Schizophrenia Research最新文献_第6页

Intentional non-adherence to antipsychotic medication in patients with schizophrenia 精神分裂症患者故意不坚持服用抗精神病药物的情况

IF 3.6 2区医学 Q1 PSYCHIATRY

Schizophrenia Research

Pub Date : 2024-11-05 DOI: 10.1016/j.schres.2024.10.018

Hodaka Yaegashi , Mizuki Haga , Fuminari Misawa , Yuya Mizuno , Takefumi Suzuki , Hiroyoshi Takeuchi

Background

Although adherence to antipsychotic medication is critical in the treatment of schizophrenia, prior studies have not adequately distinguished between intentional and unintentional non-adherence.

Methods

This study included outpatients with schizophrenia. Self-reported intentional non-adherence was assessed cross-sectionally using the Japanese version of the Intentional Non-Adherence Scale (INAS-J). Item G12 of the Positive and Negative Syndrome Scale (PANSS), Medication Possession Ratio (MPR), psychiatric symptoms, side effects, and medication status were also assessed. An exploratory factor analysis was carried out to examine the factor structure of the INAS. Multiple regression analyses were conducted to examine factors associated with intentional non-adherence.

Results

A total of 93 patients were included. The mean ± SD of INAS total score was 36.6 ± 16.2 (out of a maximum score of 110), with 33 subjects (35.5 %) having a minimum score of 22. The mean MPR was 98.2 ± 10.0 %, and the mean score for PANSS G12 was 1.8 ± 1.1. These suggested that they had well-preserved illness insight and good medication adherence. Exploratory factor analysis of the INAS revealed two factors, “Concern about medication” and “Confirming medication need”. No variables were significantly associated with the INAS total score.

Conclusions

This is the first study to evaluate intentional non-adherence in patients with schizophrenia. Intentional non-adherence was low in this population. Our findings should be interpreted in the context of patients presenting with relatively well-preserved insight and good medication adherence. Further investigations using the INAS are warranted to examine intentional non-adherence in patients with more diverse backgrounds.

背景虽然抗精神病药物治疗的依从性对精神分裂症的治疗至关重要，但之前的研究并未充分区分有意和无意的不依从性。采用日文版有意不依从量表（INAS-J）对自我报告的有意不依从进行横断面评估。此外，还评估了阳性和阴性综合征量表（PANSS）的 G12 项、药物持有率（MPR）、精神症状、副作用和用药状况。对 INAS 进行了探索性因素分析，以研究其因素结构。结果共纳入 93 名患者。INAS 总分的平均值（± SD）为 36.6 ± 16.2（最高分 110 分），其中 33 名受试者（35.5%）的最低分为 22 分。MPR的平均值为98.2 ± 10.0 %，PANSS G12的平均值为1.8 ± 1.1。这表明他们对疾病的洞察力保持良好，对药物的依从性也很好。对 INAS 进行探索性因子分析后发现了两个因子，即 "关注药物治疗 "和 "确认药物治疗需求"。结论这是第一项评估精神分裂症患者故意不坚持服药情况的研究。在这一人群中，故意不坚持用药的比例较低。我们的研究结果应结合患者相对较好的洞察力和良好的服药依从性来解释。有必要使用 INAS 进行进一步调查，以研究具有更多不同背景的患者的有意不依从性。

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引用次数: 0

A novel digital intervention for improving cognitive impairment in patients with chronic schizophrenia: A randomized clinical trial 改善慢性精神分裂症患者认知障碍的新型数字干预：随机临床试验

IF 3.6 2区医学 Q1 PSYCHIATRY

Schizophrenia Research

Pub Date : 2024-11-05 DOI: 10.1016/j.schres.2024.10.023

Lingzi Xu , Wenjing Yang , Ruoxin Fan , Yingying Wu , Yajing Tang , Ruobing Zhang , Xianmei Yang

Background

There is an unmet need for stand-alone digital therapeutics for cognitive impairment in schizophrenia. This study aimed to evaluate the efficacy and acceptability of a novel digital therapeutic, IBT-SC02, for cognitive impairment in stable schizophrenia patients.

