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Publisher Correction: Longitudinal study on hippocampal subfields and glucose metabolism in early psychosis. 出版商更正:早期精神病海马亚区和葡萄糖代谢的纵向研究。
IF 3 Q2 PSYCHIATRY Pub Date : 2024-09-02 DOI: 10.1038/s41537-024-00495-9
Reetta-Liina Armio, Heikki Laurikainen, Tuula Ilonen, Maija Walta, Elina Sormunen, Arvi Tolvanen, Raimo K R Salokangas, Nikolaos Koutsouleris, Lauri Tuominen, Jarmo Hietala
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引用次数: 0
Structural and functional connectivity in relation to executive functions in antipsychotic-naïve patients with first episode schizophrenia and levels of glutamatergic metabolites. 抗精神病药物无效的首发精神分裂症患者执行功能的结构和功能连通性与谷氨酸代谢物水平的关系。
IF 3 Q2 PSYCHIATRY Pub Date : 2024-08-31 DOI: 10.1038/s41537-024-00487-9
Tina D Kristensen, Karen S Ambrosen, Jayachandra M Raghava, Warda T Syeda, Thijs Dhollander, Cecilie K Lemvigh, Kirsten B Bojesen, Anita D Barber, Mette Ø Nielsen, Egill Rostrup, Christos Pantelis, Birgitte Fagerlund, Birte Y Glenthøj, Bjørn H Ebdrup

Patients with schizophrenia exhibit structural and functional dysconnectivity but the relationship to the well-documented cognitive impairments is less clear. This study investigates associations between structural and functional connectivity and executive functions in antipsychotic-naïve patients experiencing schizophrenia. Sixty-four patients with schizophrenia and 95 matched controls underwent cognitive testing, diffusion weighted imaging and resting state functional magnetic resonance imaging. In the primary analyses, groupwise interactions between structural connectivity as measured by fixel-based analyses and executive functions were investigated using multivariate linear regression analyses. For significant structural connections, secondary analyses examined whether functional connectivity and associations with executive functions also differed for the two groups. In group comparisons, patients exhibited cognitive impairments across all executive functions compared to controls (p < 0.001), but no group difference were observed in the fixel-based measures. Primary analyses revealed a groupwise interaction between planning abilities and fixel-based measures in the left anterior thalamic radiation (p = 0.004), as well as interactions between cognitive flexibility and fixel-based measures in the isthmus of corpus callosum and cingulum (p = 0.049). Secondary analyses revealed increased functional connectivity between grey matter regions connected by the left anterior thalamic radiation (left thalamus with pars opercularis p = 0.018, and pars orbitalis p = 0.003) in patients compared to controls. Moreover, a groupwise interaction was observed between cognitive flexibility and functional connectivity between contralateral regions connected by the isthmus (precuneus p = 0.028, postcentral p = 0.012), all p-values corrected for multiple comparisons. We conclude that structural and functional connectivity appear to associate with executive functions differently in antipsychotic-naïve patients with schizophrenia compared to controls.

精神分裂症患者表现出结构性和功能性连通性障碍,但其与认知障碍之间的关系尚不清楚。本研究调查了抗精神病药物无效的精神分裂症患者的结构和功能连通性与执行功能之间的关系。64名精神分裂症患者和95名匹配的对照组患者接受了认知测试、弥散加权成像和静息状态功能磁共振成像。在主要分析中,使用多变量线性回归分析研究了基于定点分析的结构连通性与执行功能之间的组间交互作用。对于重要的结构连通性,二次分析研究了两组患者的功能连通性和与执行功能的关联是否也存在差异。在组间比较中,与对照组相比,患者在所有执行功能方面都表现出认知障碍(p
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引用次数: 0
Elevated plasma matrix metalloproteinase 9 in schizophrenia patients associated with poor antipsychotic treatment response and white matter density deficits. 精神分裂症患者血浆基质金属蛋白酶9升高与抗精神病治疗反应差和白质密度缺陷有关
IF 3 Q2 PSYCHIATRY Pub Date : 2024-08-27 DOI: 10.1038/s41537-024-00494-w
Xiaojing Li, Xiujuan Wang, Yongfeng Yang, Jiahui Zhou, Xufei Wu, Jingyuan Zhao, Jianhong Zhang, Xiaoge Guo, Minglong Shao, Meng Song, Xi Su, Yong Han, Qing Liu, Tengfei Chen, Luwen Zhang, Bing Liu, Weihua Yue, Luxian Lv, Wenqiang Li

