双相Ⅱ型障碍伴冲动攻击行为患者的全基因组DNA 甲基化修饰研究

目的 探讨双相Ⅱ型障碍伴冲动攻击行为患者的全基因组DNA 甲基化修饰情况。 方法 纳入5 例有冲动攻击行为的双相Ⅱ型障碍患者（攻击组）及5 例无冲动攻击行为的双相Ⅱ型障碍 患者（非攻击组）,采用Illumina 公司的人类450K 甲基化芯片技术对10 例患者的全血进行甲基化水平的 分析。利用R 软件对原始数据进行预处理并筛选出样本分组间的差异甲基化位点采用GCBI 在线分 析软件对差异候选基因进行功能富集分析。结果 （1）攻击组与非攻击组样本比较甲基化水平有差异。 （2）攻击组与非攻击组样本差异甲基化位点在染色体上的分布有差异。（3）按基因注释分类和CpG 岛注 释分类筛选攻击组与非攻击组样本间的差异甲基化区域,差异甲基化区域在11个注释区域内均有分布。 （4）GO 分析结果显示,差异甲基化位点参与信号传递等功能。Pathway 分析中,主要参与多巴胺能神经 突触信号通路、趋化因子信号通路。结论 有无冲动攻击行为的双相Ⅱ型障碍患者的全基因组DNA 甲 基化水平及差异甲基化DNA 在染色体上的分布均有差异,差异甲基化位点主要参与信号传递等。     

双相障碍患者DNA甲基化水平分析

目的 探讨双相障碍患者全血样本基因组DNA甲基化水平的改变.方法 采用Illumina公司人类450K甲基化芯片分析10例双相障碍患者和5名健康对照样本全血基因组DNA甲基化水平.采用R软件minfi包进行数据预处理,应用R软件IMA包筛选样本分组间的甲基化位点.采用GCBI在线分析软件对差异候选基因进行Gene ontology、Pathway分析.结果 双相障碍患者和对照组相比,SLC6A3、ARNTL、MAGI2、FAM111A、ZNF578、FAM196A基因甲基化率明显上调,SMPD1、ZEB2、KCNQ5、FAM41C、RGS18基因甲基化率明显下调.结论 双相障碍与DNA甲基化水平改变有关.     

DNA甲基化在双相障碍中的研究

本文对近年来双相障碍的发病与X染色体、五羟色胺、脑源性神经营养因子、儿茶酚氧位甲基转移酶等基因的DNA甲基化之间关系的相关研究进行了综述。     

有自杀意念的儿童青少年双相障碍抑郁发作患者SLC6A4 基因甲基化研究

目的 探讨儿童青少年双相障碍（PBD）抑郁发作患者自杀意念与SLC6A4基因甲基化 的关系。方法 选取 2020 年 12 月至 2022 年 12 月于新疆维吾尔自治区人民医院临床心理科住院的 43 例 PBD 抑郁发作患者为研究对象。采用自杀意念自评量表（SIOSS）评估患者的自杀意念，将总分≥ 12 分且掩饰因子得分＜ 4 分的患者纳入有自杀意念组（n=29），将总分＜ 12 分的患者纳入无自杀意念组 （n=14）。采用 Methprimer 软件对SLC6A4基因启动子区进行甲基化岛预测和甲基化引物设计，将提取好 的DNA经亚硫酸盐转化后进行PCR扩增和焦磷酸盐测序，确定甲基化的CpG位点和甲基化率。比较两组 患者SLC6A4基因不同位点甲基化的差异，采用 Spearman 相关分析基因甲基化与自杀意念的相关性。 结果 基因甲基化检测结果显示，两组患者SLC6A4基因甲基化的位点包括 CpG1、CpG2.3、CpG4、 CpG5.6位点。有自杀意念组与无自杀意念组患者CpG1、CpG2.3、CpG4位点的基因甲基化率比较［48.28% （14/29）比 8/14、96.55%（28/29）比 14/14、20.69%（6/29）比 6/14］，差异无统计学意义（χ2 =0.297、0.494、2.306； P＞ 0.05）。有自杀意念组患者的 CpG5.6 位点基因甲基化率高于无自杀意念组［68.97%（20/29）比 5/14］， 差异有统计学意义（χ2 =4.289，P＜ 0.05）。相关分析结果显示，PBD 抑郁发作患者的 SIOSS 得分与 SLC6A4基因甲基化CpG1位点、CpG2.3位点、CpG4位点不存在相关性（r=-0.244、-0.210、-0.281；P＞0.05）； 与甲基化 CpG5.6 位点呈正相关（r=0.312，P＜ 0.05）。结论 PBD 抑郁发作患者的自杀意念与SLC6A4基 因甲基化 CpG5.6 位点有关，为明确其自杀意念的发生原因提供了基础。     

