Schizophrenia Bulletin最新文献

Background and hypothesis: This study aims to develop a placebo response and dropout rate model for acute-phase schizophrenia medication trials and assess factors affecting this response to inform future trial design.

Study design: We conducted a literature update using a comprehensive meta-analysis of schizophrenia medication trials, focusing on oral placebo-controlled studies. We modeled the placebo response on the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impressions-Severity of Illness (CGI-S) scale over time and analyzed dropout rates. Influential factors were explored using covariate models and subgroup analyses.

Study results: Aggregate-level data from 48 publications were analyzed. The placebo response reached a plateau at different weeks for PANSS and CGI-S scale scores. The lower the baseline of PANSS total score, older age, heavier body weight, a higher proportion of male or Black patients, smaller sample sizes, single-country trials, older studies, and the use of the Last Observation Carried Forward imputation were associated with a lower placebo response. Maximum response of PANSS Total score and gender significantly influenced dropout rates.

Conclusions: We present a model predicting placebo response in schizophrenia trials, offering insights into the impact of various trial characteristics, aiding in the design and interpretation of future clinical studies.

Background: Cognitive impairment associated with schizophrenia (CIAS) negatively impacts daily functioning, quality of life, and recovery, yet effective pharmacotherapies and practical assessments for clinical practice are lacking. Despite the pivotal progress made with establishment of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) for clinical research, implementation of the full MCCB is too time-consuming and cost-ineffective for most clinicians in clinical practice.

Study design: Here we discuss current assessments in relation to delivery format (interview-based and performance-based), validity, ease of use for clinicians and patients, reliability/reproducibility, cost-effectiveness, and suitability for clinical implementation. Key challenges and future opportunities for improving cognitive assessments are also presented.

Study results: Current assessments that require 30 min to complete would have value in clinical settings, but the associated staff training and time required might preclude their application in most clinical settings. Initial profiling of cognitive deficits may require about 30 min to assist in the selection of evidence-based treatments; follow-up monitoring with brief assessments (10-15 min in duration) to detect treatment-related effects on global cognition may complement this approach. Guidance on validated brief cognitive tests for the strategic monitoring of treatment effects on CIAS is necessary.

Conclusions: With increased advancements in technology-based and remote assessments, development of validated formats of remote and in-person assessment, and the necessary training models and infrastructure required for implementation, are likely to be of increasing clinical relevance for future clinical practice.

Background and hypothesis: Cognitive impairment is a core feature of schizophrenia that worsens with aging and interferes with quality of life. Recent work identifies sleep as an actionable target to alleviate cognitive deficits. Cardinal non-rapid eye movement (NREM) sleep oscillations such as sleep spindles and slow oscillations are critical for cognition. People living with schizophrenia (PLWS) and their first-degree relatives have a specific reduction in sleep spindles and an abnormality in their temporal coordination with slow oscillations that predict impaired memory consolidation. While NREM oscillatory activity is reduced in typical aging, it is not known how further disruption in these oscillations contributes to cognitive decline in older PLWS. Another understudied risk factor for cognitive deficits among older PLWS is obstructive sleep apnea (OSA) which may contribute to cognitive decline.

Study design: We conducted a narrative review to examine the published literature on aging, OSA, and NREM sleep oscillations in PLWS.

Study results: Spindles are propagated via thalamocortical feedback loops, and this circuitry shows abnormal hyperconnectivity in schizophrenia as revealed by structural and functional MRI studies. While the risk and severity of OSA increase with age, older PLWS are particularly vulnerable to OSA-related cognitive deficits because OSA is often underdiagnosed and undertreated, and OSA adds further damage to the circuitry that generates NREM sleep oscillations.

Conclusions: We highlight the critical need to study NREM sleep in older PWLS and propose that identifying and treating OSA in older PLWS will provide an avenue to potentially mitigate and prevent cognitive decline.