Oxidative stress and neuroinflammation contribute to schizophrenia (SCZ) pathology and may influence treatment efficacy. Matrix metalloproteinase 9 (MMP9) is a critical molecular node mediating the interaction between oxidative stress and inflammation, and so may influence treatment efficacy. Here we examined the associations of plasma MMP9 concentration with antipsychotic drug responses, clinical symptoms, and brain structure. A total of 129 healthy controls and 124 patients with SCZ were included in this study. Patients were monitored clinically during 8 weeks of antipsychotic treatment and classified as poor responders (n = 49) or good responders (n = 75). We then compared plasma MMP9 concentrations in healthy controls at baseline and both SCZ responder groups at baseline and after the 8-week antipsychotic treatment regimen. Cognitive function was also examined using the MATRICS Consensus Cognitive Battery. In addition, we extracted regional white matter density from magnetic resonance images of patients. Compared to healthy controls, plasma MMP9 levels were significantly elevated in poor responders at baseline and negatively correlated with both white matter density in the right superior temporal gyrus and the change in cognitive symptoms after treatment. Conversely, there was no significant difference in plasma MMP9 between good responders and healthy controls, and no associations of plasma MMP9 with cognitive symptoms or regional white matter density among good responders. Elevated plasma MMP9 is associated with poor antipsychotic drug efficacy and white matter deficits in SCZ patients, and so may be a useful biomarker to guide personalized treatment.

氧化应激和神经炎症是精神分裂症(SCZ)的病理因素,并可能影响治疗效果。基质金属蛋白酶9(MMP9)是介导氧化应激和炎症之间相互作用的关键分子节点,因此可能影响治疗效果。在此,我们研究了血浆 MMP9 浓度与抗精神病药物反应、临床症状和大脑结构之间的关系。本研究共纳入了129名健康对照者和124名SCZ患者。患者在接受为期8周的抗精神病药物治疗期间接受临床监测,并被分为反应差者(49人)和反应良好者(75人)。然后,我们比较了健康对照组在基线时的血浆MMP9浓度、SCZ应答组在基线时的血浆MMP9浓度以及8周抗精神病治疗方案后的血浆MMP9浓度。我们还使用 MATRICS 共识认知测验对认知功能进行了检测。此外,我们还从患者的磁共振图像中提取了区域白质密度。与健康对照组相比,基线反应差的患者血浆MMP9水平显著升高,并与右颞上回白质密度和治疗后认知症状的变化呈负相关。相反,良好反应者与健康对照组之间的血浆 MMP9 没有明显差异,良好反应者的血浆 MMP9 与认知症状或区域白质密度也没有关联。血浆MMP9升高与SCZ患者抗精神病药物疗效差和白质缺损有关,因此可能是指导个性化治疗的有用生物标志物。
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引用次数: 0
Long-term clinical recovery and treatment resistance in first-episode psychosis: a 10-year follow-up study. 首发精神病患者的长期临床康复和治疗阻力:一项为期 10 年的随访研究。
IF 3 Q2 PSYCHIATRY Pub Date : 2024-08-22 DOI: 10.1038/s41537-024-00489-7
Kristin Fjelnseth Wold, Isabel Viola Kreis, Gina Åsbø, Camilla Bärthel Flaaten, Line Widing, Magnus Johan Engen, Siv Hege Lyngstad, Erik Johnsen, Torill Ueland, Carmen Simonsen, Ingrid Melle