Methods

A randomized, parallel-group trial was conducted at the Sichuan Province Institute of Mental Health, China. Participants aged 18–50 diagnosed with schizophrenia were randomized to either the IBT-SC02 intervention or a wait-list control. The primary outcome was cognitive performance measured using the MATRICS Consensus Cognitive Battery (MCCB) composite score.

Results

A total of 80 patients were randomized (40 intervention, 40 control). The dropout rate was 5 %. The intervention group exhibited significant improvements in the MCCB composite score compared to the control, though the improvement lessened after excluding data collected by unmasked raters. Post-hoc analyses revealed that participants in the intervention group improved in four out of the seven MCCB domains (speed of processing, verbal learning, visual learning and reasoning and problem solving). No adverse events were reported.

Conclusions

These results suggest that IBT-SC02, a fully automated digital therapeutic, improved cognitive performance in patients with stable schizophrenia and can potentially be a treatment option for patients without access to trained professionals.

背景独立数字疗法治疗精神分裂症认知障碍的需求尚未得到满足。本研究旨在评估新型数字疗法 IBT-SC02 对稳定型精神分裂症患者认知障碍的疗效和可接受性。年龄在18-50岁之间的精神分裂症患者被随机分为IBT-SC02干预组和等待对照组。主要结果是认知表现，采用MATRICS共识认知电池（MCCB）综合评分进行测量。辍学率为 5%。与对照组相比，干预组患者的 MCCB 综合得分有了明显提高，但在排除了未蒙面评分者收集的数据后，提高幅度有所减小。事后分析显示，干预组的参与者在 MCCB 七个领域中的四个领域（处理速度、语言学习、视觉学习、推理和问题解决）都有所改善。结论这些结果表明，IBT-SC02 是一种全自动数字治疗方法，它可以改善稳定期精神分裂症患者的认知能力，并有可能成为无法获得训练有素的专业人员治疗的患者的一种治疗选择。

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引用次数: 0

Modeling common and rare genetic risk factors of neuropsychiatric disorders in human induced pluripotent stem cells 在人类诱导多能干细胞中模拟神经精神疾病的常见和罕见遗传风险因素。

IF 3.6 2区医学 Q1 PSYCHIATRY

Schizophrenia Research

Pub Date : 2024-11-01 DOI: 10.1016/j.schres.2022.04.003

Abdurrahman W. Muhtaseb , Jubao Duan

Recent genome-wide association studies (GWAS) and whole-exome sequencing of neuropsychiatric disorders, especially schizophrenia, have identified a plethora of common and rare disease risk variants/genes. Translating the mounting human genetic discoveries into novel disease biology and more tailored clinical treatments is tied to our ability to causally connect genetic risk variants to molecular and cellular phenotypes. When combined with the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated (Cas) nuclease-mediated genome editing system, human induced pluripotent stem cell (hiPSC)-derived neural cultures (both 2D and 3D organoids) provide a promising tractable cellular model for bridging the gap between genetic findings and disease biology. In this review, we first conceptualize the advances in understanding the disease polygenicity and convergence from the past decade of iPSC modeling of different types of genetic risk factors of neuropsychiatric disorders. We then discuss the major cell types and cellular phenotypes that are most relevant to neuropsychiatric disorders in iPSC modeling. Finally, we critically review the limitations of iPSC modeling of neuropsychiatric disorders and outline the need for implementing and developing novel methods to scale up the number of iPSC lines and disease risk variants in a systematic manner. Sufficiently scaled-up iPSC modeling and a better functional interpretation of genetic risk variants, in combination with cutting-edge CRISPR/Cas9 gene editing and single-cell multi-omics methods, will enable the field to identify the specific and convergent molecular and cellular phenotypes in precision for neuropsychiatric disorders.

