical management, societal, humanistic, and economic burdens experienced by patients and caregivers. The review identified 156 journal publications, 73 conference proceedings, and 37 additional data sources. Obesity, depression, and type 2 diabetes were highlighted as frequent comorbidities. Cognitive impairment in schizophrenia, assessed by the Brief Assessment of Cognition in Schizophrenia, indicated severe functional deficits with a Z-score of -2.1. Issues related to long-term hospitalization, including social isolation and inadequate post-discharge support, were also reported. Interventions aimed at improving cognitive function, fostering self-care, and strengthening community cooperation were identified as key factors in reducing early readmission rates. Caregivers experienced significant productivity losses, particularly due to presenteeism, leading to an estimated annual loss of JPY 2.4 million. The hand search further revealed a lack of stakeholder-driven initiatives to address the comprehensive burdens of schizophrenia, such as awareness campaigns, educational programs, and multidisciplinary approaches. This review underscores the multifaceted burdens of schizophrenia in Japan, emphasizing the urgent need for coordinated, evidence-based countermeasures involving multiple stakeholders, including patients, caregivers, healthcare professionals, and policymakers. To reduce burdens and improve healthcare, further research is needed to bridge the gap between required interventions and stakeholder engagement.

Schizophrenia spectrum disorders (SCZ_spect) are associated with altered function in the auditory cortex (AC), indicated by lower N100 amplitude of the auditory evoked potential (AEP). Although the neural substrate behind lower N100 amplitude remains elusive, myelination in the AC may play a role. This study compared N100 amplitude and magnetic resonance imaging (MRI) T1 weighted and T2 weighted ratio (T1w/T2w-ratio), as a proxy of myelination, in the primary AC (AC1) and secondary AC (AC2) between SCZ_spect (n = 33, 48% women) and healthy controls (HC, n = 144, 49% women). We also examined the associations between N100 amplitude and T1w/T2w-ratios across groups. We finally explored N100 amplitude and T1w/T2w-ratios and the N100-T1w/T2w-ratio associations between male and female SCZ_spect and HC. N100 amplitude was significantly lower in male SCZ_spect compared to male HC (p = 0.01) and nominally lower in SCZ_spect compared to HC (p = 0.03). However, T1w/T2w-ratios in AC1/AC2 did not differ between groups, and no association was found between N100 amplitude and T1w/T2w-ratio in either group. These findings suggest that sex-specific effects should be considered in SCZ_spect neurophysiology research. Our results do not support the hypothesis of an association between lower N100 amplitude and lower T1w/T2w-ratio in the AC1/AC2 in SCZ_spect. More precise assessments of intracortical myelin are needed to understand the relationship between N100 amplitude and cortical myelination in the AC in SCZ_spect and in healthy controls.

While individuals with schizophrenia (SZ) exhibit deficits in social cognition, the specific profile of these deficits across multiple domains and their relationship with clinical symptoms warrants further characterization. This study aimed to systematically assess key social-cognitive domains-theory of mind (ToM), emotion recognition, attributional style, and social perception-and examine their associations with psychopathology in SZ. Sixty-eight individuals with SZ and 68 matched healthy controls (HC) completed a comprehensive battery of social-cognitive measures, including the false-belief task (assessing first- and second-order ToM), the Faux Pas task, the emotional recognition task, the attributional style questionnaire, and the social perception scale. Clinical symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). Compared to HC, individuals with SZ showed significant deficits across all social-cognitive measures. Specifically, the SZ group exhibited deficits in emotion recognition for all negative emotions (fear, anger, sadness, disgust) but not for happiness, and in attributional style for positive but not negative events. Correlation analyses identified a statistically significant inverse relationship between attributional stability for negative events (i.e., the tendency to attribute the causes of negative events to factors that are persistent over time) and PANSS general psychopathology scores (τ = -0.25, P < 0.043). Furthermore, no other social-cognitive domains (ToM, emotion recognition, social perception) showed significant correlations with any PANSS symptom dimensions. Network analysis further characterized second-order ToM as the core deficit, exhibiting the highest strength and centrality within the social-cognitive network, with mediation effects most pronounced for sadness and happiness recognition. These findings highlight second-order ToM as a core deficit in individuals with schizophrenia and suggest that a stable attributional style may be associated with a lower overall burden of general psychopathology. These social-cognitive domains may represent promising targets for future cognitive remediation interventions for people living with schizophrenia.

Despite notable progress in psychiatric genomics, there are no validated blood-based biomarkers for psychosis. Previous studies have failed to establish a link between schizophrenia polygenic scores (PGS) and blood protein levels. We aimed to identify associations between schizophrenia PGS and blood-based proteins, and to determine whether levels of 2077 proteins differ in individuals with psychosis. We analysed proteomic and genomic data from 47,969 participants in the UK Biobank. Association analyses in the 47,678 participants without psychosis (mean age 57.1 years, standard deviation 8.1 years; 54% female) identified nominal associations (p < 0.05) of schizophrenia PGS with 102 proteins. Four of these (TMPRSS15, ADGRB3, CEACAM21, and KLK1) met the false discovery rate (FDR) threshold of < 0.05. We investigated the association of these four proteins with psychosis in a matched case-control sample (283 cases, 849 controls, mean age 56.9 years, standard deviation 8.4 years; 48% female). In individuals with psychosis, we observed significantly lower levels of KLK1, even after adjusting for potential confounders (effect size -0.25, SE 0.09, FDR 0.049). This direction of effect was opposite to that observed in the primary analysis of individuals without psychosis (effect size 324.67, SE 48.32, FDR 3.85 × 10^-8). The effect of antipsychotic medication did not explain this difference. This protein should be taken forward for further study and validation to investigate its potential as a psychosis biomarker.

Cognitive deficits in schizophrenia significantly hinder functional outcomes and often remain unresponsive to conventional treatments. While initial evidence suggested potential pro-cognitive effects of electrical brain stimulation in schizophrenia, recent meta-analyses have not supported these findings, warranting further investigation on intervention optimization. This sham-controlled crossover study explored cognitive and emotional effects of bilateral dorsolateral prefrontal cortex (DLPFC) anodal transcranial direct current stimulation (tDCS) and high-frequency transcranial random noise stimulation (tRNS) in schizophrenia. Thirty-six male patients with schizophrenia participated in a crossover trial, receiving three sessions (tDCS, tRNS, sham) in counterbalanced order with 1-week intervals. tDCS and tRNS sessions involved 20-min 2 mA anodal stimulation and 2 mA 100-640 Hz random noise stimulation targeting the left and right DLPFCs (F3-F4) with two extracephalic return electrodes. Executive functions (working memory, spatial planning) were assessed during stimulation, and emotional changes were measured with the Positive and Negative Affect Schedule (PANAS) pre- and post-stimulation. Additionally, side effects and blinding efficacy were evaluated. Both bilateral DLPFC anodal tDCS and high-frequency tRNS significantly improved planning performance (mean problems solved, mean number of moves) compared to sham, with tRNS additionally enhancing working memory accuracy and strategy score. Both interventions increased positive affect and reduced negative affect after the intervention, with tRNS showing greater enhancement of positive emotions. Reduced negative affect tRNS was correlated with improved executive planning. Side effects were minimal, and blinding was effective for the sham condition. Bilateral DLPFC anodal tDCS and high-frequency tRNS show promise as adjunctive treatments for schizophrenia, especially for cognitive deficits, with broader cognitive and emotional benefits observed with tRNS. ClinicalTrials.gov Identifier: NCT06155786 https://clinicaltrials.gov/study/NCT06155786.