Illness trajectories in people with first-episode psychosis (FEP) vary significantly over time. Identifying early-course parameters predicting outcomes is essential, but long-term data still needs to be provided. We conducted a 10-year follow-up study of a comprehensive first-episode psychosis (FEP) cohort investigating the prevalence of clinical recovery (CR) and treatment resistance (TR) after ten years, as well as clinical, demographic, and pre-illness predictors of long-term outcomes. 102 participants with FEP DSM-IV Schizophrenia spectrum disorders were recruited within their first year of treatment. The Treatment Response and Resistance in Psychosis Working Group (TRRIP) and the Remission in Schizophrenia Working Group (RSWG) criteria were used to define TR and CR, respectively. At 10-year follow-up, 29 (29%) of the participants were classified as in CR, while 32 (31%) were classified as TR. We also identified a larger middle group (n = 41, 40%) consisting of participants in partial recovery. 7% of all participants had tried Clozapine at the 10-year follow-up. Logistic regression analyses identified insidious onset (OR = 4.16) and baseline disorganized symptoms (OR = 2.96) as significantly associated with an increased risk of developing TR. Good premorbid academic adjustment (OR = 1.60) and acute onset (OR = 3.40) were associated with an increased chance of CR. We identified three long-term outcome groups by using recent consensus definitions. We also identified the potential importance of assessing baseline disorganized symptoms and monitoring patients with insidious onset more closely. Further, the findings suggest that clinicians should pay close attention to early-course parameters and provide adequate treatment to improve long-term outcomes of FEP.

首发精神病(FEP)患者的病情轨迹随着时间的推移而变化很大。确定预测结果的早期病程参数至关重要,但仍需提供长期数据。我们对一个综合性首发精神病(FEP)队列进行了一项为期十年的随访研究,调查十年后临床康复(CR)和治疗阻力(TR)的发生率,以及长期预后的临床、人口学和病前预测因素。102 名患有 FEP DSM-IV 精神分裂症谱系障碍的患者是在接受治疗的第一年内被招募的。精神病治疗反应和抵抗工作组(TRRIP)和精神分裂症缓解工作组(RSWG)的标准分别用于定义TR和CR。在 10 年的随访中,29 名参与者(29%)被归类为 CR,32 名参与者(31%)被归类为 TR。我们还发现了一个较大的中间组(n = 41,40%),由部分康复的参与者组成。在 10 年的随访中,7% 的参与者尝试过氯氮平。逻辑回归分析表明,隐匿起病(OR = 4.16)和基线紊乱症状(OR = 2.96)与罹患 TR 的风险显著相关。病前学习适应良好(OR = 1.60)和急性发病(OR = 3.40)与 CR 发生几率增加有关。通过使用最近达成共识的定义,我们确定了三个长期结果组。我们还发现了评估基线紊乱症状和更密切地监测隐匿性发病患者的潜在重要性。此外,研究结果还表明,临床医生应密切关注早期病程参数,并提供适当的治疗,以改善 FEP 的长期预后。
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引用次数: 0
Prevalence and incidence measures for schizophrenia among commercial health insurance and medicaid enrollees. 商业健康保险和医疗补助参保者中精神分裂症的流行率和发病率测量。
IF 3 Q2 PSYCHIATRY Pub Date : 2024-08-22 DOI: 10.1038/s41537-024-00490-0
Molly T Finnerty, Atif Khan, Kai You, Rui Wang, Gyojeong Gu, Deborah Layman, Qingxian Chen, Noémie Elhadad, Shalmali Joshi, Paul S Appelbaum, Todd Lencz, Sander Markx, Steven A Kushner, Andrey Rzhetsky

Given the chronic nature of schizophrenia, it is important to examine age-specific prevalence and incidence to understand the scope of the burden of schizophrenia across the lifespan. Estimates of lifetime prevalence of schizophrenia have varied widely and have often relied upon community-based data estimates from over two decades ago, while more recent studies have shown considerable promise by leveraging pooled datasets. However, the validity of measures of schizophrenia, particularly new onset schizophrenia, has not been well studied in these large health databases. The current study examines prevalence and validity of incidence measures of new diagnoses of schizophrenia in 2019 using two U.S. administrative health databases: MarketScan, a national database of individuals receiving employer-sponsored commercial insurance (N = 16,365,997), and NYS Medicaid, a large state public insurance program (N = 4,414,153). Our results indicate that the prevalence of schizophrenia is over 10-fold higher, and the incidence two-fold higher, in the NYS Medicaid population compared to the MarketScan database. In addition, prevalence increased over the lifespan in the Medicaid population, but decreased in the employment based MarketScan database beginning in early adulthood. Incident measures of new diagnoses of schizophrenia had excellent validity, with positive predictive values and specificity exceeding 95%, but required a longer lookback period for Medicaid compared to MarketScan. Further work is needed to leverage these findings to develop robust clinical outcome predictors for new onset of schizophrenia within large administrative health data systems.

