Schizophrenia Research最新文献_第9页

The theoretical sensitivity of virtual assessment of catatonia 紧张症虚拟评估的理论敏感性。

IF 3.6 2区医学 Q1 PSYCHIATRY

Schizophrenia Research

Pub Date : 2024-11-08 DOI: 10.1016/j.schres.2024.10.020

James Luccarelli , Joshua Ryan Smith , Stephan Heckers , Gregory Fricchione , Jo Ellen Wilson

引用次数: 0

Plasma NGAL, not IFN-γ, predicts early treatment response in drug-naïve Chinese Han schizophrenia patients 血浆 NGAL（而非 IFN-γ）可预测药物治疗无效的中国汉族精神分裂症患者的早期治疗反应。

IF 3.6 2区医学 Q1 PSYCHIATRY

Schizophrenia Research

Pub Date : 2024-11-07 DOI: 10.1016/j.schres.2024.10.025

Xiaoxiao Sun , Meijuan Li , Yuying Qiu , Qiao Su, Jiayue Wang, Fuyou Bi, Jie Li

Background

Early prediction of treatment efficacy can assist psychiatrists in optimizing personalized treatment strategies for drug-naïve schizophrenia patients. This study aimed to explore the predictive value of plasma concentrations of Interferon-γ (IFN-γ) and Neutrophil gelatinase-associated lipocalin (NGAL) in early treatment responses.

Methods

We conducted a longitudinal study involving 125 drug-naïve schizophrenia patients and 75 healthy controls. Plasma samples were collected and analyzed at baseline and after 8 weeks of treatment. Based on treatment outcomes, patients were classified as Responders (R, n = 84) or Non-responders (NR, n = 41).

Results

At baseline, schizophrenia patients showed significantly lower IFN-γ and NGAL concentrations compared to healthy controls. NGAL levels were notably lower in the NR group compared to the R group. After treatment, both IFN-γ and NGAL concentrations increased in all patients, with a marked rise in IFN-γ levels. NGAL concentration negatively correlated with the positive factor at baseline, adjusting for confounders such as age, BMI, smoking, and duration of untreated illness. Logistic regression analysis identified lower baseline NGAL concentrations as a predictor of poor early treatment response.

Conclusion

Pre-treatment plasma NGAL concentrations may serve as a potential biomarker for predicting early treatment response in drug-naïve Chinese Han schizophrenia patients. These findings highlight NGAL as a possible target for future therapeutic development in schizophrenia.

背景：早期预测疗效有助于精神科医生优化对药物治疗无效的精神分裂症患者的个性化治疗策略。本研究旨在探讨干扰素-γ（IFN-γ）和中性粒细胞明胶酶相关脂质体（NGAL）的血浆浓度在早期治疗反应中的预测价值：我们进行了一项纵向研究，涉及 125 名药物治疗前精神分裂症患者和 75 名健康对照者。在基线期和治疗 8 周后收集血浆样本并进行分析。根据治疗结果，患者被分为应答者（R，n = 84）或无应答者（NR，n = 41）：基线时，精神分裂症患者的 IFN-γ 和 NGAL 浓度明显低于健康对照组。NR 组的 NGAL 水平明显低于 R 组。治疗后，所有患者的IFN-γ和NGAL浓度都有所增加，其中IFN-γ浓度明显升高。在对年龄、体重指数、吸烟和未治疗病程等混杂因素进行调整后，NGAL浓度与基线阳性因子呈负相关。逻辑回归分析表明，较低的基线NGAL浓度可预测较差的早期治疗反应：结论：治疗前血浆NGAL浓度可作为一种潜在的生物标志物，用于预测药物治疗无效的中国汉族精神分裂症患者的早期治疗反应。结论：治疗前血浆NGAL浓度可作为潜在的生物标志物，用于预测药物治疗无效的中国汉族精神分裂症患者的早期治疗反应。这些发现强调了NGAL可能是未来精神分裂症治疗开发的一个靶点。

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引用次数: 0

Sex versus gender associations with depressive symptom trajectories over 24 months in first-episode schizophrenia spectrum disorders 首次发病的精神分裂症谱系障碍患者在 24 个月内的抑郁症状轨迹与性别的关系。

IF 3.6 2区医学 Q1 PSYCHIATRY

Schizophrenia Research

Pub Date : 2024-11-07 DOI: 10.1016/j.schres.2024.10.022

H.K. Luckhoff , E.C. del Re , R. Smit , S. Kilian , L. Phahladira , R. Emsley , L. Asmal

Background

Females with schizophrenia often experience more severe and persistent depressive symptoms than males, in particular during the acute phase of the illness. In contrast to sex (a biological distinction), little is known about the associations between gender (a societal construct) and depression in schizophrenia.