最近的全基因组关联研究（GWAS）和神经精神疾病，特别是精神分裂症的全外显子组测序，已经确定了大量常见和罕见疾病风险变异/基因。将越来越多的人类基因发现转化为新的疾病生物学和更具针对性的临床治疗，与我们将遗传风险变异与分子和细胞表型因果联系起来的能力息息相关。当与聚集性规则间隔短回文重复序列（CRISPR）/CRISPR相关（Cas）核酸酶介导的基因组编辑系统相结合时，人类诱导多能干细胞（hiPSC）衍生的神经培养物（2D和3D类器官）为弥合遗传发现和疾病生物学之间的差距提供了一个有前途的可处理的细胞模型。在这篇综述中，我们首先概念化了过去十年对神经精神疾病不同类型遗传风险因素的iPSC建模在理解疾病多原性和趋同方面的进展。然后，我们讨论了iPSC建模中与神经精神疾病最相关的主要细胞类型和细胞表型。最后，我们批判性地回顾了神经精神障碍iPSC建模的局限性，并概述了实施和开发新方法的必要性，以系统的方式扩大iPSC系和疾病风险变体的数量。充分放大的iPSC建模和对遗传风险变体的更好功能解释，结合尖端的CRISPR/Cas9基因编辑和单细胞多组学方法，将使该领域能够准确识别神经精神疾病的特异性和收敛性分子和细胞表型。

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引用次数: 0

Cell line specific alterations in genes associated with dopamine metabolism and signaling in midbrain dopaminergic neurons derived from 22q11.2 deletion carriers with elevated dopamine synthesis capacity 22q11.2 缺失携带者中脑多巴胺能神经元的多巴胺代谢和信号转导相关基因的细胞系特异性改变，这些携带者的多巴胺合成能力较强。

IF 3.6 2区医学 Q1 PSYCHIATRY

Schizophrenia Research

Pub Date : 2024-11-01 DOI: 10.1016/j.schres.2022.05.010

Matthew J. Reid , Maria Rogdaki , Lucia Dutan , Bjørn Hanger , Kaarin Sabad , Roland Nagy , Dwaipayan Adhya , Simon Baron-Cohen , Grainne McAlonan , Jack Price , Anthony C. Vernon , Oliver D. Howes , Deepak P. Srivastava

Microdeletions at the 22q11.2 locus are associated with increased risk for schizophrenia. Recent work has demonstrated that antipsychotic naïve 22q11.2 carriers display elevated levels of dopamine synthesis capacity (DSC) as assessed by ¹⁸F-DOPA PET imaging. While this is consistent with a role for abnormal dopamine function in schizophrenia, it is unclear what molecular changes may be associated with this neuro-imaging endophenotype, and moreover, if these alterations occur independently of clinical presentation. We therefore conducted a pilot study in which we generated human induced pluripotent stem cells (hiPSCs) from two 22q11.2 deletion carriers with elevated DSC in vivo, but distinct clinical presentations. From these and neurotypical control lines we were able to robustly generate midbrain dopaminergic neurons (mDA-neurons). We then assessed whether genes associated with dopamine synthesis, metabolism or signaling show altered expression between genotypes and further between the 22q11.2 deletion lines. Our data showed alterations in expression of genes associated with dopamine metabolism and signaling that differed between the two 22q11.2 hiPSC lines with distinct clinical presentations. This reinforces the importance of considering clinical, genetic and molecular information, when possible, when choosing which donors to generate hiPSCs from, to carry out mechanistic studies.

22q11.2 基因座的微缺失与精神分裂症风险的增加有关。最近的研究表明，通过 18F-DOPA PET 成像评估，抗精神病药物天真 22q11.2 基因携带者的多巴胺合成能力（DSC）水平升高。虽然这与多巴胺功能异常在精神分裂症中的作用一致，但目前还不清楚这种神经影像学终末表型可能与哪些分子变化有关，更不清楚这些变化是否与临床表现无关。因此，我们进行了一项试验性研究，从两个体内DSC升高但临床表现不同的22q11.2缺失携带者体内产生了人类诱导多能干细胞（hiPSCs）。从这些细胞系和神经典型对照细胞系中，我们能够稳健地生成中脑多巴胺能神经元（mDA-neurons）。然后，我们评估了与多巴胺合成、代谢或信号转导相关的基因在不同基因型之间以及进一步在 22q11.2 缺失系之间的表达是否发生了改变。我们的数据显示，与多巴胺代谢和信号转导相关的基因表达发生了改变，这在具有不同临床表现的两个 22q11.2 hiPSC 株系之间存在差异。这进一步说明，在选择供体生成 hiPSCs 以进行机理研究时，尽可能考虑临床、遗传和分子信息非常重要。

