大学生抑郁状态早期筛查、干预及循环microRNA测序研究
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摘要
目的
1通过问卷调查,对大学生抑郁状态发生情况进行评价,并对人格特质、生活事件与抑郁状态及生存质量评价的相关性进行分析,明确抑郁状态的易感人格特质、潜在应激源以及影响生存质量评价的主导因素。
2对抑郁状态大学生进行电针、心理及电针结合心理三种方案的早期干预,明确早期干预的有效性及必要性,同时对不同干预方法的差异性进行分析比较,探明不同干预方案的疗效优势,为抑郁状态干预最优方案的筛选提供依据。
3通过对大学生血清microRNA高通量测序结果差异性分析,探索抑郁状态相关生物标志物及其发病机理,同时对抑郁受试者干预前后血清microRNA表达模式进行比较,探讨早期干预的潜在作用机制。
方法
1采用典型整群抽样的方法,对内蒙古医科大学临床医学院、药学院、中医学院、管理学院以及护理学院的在校生进行问卷调查。采用流调用抑郁自评量表(CES-D)评价抑郁状态(CES-D>=16归为抑郁组,CES-D<16归为非抑郁组),大五人格简表(NEO-FFI,由神经质、外向性、开明性、宜人性及责任感五个子量表组成)评价人格特质,生活事件量表(LES)评价生活事件发生情况及情绪刺激量,世界卫生组织生存质量简表(WHOQOL-BREF)测量生存质量主观评价。采用独立样本t检验对抑郁组与非抑郁组大学生的NEO-FFI、WHOQOL_BREF及LES评分进行比较,同时采用AMOS构建结构式方程模型(SEM)分析各变量相关性及中介效应。
2通过汉密尔顿抑郁量表-17项(HDRS-17)测评以及简明国际神经精神科访谈(M.I.N.I.)对抑郁组大学生(CES-D(?)16)进一步评价,以7-HDRS-17<17并排除精神疾患为纳入标准,结合排除标准,共纳入受试者33人：全分析数据集者33人,其中电针干预组6人,认知行为疗法心理干预组10人,电针结合心理综合干预组6人,高危观察组11人；符合方案数据集29人,其中电针干预组5人,认知行为疗法心理干预组9人,电针结合心理综合干预组5人,高危观察组11人。采用意向性分析(ITT)和符合方案数据集分析(PP)两种方法评价受试者主要疗效评价指标(HDRS-17减分率,抑郁症状缓解率,疗后HDRS·-17得分),同时对组间疗后HDRS-17各因子分、CES-D评分、WHOQOL-BREF评分进行方差分析。
3采集上述抑郁状态入组受试者疗前血清样本6例、疗后血清样本3例,同时采集正常受试者血清样本8例。采用Trizol法提取血清总RNA,制备microRNA文库,Illumina高通量测序绘制microRNA表达图谱,比较抑郁状态受试者与正常受试者之间、抑郁状态受试者治疗前后的microRNA表达差异。通过靶基因预测软件对差异表达microRNA进行分析,并进行KEGG通路分析,预测差异microRNA作用的潜在靶基因及目标蛋白。
结果
1共回收有效问卷2262份,内蒙古医科大学在校生CES-D均分为10.98±7.95,WHOQOL-BREF的生存质量总评、健康状况总评以及生理、心理、社交和环境领域均分分别为3.62±0.84,3.67±0.86,69.02±12.96,65.44±13.90,67.35±17.45,60.12±13.86。抑郁组大学生的WHOQOL-BREF的生存质量总评、健康状况总评以及生理、心理、社交和环境领域得分均显著低于非抑郁组(P<0.01)、LES的正负性生活事件评分均显著高于非抑郁组(P<0.01),NEO-FFI中神经质维度高于非抑郁组,外向性、开明性、宜人性以及责任感低于非抑郁组(P<0.01)。结构式方程模型显示,神经质、外向性、宜人性、责任感维度以及大学生活、高考失败、恋爱等生活事件因子对与抑郁状态具有显著预测作用(P<0.01),标准化回归系数系数分别为0.4926,-0.2257,-0.0725,-0.0581,0.0588,0.0556,0.0373,外向性、责任感、神经质维度以及大学生活、经济和个人成就对生存质量评价有显著预测作用,标准化回归系数分别为：0.2642,0.2229,-0.1983,-0.0796,-0.0455,0.0043。抑郁状态对生存质量评价有显著预测作用,标准化回归系数为-0.207。人格特质、生活事件对生存质量评价的直接效应高于抑郁状态中介的间接效应,外向性、神经质、责任感等人格特质对生存质量评价的总效应高于生活事件。