鉴于精神分裂症的慢性性质,研究特定年龄段的患病率和发病率对于了解精神分裂症对整个生命周期造成的负担范围非常重要。对精神分裂症终生患病率的估计差异很大,而且往往依赖于二十多年前基于社区的数据估计,而最近的研究则通过利用集合数据集显示出了相当大的前景。然而,在这些大型健康数据库中,对精神分裂症(尤其是新发精神分裂症)测量指标的有效性还没有进行过深入研究。本研究利用两个美国行政卫生数据库对 2019 年精神分裂症新诊断发病率测量的流行性和有效性进行了研究:这两个数据库分别是:MarketScan,这是一个关于接受雇主赞助的商业保险的个人的全国性数据库(N = 16,365,997),以及纽约州医疗补助(NYS Medicaid),这是一个大型的州公共保险项目(N = 4,414,153)。我们的研究结果表明,与 MarketScan 数据库相比,纽约州医疗补助人群的精神分裂症患病率高出 10 倍以上,发病率高出 2 倍。此外,在医疗补助人群中,精神分裂症的患病率随年龄增长而增加,但在以就业为基础的 MarketScan 数据库中,患病率则从成年早期开始下降。精神分裂症新诊断的事件测量具有良好的有效性,阳性预测值和特异性均超过 95%,但与 MarketScan 相比,Medicaid 需要更长的回溯期。需要进一步开展工作,利用这些发现在大型健康管理数据系统中开发出稳健的精神分裂症新发临床结果预测指标。
{"title":"Prevalence and incidence measures for schizophrenia among commercial health insurance and medicaid enrollees.","authors":"Molly T Finnerty, Atif Khan, Kai You, Rui Wang, Gyojeong Gu, Deborah Layman, Qingxian Chen, Noémie Elhadad, Shalmali Joshi, Paul S Appelbaum, Todd Lencz, Sander Markx, Steven A Kushner, Andrey Rzhetsky","doi":"10.1038/s41537-024-00490-0","DOIUrl":"10.1038/s41537-024-00490-0","url":null,"abstract":"<p><p>Given the chronic nature of schizophrenia, it is important to examine age-specific prevalence and incidence to understand the scope of the burden of schizophrenia across the lifespan. Estimates of lifetime prevalence of schizophrenia have varied widely and have often relied upon community-based data estimates from over two decades ago, while more recent studies have shown considerable promise by leveraging pooled datasets. However, the validity of measures of schizophrenia, particularly new onset schizophrenia, has not been well studied in these large health databases. The current study examines prevalence and validity of incidence measures of new diagnoses of schizophrenia in 2019 using two U.S. administrative health databases: MarketScan, a national database of individuals receiving employer-sponsored commercial insurance (N = 16,365,997), and NYS Medicaid, a large state public insurance program (N = 4,414,153). Our results indicate that the prevalence of schizophrenia is over 10-fold higher, and the incidence two-fold higher, in the NYS Medicaid population compared to the MarketScan database. In addition, prevalence increased over the lifespan in the Medicaid population, but decreased in the employment based MarketScan database beginning in early adulthood. Incident measures of new diagnoses of schizophrenia had excellent validity, with positive predictive values and specificity exceeding 95%, but required a longer lookback period for Medicaid compared to MarketScan. Further work is needed to leverage these findings to develop robust clinical outcome predictors for new onset of schizophrenia within large administrative health data systems.</p>","PeriodicalId":74758,"journal":{"name":"Schizophrenia (Heidelberg, Germany)","volume":"10 1","pages":"68"},"PeriodicalIF":3.0,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11341906/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142037947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Interaction between BDNF Val66Met polymorphism and mismatch negativity for working memory capacity in schizophrenia. BDNF Val66Met多态性与错配负性对精神分裂症工作记忆能力的相互作用
IF 3 Q2 PSYCHIATRY Pub Date : 2024-08-22 DOI: 10.1038/s41537-024-00493-x
Wenpeng Hou, Xiangqin Qin, Hang Li, Qi Wang, Yushen Ding, Xiongying Chen, Ru Wang, Fang Dong, Qijing Bo, Xianbin Li, Fuchun Zhou, Chuanyue Wang