有冲动攻击行为的双相情感障碍患者与基因甲基化的研究新进展

双相情感障碍(Bipolar Disorder,BD)是以反复发作的躁狂和抑郁为主要临床表现的一种重型精神障碍,具有高患病率,高复发率,高致残率(联合国卫生组织将其列为十大致残疾病),高死亡率(其中25%~50%的患者自杀未遂,11%~19%的患者自杀身亡)等特点.     

儿童青少年注意缺陷多动障碍外周血全基因组DNA甲基化研究

目的 应用甲基化芯片技术对注意缺陷多动障碍（ADHD）患儿DNA甲基化特征进行研究, 探讨 DNA 甲基化在 ADHD 发病机制中的作用。方法 于 2018 年 10 月至 2019 年 5 月选取在首都医科大 学附属北京安定医院门诊确诊的 8 例 8～16 岁的儿童青少年 ADHD 患儿作为 ADHD 组;招募 8 名年龄、 性别与 ADHD 组匹配的健康儿童青少年作为对照组。采用 Illumina Infinium Methylation EPIC Bead Chip 芯片（850K 芯片）技术对受试者进行全基因组 DNA 甲基化检测,分析和筛选差异甲基化位点。采用 gene ontology（GO）富集分析和 pathway 分析对筛选基因进行功能分类和通路分析。结果 与对照组比较, ADHD 组共有 2 068 个 CpG 位点甲基化水平发生改变,差异有统计学意义（P＜ 0.05）。其中有 842 个高 甲基化位点,1 226 个低甲基化位点,对应 468 个高甲基化基因如 GPR88、ARHGEF10 等,对应 705 个低 甲基化基因如 SKI、PMP2、PRR12、EBF3、BRSK2 等。GO 富集分析显示,差异甲基化基因参与生物学过 程富集于系统发育、神经系统发育以及细胞黏附等。pathway 分析显示,差异甲基化基因与钙黏蛋白信 号通路、神经元系统、Wnt 信号通路、谷氨酸能突触等信号通路相关。结论 DNA 甲基化的异常参与了 ADHD 的发生发展,检测出的差异甲基化基因可能成为 ADHD 的生物标志物或预测因子,差异甲基化基 因相关的信号通路可能与 ADHD 的发病机制相关。     

双相障碍患者的攻击行为

综述国内外近年来有关双相障碍患者攻击行为的研究。     

青少年双相抑郁患者冲动攻击行为神经代谢改变：一项质子磁共振波谱成像研究

目的 基于质子磁共振波谱成像（1 H-MRS）技术分析青少年双相抑郁（ABD）患者冲动攻 击行为（IAB）与腹内侧前额叶（vmPFC）神经代谢的关系。方法 回顾性选取 2023 年 1— 7 月新疆维吾尔 自治区人民医院临床心理科门诊及住院部收治的 23 例 30 d 内未经任何治疗的 ABD 患者为研究对象。 将 Barratt 冲动量表（BIS-11）总分≥ 70 分、外显攻击行为量表（MOAS）加权总分≥ 5 分且体力攻击条目 得分≥ 1 分的患者纳入伴 IAB 组,将 BIS-11 总分＜ 70 分、MOAS 加权总分＜ 5 分且体力攻击条目得分为 0 分的患者纳入不伴 IAB 组。采用1 H-MRS 单体素扫描 vmPFC,比较两组患者 vmPFC 脑区 N- 乙酰天门 冬氨酸 / 肌酸（NAA/Cr）、胆碱 / 肌酸（Cho/Cr）、肌醇 / 肌酸（mI/Cr）的比值。结果 伴 IAB 组有 11 例患者,不 伴 IAB 组有 12 例患者。伴 IAB 组 ABD 患者的 NAA/Cr 值为（1.45±0.16）,低于不伴 IAB 组的（1.69±0.08）, 差异有统计学意义（t=4.548,P＜0.001）。两组患者的Cho/Cr值、mI/Cr值比较［（0.64±0.10）比（0.66±0.08）、 （0.49±0.19）比（0.54±0.08）］,差异均无统计学意义（t=0.530、0.751;均P＞ 0.05）。结论 ABD 伴 IAB 患 者的 NAA/Cr 值下降,ABD 患者的 IAB 可能与 vmPFC 神经元密度减少或存在神经元功能障碍有关。     