2早期干预研究
2.1ITT及PP分析结果显示,干预组在HDRS-17减分率、抑郁症状缓解率以及疗后HDRS-17评分方面均优于高危观察组,差异有统计学意义(P<0.01)。
2.2ITT及PP分析结果显示,电针组、心理组及综合组在HDRS减分率、抑郁症状缓解率以及疗后HDRS评分方面均优于高危组,差异有统计学意义(P<0.01),但干预组间比较差异无统计学意义(P>0.05)
2.3HDRS靶症状群因子分比较结果显示,电针组、心理组及综合组在焦虑/躯体化因子、睡眠障碍因子、迟滞因子以及认知障碍因子方面疗后得分均显著降低(P<0.01),高危组观察前后均无显著差异(P>0.05)。干预组组间比较结果显示,综合组焦虑/躯体化因子疗后得分显著低于电针组及心理组(P<0.01)；电针组睡眠障碍因子疗后得分显著低于综合组及心理组(P<0.01)；心理组及综合组迟滞因子疗后得分显著低于电针组(P<0.01)；认知障碍因子三组间差异无统计学意义(P>0.05)。四组体重因子干预前后均有显著差异(P<0.05)。
2.4疗后CES-D得分比较结果显示,针刺组、心理组及综合组疗后评分均低于高危组(P<0.01),干预组间差异无统计学意义(P>0.05)
2.5WHOQOL-BREF得分比较结果显示,电针组、心理组及综合组在健康状况总评、生理领域、心理领域以及社交领域的疗后得分显著高于提高(P<0.01),高危组观察前后无显著差异(P>0.05)。干预组间比较结果显示,三组间疗后健康状况总评、生理领域、心理领域以及社交领域差异均无统计学意义(P>0.05)。四组生存质量总评以及环境领域得分干预前后比较差异均无统计学意义(P>0.05)。
3抑郁高危受试者样本与正常受试者样本比较,共有90种已知microRNA表达存在显著差异,其中表达上调者82种,表达下调者8种；共有87种预测micorRNA表达存在显著差异,其中表达上调者64种,表达下调者23种；抑郁高危受试者疗前与疗后比较,有173种已知microRNA表达存在显著差异,其中表达上调者85种,表达下调者88种；共有63种预测micorRNA表达存在显著差异,其中表达上调者19种,表达下调者44种；GO富集性分析及KEGG通路分析结果显示,差异表达的microRNA与细胞凋亡、生物昼夜节律、神经营养因子、丝裂原活化蛋白激酶、炎症反应信号因子TGF-beta以及血管内皮生长因子等通路蛋白相关。
结论
1本研究中内蒙古医科大学在校生情绪状态良好,生存质量评价高于全国常模水平。抑郁状态发生与生活应激事件及人格特质相关,并导致生活质量评价下降。主要应激源包括学习压力大、生活规律改变、被人误会以及经济困难等,应针对以上问题进行干预疏导；人格特质是导致抑郁状态及影响生存质量评价的主导因素,培养良好的人格特质对保障大学生心理健康以及提高生活满意度具有重要意义。
2早期干预能够有效缓解大学生抑郁高危状态,并提高主观生存质量评价,不同干预方案的治疗靶点存在差异：电针治疗能够有效缓解躯体症状及睡眠障碍；心理治疗侧重于缓解抑郁情绪及认知障碍等,电针结合心理的综合治疗对生理、心理症状均有显著缓解作用,并显著提高健康状况总评,因此认为是较理想的抑郁高危状态早期干预方案。
3抑郁高危状态发生与抑郁症病理相关microRNA异常表达存在密切联系,microRNA介导的多条信号通路变化是抑郁高危状态早期干预有效的潜在机制,涉及神经-内分泌-免疫网络的整体调节。microRNA作为抑郁状态生物标志物及其介导早期干预的生理病理机制须进一步的验证实验进行明确。
Objectives
1Applying questionnaires survey, we are aiming to evaluate incidence of depressive status among undergraduates as well as the correlations between personality traits, life events and depressive status, subjective assement quality of life, further to elucidate the susceptible personality traits and potential stressor related to depressive status and key factors impacting quality of life assessment..