Both the brain-derived neurotrophic factor (BDNF) valine (Val)/methionine (Met) polymorphism and mismatch negativity (MMN) amplitude are reportedly linked to working memory impairments in schizophrenia. However, there is evident scarcity of research aimed at exploring the relationships among the three factors. In this secondary analysis of a randomized, controlled, double-blind trial, we investigated these relationships. The trial assessed the efficacy of transcranial direct current stimulation for enhancing working memory in clinically stable schizophrenia patients, who were randomly divided into three groups: dorsolateral prefrontal cortex stimulation, posterior parietal cortex stimulation, and sham stimulation groups. Transcranial direct current stimulation was administered concurrently with a working memory task over five days. We assessed the BDNF genotype, MMN amplitude, working memory capacity, and interference control subdomains. These assessments were conducted at baseline with 54 patients and followed up post-intervention with 48 patients. Compared to BDNF Met-carriers, Val homozygotes exhibited fewer positive and general symptoms and increased working memory capacity at baseline. A correlation between MMN amplitude and working memory capacity was noted only in BDNF Val homozygotes. The correlations were significantly different in the two BDNF genotype groups. Furthermore, in the intervention group that showed significant improvement in MMN amplitude, BDNF Val homozygotes exhibited greater enhancement in working memory capacity than Met-carriers. This study provides in vivo evidence for the interaction between MMN and BDNF Val/Met polymorphism for working memory capacity. As MMN has been considered a biomarker of N-methyl-D-aspartate receptor (NMDAR) function, these data shed light on the complex interactions between BDNF and NMDAR in terms of working memory in schizophrenia.

据报道,脑源性神经营养因子(BDNF)缬氨酸(Val)/蛋氨酸(Met)多态性和错配负性(MMN)振幅都与精神分裂症患者的工作记忆障碍有关。然而,旨在探索这三个因素之间关系的研究明显不足。在这项随机对照双盲试验的二次分析中,我们对这些关系进行了调查。该试验评估了经颅直流电刺激对临床稳定的精神分裂症患者增强工作记忆的疗效,这些患者被随机分为三组:背外侧前额叶皮层刺激组、后顶叶皮层刺激组和假刺激组。经颅直流电刺激与工作记忆任务同时进行,为期五天。我们对 BDNF 基因型、MMN 振幅、工作记忆能力和干扰控制子域进行了评估。54名患者接受了基线评估,48名患者接受了干预后随访。与BDNF Met携带者相比,Val同卵双生者在基线时表现出较少的积极症状和一般症状,工作记忆能力也有所提高。只有 BDNF Val 基因同型携带者的 MMN 振幅与工作记忆能力之间存在相关性。两个 BDNF 基因型组的相关性存在明显差异。此外,在MMN振幅有明显改善的干预组中,BDNF Val同型基因携带者的工作记忆能力比Met基因携带者有更大的提高。这项研究为 MMN 与 BDNF Val/Met 多态性在工作记忆能力方面的相互作用提供了体内证据。由于 MMN 被认为是 N-甲基-D-天冬氨酸受体(NMDAR)功能的生物标志物,这些数据揭示了 BDNF 和 NMDAR 在精神分裂症患者工作记忆方面的复杂相互作用。
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引用次数: 0
Messiah or pariah? Psychosis, science, and finding meaning in lived experience. 救世主还是贱民?精神病、科学以及从生活经验中寻找意义。
IF 3 Q2 PSYCHIATRY Pub Date : 2024-08-05 DOI: 10.1038/s41537-024-00486-w
Carlos A Larrauri
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引用次数: 0
Longitudinal study on hippocampal subfields and glucose metabolism in early psychosis. 早期精神病海马亚区和葡萄糖代谢的纵向研究。
IF 3 Q2 PSYCHIATRY Pub Date : 2024-07-31 DOI: 10.1038/s41537-024-00475-z
Reetta-Liina Armio, Heikki Laurikainen, Tuula Ilonen, Maija Walta, Elina Sormunen, Arvi Tolvanen, Raimo K R Salokangas, Nikolaos Koutsouleris, Lauri Tuominen, Jarmo Hietala

