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Innovations in Clinical Neuroscience 2024
Responding to Correspondence on "Clinical Outcome Assessment Instruments in Schizophrenia: A Scoping Literature Review with a Focus on the Potential of Patient-reported Outcomes".
PubMed: 38938536
DOI: No ID Found -
Schizophrenia Research Jun 2024The cognitive model of negative symptoms of schizophrenia suggests that defeatist performance beliefs (DPB), or overgeneralized negative beliefs about one's performance,...
BACKGROUND
The cognitive model of negative symptoms of schizophrenia suggests that defeatist performance beliefs (DPB), or overgeneralized negative beliefs about one's performance, are an intermediary variable along the pathway from impaired neurocognitive performance to negative symptoms and functioning in daily life. Although reliable associations between these variables have been established in chronic schizophrenia, less is known about the nature of these relationships in recent-onset schizophrenia (ROSz). This current study tested the associations between DPB and variables in the cognitive model (neurocognitive performance, negative symptoms, functioning) as well as mediation by DPB of the association between neurocognitive performance and negative symptoms in ROSz.
METHODS
A total of 52 participants (32 adults with ROSz and 20 non-psychiatric healthy comparators; HC) completed in-lab measures of neurocognitive performance, self-reported defeatist performance beliefs, and clinician administered measures of negative symptoms and functional outcome. Bivariate relationships among these variables were tested with Pearson correlations. Bootstrapped regression analyses were conducted to test the strength of the indirect effect of neurocognitive performance on negative symptoms through DPB.
RESULTS
Defeatist performance beliefs were significantly elevated in ROSz, and were associated with neurocognitive performance, negative symptoms, and functional outcome as predicted by the cognitive model. There was a significant indirect effect of neurocognition on experiential negative symptoms through DPB, indicating DPB are a partial mediator of the relationship between neurocognitive performance and negative symptoms.
CONCLUSION
These findings are consistent with the cognitive model of negative symptoms and extend previous findings in both ROSz and established schizophrenia. Specifically, these data demonstrate that DPB are elevated among ROSz and the associations with neurocognition and clinical outcomes (e.g., negative symptoms and functioning) are of similar magnitude to those reported in chronic schizophrenia. DPB may therefore be a viable treatment target in the early course of illness.
PubMed: 38924939
DOI: 10.1016/j.schres.2024.06.021 -
JAMA Network Open Jun 2024The ELEKT-D: Electroconvulsive Therapy (ECT) vs Ketamine in Patients With Treatment Resistant Depression (TRD) (ELEKT-D) trial demonstrated noninferiority of intravenous... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
The ELEKT-D: Electroconvulsive Therapy (ECT) vs Ketamine in Patients With Treatment Resistant Depression (TRD) (ELEKT-D) trial demonstrated noninferiority of intravenous ketamine vs ECT for nonpsychotic TRD. Clinical features that can guide selection of ketamine vs ECT may inform shared decision-making for patients with TRD.
OBJECTIVE
To evaluate whether selected clinical features were associated with differential improvement with ketamine vs ECT.
DESIGN, SETTING, AND PARTICIPANTS
This secondary analysis of an open-label noninferiority randomized clinical trial was a multicenter study conducted at 5 US academic medical centers from April 7, 2017, to November 11, 2022. Analyses for this study, which were not prespecified in the trial protocol, were conducted from May 10 to Oct 31, 2023. The study cohort included patients with TRD, aged 21 to 75 years, who were in a current nonpsychotic depressive episode of at least moderate severity and were referred for ECT by their clinicians.
EXPOSURES
Eligible participants were randomized 1:1 to receive either 6 infusions of ketamine or 9 treatments with ECT over 3 weeks.
MAIN OUTCOMES AND MEASURES
Association between baseline factors (including 16-item Quick Inventory of Depressive Symptomatology Self-Report [QIDS-SR16], Montgomery-Asberg Depression Rating Scale [MADRS], premorbid intelligence, cognitive function, history of attempted suicide, and inpatient vs outpatient status) and treatment response were assessed with repeated measures mixed-effects model analyses.