2We conducted electroacupuncture, psychology and combination of electro-acupuncture and psychology treatments to undergraduates under depressive status to illuminate the effectiveness and necessarity of early interventions. Moreover, we analyzed the differentcs among interventions to figure out the advantages of different treatments, further to offer suggestions for the optimization of superior depressive status treatment strategy.
3Applying circulating microRNA high throughput sequencing, we are aiming to explore bio-markers, related to depressive status and its pathogenesis. Meanwhile, we are aiming to shed light on the potential mechanism of early intervention based on analysis on differences in microRNA profiles pre-and post-interventions.
Methods
1Applying classic cluster sampling, undergraduates from school of medicine, pharmacy, Chinese medicine, administration and nursing, Inner Mongolia Medical University were recruited for questionnaire survey. Center for Epidemiologic Studies-Depression scale (CES-D) was used to measure depressive status (CES-D≥16was defined as depressive while CES-D<16as non-depressive), NEO-Five Factor Inventory (NEO-FFI, consisted of five dimensions:neuroticism, extraversion, openness to experience, agreeableness and conscientiousness) was applied to measure personality traits, Life Events Scale (LES) was used to evaluate the incidence of life events and their effects, and World Health Organization Quality Of Life Scale Abbreviated Version (WHOQOL-BREF) was employed to measure the subjective assessment of quality of life. Independent t-test were used to compare the differences of NEO-FFI, WHOQOL-BREF and LES scores, futhrermore, we applied AMOS to construct Structural Equation Model (SEM) to analyze the correlations and mediation effects of all variables
2Individuals with CES-D≥16were futher evaluated with Hamilton Depression Rating Scale-17(HDRS-17) and Mini International Neuropsychiatric Interview (M.I.N.I.). Based on the inclusion criteria (7≤HDRS-17<1and excluding psychiatric disorders) and exclusion criteria,33subjects were recruited:33subjects were included for Full Analysis Set (FAS), with6in Electroacupuncture (EA) group,10in Cognitive Behavior Therapy (CBT) group and6in combination EA and CBT group and11in group;29subjects were included for Per Protocol Set (PPS), with5in EA group,9in CBT group,5in combination group and11in group. Intention To Treat (ITT) analysis and Per Protocol (PP) analysis were employed to evaluate the primary outcome measures (clinical response rate based on rate of HDRS-17score changes, clinical remission defined as an endpoint HDRS-17score<7and HDRS-17score after intervention). Meanwhile differences of HDRS-17factor scores, CES-D scores and WHOQOL-BREF scores were compared via Analysis of Variances (ANOVA).
36samples from depressvie subjects prior to intervention,3samples form depressvie subjects after intervention and8samples from normal subjects were obtained. Total circulating RNA was extacted from serum sample via Trizol method. Then microRNA library were built and microRNA expression were profiled with Illumina high throughput sequencing. Target predction analysis, GO Enrichment analysis and KEGG pathway analysis were applied to predict potential targeting gene and protein of microRNA expressed differentially between depressive and normal subjects as well as those between prior to and after treatment
Results
12262valid questionnaires were withdrawn for analysis. The mean score of CES-D was10.64±7.95. General quality of life score, overall health score, physical, psychological, social relationship and environment domain scores in WHOQOL-BREF were3.62±0.84,3.67±0.86,69.02±12.96,65.44±13.90,67.35±17.45,60.12±13.86respectively. Compared with non-depressive group, general quality of life score, overall health score, physical health, psychological, social relationship and environment domain scores in WHOQOL-BREF, extraversion, openness to experience, agreeableness, conscientiousness scores in NEO-FFI of depressive group were significantly lower (P<0.01), while positive and negative life events scores in LES and neuroticism scores in NEO-FFI were remarkably higher (P<0.01).. The results of SEM demonstrated neuroticism, extraversion, openness to experience, agreeableness and conscientiousness as well as life events factors including university life, failure in college entrance examination, being in or broken up relationships are predive to depressive status (P<0.01), standardized regression weights are0.4926,-0.2257,-0.0725,-0.0581,0.0588,0.0556,0.0373respectively. Extraversion, conscientiousness, neuroticism as well as life events factors including university life, economic factors and personal achievement can predict quality of life assessment, standardized regression weight are0.2642,0.2229,-0.1983,-0.0796,-0.0455,0.0043respectivly. Depressvie status is predictive to quality of life assessment with standardized regression weight-0.207. Direct effects of personality traits, life events on quality of life assessment are higher than indirect effects mediated by depressive status. Total effects exerted by personality traits including extraversion, neuroticism and conscientiousness outweigh those by life events.