儿童及青少年双相障碍的研究进展

儿童及青少年双相障碍诊断与治疗的研究进展进行综述。     

儿童青少年双相情感障碍治疗研究进展

儿童青少年双相情感障碍(BPD)是临床上一种常见的精神疾病，现复习了其治疗的研究进展文献，作一综述。     

Clozapine: its impact on aggressive behavior among children and adolescents with schizophrenia

OBJECTIVE: To evaluate the effectiveness of clozapine on aggressive behavior for treatment-refractory adolescents (age range 8.5-18) with schizophrenia (295.x) at Bronx Children's Psychiatric Center. METHOD: Clozapine treatment was administered in an open-label fashion using a flexible titration schedule. The frequency of administration of emergency oral and injectable medications and the frequency of seclusion events 3 months immediately before and from 12 to 24 weeks of clozapine treatment (when optimal clozapine levels were achieved) were compared. RESULTS: Twenty clozapine-treated children (mean +/- SD dose at week 24, 476 +/- 119 mg) were included. A statistically significant decrease in the frequency of the administration of emergency oral medications, the administration of emergency injectable medications, and seclusion events was found in adolescents during weeks 12 to 24 of clozapine treatment compared with their baseline condition before clozapine initiation. CONCLUSIONS: These preliminary data indicate the benefits of clozapine treatment in adolescents with treatment-refractory schizophrenia for aggressive behaviors. Although open data limit conclusions from this study, it is important that there was a clinically significant improvement in aggressive behaviors that enabled patients to be discharged to a less restrictive setting. Additional controlled clinical trials of clozapine are needed in treatment-refractory children and adolescents.     

Genome-wide methylation study on depression: differential methylation and variable methylation in monozygotic twins

Depressive disorders have been shown to be highly influenced by environmental pathogenic factors, some of which are believed to exert stress on human brain functioning via epigenetic modifications. Previous genome-wide methylomic studies on depression have suggested that, along with differential DNA methylation, affected co-twins of monozygotic (MZ) pairs have increased DNA methylation variability, probably in line with theories of epigenetic stochasticity. Nevertheless, the potential biological roots of this variability remain largely unexplored. The current study aimed to evaluate whether DNA methylation differences within MZ twin pairs were related to differences in their psychopathological status. Data from the Illumina Infinium HumanMethylation450 Beadchip was used to evaluate peripheral blood DNA methylation of 34 twins (17 MZ pairs). Two analytical strategies were used to identify (a) differentially methylated probes (DMPs) and (b) variably methylated probes (VMPs). Most DMPs were located in genes previously related to neuropsychiatric phenotypes. Remarkably, one of these DMPs (cg01122889) was located in the WDR26 gene, the DNA sequence of which has been implicated in major depressive disorder from genome-wide association studies. Expression of WDR26 has also been proposed as a biomarker of depression in human blood. Complementarily, VMPs were located in genes such as CACNA1C, IGF2 and the p38 MAP kinase MAPK11, showing enrichment for biological processes such as glucocorticoid signaling. These results expand on previous research to indicate that both differential methylation and differential variability have a role in the etiology and clinical manifestation of depression, and provide clues on specific genomic loci of potential interest in the epigenetics of depression.     

Open-label treatment with risperidone of 26 psychiatrically-hospitalized children and adolescents with mixed diagnoses and aggressive behavior

Open-label risperidone was administered to 26 subjects (24 boys: 19 with borderline IQ and 5 with mild mental retardation), 10-18 years old, who were hospitalized for treatment of psychiatric disorders associated with aggressive behavior. Risperidone was given in daily doses ranging from 0.5 to 4 mg for periods of 2-12 months. Treatment response was monitored by means of the improvement scale of the CGI and the modified OAS. Extrapyramidal side effects were measured on the ESRS. Fourteen (54%) of 26 subjects had a marked reduction in aggression; 10 subjects had a moderate reduction; two subjects had mild changes; and none worsened. Two subjects had a marked weight gain in the first 8 weeks of treatment. In seven of the 22 children who continued taking risperidone after week 8, tiredness and sedation that necessitated dose reduction emerged between weeks 8 and 16. These results suggest that risperidone may be useful when treating severe aggressive behavior in children and adolescents. Weight gain and sedation can be troublesome side effects.     

Frontal alpha power asymmetry in aggressive children and adolescents with mood and disruptive behavior disorders.