Aim

We examined the associations of sex versus gender with visit-wise changes in depressive symptoms over 24 months in patients with first-episode schizophrenia spectrum disorders (FES) (n = 77) compared to matched healthy controls (n = 64).

Methods

The Bem Sex Role Inventory was used to measure feminine gender role endorsement. The Calgary Depression Scale for Schizophrenia was used to measure depressive symptoms at baseline, weeks 2, 4, and 6, and months 3, 6, 9, 12, 15, 18, 21, and 24. We used mixed models for continuous repeated measures to examine the moderating effects of childhood trauma, premorbid adjustment, age of psychosis onset, and cannabis use on the associations of sex and gender with depressive symptoms.

Results

Higher feminine gender role endorsement, independent of biological sex, was associated with more severe baseline depression and worse initial treatment trajectories. Childhood trauma exposure was also associated with worse depression outcomes, and mediated the association between gender and pre-treatment depression severities.

Conclusions

Gender, but not sex, was associated with depressive symptom trajectories in FES. The consideration of both sex and gender offered a more nuanced insight into depressive symptoms compared to biological sex alone.

背景：女性精神分裂症患者的抑郁症状往往比男性患者更严重、更持久，尤其是在疾病的急性期。目的：我们研究了首次发作精神分裂症谱系障碍（FES）患者（n = 77）与相匹配的健康对照组（n = 64）在24个月内就诊时抑郁症状变化的性别关联：方法：使用贝姆性别角色量表来测量女性性别角色认同。卡尔加里精神分裂症抑郁量表用于测量基线、第 2 周、第 4 周和第 6 周以及第 3 个月、第 6 个月、第 9 个月、第 12 个月、第 15 个月、第 18 个月、第 21 个月和第 24 个月的抑郁症状。我们使用连续重复测量的混合模型来研究童年创伤、病前适应、精神病发病年龄和大麻使用对性别与抑郁症状关联的调节作用：结果：与生理性别无关，女性性别角色认可度越高，基线抑郁越严重，初始治疗效果越差。童年时期遭受的创伤也与抑郁症的恶化有关，并在性别与治疗前抑郁症严重程度之间起中介作用：结论：性别与 FES 的抑郁症状轨迹有关，但与性别无关。与仅考虑生理性别相比，同时考虑性别和生理性别能更细致地了解抑郁症状。

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引用次数: 0

Meta-analysis of the factor structure of the Scale for the Assessment of Negative Symptoms (SANS) and the Scale for the Assessment of Positive Symptoms (SAPS) 消极症状评估量表（SANS）和积极症状评估量表（SAPS）因子结构的元分析。

IF 3.6 2区医学 Q1 PSYCHIATRY

Schizophrenia Research

Pub Date : 2024-11-07 DOI: 10.1016/j.schres.2024.10.027

Federico Dazzi , Alan Shafer

Introduction

The SAPS and SANS was designed to measure two broad factors, but the majority of factor analyses conducted have found substantially more dimensions. To investigate their structure a meta-analysis was conducted of SAPS and SANS factor analysis.

Method

A total of 42 articles reporting 55 factor analyses were retrieved from database searches (PubMed, PsychINFO) supplemented by searches of references. Reproduced correlations were calculated from retrieved factor analyses and 3 separate meta-analyses were conducted.

Results

The meta-analysis of the SAPS SANS global ratings (k = 34; n = 5219) yielded a 3-factor solution including Positive Symptoms (Hallucinations and Delusions), Negative Symptoms (Affective Flattening, Alogia, Avolition/Apathy, Anhedonia/Asociality and Attentional Impairment), and Disorganization (Positive Formal Thought Disorder and Bizarre Behavior). The item analysis of the SAPS SANS combined (k = 11; n = 3146) found 4 factors, with the Negative Symptoms splitting into Affective Flattening/Alogia and Avolition/Asociality as main difference. The SANS only item analysis (k = 10; n = 2073) identified 3 factors, Affective Flattening, Avolition/Asociality, and Alogia/Inattentiveness. Importantly, our data suggests that the items Inappropriate Affect and Poverty of Content of Speech should be moved from Negative Symptoms to the Disorganization factor. Attentional Impairment shows the highest loading on Negative Symptoms but its inclusion under this dimension is conceptually unclear and it may be better considered as a non-specific domain.