Altered hippocampal morphology and metabolic pathology, but also hippocampal circuit dysfunction, are established phenomena seen in psychotic disorders. Thus, we tested whether hippocampal subfield volume deficits link with deviations in glucose metabolism commonly seen in early psychosis, and whether the glucose parameters or subfield volumes change during follow-up period using one-year longitudinal study design of 78 first-episode psychosis patients (FEP), 48 clinical high-risk patients (CHR) and 83 controls (CTR). We also tested whether hippocampal morphology and glucose metabolism relate to clinical outcome. Hippocampus subfields were segmented with Freesurfer from 3T MRI images and parameters of glucose metabolism were determined in fasting plasma samples. Hippocampal subfield volumes were consistently lower in FEPs, and findings were more robust in non-affective psychoses, with strongest decreases in CA1, molecular layer and hippocampal tail, and in hippocampal tail of CHRs, compared to CTRs. These morphometric differences remained stable at one-year follow-up. Both non-diabetic CHRs and FEPs had worse glucose parameters compared to CTRs at baseline. We found that, insulin levels and insulin resistance increased during the follow-up period only in CHR, effect being largest in the CHRs converting to psychosis, independent of exposure to antipsychotics. The worsening of insulin resistance was associated with deterioration of function and symptoms in CHR. The smaller volume of hippocampal tail was associated with higher plasma insulin and insulin resistance in FEPs, at the one-year follow-up. Our longitudinal study supports the view that temporospatial hippocampal subfield volume deficits are stable near the onset of first psychosis, being more robust in non-affective psychoses, but less prominent in the CHR group. Specific subfield defects were related to worsening glucose metabolism during the progression of psychosis, suggesting that hippocampus is part of the circuits regulating aberrant glucose metabolism in early psychosis. Worsening of glucose metabolism in CHR group was associated with worse clinical outcome measures indicating a need for heightened clinical attention to metabolic problems already in CHR.

海马形态和代谢病理改变以及海马回路功能障碍是精神病性障碍的既定现象。因此,我们通过对 78 名首发精神病患者(FEP)、48 名临床高危患者(CHR)和 83 名对照组(CTR)进行为期一年的纵向研究,检验了海马亚区体积缺陷是否与早期精神病中常见的葡萄糖代谢偏差有关,以及葡萄糖参数或亚区体积在随访期间是否会发生变化。我们还测试了海马形态和葡萄糖代谢是否与临床结果有关。我们使用 Freesurfer 对 3T MRI 图像中的海马子场进行了分割,并对空腹血浆样本中的葡萄糖代谢参数进行了测定。与CTR相比,FEPs患者的海马子野体积一直较低,而非情感性精神病患者的海马子野体积更低,CA1、分子层和海马尾部以及CHRs患者的海马尾部的体积下降幅度最大。这些形态学差异在一年的随访中保持稳定。与基线时的CTR相比,非糖尿病CHR和FEP的血糖参数都更差。我们发现,在随访期间,胰岛素水平和胰岛素抵抗仅在CHR中增加,在转化为精神病的CHR中影响最大,与抗精神病药物的暴露无关。胰岛素抵抗的恶化与CHR功能和症状的恶化有关。在为期一年的随访中,海马尾部较小的体积与FEPs较高的血浆胰岛素和胰岛素抵抗有关。我们的纵向研究支持这样一种观点,即颞叶海马子场体积缺陷在首次精神病发病时较为稳定,在非情感性精神病中更为明显,但在CHR组中不那么突出。在精神病进展过程中,特定的子野缺陷与糖代谢恶化有关,这表明海马是调节早期精神病异常糖代谢回路的一部分。CHR组患者的糖代谢恶化与更差的临床结果测量有关,这表明临床上需要更加关注CHR患者的代谢问题。
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引用次数: 0
Advances in the study of phencyclidine-induced schizophrenia-like animal models and the underlying neural mechanisms. 苯环利定诱导的精神分裂症样动物模型及其潜在神经机制的研究进展。
IF 3 Q2 PSYCHIATRY Pub Date : 2024-07-23 DOI: 10.1038/s41537-024-00485-x
Dabing Li, Qiangwen Pan, Yewei Xiao, Kehui Hu