2Early intervention research
2.1ITT and PP analysis demonstrated that primary outcome measures in intervention group were significantly superior to those in non-intervention group.(P<0.01)
2.2ITT and PP analysis demonstrated that primary outcome measures in EA group, CBT group and combination group were superior to those in non-intervention group, no statistically significant differences were found among EA, CBT and combination group.
2.3Comparisons of HDRS-17factor scores showed that post-treatment anxiety/somatization, insomnia, retardation and cognition scores in EA group, CBT group and combination group were remarkably lower than pre-treatment scores(P<0.01), while no significant difference was found between pre-and post-treatment in depressive control group(P>0.05). Post-treatment anxiety/somatization score in combination group was lower than those in EA group and CBT group (P<0.01); post-treatment insomnia score in EA group was siginificantly lower than those in combination group and CBT group (P<0.01); post-treatment retardation score was lower in CBT and combination group compared with those in EA group (P<0.01). No significant differences was found in cognition score among EA, CBT and combination group (P>0.05). No great difference was found between pre-and post-treatment in body weight scores in four groups (P>0.05).
2.4CES-D score in EA group, CBT group and combination group were lower than that in non-intervention group (P<0.01), no statistically significant differences was found among EA, CBT and combination group (P>0.05).
2.5Post-treatment general quality of life score, overall health score, physical health, psychological and social relationship domain scores from WHOQOL-BREF in EA, CBT and combination group improved compared with pre-treatment scores (P<0.01), while no significant difference was found between pre-and post-treatment in depressive control group(P>0.05). No significant differences was found in post-treatment general quality of life score, overall health score, physical health, psychological and social relationship domain scores among EA, CBT and combination group (P>0.05). No great difference was found between pre-and post-treatment in general quality of life and environmental domain scores in four groups.
390types of known microRNA expressed differentially between depressive group and normal group, among which82were upregulated and8were downregulated; while87types of novel microRNA expressed differentially between depressive group and normal group, among which64were upregulated and23were downregulated.173types of known microRNA expressed differentially between pre-treatment group and post-treatment group, among which85were upregulated and88were downregulated; while63types of novel microRNA expressed differentially between pre-treatment group and post-treatment group, among which19were upregulated and44were downregulated. GO enrichment and KEGG pathway analysis displayed that differentially expressed microRNA were predicted to be correlated to pathways including apoptosis, circardian rhythm, neurotrophins, mitogen-activated protein kinase (MAPK), inflammatory response signal factor TGF-beta and vascular endothelial grow factor(VEGF).
Conclusions
1The undergraduates in the current study showed favorable emotional status and relatively high quality of life assessment. Life events and personality traits contributs to the occunce of depressive status which furher leads to decline in quality of life assessment. Main stressors including academic stress, changes in life regularity, misunderstood by others, econominc problems warrant great attention. Personality traits play a crutial role in depressive status occurrence and quality of life assessement, indicating that fostering favorable personaties may be of significant importance to maintain undergraduates' mental health and life satisfaction.
2Early intervention could alleviate depressive symptoms and improve subjective assessment of quality of life. Different intervention target different symptoms, specifically, EA could improve somatic symptoms and insomnia while CBT favors mitigating cognition and mood dysfunction. The combination treatment targent both physical and psychological symptoms and can substantially improve overall health, thus might be an ideal stratugy for depressive status intervention.
3The occurence of depressive status might be closely correlated to alterated levels of microRNA related to depression pathology, and changes in several signal pathways mediated by certain microRNAs were predicted to be the underlying mechanism of early intervention which is related to modulations of neuro-endocrine-immune network. However, these predictions of microRNA as bio-markers and their roles in ealy internvention warrant further investigation via verification tests.