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引用次数: 0

Probing the biological consequences of a previously undescribed de novo mutation of ZMYND11 in a schizophrenia patient by CRISPR genome editing and induced pluripotent stem cell based in vitro disease-modeling 通过 CRISPR 基因组编辑和基于体外疾病模型的诱导多能干细胞，探究精神分裂症患者体内 ZMYND11 基因突变的生物学后果

IF 3.6 2区医学 Q1 PSYCHIATRY

Schizophrenia Research

Pub Date : 2024-11-01 DOI: 10.1016/j.schres.2024.01.024

Csongor Tordai , Edit Hathy , Hella Gyergyák , Katalin Vincze , Máté Baradits , Júlia Koller , Ádám Póti , Bálint Jezsó , László Homolya , Mária Judit Molnár , László Nagy , Dávid Szüts , Ágota Apáti , János M. Réthelyi

Background

Schizophrenia (SCZ) is a severe neuropsychiatric disorder of complex, poorly understood etiology, associated with both genetic and environmental factors. De novo mutations (DNMs) represent a new source of genetic variation in SCZ, however, in most cases their biological significance remains unclear. We sought to investigate molecular disease pathways connected to DNMs in SCZ by combining human induced pluripotent stem cell (hiPSC) based disease modeling and CRISPR-based genome editing.

Methods

We selected a SCZ case-parent trio with the case individual carrying a potentially disease causing 1495C > T nonsense DNM in the zinc finger MYND domain-containing protein 11 (ZMYND11), a gene implicated in biological processes relevant for SCZ. In the patient-derived hiPSC line the mutation was corrected using CRISPR, while monoallelic or biallelic frameshift mutations were introduced into a control hiPSC line. Isogenic cell lines were differentiated into hippocampal neuronal progenitor cells (NPCs) and functionally active dentate gyrus granule cells (DGGCs). Immunofluorescence microscopy and RNA sequencing were used to test for morphological and transcriptomic differences at NPC and DGCC stages. Functionality of neurons was investigated using calcium-imaging and multi-electrode array measurements.

Results

Morphology in the mutant hippocampal NPCs and neurons was preserved, however, we detected significant transcriptomic and functional alterations. RNA sequencing showed massive upregulation of neuronal differentiation genes, and downregulation of cell adhesion genes. Decreased reactivity to glutamate was demonstrated by calcium-imaging.

Conclusions

Our findings lend support to the involvement of glutamatergic dysregulation in the pathogenesis of SCZ. This approach represents a powerful model system for precision psychiatry and pharmacological research.

背景精神分裂症（SCZ）是一种严重的神经精神疾病，其病因复杂且不甚明了，与遗传和环境因素都有关系。新发突变（DNMs）是精神分裂症遗传变异的新来源，但在大多数情况下，其生物学意义仍不清楚。我们试图通过结合基于疾病建模的人类诱导多能干细胞（hiPSC）和基于CRISPR的基因组编辑，研究与SCZ中DNMs相关的分子疾病通路。方法我们选择了一个SCZ病例-父母三人组，病例个体携带锌指MYND结构域含蛋白11（ZMYND11）中可能致病的1495C >T无义DNM，该基因与SCZ相关的生物过程有牵连。在患者来源的 hiPSC 株系中，使用 CRISPR 对突变进行了校正，同时在对照 hiPSC 株系中引入了单拷贝或双拷贝移帧突变。同源细胞系被分化成海马神经元祖细胞（NPC）和功能活跃的齿状回颗粒细胞（DGGC）。免疫荧光显微镜和 RNA 测序用于检测 NPC 和 DGCC 阶段的形态学和转录组差异。结果突变体海马 NPCs 和神经元的形态保持不变，但我们检测到了显著的转录组和功能改变。RNA 测序显示神经元分化基因大量上调，细胞粘附基因下调。结论我们的研究结果支持谷氨酸能失调参与 SCZ 的发病机制。这种方法为精准精神病学和药理学研究提供了一个强大的模型系统。