Schizophrenia (SZ) is a chronic, severe mental disorder with heterogeneous clinical manifestations and unknown etiology. Research on SZ has long been limited by the low reliability of and ambiguous pathogenesis in schizophrenia animal models. Phencyclidine (PCP), a noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist, rapidly induces both positive and negative symptoms of SZ as well as stable SZ-related cognitive impairment in rodents. However, the neural mechanism underlying PCP-induced SZ-like symptoms is not fully understood. Nondopaminergic pathophysiology, particularly excessive glutamate release induced by NMDAR hypofunction in the prefrontal cortex (PFC), may play a key role in the development of PCP-induced SZ-like symptoms. In this review, we summarize studies on the behavioral and metabolic effects of PCP and the cellular and circuitary targets of PCP in the PFC and hippocampus (HIP). PCP is thought to target the ventral HIP-PFC pathway more strongly than the PFC-VTA pathway and thalamocortical pathway. Systemic PCP administration might preferentially inhibit gamma-aminobutyric acid (GABA) neurons in the vHIP and in turn lead to hippocampal pyramidal cell disinhibition. Excitatory inputs from the HIP may trigger sustained, excessive and pathological PFC pyramidal neuron activation to mediate various SZ-like symptoms. In addition, astrocyte and microglial activation and oxidative stress in the cerebral cortex or hippocampus have been observed in PCP-induced models of SZ. These findings perfect the hypoglutamatergic hypothesis of schizophrenia. However, whether these effects direct the consequences of PCP administration and how about the relationships between these changes induced by PCP remain further elucidation through rigorous, causal and direct experimental evidence.

精神分裂症(SZ)是一种慢性严重精神障碍,临床表现多样,病因不明。长期以来,精神分裂症动物模型的可靠性低、发病机制不明确,限制了对 SZ 的研究。苯环利定(PCP)是一种非竞争性的 N-甲基-D-天冬氨酸受体(NMDAR)拮抗剂,能迅速诱导啮齿类动物出现 SZ 的阳性和阴性症状以及稳定的 SZ 相关认知障碍。然而,五氯苯酚诱发类似 SZ 症状的神经机制尚未完全明了。非多巴胺能病理生理学,特别是前额叶皮质(PFC)中 NMDAR 功能减退所诱发的谷氨酸过度释放,可能在 PCP 诱导的 SZ 类症状的发展过程中起着关键作用。在本综述中,我们总结了有关五氯苯酚的行为和代谢效应以及五氯苯酚在前额叶皮质和海马(HIP)中的细胞和环路靶点的研究。人们认为五氯苯酚对腹侧 HIP-PFC 通路的靶向作用强于 PFC-VTA 通路和丘脑皮层通路。全身服用五氯苯酚可能会优先抑制 vHIP 中的γ-氨基丁酸(GABA)神经元,进而导致海马锥体细胞失抑制。来自 HIP 的兴奋性输入可能会引发持续、过度和病理性的 PFC 锥体神经元激活,从而介导各种类似 SZ 的症状。此外,在五氯苯酚诱导的 SZ 模型中还观察到大脑皮层或海马的星形胶质细胞和小胶质细胞活化和氧化应激。这些发现完善了精神分裂症的低谷氨酸能假说。然而,这些效应是否是服用五氯苯酚的直接后果,以及五氯苯酚诱导的这些变化之间的关系如何,仍有待通过严格、因果和直接的实验证据来进一步阐明。
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引用次数: 0
Exploration on the potential efficacy and mechanism of methyl salicylate glycosides in the treatment of schizophrenia based on bioinformatics, molecular docking and dynamics simulation. 基于生物信息学、分子对接和动力学模拟,探讨水杨酸甲酯苷治疗精神分裂症的潜在疗效和机制。
IF 3 Q2 PSYCHIATRY Pub Date : 2024-07-17 DOI: 10.1038/s41537-024-00484-y
Xiuhuan Wang, Jiamu Ma, Ying Dong, Xueyang Ren, Ruoming Li, Guigang Yang, Gaimei She, Yunlong Tan, Song Chen