1通过问卷调查,对大学生抑郁状态发生情况进行评价,并对人格特质、生活事件与抑郁状态及生存质量评价的相关性进行分析,明确抑郁状态的易感人格特质、潜在应激源以及影响生存质量评价的主导因素。
2对抑郁状态大学生进行电针、心理及电针结合心理三种方案的早期干预,明确早期干预的有效性及必要性,同时对不同干预方法的差异性进行分析比较,探明不同干预方案的疗效优势,为抑郁状态干预最优方案的筛选提供依据。
3通过对大学生血清microRNA高通量测序结果差异性分析,探索抑郁状态相关生物标志物及其发病机理,同时对抑郁受试者干预前后血清microRNA表达模式进行比较,探讨早期干预的潜在作用机制。
方法
1采用典型整群抽样的方法,对内蒙古医科大学临床医学院、药学院、中医学院、管理学院以及护理学院的在校生进行问卷调查。采用流调用抑郁自评量表(CES-D)评价抑郁状态(CES-D>=16归为抑郁组,CES-D<16归为非抑郁组),大五人格简表(NEO-FFI,由神经质、外向性、开明性、宜人性及责任感五个子量表组成)评价人格特质,生活事件量表(LES)评价生活事件发生情况及情绪刺激量,世界卫生组织生存质量简表(WHOQOL-BREF)测量生存质量主观评价。采用独立样本t检验对抑郁组与非抑郁组大学生的NEO-FFI、WHOQOL_BREF及LES评分进行比较,同时采用AMOS构建结构式方程模型(SEM)分析各变量相关性及中介效应。
2通过汉密尔顿抑郁量表-17项(HDRS-17)测评以及简明国际神经精神科访谈(M.I.N.I.)对抑郁组大学生(CES-D(?)16)进一步评价,以7-HDRS-17<17并排除精神疾患为纳入标准,结合排除标准,共纳入受试者33人：全分析数据集者33人,其中电针干预组6人,认知行为疗法心理干预组10人,电针结合心理综合干预组6人,高危观察组11人；符合方案数据集29人,其中电针干预组5人,认知行为疗法心理干预组9人,电针结合心理综合干预组5人,高危观察组11人。采用意向性分析(ITT)和符合方案数据集分析(PP)两种方法评价受试者主要疗效评价指标(HDRS-17减分率,抑郁症状缓解率,疗后HDRS·-17得分),同时对组间疗后HDRS-17各因子分、CES-D评分、WHOQOL-BREF评分进行方差分析。
3采集上述抑郁状态入组受试者疗前血清样本6例、疗后血清样本3例,同时采集正常受试者血清样本8例。采用Trizol法提取血清总RNA,制备microRNA文库,Illumina高通量测序绘制microRNA表达图谱,比较抑郁状态受试者与正常受试者之间、抑郁状态受试者治疗前后的microRNA表达差异。通过靶基因预测软件对差异表达microRNA进行分析,并进行KEGG通路分析,预测差异microRNA作用的潜在靶基因及目标蛋白。
结果
1共回收有效问卷2262份,内蒙古医科大学在校生CES-D均分为10.98±7.95,WHOQOL-BREF的生存质量总评、健康状况总评以及生理、心理、社交和环境领域均分分别为3.62±0.84,3.67±0.86,69.02±12.96,65.44±13.90,67.35±17.45,60.12±13.86。抑郁组大学生的WHOQOL-BREF的生存质量总评、健康状况总评以及生理、心理、社交和环境领域得分均显著低于非抑郁组(P<0.01)、LES的正负性生活事件评分均显著高于非抑郁组(P<0.01),NEO-FFI中神经质维度高于非抑郁组,外向性、开明性、宜人性以及责任感低于非抑郁组(P<0.01)。结构式方程模型显示,神经质、外向性、宜人性、责任感维度以及大学生活、高考失败、恋爱等生活事件因子对与抑郁状态具有显著预测作用(P<0.01),标准化回归系数系数分别为0.4926,-0.2257,-0.0725,-0.0581,0.0588,0.0556,0.0373,外向性、责任感、神经质维度以及大学生活、经济和个人成就对生存质量评价有显著预测作用,标准化回归系数分别为：0.2642,0.2229,-0.1983,-0.0796,-0.0455,0.0043。抑郁状态对生存质量评价有显著预测作用,标准化回归系数为-0.207。人格特质、生活事件对生存质量评价的直接效应高于抑郁状态中介的间接效应,外向性、神经质、责任感等人格特质对生存质量评价的总效应高于生活事件。
2早期干预研究