{"title":"Probing the biological consequences of a previously undescribed de novo mutation of ZMYND11 in a schizophrenia patient by CRISPR genome editing and induced pluripotent stem cell based in vitro disease-modeling","authors":"Csongor Tordai , Edit Hathy , Hella Gyergyák , Katalin Vincze , Máté Baradits , Júlia Koller , Ádám Póti , Bálint Jezsó , László Homolya , Mária Judit Molnár , László Nagy , Dávid Szüts , Ágota Apáti , János M. Réthelyi","doi":"10.1016/j.schres.2024.01.024","DOIUrl":"10.1016/j.schres.2024.01.024","url":null,"abstract":"<div><h3>Background</h3><div>Schizophrenia (SCZ) is a severe neuropsychiatric disorder of complex, poorly understood etiology, associated with both genetic and environmental factors. De novo mutations (DNMs) represent a new source of genetic variation in SCZ, however, in most cases their biological significance remains unclear. We sought to investigate molecular disease pathways connected to DNMs in SCZ by combining human induced pluripotent stem cell (hiPSC) based disease modeling and CRISPR-based genome editing.</div></div><div><h3>Methods</h3><div>We selected a SCZ case-parent trio with the case individual carrying a potentially disease causing 1495C > T nonsense DNM in the zinc finger MYND domain-containing protein 11 (ZMYND11), a gene implicated in biological processes relevant for SCZ. In the patient-derived hiPSC line the mutation was corrected using CRISPR, while monoallelic or biallelic frameshift mutations were introduced into a control hiPSC line. Isogenic cell lines were differentiated into hippocampal neuronal progenitor cells (NPCs) and functionally active dentate gyrus granule cells (DGGCs). Immunofluorescence microscopy and RNA sequencing were used to test for morphological and transcriptomic differences at NPC and DGCC stages. Functionality of neurons was investigated using calcium-imaging and multi-electrode array measurements.</div></div><div><h3>Results</h3><div>Morphology in the mutant hippocampal NPCs and neurons was preserved, however, we detected significant transcriptomic and functional alterations. RNA sequencing showed massive upregulation of neuronal differentiation genes, and downregulation of cell adhesion genes. Decreased reactivity to glutamate was demonstrated by calcium-imaging.</div></div><div><h3>Conclusions</h3><div>Our findings lend support to the involvement of glutamatergic dysregulation in the pathogenesis of SCZ. This approach represents a powerful model system for precision psychiatry and pharmacological research.</div></div>","PeriodicalId":21417,"journal":{"name":"Schizophrenia Research","volume":"273 ","pages":"Pages 107-120"},"PeriodicalIF":3.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139591756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mitochondrial dysfunction in psychiatric disorders 精神疾病中的线粒体功能障碍。

IF 3.6 2区医学 Q1 PSYCHIATRY

Schizophrenia Research

Pub Date : 2024-11-01 DOI: 10.1016/j.schres.2022.08.027

Peiyan Ni , Yao Ma , Sangmi Chung

Psychiatric disorders are a heterogeneous group of mental disorders with abnormal mental or behavioral patterns, which severely distress or disable affected individuals and can have a grave socioeconomic burden. Growing evidence indicates that mitochondrial function plays an important role in developing psychiatric disorders. This review discusses the neuropsychiatric consequences of mitochondrial abnormalities in both animal models and patients. We also discuss recent studies associated with compromised mitochondrial function in various psychiatric disorders, such as schizophrenia (SCZ), major depressive disorder (MD), and bipolar disorders (BD). These studies employ various approaches including postmortem studies, imaging studies, genetic studies, and induced pluripotent stem cells (iPSCs) studies. We also summarize the evidence from animal models and clinical trials to support mitochondrial function as a potential therapeutic target to treat various psychiatric disorders. This review will contribute to furthering our understanding of the metabolic etiology of various psychiatric disorders, and help guide the development of optimal therapies.