RESULTS
Among the 365 participants included in this study (mean [SD] age, 46.0 [14.5] years; 191 [52.3%] female), 195 were randomized to the ketamine group and 170 to the ECT group. In repeated measures mixed-effects models using depression levels over 3 weeks and after false discovery rate adjustment, participants with a baseline QIDS-SR16 score of 20 or less (-7.7 vs -5.6 points) and those starting treatment as outpatients (-8.4 vs -6.2 points) reported greater reduction in the QIDS-SR16 with ketamine vs ECT. Conversely, those with a baseline QIDS-SR16 score of more than 20 (ie, very severe depression) and starting treatment as inpatients reported greater reduction in the QIDS-SR16 earlier in course of treatment (-8.4 vs -6.7 points) with ECT, but scores were similar in both groups at the end-of-treatment visit (-9.0 vs -9.9 points). In the ECT group only, participants with higher scores on measures of premorbid intelligence (-14.0 vs -11.2 points) and with a comorbid posttraumatic stress disorder diagnosis (-16.6 vs -12.0 points) reported greater reduction in the MADRS score. Those with impaired memory recall had greater reduction in MADRS during the second week of treatment (-13.4 vs -9.6 points), but the levels of MADRS were similar to those with unimpaired recall at the end-of-treatment visit (-14.3 vs -12.2 points). Other results were not significant after false discovery rate adjustment.
CONCLUSIONS AND RELEVANCE
In this secondary analysis of the ELEKT-D randomized clinical trial of ECT vs ketamine, greater improvement in depression was observed with intravenous ketamine among outpatients with nonpsychotic TRD who had moderately severe or severe depression, suggesting that these patients may consider ketamine over ECT for TRD.
Topics: Humans; Ketamine; Electroconvulsive Therapy; Female; Male; Middle Aged; Depressive Disorder, Treatment-Resistant; Adult; Aged; Treatment Outcome
PubMed: 38916891
DOI: 10.1001/jamanetworkopen.2024.17786 -
Journal of Immunology (Baltimore, Md. :... Jun 2024We analyzed bulk RNA sequencing and single-cell RNA sequencing (scRNA-seq) data to identify alternative splicing (AS) events and regulatory RNA-binding proteins (RBPs)...
We analyzed bulk RNA sequencing and single-cell RNA sequencing (scRNA-seq) data to identify alternative splicing (AS) events and regulatory RNA-binding proteins (RBPs) associated with immune infiltration in human laryngeal squamous cell carcinoma (LSCC). Whole-transcriptome sequencing data of 20 human laryngeal cancer and paracancerous tissues were downloaded from the Gene Expression Omnibus public database, using newly published splicing-site usage variation analysis software to obtain highly conserved regulated AS (RAS) events, and scientific reverse convolution algorithm analysis was used to identify significantly different immune cells and perform a correlation analysis between the two. The software package edgeR was used to identify differentially expressed RBPs and the immune infiltration-related LSCC-RAS they may regulate. Finally, we present the expression profiles and survival curves of 117 human laryngeal cancer samples from The Cancer Genome Atlas dataset for the identified RBPs and LSCC-RAS. We also downloaded the gene set enrichment 150321 scRNA-seq data for two human LSCC tissue samples. The RBP expression pattern and the expression of prophase RBP genes were analyzed in different LSCC cell populations. RNA-binding motif protein 47 (RBM47) and filamin A, as well as the RBP-RAS events that were screened in both the fibulin 2 and fibronectin 1 genes, were all significantly associated with the prognosis, and the RBM47 gene was upregulated in myeloid cells. Because the prognosis was significantly associated with two RBP regulators and two LSCC-RAS events, they may be critical regulators of immune cell survival during laryngeal cancer progression, and RBM47 may regulate macrophage-associated AS and affect immunity.
PubMed: 38912837
DOI: 10.4049/jimmunol.2300498 -
Neuropsychiatric Disease and Treatment 2024Schizophrenia is most times a chronic and often debilitating illness associated with poor mental health outcomes. Early and effective treatment of schizophrenia in the... (Review)
Review
BACKGROUND
Schizophrenia is most times a chronic and often debilitating illness associated with poor mental health outcomes. Early and effective treatment of schizophrenia in the most appropriate setting can make a significant difference in the long-term recovery. The aim of this narrative review was to provide suggestions and recommendations for effectively managing patients with schizophrenia during acute exacerbations and to enhance awareness and skills related to personalized medicine.
METHODS
A panel of academics and clinicians with experience in the field of psychosis met virtually on July 13 2023 to narratively review and discuss the research evidence and their clinical experience about the most appropriate acute treatments for patients with schizophrenia. This manuscript represents a synthesis of the panel analysis and discussion.
RESULTS
First contact is very important for service users, as is finding the most adequate treatment setting. If patients present to the emergency department, which may be a traumatic setting for service users, a dedicated environment with adequate space and specialized mental health support, including personnel trained in de-escalation techniques, is recommended. A well-connected continuum of care is strongly recommended, possibly with seamless links between inpatient units, day hospital services, outpatient facilities and rehabilitation services. Ideally, this should be structured as part of a coordinated step-down service line. Treatment challenges include suboptimal response, side effects, and nonadherence, which is reduced by the use of long-acting injectable antipsychotics.