Background and hypothesis: Psychotic-like experiences (PLEs) are prevalent in the general population and, because they represent a lower end of the psychosis vulnerability spectrum, may be useful in informing mechanistic understanding. Although it is well-understood that motor signs characterize formal psychotic disorders, the developmental trajectory of these features and their relationships with PLEs are less well-understood.

Study design: Data from 7559 adolescents and young adults (age 11-21) in the Philadelphia Neurodevelopmental Cohort were used to investigate whether early-life milestone-attainment delays relate to current adolescent sensorimotor functioning and positive and negative PLEs. Current sensorimotor functioning was assessed using the Computerized Finger Tapping task (assessing motor slowing) and Mouse Practice task (assessing sensorimotor planning).

Study results: Early developmental abnormalities were related to current adolescent-aged motor slowing (t(7415.3) = -7.74, corrected-P < .001) and impaired sensorimotor planning (t(7502.5) = 5.57, corrected-P < .001). There was a significant interaction between developmental delays and current sensorimotor functioning on positive and negative PLEs (t = 1.67-4.51), such that individuals with early developmental delays had a stronger positive relationship between sensorimotor dysfunction and PLEs. Importantly, interaction models were significantly better at explaining current PLEs than those treating early and current sensorimotor dysfunction independently (χ2 = 4.89-20.34).

Conclusions: These findings suggest a relationship between early developmental delays and current sensorimotor functioning in psychosis proneness and inform an understanding of heterotypic continuity as well as a neurodevelopmental perspective of motor circuits. Furthermore, results indicate that motor signs are a clear factor in the psychosis continuum, suggesting that they may represent a core feature of psychosis vulnerability.

Background and hypothesis: Up to 43% of people with schizophrenia have a lifetime cannabis use disorder (CUD). Tetrahydrocannabinol (THC) has been shown to exacerbate psychosis in a dose-dependent manner, but little research has assessed its effects on schizophrenia and co-occurring CUD (SCZ-CUD). In this double-dummy, placebo-controlled trial (total n = 130), we hypothesized that a modest dose of THC would worsen cognitive function but not psychosis.

Study design: Effects of single-dose oral THC (15 mg dronabinol) or smoked 3.5% THC cigarettes vs placebo in SCZ-CUD or CUD-only on positive and negative symptoms of schizophrenia (only for SCZ-CUD), cognition, and drug experiences assessed several hours after drug administration. SCZ-only and healthy control participants were also assessed.

Study results: Drug liking was higher in THC groups vs placebo. Neither smoked THC nor oral dronabinol predicted positive or negative symptom subscale scores 2 and 5 h, respectively, after drug exposure in SCZ-CUD participants. The oral dronabinol SCZ-CUD group, but not smoked THC SCZ-CUD group, performed worse than placebo on verbal learning (B = -9.89; 95% CI: -16.06, -3.18; P = .004) and attention (B = -0.61; 95% CI: -1.00, -0.23; P = .002). Every 10-point increment in serum THC + THCC ng/ml was associated with increased negative symptoms (0.40 points; 95% CI: 0.15, 0.65; P = .001; subscale ranges 7-49) and trends were observed for worse positive symptoms and performance in verbal learning, delayed recall, and working memory.

Conclusions: In people with SCZ-CUD, a modest single dose of oral THC was associated with worse cognitive functioning without symptom exacerbation several hours after administration, and a THC dose-response effect was seen for negative symptoms.

Background: Schizophrenia (SCZ) is a serious mental illness with complex pathology, including abnormalities in the glutamate system. Glutamate is rapidly removed from the synapse by excitatory amino acid transporters (EAATs). Changes in the expression and localization of the primary glutamate transporter EAAT2 are found in the brain in central nervous system (CNS) disorders including SCZ. We hypothesize that neuronal expression and function of EAAT2 are increased in the frontal cortex in subjects diagnosed with SCZ.

Study design: EAAT2 protein expression and glutamate transporter function were assayed in synaptosome preparations from the dorsolateral prefrontal cortex (DLPFC) of SCZ subjects and age- and sex-matched nonpsychiatrically ill controls. EAAT2 splice variant transcript expression was assayed in enriched populations of neurons and astrocytes from the DLPFC. Pathway analysis of publicly available transcriptomic datasets was carried out to identify biological changes associated with EAAT2 perturbation in different cell types.