精神障碍是一组具有异常心理或行为模式的异质性精神疾病，严重困扰患者或使其丧失能力，并可能造成严重的社会经济负担。越来越多的证据表明，线粒体功能在精神疾病的发生中扮演着重要角色。本综述将讨论线粒体异常在动物模型和患者中造成的神经精神后果。我们还讨论了与精神分裂症（SCZ）、重度抑郁障碍（MD）和双相情感障碍（BD）等各种精神疾病中线粒体功能受损有关的最新研究。这些研究采用了各种方法，包括尸体研究、成像研究、遗传研究和诱导多能干细胞（iPSCs）研究。我们还总结了动物模型和临床试验的证据，以支持线粒体功能作为治疗各种精神疾病的潜在治疗靶点。这篇综述将有助于我们进一步了解各种精神疾病的代谢病因，并有助于指导开发最佳疗法。

引用次数: 0

Current progress in understanding schizophrenia using genomics and pluripotent stem cells: A meta-analytical overview 利用基因组学和多能干细胞了解精神分裂症的最新进展：荟萃分析综述。

IF 3.6 2区医学 Q1 PSYCHIATRY

Schizophrenia Research

Pub Date : 2024-11-01 DOI: 10.1016/j.schres.2022.11.001

Ashwani Choudhary, David Peles, Ritu Nayak, Liron Mizrahi, Shani Stern

Schizophrenia (SCZ) is a complex, heritable and polygenic neuropsychiatric disease, which disables the patients as well as decreases their life expectancy and quality of life. Common and rare variants studies on SCZ subjects have provided >100 genomic loci that hold importance in the context of SCZ pathophysiology. Transcriptomic studies from clinical samples have informed about the differentially expressed genes (DEGs) and non-coding RNAs in SCZ patients. Despite these advancements, no causative genes for SCZ were found and hence SCZ is difficult to recapitulate in animal models. In the last decade, induced Pluripotent Stem Cells (iPSCs)-based models have helped in understanding the neural phenotypes of SCZ by studying patient iPSC-derived 2D neuronal cultures and 3D brain organoids. Here, we have aimed to provide a simplistic overview of the current progress and advancements after synthesizing the enormous literature on SCZ genetics and SCZ iPSC-based models. Although further understanding of SCZ genetics and pathophysiological mechanisms using these technological advancements is required, the recent approaches have allowed to delineate important cellular mechanisms and biological pathways affected in SCZ.

精神分裂症（SCZ）是一种复杂的、可遗传的多基因神经精神疾病，它不仅使患者丧失能力，还降低了他们的预期寿命和生活质量。对 SCZ 患者进行的常见和罕见变异研究提供了超过 100 个基因组位点，这些位点在 SCZ 病理生理学方面具有重要意义。对临床样本进行的转录组学研究则揭示了SCZ患者的差异表达基因（DEGs）和非编码RNAs。尽管取得了这些进展，但仍未找到 SCZ 的致病基因，因此 SCZ 难以在动物模型中再现。在过去十年中，基于诱导多能干细胞（iPSCs）的模型通过研究患者iPSC衍生的二维神经元培养物和三维脑器官组织，帮助人们了解了SCZ的神经表型。在此，我们旨在综合有关 SCZ 遗传学和基于 SCZ iPSC 模型的大量文献后，对当前的进展和进步做一个简单的概述。虽然还需要利用这些技术进步进一步了解 SCZ 遗传学和病理生理学机制，但最近的研究方法已经能够描述 SCZ 重要的细胞机制和生物通路。

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引用次数: 0

Harnessing stem cell-based approaches for clinically meaningful discoveries in schizophrenia 利用基于干细胞的方法，发现对临床有意义的精神分裂症。

IF 3.6 2区医学 Q1 PSYCHIATRY

Schizophrenia Research

Pub Date : 2024-11-01 DOI: 10.1016/j.schres.2024.08.006

Paulo Lizano , Rakesh Karmacharya

引用次数: 0

Probing the molecular and cellular pathological mechanisms of schizophrenia using human induced pluripotent stem cell models 利用人类诱导多能干细胞模型探究精神分裂症的分子和细胞病理机制。