CONCLUSION
Individual circumstances, including age, gender, and presence of hostility/aggression or self-harm, cognitive impairment and negative symptoms, comorbidities (depression, substance use disorders) or associated symptoms (anxiety, insomnia), should be considered when selecting the most appropriate treatment for the acute phase of schizophrenia. Efficacy and feasibility, as well as acceptability and tolerability of treatments, require joint consideration from the early stages of schizophrenia, thereby enhancing the possibility of improved short- and long-term outcomes.
PubMed: 38911102
DOI: 10.2147/NDT.S459450 -
Schizophrenia Research Jun 2024Antipsychotic polypharmacy (APP) is frequent but evidence-based guidelines on reducing APP to antipsychotic monotherapy (APM) are sparse. We aimed to systematically...
BACKGROUND
Antipsychotic polypharmacy (APP) is frequent but evidence-based guidelines on reducing APP to antipsychotic monotherapy (APM) are sparse. We aimed to systematically review clinical interventions randomizing patients to reducing APP to APM versus continuing APP.
METHODS
Systematic literature review searching Medline and Embase (latest search January 10, 2024) for randomized clinical trials (RCTs) studying interventions comparing individuals randomized to reduction of APP to APM with individuals continuing on APP. Two independent reviewers performed the literature screening, data extraction, and risk of bias assessment (RoB2). We performed random effects meta-analyses on the main outcome all-cause discontinuation/"acceptability" of the treatment strategy and secondary outcomes change in psychopathology, functional level, and side effects.
RESULTS
The search identified 4672 hits, whereof 8 trials (N = 1204, 6 patient-level RCTs and 2 cluster-RCTs) were included, primarily in patients with schizophrenia. All trials were associated with high risk of bias. Compared to APP continuation, reduction to APM was associated with no significant change in all-cause discontinuation (studies = 6, n = 455, RR = 1.48, 95%CI = 0.74-2.95, I = 78 %) or inefficacy-related discontinuation (studies = 5, n = 351, RR = 1.60, 95%CI = 0.46-5.55, I = 70 %). Patients randomized to APM showed a trend towards greater reduction in psychopathology (studies = 5, n = 244, SMD = -0.24, 95%CI = -0.49, 0.02, I = 0 %) but no difference in functional level nor side effects. The cluster-RCTs found that interventions at the departmental level can result in lower rates of APP.
CONCLUSION
Although switching patients from APP to APM can be a viable approach, too few RCTs exist on this important topic. Clinicians need to evaluate potential benefits and risks of APP and APM on an individual basis.
PROSPERO REGISTRATION
CRD42022329955.
PubMed: 38908279
DOI: 10.1016/j.schres.2024.06.001 -
International Journal of Biological... 2024Cysteine-rich angiogenic inducer 61 (CYR61), also called CCN1, has long been characterized as a secretory protein. Nevertheless, the intracellular function of CYR61...
Cysteine-rich angiogenic inducer 61 (CYR61), also called CCN1, has long been characterized as a secretory protein. Nevertheless, the intracellular function of CYR61 remains unclear. Here, we found that CYR61 is important for proper cell cycle progression. Specifically, CYR61 interacts with microtubules and promotes microtubule polymerization to ensure mitotic entry. Moreover, CYR61 interacts with PLK1 and accumulates during the mitotic process, followed by degradation as mitosis concludes. The proteolysis of CYR61 requires the PLK1 kinase activity, which directly phosphorylates two conserved motifs on CYR61, enhancing its interaction with the SCF E3 complex subunit FBW7 and mediating its degradation by the proteasome. Mutations of phosphorylation sites of Ser167 and Ser188 greatly increase CYR61's stability, while deletion of CYR61 extends prophase and metaphase and delays anaphase onset. In summary, our findings highlight the precise control of the intracellular CYR61 by the PLK1-FBW7 pathway, accentuating its significance as a microtubule-associated protein during mitotic progression.
Topics: Protein Serine-Threonine Kinases; Humans; Polo-Like Kinase 1; Mitosis; Cell Cycle Proteins; Proto-Oncogene Proteins; Cysteine-Rich Protein 61; Microtubules; F-Box-WD Repeat-Containing Protein 7; HeLa Cells; Phosphorylation; Ubiquitin-Protein Ligases; Microtubule-Associated Proteins
PubMed: 38904029
DOI: 10.7150/ijbs.93335 -
BioRxiv : the Preprint Server For... Mar 2024When germ cells transition from the mitotic cycle into meiotic prophase I (MPI), chromosomes condense into an array of chromatin loops that are required to promote...