The etiological and therapeutic complexities of schizophrenia (SCZ) persist, prompting exploration of anti-inflammatory therapy as a potential treatment approach. Methyl salicylate glycosides (MSGs), possessing a structural parent nucleus akin to aspirin, are being investigated for their therapeutic potential in schizophrenia. Utilizing bioinformation mining, network pharmacology, molecular docking and dynamics simulation, the potential value and mechanism of MSGs (including MSTG-A, MSTG-B, and Gaultherin) in the treatment of SCZ, as well as the underlying pathogenesis of the disorder, were examined. 581 differentially expressed genes related to SCZ were identified in patients and healthy individuals, with 349 up-regulated genes and 232 down-regulated genes. 29 core targets were characterized by protein-protein interaction (PPI) network, with the top 10 core targets being BDNF, VEGFA, PVALB, KCNA1, GRIN2A, ATP2B2, KCNA2, APOE, PPARGC1A and SCN1A. The pathogenesis of SCZ primarily involves cAMP signaling, neurodegenerative diseases and other pathways, as well as regulation of ion transmembrane transport. Molecular docking analysis revealed that the three candidates exhibited binding activity with certain targets with binding affinities ranging from -4.7 to -109.2 kcal/mol. MSTG-A, MSTG-B and Gaultherin show promise for use in the treatment of SCZ, potentially through their ability to modulate the expression of multiple genes involved in synaptic structure and function, ion transport, energy metabolism. Molecular dynamics simulation revealed good binding abilities between MSTG-A, MSTG-B, Gaultherin and ATP2B2. It suggests new avenues for further investigation in this area.

精神分裂症(SCZ)的病因和治疗仍然十分复杂,这促使人们探索抗炎疗法作为一种潜在的治疗方法。水杨酸甲酯苷(MSGs)具有类似阿司匹林的结构母核,目前正在研究其治疗精神分裂症的潜力。利用生物信息挖掘、网络药理学、分子对接和动力学模拟,研究了MSGs(包括MSTG-A、MSTG-B和Gaultherin)治疗SCZ的潜在价值和机制,以及该疾病的潜在发病机制。在患者和健康人中发现了 581 个与 SCZ 相关的差异表达基因,其中 349 个基因上调,232 个基因下调。通过蛋白-蛋白相互作用(PPI)网络确定了29个核心靶点,其中前10个核心靶点分别是BDNF、VEGFA、PVALB、KCNA1、GRIN2A、ATP2B2、KCNA2、APOE、PPARGC1A和SCN1A。SCZ 的发病机制主要涉及 cAMP 信号传导、神经退行性疾病和其他途径,以及离子跨膜转运的调控。分子对接分析表明,三种候选化合物与某些靶点具有结合活性,结合亲和力在-4.7至-109.2 kcal/mol之间。MSTG-A、MSTG-B和Gaultherin有望用于治疗SCZ,这可能是由于它们能够调节涉及突触结构和功能、离子转运、能量代谢的多个基因的表达。分子动力学模拟揭示了 MSTG-A、MSTG-B、Gaultherin 和 ATP2B2 之间良好的结合能力。这为该领域的进一步研究提供了新的途径。
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Schizophrenia (Heidelberg, Germany)
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