Results: We found no significant changes in EAAT2 protein expression or glutamate uptake in the DLPFC in SCZ subjects compared with controls (n = 10/group). Transcript expression of EAAT2 and signaling molecules associated with EAAT2b trafficking (CaMKIIa and DLG1) were significantly altered in enriched populations of astrocytes and pyramidal neurons (P < .05) in SCZ (n = 16/group). These changes were not associated with antipsychotic medications. Pathway analysis also identified cell-type-specific enrichment of biological pathways associated with perturbation of astrocyte (immune pathways) and neuronal (metabolic pathways) EAAT2 expression.

Conclusions: Overall, these data support the growing body of evidence for the role of dysregulation of the glutamate system in the pathophysiology of SCZ.

Background and hypothesis: The ClozaGene Study is a nationwide cohort of adults who have been treated with clozapine. While clozapine is indicated in the management of treatment-resistant schizophrenia, it is associated with a considerable adverse drug reaction (ADR) burden, and not all patients achieve adequate symptomatic response. The current study focuses on self-reported experiences of clozapine use and response, clozapine-associated ADRs, and mental health comorbidity.

Study design: A total of 1021 participants (41.0% female; aged 46.2 ± 10.6 years [range 18-66]) were recruited via a mail-out based on prescriptions for clozapine. Participants completed a self-report questionnaire.

Study results: Most participants (90.1%, n = 912) were living with schizophrenia while 41.5% reported a lifetime diagnosis of depression, 15.6% bipolar disorder, and 8.1% schizoaffective disorder. Clozapine was currently prescribed to 944 (92.5%) participants and 37.8% of these participants self-reported currently taking additional antipsychotic medication. Nearly 3 quarters of participants living with schizophrenia reported that clozapine helped control their schizophrenia symptoms moderately to very well. The most commonly reported ADRs were sialorrhea (80.3%), weight gain (71.0%), constipation (56.9%), and sedation (52.8%). The prevalence of clozapine cessation due to clozapine-induced myocarditis and neutropenia was 1% and 0.4%, respectively.

Conclusions: Our findings highlight the high rate of psychotic and metabolic symptoms and ADRs among adults prescribed clozapine in the general Australian population. Future genomic analyses will focus on identifying genetic variants influencing clozapine treatment response and side effects.

Background and hypothesis: Schizophrenia (SZ) is characterized by significant cognitive and behavioral disruptions. Neuroimaging techniques, particularly magnetic resonance imaging (MRI), have been widely utilized to investigate biomarkers of SZ, distinguish SZ from healthy conditions or other mental disorders, and explore biotypes within SZ or across SZ and other mental disorders, which aim to promote the accurate diagnosis of SZ. In China, research on SZ using MRI has grown considerably in recent years.

Study design: The article reviews advanced neuroimaging and artificial intelligence (AI) methods using single-modal or multimodal MRI to reveal the mechanism of SZ and promote accurate diagnosis of SZ, with a particular emphasis on the achievements made by Chinese scholars around the past decade.

Study results: Our article focuses on the methods for capturing subtle brain functional and structural properties from the high-dimensional MRI data, the multimodal fusion and feature selection methods for obtaining important and sparse neuroimaging features, the supervised statistical analysis and classification for distinguishing disorders, and the unsupervised clustering and semi-supervised learning methods for identifying neuroimage-based biotypes. Crucially, our article highlights the characteristics of each method and underscores the interconnections among various approaches regarding biomarker extraction and neuroimage-based diagnosis, which is beneficial not only for comprehending SZ but also for exploring other mental disorders.

Conclusions: We offer a valuable review of advanced neuroimage analysis and AI methods primarily focused on SZ research by Chinese scholars, aiming to promote the diagnosis, treatment, and prevention of SZ, as well as other mental disorders, both within China and internationally.