When germ cells transition from the mitotic cycle into meiotic prophase I (MPI), chromosomes condense into an array of chromatin loops that are required to promote homolog pairing and genetic recombination. To identify the changes in chromosomal conformation, we isolated nuclei on a trajectory from spermatogonia to the end of MPI. At each stage along this trajectory, we built genomic interaction maps with the highest temporal and spatial resolution to date. The changes in chromatin folding coincided with a concurrent decline in mitotic cohesion and a rise in meiotic cohesin complexes. We found that the stereotypical large-scale A and B compartmentalization was lost during meiotic prophase I alongside the loss of topological associating domains (TADs). Still, local subcompartments were detected and maintained throughout meiosis. The enhanced Micro-C resolution revealed that, despite the loss of TADs, higher frequency contact sites between two loci were detectable during meiotic prophase I coinciding with CTCF bound sites. The pattern of interactions around these CTCF sites with their neighboring loci showed that CTCF sites were often anchoring the meiotic loops. Additionally, the localization of CTCF to the meiotic axes indicated that these anchors were at the base of loops. Strikingly, even in the face of the dramatic reconfiguration of interphase chromatin into a condensed loop-array, the interactions between regulatory elements remained well preserved. This establishes a potential mechanism for how the meiotic chromatin maintains active transcription within a highly structured genome. In summary, the high temporal and spatial resolution of these data revealed previously unappreciated aspects of mammalian meiotic chromatin organization.
PubMed: 38903112
DOI: 10.1101/2024.03.25.586627 -
Psychiatry Research Jun 2024The risk of fatal choking for people with schizophrenia and associations with antipsychotic medication are largely unknown. Therefore, we calculated the choking-related...
The risk of fatal choking for people with schizophrenia and associations with antipsychotic medication are largely unknown. Therefore, we calculated the choking-related standardized mortality ratio for schizophrenia relative to the general population (SMR). We also computed adjusted hazard ratios (aHR) of choking-related mortality for antipsychotics in a nationwide cohort of patients with schizophrenia (N = 59,916). SMR was 20.5 (95 % confidence interval (CI)=17.1-23.9). The aHR was 1.74 (95 %CI=1.19-2.55) for strong dopamine 2-antagonists. For other antipsychotics, CIs included 1. Importantly, aHRs were particularly high for high dose categories of strong dopamine D2 receptor (D2R) antagonists. In conclusion, a schizophrenia diagnosis is associated with a 20-fold risk of death due to choking. This risk is elevated during use of strong D2R antagonist antipsychotics, particularly when prescribed in high dosages.
PubMed: 38901365
DOI: 10.1016/j.psychres.2024.116012 -
Experimental Cell Research Jul 2024Mouse HORMAD1 is a phospho-protein involved in multiple functions during meiotic prophase I. To obtain insight into the significance of its phosphorylation, we generated...
Mouse HORMAD1 is a phospho-protein involved in multiple functions during meiotic prophase I. To obtain insight into the significance of its phosphorylation, we generated phospho-specific antibodies against two serine residues, Ser307 and Ser378, representing each of two serine clusters in mouse HORMAD1. The Ser307 phosphorylation is detectable from early leptotene substage in both wild-type and Spo11 spermatocytes, indicating that Ser307 is a primary and SPO11-independent phosphorylation site. In contrast, the Ser378 phosphorylation is negligible at earlier substages in wild-type and Spo11 spermatocytes. After mid-zygotene substage, the Ser378 phosphorylation is abundant on unsynapsed chromosome axes in wild-type spermatocytes and is detected only in a part of unsynapsed chromosome axes in Spo11 spermatocytes. We also generated a non-phosphorylated Ser307-specific antibody and found that Ser307 is phosphorylated on sex chromosome axes but is almost entirely unphosphorylated on desynapsed chromosome axes in diplotene spermatocytes. These results demonstrated a substage-specific phosphorylation status of mouse HORMAD1, which might be associated with multiple substage-specific functions.
Topics: Animals; Meiotic Prophase I; Phosphorylation; Male; Mice; Serine; Spermatocytes; Endodeoxyribonucleases; Mice, Inbred C57BL; Cell Cycle Proteins; Mice, Knockout; Sex Chromosomes
PubMed: 38897409
DOI: 10.1016/j.yexcr.2024.114133