2.1ITT及PP分析结果显示,干预组在HDRS-17减分率、抑郁症状缓解率以及疗后HDRS-17评分方面均优于高危观察组,差异有统计学意义(P<0.01)。
2.2ITT及PP分析结果显示,电针组、心理组及综合组在HDRS减分率、抑郁症状缓解率以及疗后HDRS评分方面均优于高危组,差异有统计学意义(P<0.01),但干预组间比较差异无统计学意义(P>0.05)
2.3HDRS靶症状群因子分比较结果显示,电针组、心理组及综合组在焦虑/躯体化因子、睡眠障碍因子、迟滞因子以及认知障碍因子方面疗后得分均显著降低(P<0.01),高危组观察前后均无显著差异(P>0.05)。干预组组间比较结果显示,综合组焦虑/躯体化因子疗后得分显著低于电针组及心理组(P<0.01)；电针组睡眠障碍因子疗后得分显著低于综合组及心理组(P<0.01)；心理组及综合组迟滞因子疗后得分显著低于电针组(P<0.01)；认知障碍因子三组间差异无统计学意义(P>0.05)。四组体重因子干预前后均有显著差异(P<0.05)。
2.4疗后CES-D得分比较结果显示,针刺组、心理组及综合组疗后评分均低于高危组(P<0.01),干预组间差异无统计学意义(P>0.05)
2.5WHOQOL-BREF得分比较结果显示,电针组、心理组及综合组在健康状况总评、生理领域、心理领域以及社交领域的疗后得分显著高于提高(P<0.01),高危组观察前后无显著差异(P>0.05)。干预组间比较结果显示,三组间疗后健康状况总评、生理领域、心理领域以及社交领域差异均无统计学意义(P>0.05)。四组生存质量总评以及环境领域得分干预前后比较差异均无统计学意义(P>0.05)。
3抑郁高危受试者样本与正常受试者样本比较,共有90种已知microRNA表达存在显著差异,其中表达上调者82种,表达下调者8种；共有87种预测micorRNA表达存在显著差异,其中表达上调者64种,表达下调者23种；抑郁高危受试者疗前与疗后比较,有173种已知microRNA表达存在显著差异,其中表达上调者85种,表达下调者88种；共有63种预测micorRNA表达存在显著差异,其中表达上调者19种,表达下调者44种；GO富集性分析及KEGG通路分析结果显示,差异表达的microRNA与细胞凋亡、生物昼夜节律、神经营养因子、丝裂原活化蛋白激酶、炎症反应信号因子TGF-beta以及血管内皮生长因子等通路蛋白相关。
结论
1本研究中内蒙古医科大学在校生情绪状态良好,生存质量评价高于全国常模水平。抑郁状态发生与生活应激事件及人格特质相关,并导致生活质量评价下降。主要应激源包括学习压力大、生活规律改变、被人误会以及经济困难等,应针对以上问题进行干预疏导；人格特质是导致抑郁状态及影响生存质量评价的主导因素,培养良好的人格特质对保障大学生心理健康以及提高生活满意度具有重要意义。
2早期干预能够有效缓解大学生抑郁高危状态,并提高主观生存质量评价,不同干预方案的治疗靶点存在差异：电针治疗能够有效缓解躯体症状及睡眠障碍；心理治疗侧重于缓解抑郁情绪及认知障碍等,电针结合心理的综合治疗对生理、心理症状均有显著缓解作用,并显著提高健康状况总评,因此认为是较理想的抑郁高危状态早期干预方案。
3抑郁高危状态发生与抑郁症病理相关microRNA异常表达存在密切联系,microRNA介导的多条信号通路变化是抑郁高危状态早期干预有效的潜在机制,涉及神经-内分泌-免疫网络的整体调节。microRNA作为抑郁状态生物标志物及其介导早期干预的生理病理机制须进一步的验证实验进行明确。
Objectives
1Applying questionnaires survey, we are aiming to evaluate incidence of depressive status among undergraduates as well as the correlations between personality traits, life events and depressive status, subjective assement quality of life, further to elucidate the susceptible personality traits and potential stressor related to depressive status and key factors impacting quality of life assessment..