Conclusions

The three factor structure of Positive Symptoms, Negative Symptoms and Disorganization accounted for most of the data. The SAPS SANS global scales are generally valid, but suggestions for a conservative revision of SAPS SANS structure, including supplementary subscales, are presented.

介绍：SAPS 和 SANS 的设计目的是测量两个广泛的因子，但所进行的大多数因子分析都发现了更多的维度。为了研究它们的结构，我们对 SAPS 和 SANS 因子分析进行了元分析：方法：通过数据库搜索（PubMed、PsychINFO）和参考文献搜索，共检索到 42 篇报道 55 项因子分析的文章。从检索到的因子分析中计算出再现相关性，并分别进行了 3 次元分析：对 SAPS SANS 整体评分的荟萃分析（k = 34；n = 5219）得出了一个 3 因子解决方案，包括阳性症状（幻觉和妄想）、阴性症状（情感平淡、嗜睡、逃避/情感淡漠、失乐症/社交障碍和注意力障碍）和组织混乱（阳性形式思维障碍和怪异行为）。SAPS SANS 合并项目分析（k=11；n=3146）发现了 4 个因子，其中消极症状分为情感平淡/自闭和逃避/社交，这是主要差异。仅对 SANS 进行的项目分析（k = 10；n = 2073）发现了 3 个因子，即情感扁平化、逃避/社交性和焦虑/注意力不集中。重要的是，我们的数据表明，"不恰当情感 "和 "言语内容贫乏 "这两个项目应从 "消极症状 "移至 "组织混乱 "因子。注意力障碍在消极症状中的负荷最高，但将其纳入这一维度在概念上并不清晰，最好将其视为一个非特异性领域：积极症状、消极症状和组织混乱的三因子结构涵盖了大部分数据。SAPS SANS总体量表总体有效，但建议对SAPS SANS结构进行保守修订，包括补充子量表。

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引用次数: 0

Sleep oscillations and their relations with sleep-dependent memory consolidation in early course psychosis and first-degree relatives 早期精神病和一级亲属的睡眠振荡及其与依赖睡眠的记忆巩固的关系。

IF 3.6 2区医学 Q1 PSYCHIATRY

Schizophrenia Research

Pub Date : 2024-11-07 DOI: 10.1016/j.schres.2024.10.026

Dan Denis , Bengi Baran , Dimitrios Mylonas , Courtney Spitzer , Nicolas Raymond , Christine Talbot , Erin Kohnke , Olivia Larson , Robert Stickgold , Matcheri Keshavan , Dara S. Manoach

Sleep spindles mediate sleep-dependent memory consolidation, particularly when coupled to neocortical slow oscillations (SOs). Schizophrenia is characterized by a deficit in sleep spindles that correlates with reduced overnight memory consolidation. Here, we examined sleep spindle activity, SO-spindle coupling, and both motor procedural and verbal declarative memory consolidation in early course, minimally medicated psychosis patients and non-psychotic first-degree relatives. Using a four-night experimental procedure, we observed significant deficits in spindle density and amplitude in patients relative to controls that were driven by individuals with schizophrenia. Schizophrenia patients also showed reduced sleep-dependent consolidation of motor procedural memory, which correlated with lower spindle density. Contrary to expectations, there were no group differences in the consolidation of declarative memory on a word pairs task. Nor did the relatives of patients differ in spindle activity or memory consolidation compared with controls, however increased consistency in the timing of SO-spindle coupling were seen in both patients and relatives. Our results extend prior work by demonstrating correlated deficits in sleep spindles and sleep-dependent motor procedural memory consolidation in early course, minimally medicated patients with schizophrenia, but not in first-degree relatives. This is consistent with other work in suggesting that impaired sleep-dependent memory consolidation has some specificity for schizophrenia and is a core feature rather than reflecting the effects of medication or chronicity.

睡眠棘介导依赖睡眠的记忆巩固，尤其是与新皮质慢振荡（SOs）结合时。精神分裂症的特征是睡眠纺锤体的缺失，而睡眠纺锤体的缺失与隔夜记忆巩固的减少有关。在这里，我们研究了病程早期、用药最少的精神病患者和非精神病患者一级亲属的睡眠主轴活动、SO-主轴耦合以及运动程序性记忆和言语陈述性记忆的巩固。通过四晚的实验过程，我们观察到相对于对照组，精神分裂症患者的纺锤体密度和振幅明显不足。精神分裂症患者还表现出依赖睡眠的运动程序记忆巩固能力下降，这与纺锤体密度较低有关。与预期相反的是，在单词配对任务中，陈述性记忆的巩固并无群体差异。与对照组相比，患者亲属在纺锤体活动或记忆巩固方面也没有差异，但在患者和亲属中，SO-纺锤体耦合的时间一致性都有所提高。我们的研究结果扩展了之前的研究，证明了早期精神分裂症患者在睡眠纺锤体和依赖睡眠的运动程序记忆巩固方面存在相关缺陷，而一级亲属中却没有这种缺陷。这与其他研究结果一致，表明依赖睡眠的记忆巩固功能受损对精神分裂症有一定的特异性，是精神分裂症的核心特征，而不是反映药物或慢性病的影响。