IF 3.6 2区医学 Q1 PSYCHIATRY

Schizophrenia Research

Pub Date : 2024-11-01 DOI: 10.1016/j.schres.2022.06.028

Rebecca Sebastian , Yoonjae Song , ChangHui Pak

With recent advancements in psychiatric genomics, as a field, “stem cell-based disease modelers” were given the exciting yet daunting task of translating the extensive list of disease-associated risks into biologically and clinically relevant information in order to deliver therapeutically meaningful leads and insights. Despite their limitations, human induced pluripotent stem cell (iPSCs) based models have greatly aided our understanding of the molecular and cellular mechanisms underlying the complex etiology of brain disorders including schizophrenia (SCZ). In this review, we summarize the major findings from studies in the past decade which utilized iPSC models to investigate cell type-specific phenotypes relevant to idiopathic SCZ and disease penetrant alleles. Across cell type differences, several biological themes emerged, serving as potential neurodevelopmental mechanisms of SCZ, including oxidative stress and mitochondrial dysfunction, depletion of progenitor pools and insufficient differentiation potential of these progenitors, and structural and functional deficits of neurons and other supporting cells. Here, we discuss both the recent progress as well as challenges and improvements needed for future studies utilizing iPSCs as a model for SCZ and other neuropsychiatric disorders.

随着精神病基因组学的最新进展，作为一个领域，"基于干细胞的疾病模型 "被赋予了令人兴奋而又艰巨的任务，即把大量与疾病相关的风险转化为生物和临床相关信息，以提供有治疗意义的线索和见解。基于人类诱导多能干细胞（iPSCs）的模型尽管有其局限性，但极大地帮助了我们对包括精神分裂症（SCZ）在内的脑部疾病复杂病因的分子和细胞机制的理解。在这篇综述中，我们总结了过去十年中利用 iPSC 模型研究与特发性 SCZ 和疾病穿透性等位基因相关的细胞类型特异性表型的主要发现。在细胞类型差异方面，出现了几个生物学主题，作为SCZ潜在的神经发育机制，包括氧化应激和线粒体功能障碍、祖细胞池耗竭和这些祖细胞的分化潜能不足，以及神经元和其他支持细胞的结构和功能缺陷。在此，我们将讨论利用 iPSCs 作为 SCZ 和其他神经精神疾病模型的最新进展以及未来研究面临的挑战和需要改进的地方。

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引用次数: 0

Human stem cell-based models to study synaptic dysfunction and cognition in schizophrenia: A narrative review 研究精神分裂症突触功能障碍和认知的人类干细胞模型：叙述性综述。

IF 3.6 2区医学 Q1 PSYCHIATRY

Schizophrenia Research

Pub Date : 2024-11-01 DOI: 10.1016/j.schres.2023.02.029

Stephanie Santarriaga , Kaia Gerlovin , Yasmine Layadi , Rakesh Karmacharya

Cognitive impairment is the strongest predictor of functional outcomes in schizophrenia and is hypothesized to result from synaptic dysfunction. However, targeting synaptic plasticity and cognitive deficits in patients remains a significant clinical challenge. A comprehensive understanding of synaptic plasticity and the molecular basis of learning and memory in a disease context can provide specific targets for the development of novel therapeutics targeting cognitive impairments in schizophrenia. Here, we describe the role of synaptic plasticity in cognition, summarize evidence for synaptic dysfunction in schizophrenia and demonstrate the use of patient derived induced-pluripotent stem cells for studying synaptic plasticity in vitro. Lastly, we discuss current advances and future technologies for bridging basic science research of synaptic dysfunction with clinical and translational research that can be used to predict treatment response and develop novel therapeutics.

认知障碍是精神分裂症功能性结果的最有力预测因素，据推测，认知障碍是突触功能障碍的结果。然而，针对患者的突触可塑性和认知障碍仍然是一项重大的临床挑战。全面了解疾病背景下的突触可塑性以及学习和记忆的分子基础，可以为开发针对精神分裂症认知障碍的新型疗法提供特定靶点。在此，我们描述了突触可塑性在认知中的作用，总结了精神分裂症突触功能障碍的证据，并展示了如何利用患者诱导多能干细胞在体外研究突触可塑性。最后，我们讨论了将突触功能障碍的基础科学研究与临床和转化研究连接起来的当前进展和未来技术，这些研究可用于预测治疗反应和开发新型疗法。

引用次数: 0