2We conducted electroacupuncture, psychology and combination of electro-acupuncture and psychology treatments to undergraduates under depressive status to illuminate the effectiveness and necessarity of early interventions. Moreover, we analyzed the differentcs among interventions to figure out the advantages of different treatments, further to offer suggestions for the optimization of superior depressive status treatment strategy.
3Applying circulating microRNA high throughput sequencing, we are aiming to explore bio-markers, related to depressive status and its pathogenesis. Meanwhile, we are aiming to shed light on the potential mechanism of early intervention based on analysis on differences in microRNA profiles pre-and post-interventions.
Methods
1Applying classic cluster sampling, undergraduates from school of medicine, pharmacy, Chinese medicine, administration and nursing, Inner Mongolia Medical University were recruited for questionnaire survey. Center for Epidemiologic Studies-Depression scale (CES-D) was used to measure depressive status (CES-D≥16was defined as depressive while CES-D<16as non-depressive), NEO-Five Factor Inventory (NEO-FFI, consisted of five dimensions:neuroticism, extraversion, openness to experience, agreeableness and conscientiousness) was applied to measure personality traits, Life Events Scale (LES) was used to evaluate the incidence of life events and their effects, and World Health Organization Quality Of Life Scale Abbreviated Version (WHOQOL-BREF) was employed to measure the subjective assessment of quality of life. Independent t-test were used to compare the differences of NEO-FFI, WHOQOL-BREF and LES scores, futhrermore, we applied AMOS to construct Structural Equation Model (SEM) to analyze the correlations and mediation effects of all variables
2Individuals with CES-D≥16were futher evaluated with Hamilton Depression Rating Scale-17(HDRS-17) and Mini International Neuropsychiatric Interview (M.I.N.I.). Based on the inclusion criteria (7≤HDRS-17<1and excluding psychiatric disorders) and exclusion criteria,33subjects were recruited:33subjects were included for Full Analysis Set (FAS), with6in Electroacupuncture (EA) group,10in Cognitive Behavior Therapy (CBT) group and6in combination EA and CBT group and11in group;29subjects were included for Per Protocol Set (PPS), with5in EA group,9in CBT group,5in combination group and11in group. Intention To Treat (ITT) analysis and Per Protocol (PP) analysis were employed to evaluate the primary outcome measures (clinical response rate based on rate of HDRS-17score changes, clinical remission defined as an endpoint HDRS-17score<7and HDRS-17score after intervention). Meanwhile differences of HDRS-17factor scores, CES-D scores and WHOQOL-BREF scores were compared via Analysis of Variances (ANOVA).
36samples from depressvie subjects prior to intervention,3samples form depressvie subjects after intervention and8samples from normal subjects were obtained. Total circulating RNA was extacted from serum sample via Trizol method. Then microRNA library were built and microRNA expression were profiled with Illumina high throughput sequencing. Target predction analysis, GO Enrichment analysis and KEGG pathway analysis were applied to predict potential targeting gene and protein of microRNA expressed differentially between depressive and normal subjects as well as those between prior to and after treatment
Results
12262valid questionnaires were withdrawn for analysis. The mean score of CES-D was10.64±7.95. General quality of life score, overall health score, physical, psychological, social relationship and environment domain scores in WHOQOL-BREF were3.62±0.84,3.67±0.86,69.02±12.96,65.44±13.90,67.35±17.45,60.12±13.86respectively. Compared with non-depressive group, general quality of life score, overall health score, physical health, psychological, social relationship and environment domain scores in WHOQOL-BREF, extraversion, openness to experience, agreeableness, conscientiousness scores in NEO-FFI of depressive group were significantly lower (P<0.01), while positive and negative life events scores in LES and neuroticism scores in NEO-FFI were remarkably higher (P<0.01).. The results of SEM demonstrated neuroticism, extraversion, openness to experience, agreeableness and conscientiousness as well as life events factors including university life, failure in college entrance examination, being in or broken up relationships are predive to depressive status (P<0.01), standardized regression weights are0.4926,-0.2257,-0.0725,-0.0581,0.0588,0.0556,0.0373respectively. Extraversion, conscientiousness, neuroticism as well as life events factors including university life, economic factors and personal achievement can predict quality of life assessment, standardized regression weight are0.2642,0.2229,-0.1983,-0.0796,-0.0455,0.0043respectivly. Depressvie status is predictive to quality of life assessment with standardized regression weight-0.207. Direct effects of personality traits, life events on quality of life assessment are higher than indirect effects mediated by depressive status. Total effects exerted by personality traits including extraversion, neuroticism and conscientiousness outweigh those by life events.