Building on prior research, which has suggested a relationship between aggression and left frontal activity, our study tested the hypothesis that proneness to impulsive aggression would be related to relative left frontal overactivation. EEG one-hertz resting alpha power frontal asymmetry was examined in 65 pediatric male psychiatric patients with a history of impulsive aggression and comorbid mood and disruptive behavior disorders. The strongest finding, which emerged from this analysis, was a finding of relative increases in left frontal activity compared with right frontal activity. The results also indicated that greater left frontal activity correlated positively with the severity of psychiatric disturbance. These findings suggest that relative increases in left frontal activity may be related to a locus of neurophysiological disruption associated with psychopathology characterized by behavioral and affective disinhibition. Results are discussed within a model of behavioral inhibition system-behavioral activation system theory.     

双相情感障碍躁狂发作患者攻击行为 与执行功能的相关性

目的 探讨双相情感障碍躁狂发作患者攻击行为与执行功能之间的相关性。方法 采用 修订版外显攻击行为量表（MOAS）对2018 年6 月—2019 年2 月在山东省精神卫生中心门诊就诊或者住 院治疗的164例双相情感障碍躁狂发作患者攻击行为进行评定，MOAS评分≥5分为攻击组，MOAS＜5分 为非攻击组。用威斯康星卡片分类测验（WCST）评估受试者的执行功能，用贝克-拉范森躁狂量表（BRMS） 评估受试者的临床症状。结果 双相情感障碍躁狂攻击组患者BRMS总分［（25.78±4.32）分］高于非攻击组 ［（24.69±4.29）分］（P＜0.05），攻击组WCST正确数［（42.52±7.23）分］、分类数［（7.61±3.48）分］低于非攻 击组［（44.29±9.14）、（8.06±2.12）分］；错误数［（43.03±8.43）分］、持续错误数［（29.08±5.55）分］、非持 续错误数［（26.84±5.78）分］均高于非攻击组［（41.32±8.18）、（28.58±7.22）、（25.03±5.80）分］，差异有统 计学意义（P＜ 0.05），双相情感障碍躁狂患者MOAS 评分与WCST错误数、持续性错误数、非持续性错误 数呈正相关（P＜ 0.05），与分类数呈负相关（P ＜ 0.05）。结论 双相情感障碍躁狂患者攻击行为与执行 功能存在相关性，执行功能受损可能与双相情感障碍躁狂攻击行为的发生机制有关。     

Suicide risk factors in children and adolescents with bipolar disorder

Suicidal behavior in children and adolescents with bipolar disorder is a major public health problem that remains understudied. Most research on suicidal behavior in bipolar disorder has been conducted in older adolescents and adults and is limited by retrospective design. Although preliminary research suggests that the early onset of bipolar disorder is associated with increased suicide risk, few studies have prospectively examined the effects of prior suicidal behavior, clinical course, comorbid psychiatric disorders, familial suicidality, and psychosocial factors on suicidal behavior in bipolar youths. More systematic research is needed to better understand suicidal behavior in bipolar children and adolescents. Increased knowledge of the risk factors that contribute to suicidal behavior should lead to better prevention and treatment.     

Adjunctive topiramate in hospitalized children and adolescents with bipolar disorders

OBJECTIVE: The aim of this study was to assess topiramate as adjunctive treatment in children and adolescents hospitalized with bipolar disorders. METHODS: Medical records of all children and adolescents with a Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV-TR) (APA, 2000) diagnosis of bipolar disorder, type I, hospitalized for an acute manic, mixed, or depressive episode, were reviewed. The primary outcome measure was the Clinical Global Impression-Severity (CGI-S) score. RESULTS: Twenty-five (25) children and adolescents received topiramate, with a mean final dose of 126 mg/day (range, 25-350 mg). Overall CGI-S scores significantly improved from 5.3+/-1.0 to 3.5+/-0.7, and mania CGI-S scores decreased from 5.4+/-1.0 to 3.3+/-0.9. Sixteen (16) of 25 (64%) bipolar patients were classified as responders (defined by an endpoint overall CGI-I score of less than or equal to 2). No serious adverse events occurred during treatment. Of 25 patients evaluated, 1 (4%) experienced mild sedation while treated with topiramate. CONCLUSIONS: Preliminary results of this retrospective chart review suggest that adjunctive topiramate may be associated with improvements in children and adolescents hospitalized for an acute manic, mixed, or depressive episode. Randomized and controlled trials with adjunctive topiramate in this population are needed to further explore this observation.