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引用次数: 0

Validation of the Amharic version of Cognitive Assessment Interview (CAI-A) in people with schizophrenia in Ethiopia 在埃塞俄比亚精神分裂症患者中验证阿姆哈拉语版认知评估访谈（CAI-A）

IF 3.6 2区医学 Q1 PSYCHIATRY

Schizophrenia Research

Pub Date : 2024-11-06 DOI: 10.1016/j.schres.2024.10.019

Yohannes Gebreegziabhere , Kassahun Habatmu , Matteo Cella , Atalay Alem

Assessing cognition with interview-based measures could be a low-resource alternative to traditional cognitive tests. We previously adapted the Cognitive Assessment Interview (CAI) into Amharic (CAI-A) for use with people with schizophrenia (PWS) in Ethiopia. This study examined the convergent and structural validity of the CAI-A in a group of 350 PWS sub-sampled from the Neuropsychiatric Genetics of African Populations – Psychosis (NeuroGAP-Psychosis) study, who fulfilled the inclusion criteria. Data were analyzed using confirmatory factor analysis (CFA), Spearman's correlation coefficient (ρ), multiple regression, and Item Response Theory (IRT). A one-factor solution best fits the items in the tool (factor loadings between 0.58 and 0.79), suggesting structural validity. The total score of the CAI-A moderately correlated with functioning (ρ = 0.44, p < 0.001) and symptom dimensions (ρ between 0.38 and 0.46, p < 0.001), suggesting convergent validity. Multiple regression showed that age (β = −0.06, 95 % CI (−0.12, 0.00), p = 0.044), the duration of illness (β = 0.08, 95 % CI (0.01, 0.14), p = 0.033), and medication side effects (β = 0.35, 95 % CI (0.21, 0.50), p < 0.001) were positively and significantly associated with the CAI-A total score. The IRT analysis suggested that the tool best functions among participants with moderate to severe impairment (difficulty coefficient between 0.05 and 2.73). We found that the CAI-A is a valid tool for use in Ethiopia. The moderate correlation with symptom and functional measures suggested that self-reported cognitive symptoms parallel other symptom dimensions and functional disability. The CAI-A can be used in clinical practice and research activities in PWS in Ethiopia when subjective assessment of cognition is desired.

以访谈为基础的认知评估方法可以在资源匮乏的情况下替代传统的认知测试。我们曾将认知评估访谈（CAI）改编成阿姆哈拉语（CAI-A），用于埃塞俄比亚的精神分裂症患者（PWS）。本研究从 "非洲人群神经精神遗传学--精神病（NeuroGAP-Psychosis）"研究中抽取了 350 名符合纳入标准的精神分裂症患者，对 CAI-A 的收敛性和结构有效性进行了研究。数据分析采用了确证因子分析（CFA）、斯皮尔曼相关系数（ρ）、多元回归和项目反应理论（IRT）。单因素解最适合工具中的项目（因素负荷在 0.58 和 0.79 之间），表明结构有效。CAI-A 的总分与功能（ρ = 0.44，p <0.001）和症状维度（ρ 在 0.38 和 0.46 之间，p <0.001）呈中度相关，表明具有收敛有效性。多元回归显示，年龄（β = -0.06，95 % CI (-0.12, 0.00)，p = 0.044）、病程（β = 0.08，95 % CI (0.01, 0.14)，p = 0.033）和药物副作用（β = 0.35，95 % CI (0.21, 0.50)，p <0.001）与 CAI-A 总分呈显著正相关。IRT 分析表明，该工具在患有中度至重度障碍的参与者中功能最佳（难度系数介于 0.05 和 2.73 之间）。我们发现，CAI-A 是一种适用于埃塞俄比亚的有效工具。与症状和功能测量的适度相关性表明，自我报告的认知症状与其他症状维度和功能障碍平行。当需要对认知能力进行主观评估时，CAI-A 可用于埃塞俄比亚 PWS 的临床实践和研究活动。

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引用次数: 0

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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