2Early intervention research
2.1ITT and PP analysis demonstrated that primary outcome measures in intervention group were significantly superior to those in non-intervention group.(P<0.01)
2.2ITT and PP analysis demonstrated that primary outcome measures in EA group, CBT group and combination group were superior to those in non-intervention group, no statistically significant differences were found among EA, CBT and combination group.
2.3Comparisons of HDRS-17factor scores showed that post-treatment anxiety/somatization, insomnia, retardation and cognition scores in EA group, CBT group and combination group were remarkably lower than pre-treatment scores(P<0.01), while no significant difference was found between pre-and post-treatment in depressive control group(P>0.05). Post-treatment anxiety/somatization score in combination group was lower than those in EA group and CBT group (P<0.01); post-treatment insomnia score in EA group was siginificantly lower than those in combination group and CBT group (P<0.01); post-treatment retardation score was lower in CBT and combination group compared with those in EA group (P<0.01). No significant differences was found in cognition score among EA, CBT and combination group (P>0.05). No great difference was found between pre-and post-treatment in body weight scores in four groups (P>0.05).
2.4CES-D score in EA group, CBT group and combination group were lower than that in non-intervention group (P<0.01), no statistically significant differences was found among EA, CBT and combination group (P>0.05).
2.5Post-treatment general quality of life score, overall health score, physical health, psychological and social relationship domain scores from WHOQOL-BREF in EA, CBT and combination group improved compared with pre-treatment scores (P<0.01), while no significant difference was found between pre-and post-treatment in depressive control group(P>0.05). No significant differences was found in post-treatment general quality of life score, overall health score, physical health, psychological and social relationship domain scores among EA, CBT and combination group (P>0.05). No great difference was found between pre-and post-treatment in general quality of life and environmental domain scores in four groups.
390types of known microRNA expressed differentially between depressive group and normal group, among which82were upregulated and8were downregulated; while87types of novel microRNA expressed differentially between depressive group and normal group, among which64were upregulated and23were downregulated.173types of known microRNA expressed differentially between pre-treatment group and post-treatment group, among which85were upregulated and88were downregulated; while63types of novel microRNA expressed differentially between pre-treatment group and post-treatment group, among which19were upregulated and44were downregulated. GO enrichment and KEGG pathway analysis displayed that differentially expressed microRNA were predicted to be correlated to pathways including apoptosis, circardian rhythm, neurotrophins, mitogen-activated protein kinase (MAPK), inflammatory response signal factor TGF-beta and vascular endothelial grow factor(VEGF).
Conclusions
1The undergraduates in the current study showed favorable emotional status and relatively high quality of life assessment. Life events and personality traits contributs to the occunce of depressive status which furher leads to decline in quality of life assessment. Main stressors including academic stress, changes in life regularity, misunderstood by others, econominc problems warrant great attention. Personality traits play a crutial role in depressive status occurrence and quality of life assessement, indicating that fostering favorable personaties may be of significant importance to maintain undergraduates' mental health and life satisfaction.
2Early intervention could alleviate depressive symptoms and improve subjective assessment of quality of life. Different intervention target different symptoms, specifically, EA could improve somatic symptoms and insomnia while CBT favors mitigating cognition and mood dysfunction. The combination treatment targent both physical and psychological symptoms and can substantially improve overall health, thus might be an ideal stratugy for depressive status intervention.
3The occurence of depressive status might be closely correlated to alterated levels of microRNA related to depression pathology, and changes in several signal pathways mediated by certain microRNAs were predicted to be the underlying mechanism of early intervention which is related to modulations of neuro-endocrine-immune network. However, these predictions of microRNA as bio-markers and their roles in ealy internvention warrant further investigation via verification tests.
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